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SUPPLEMENTARY MATERIAL Supplementary Figure 1. Pain Evaluation as assessed by Present Pain Intensity Score. Absolute changes between cycle 2 and baseline. Absolute change from C1D1 to C2D1 PPI 2 1 worsening 0 baseline improvement -1 arm A arm B -2 treatment groups Supplementary Table 1. Molecular Profiling Results (Sequenom and MiSeq Analyses) on FormalinFixed Paraffin Embedded Tumor Samples. i Con= concentration; Freq= Frequency. In blue: samples analyzed with Sequenom Panel. In black: samples analyzed with MiSeq. Supplementary Table 2. Molecular Profiling Results performed on Formalin-Fixed Paraffin Embedded Tumor Samples of prostate cancer patients. ii Gene Mutation Functional Impact Protein Domain Previously Reported Where HNF1A c.862G>T p.G288W UNKNOWN Hepatocyte nuclear factor 1, beta isoform, C-terminal NO N/A SMARCB1 c.193G>T p.A65S UNKNOWN SWI/SNF chromatin-remodeling complex, component hSNF5/Ini NO N/A TP53 c.527G>T p.C176F PREDICTED DELETERIOUS p53 tumor suppressor family; p53, DNAbinding domain YES TP53 IARC 3 prior occurrences in Prostate 205 prior reports in the same database COSMIC Deleterious missense mutation; partially functional Reported in 0.2% of prostate cases LOVD Reported 3 times (recorded as PolyPhen benign, probably nonpathogenic and found together with pathogenic S1198X) dbSNP and Exome Seq Project Reported at a MAF of 0.24% in normal populations APC c.3386T>C p.L1129S PREDICTED BENIGN Unknown YES Annotations COSMIC Reported in colon cancers EGFR T790M PREDICTED DELETERIOUS Serine-threonine/tyrosine-protein kinase catalytic domain, Protein kinase, catalytic domain Serine/threonine- / dual-specificity protein kinase, catalytic domain Tyrosine-protein kinase, catalytic domain Tyrosine protein kinase, EGF/ERB/XmrK receptor YES COSMIC Never reported in prostate cancer Common “resistance mutation” in lung cancer EGFR S768I PREDICTED DELETERIOUS Serine-threonine/tyrosine-protein kinase catalytic domain Protein kinase, catalytic domain Serine/threonine- / dual-specificity protein kinase, catalytic domain Tyrosine-protein kinase, catalytic domain Tyrosine protein kinase, EGF/ERB/XmrK receptor YES COSMIC Rare mutation in lung adenocarcinoma occurring in about 0.2 % of cases. Little is reported in the literature on the effect of this mutation on patient outcome. KIT D816V PREDICTED DELETERIOUS Serine-threonine/tyrosine-protein kinase catalytic domain Protein kinase, catalytic domain Serine/threonine- / dual-specificity protein kinase, catalytic domain Tyrosine-protein kinase, catalytic domain Tyrosine-protein kinase, CSF-1/PDGF receptor YES COMSIC Known pathogenic variant in acute myeloid leukemia and other hematologic malignancies, as well as in GIST. MAF: Minor Allele Frequency; LOVD: Leiden Open Variation Database iii Supplementary Appendix 1. NCI8476/PJC-002 Protocol. NCI Protocol #: Local Protocol #: 8476 PJC-002 TITLE: A Phase 2 Randomized Study of Cediranib (AZD2171) Alone Compared with the Combination of Cediranib (AZD2171) plus BMS-354825 (dasatinib, Sprycel) in Docetaxel Resistant, Castration Resistant Prostate Cancer Coordinating Center: Princess Margaret Hospital Phase I Consortium *Principal Investigator: Dr. Sebastien Hotte Juravinski Cancer Centre 699 Concession Street Hamilton, Ontario L8V 5C2 Canada Tel: 905-387-9495 Fax: 905-575-6326 Email: [email protected] Co-Investigators: Dr. Srikala Sridhar Princess Margaret Hospital 610 University Avenue, Suite 5-222 Toronto, Ontario M5G 2M9 Canada Tel: 416-946-4501 ext 2520 Fax: 416-946-6546 Email: [email protected] Dr. Lillian Siu Princess Margaret Hospital 610 University Avenue, Suite 5-718 Toronto, Ontario M5G 2M9 Canada Tel: 416-946-2911 Fax: 416-946-4467 Email: [email protected] iv Co-Investigators: Dr. Michael Carducci Johns Hopkins University Hopkins Kimmel Cancer Center 1650 Orleans Street 1M59CRB Baltimore, MD 21231-1000 USA Tel: 410-614-3977 Fax: 410-614-8160 Email: [email protected] Dr. Hans Hammer Johns Hopkins University Hopkins Kimmel Cancer Center 1650 Orleans Street 1M59CRB Baltimore, MD 21231-1000 USA Tel: 410-502-4658 Fax: 410-614-8397 Email: [email protected] Dr. Robert DiPaola UMDNJ-The Cancer Institute of New Jersey 195 Little Albany Street, Suite 2002B New Brunswick, NJ 08903 USA Tel: 732-235-8064 Fax: 732-235-8094 Email: [email protected] Dr. Kim Chi BC Cancer Agency 600 West 10th Avenue Vancouver, British Columbia V5Z 4E6 Canada Tel: 604-877-6000 Fax: 604-877-0585 Email: [email protected] v Co-Investigators: Dr. David C. Smith University of Michigan 1500 E. Medical Center Dr. 7302 Cancer Center, SPC 5946 Ann Arbor, MI 48109-5946 Tel : 734-936-6884 Fax : 734-615-2719 Email : [email protected] Statistician: Study Coordinator: Lisa Wang Tracy Wong Princess Margaret Hospital Princess Margaret Hospital 610 University Avenue 620 University Avenue, Room 6-606 Toronto, Ontario M5G 2M9 Toronto, Ontario, M5G 2M9 Canada Canada Tel: 416-946-4501 ext 4883 Tel: 416-946-4501 ext 5509 Fax: 416-946-2048 Fax: 416-946-4607 E-mail: [email protected] E-mail: [email protected] Program Manager: Robin Cheiken Princess Margaret Hospital 610 University Avenue, Room 4-743 Toronto, Ontario M5G 2M9 Canada Tel: 416-946-4616 Fax: 416-946-4607 Email: [email protected] NCI Supplied Agents: Cediranib (AZD2171, Recentin™, NSC#732208, IND#72740) and Dasatinib (BMS-354825) (NSC 732517; IND 73969) Protocol version date: Amendment # 1: Amendment #2: Amendment #3: Amendment #4: Amendment #5: Amendment #6: Amendment #7: July 05, 2010 October 25, 2010 December 23, 2010 February 7, 2011 March 21, 2011 July 15, 2011 December 15, 2011 April 25, 2012 vi SCHEMA This is a randomized, phase II trial of cediranib (AZD2171) with or without dasatinib (BMS354825) in patients with docetaxel-resistant, castration resistant prostate cancer (CRPC) Key Eligibility: Patients with castration resistant prostate cancer that progressed on or after first-line chemotherapy treatment with docetaxel Patients must have radiological documentation of either measurable or non-measurable disease ECOG 0-2, with adequate organ function Treatment: Arm A cediranib (AZD2171) 20 mg PO daily and continuously starting day 1 on a 28-day cycle Arm B cediranib (AZD2171) 20 mg PO daily and continuously starting day 1 on a 28-day cycle dasatinib (BMS-354825) 100 mg PO daily and continuously starting day 1 on a 28-day cycle Design: Randomized phase II trial with a comparative design, α = 0.15 (one-sided) and power = 0.8 Total sample size = 50 evaluable patients Primary endpoint: progression free survival (PFS) as per the Prostate Cancer Clinical Trials Working Group (PCWG2) which is a composite endpoint of PSA, bone scan, CT scan assessments(1) Secondary endpoints: o Safety and tolerability of the combination and cediranib alone o For patients with measurable disease, objective response rates will be calculated according to RECIST criteria o Symptom assessment by FACT-P questionnaire and Present Pain Intensity (PPI) scale from the McGill-Melzack questionnaire o Laboratory-based biomarkers to correlate to clinical outcome: bone resorption markers (e.g. c-telopeptide and bone alkaline phosphatase) vii SCHEMA Patients with CRPC that progressed on or after first line chemotherapy treatment with docetaxel Patients must have radiological documentation of either measurable or non-measurable disease ECOG 0-2, with adequate organ function R A N D O M I Z E Physical exam: q4w Blood tests: q2-4w PSA: q4w Bone resorption markers: at baseline, end of cycle 1 and end of cycle 3 FACT-P questionnaire and PPI scale: q4w Conventional radiologic assessment: q12w Bone scan: q12w Arm A (n = 25): Arm B (n = 25): Cediranib (AZD2171) 20 mg PO daily and continuously starting day 1 on a 28-day cycle Cediranib (AZD2171) 20 mg PO daily and continuously starting day 1 on a 28-day cycle + Dasatinib (BMS-354825) 100 mg PO daily and continuously starting day 1 on a 28-day cycle viii TABLE OF CONTENTS Page SCHEMA .................................................................................................................................................................. iv 1. OBJECTIVES .................................................................................................................................................... 1 1.1 Primary Objectives ...................................................................................................................... 1 1.2 Secondary Objectives ................................................................................................................. 1 2. BACKGROUND ............................................................................................................................................... 1 2.1 Castration Resistant Prostate Cancer ................................................................................. 1 2.2 Dasatanib (BMS-354825).......................................................................................................... 2 2.3 Cediranib (AZD2171) ................................................................................................................10 2.4 Rationale for Combining Cediranib and Dasatinib in CRPC .................................13 2.5 Correlative Studies Background .........................................................................................15 3. PATIENT SELECTION ...............................................................................................................................16 3.1 Eligibility Criteria ......................................................................................................................16 3.2 Exclusion Criteria ........................................................................................................................18 3.3 Inclusion of Minorities .............................................................................................................21 4. REGISTRATION PROCEDURES ............................................................................................................22 4.1 General Guidelines .....................................................................................................................22 4.2 Registration Process .................................................................................................................23 4.3 Randomization and Stratification........................................................................... 23 5. TREATMENT PLAN ....................................................................................................................................24 5.1 Cediranib (AZD2171) and Dasatinib (BMS-34825) Administration................24 5.1.1 Arm A: Cediranib (AZD2171) Alone....................................................................24 5.1.2 Arm B: Cediranib (AZD2171) and Dasatinib (BMS-354825) .................25 5.2 General Concomitant Medication and Supportive Care Guidelines .................26 5.2.1 Risk Mitigation for Pulmonary Arterial Hypertension…………….………28 5.3 Duration of Therapy ..................................................................................................................28 5.4 Duration of Follow Up ...............................................................................................................29 6. DOSING DELAYS/DOSE MODIFICATIONS ......................................................................................29 7. ADVERSE EVENTS: LIST AND REPORTING REQUIREMENTS ..............................................37 7.1 Comprehensive Adverse Events and Potential Risks Lists (CAEPRs) .............37 7.2 Adverse Event Characteristics .............................................................................................43 7.3 Expedited Adverse Event Reporting .................................................................................43 7.4 Routine Adverse Event Reporting ......................................................................................45 7.5 Secondary AML/MDS reporting ..........................................................................................45 8. PHARMACEUTICAL INFORMATION ..................................................................................................46 8.1 Cediranib (AZD2171) ................................................................................................................46 ix 8.2 8.3 Dasatinib (BMS-354825).........................................................................................................47 Agent Ordering, Accountability, and Returns ..............................................................48 9. CORRELATIVE/SPECIAL STUDIES .....................................................................................................50 9.1 Archival Specimens ....................................................................................................................50 9.2 Bone Resorption Markers ......................................................................................................50 9.3 Quality of Life Questionnaires and Pain Assessment ..............................................51 10. STUDY CALENDAR .....................................................................................................................................52 11. MEASUREMENT OF EFFECT ..................................................................................................................54 12. DATA REPORTING / REGULATORY REQUIREMENTS ..............................................................61 12.1 Data Reporting…………………………………………………………………….. 61 12.2 CTEP Multicenter Guidelines……………………………………………………. 62 12.3 Cooperative Research and Development Agreement (CRADA)/ Clinical Trials Agreement (CTA)…………………………………………………. 62 13. STATISTICAL CONSIDERATIONS........................................................................................................65 REFERENCES........................................................................................................................................................67 SAMPLE CONSENT ............................................................................................................................................71 APPENDICES APPENDIX A Drugs Known to be Metabolized by Selected CYP450 Isoenzymes.………………………..86 APPENDIX B Performance Status Criteria ....................................................................................................................91 APPENDIX C NYHA Cardiovascular Disability Classification ................................................................................92 APPENDIX D Patient Pill Diary ..........................................................................................................................................93 APPENDIX E Patient’s Blood Pressure Diary ...............................................................................................................97 APPENDIX F FACT-P Questionnaire (version 4) ........................................................................................................99 APPENDIX G Present Pain Intensity (PPI) Questionnaire (version 4)............................................................ 102 x APPENDIX H Data Management Guidelines .............................................................................................................. 103 APPENDIX I CTEP Multicenter Guidelines ............................................................................................................... 105 xi 1. OBJECTIVES 1.1. Primary Objectives 1.1.1 To determine and compare the efficacy of cediranib versus cediranib plus dasatinib in the treatment of docetaxel-resistant, castration resistant prostate cancer (CRPC) using progression free survival (PFS) as per the Prostate Cancer Clinical Trials Working Group (PCWG2) which is a composite endpoint of PSA, bone scan, and CT scan assessments 1.2. Secondary Objectives 1.2.1 To confirm the safety and tolerability of cediranib with or without dasatinib 1.2.2 To calculate objective response rates of cediranib with or without dasatinib according to RECIST criteria for patients with measurable disease at baseline 1.2.3 To perform symptom assessment using the FACT-P questionnaire and the present pain intensity (PPI) scale from the McGill-Melzack questionnaire 1.2.4 To explore bone resorption markers (e.g. c-telopeptide and bone alkaline phosphatase), and to correlate these biomarkers with clinical outcome 2. BACKGROUND 2.1. Castration Resistant Prostate Cancer Prostate cancer is the most common cancer diagnosed and the second most common cause of cancer death in men in North America.(2) Because patients with locally advanced and metastatic disease have a poor prognosis, identification of novel targets and therapeutic agents that act against them is a main goal. Prostate cancer is a hormone sensitive tumor. However, after receiving hormonal treatment, the majority of prostate cancer patients become resistant to this approach over time. Indeed, the development of androgen independent disease or castration resistant prostate cancer (CRPC) is inevitable. Once patients develop clinical CRPC, therapeutic options are limited and prognosis is poor.(3) Chemotherapy is the standard of care for CRPC. Docetaxel has recently been considered the new standard cytotoxic agent based on the results of two randomized trials that reported a statistically significant increase in median survival.(4, 5) For patients that progressed despite docetaxel based chemotherapy, no standard treatment has yet demonstrated any significant clinical benefit. In this context, the development of therapeutic strategies for docetaxel-resistant and castration resistant patients would fulfill a relevant unmet need in prostate cancer research. 1 Different biologic mechanisms have been associated with the development of CRPC. Activation of growth factor receptors including the vascular endothelial growth factor receptor (VEGFR), and its downstream pathway mediators such as the oncogenic Src pathway have been implicated in this neoplastic process(6) and represent potential targets. 2.2. Dasatinib (BMS-354825) Dasatinib (BMS-354825), an aminothiazole analogue, is an orally administered (PO) protein tyrosine kinase (PTK) inhibitor with specificity for five kinases/kinase families that have been strongly linked to multiple forms of human malignancies.(79) These targets include: BCR-ABL, c-Src, c-KIT, PDGFβ receptor, and EPHA2. In vivo and in vitro studies have established that dasatinib demonstrates potent antiproliferative activity in a wide spectrum of cancer cell lines/types, and early clinical results also suggest anticancer activity of dasatinib in chronic myelogenous leukemia (CML) and solid tumor patients.(10-13) Dasatinib potently and selectively inhibits the five oncogenic PTKs/kinase families by competing with ATP for the ATP-binding sites in the kinases: Src family kinases (IC50: Src = 0.55 nM, LCK = 1.1 nM, YES = 0.41 nM, FYN = 0.2 nM); BCR-ABL (<3 nM); c-KIT (13 nM); EPHA2 (17 nM) and PDGF receptor (28 nM) (Investigator’s Brochure, 2009). The agent was found to be less potent against unrelated PTKs and several serine/threonine kinases. Dasatinib also demonstrates potent inhibition of VEGF- and bFGF-driven proliferation of human umbilical vein endothelial cells (HUVECs), with IC50 values of 43 and 248 nM, respectively. The Src family of protein tyrosine kinases is comprised of nine homologues that are highly conserved throughout evolution, and members of the family are ubiquitously expressed in virtually all metazoan cells, including human epithelia.(14) Platelets, osteoclasts, and neural cells are the only normal cell types known to contain high levels of Src. Src TK activity is important in the epithelia to mesenchymal transition that occurs in the early stages of invasion of carcinoma cells. (15) Although the evidence for mutational activation in epithelial cells is weak, there is clear evidence that Src expression and activity are increased at various stages in tumor development including pre-malignant epithelial changes (e.g., ulcerative colitis, Barrett’s esophagus), in primary tumors (e.g., breast, colon, ovary, bladder, lung, esophagus), and in metastatic sites (e.g., colon cancer, where activity is increased compared to a synchronous primary). The underlying epithelial cell biology implicates Src kinases in the processes of invasion, adhesion, cell motility, regulation of cell junctions, and migration. Studies have shown that focal adhesion kinase (FAK) and Src cooperate to control cell adhesion and migration through modulation of focal adhesion formation and its turnover. It was previously observed that upon acquisition of an endocrine-resistant state, MCF-7 cells possess elevated Src activity and gain a motile and invasive phenotype.(16) Increased Src TK activity in tumors may promote a tumor-invasive phenotype through both its disruption of normal cell-cell adhesion and by facilitating a motile tumor cell phenotype. 2 This observation is supported by clinical evidence that indicates a relationship between deregulated Src TK activity and the increased invasive potential of tumor cells. Src is also involved in signaling pathways regulating survival, angiogenesis, steroid receptor activation, and growth factor receptors. Increased Src activity has been shown to correlate with disease progression, with the highest activity found in metastatic tissues. Furthermore, Src expression and activity have been linked to adverse prognosis in colorectal and prostate cancer.(17, 18) Nonclinical Studies Nonclinical Efficacy Dasatinib inhibits growth of multiple BCR-ABL-dependent leukemic cell lines and also shows activity against 14 of 15 imatinib-resistant BCR-ABL kinase mutants.(19) Inhibition of CML cell lines established from patients who were resistant to imatinib therapy has also been reported (Wu et al., 2004). Dasatinib potently inhibits wildtype (IC50: 1-10 nM) and mutant (IC50: 10-100 nM) KIT kinases in M07E cells and human mast cell leukemia cell lines, respectively (Schittenhelm et al., 2006). Also of note, dasatinib selectively killed primary neoplastic bone marrow mast cells from patients with systemic mastocytosis while sparing other hematopoietic cells.(20) Dasatinib demonstrated antiproliferative activity in a wide-spectrum of solid tumor types, including mastocytoma, prostate, colon, breast, and rhabdomyosarcoma cell lines with IC50 values ranging from 5.4-845 nM.(8) The agent also inhibited stem cell factor-driven proliferation of three small cell lung cancer (SCLC) cell lines with IC50 values in the range of 114-220 nM and showed activity in head and neck squamous cell carcinoma and non-small cell lung cancer cell lines.(21) When dasatinib was administered twice daily (BID) on a 5-days-on/2-days-off schedule for a total of 14 to 25 days at doses of 10-50 mg/kg/dose, in vivo antitumor activity of dasatinib was seen in prostate, colon, SCLC, and rhabdomyosarcoma xenograft models. Similarly, dasatinib was effective against K562 and imatinibresistant K562-R human CML xenografts in SCID mice at doses as low as 2.5-5 mg/kg/day.(22) In combination with paclitaxel, dasatinib produced antitumor effects against PC3 human prostate carcinoma xenografts that were significantly better than the effects of either single agent alone (P = 0.05).(8) Dasatinib at 20 or 50 mg/kg inhibited the T-cell proliferation response in mice following the transfer of lymphocytes from allogeneic donor mice.(8) In addition, treatment of mice with dasatinib 25 mg/kg BID inhibited the graft-versus-host response in a non-vascularized model of murine heart transplant. The 5-days-on/2days-off regimen almost completely eliminated immunosuppressive activity in this model. 3 Src kinase is known to play a major role in osteoclast function. In short-term studies, dasatinib acted as a potent inhibitor of bone resorption as measured by its ability to reduce the release of 45calcium into the culture medium by fetal rat long bones in vitro (IC50 = 2 nM). Dasatinib also inhibited parathyroid hormone (PTH)stimulated release of 45calcium in a dose-dependent manner with an apparent IC50 of 2 nM. At 5 nM, dasatinib completely blocked PTH-stimulated bone resorption in thyro-parathyroidectomized rats. The therapeutic utility of dasatinib in the treatment of cancer-related hypercalcemic syndromes has not been fully explored, and the long-term effects of dasatinib on bone physiology are also unknown. Nonclinical Pharmacokinetic and Pharmacodynamic Studies Nonclinical metabolic and pharmacokinetic (PK) studies were conducted with dasatinib in several species including mouse, rat, dog, and monkeys to assess the absorption, distribution, metabolism, and excretion of the compound in animals. These studies showed that dasatinib has varying degrees of oral bioavailability, ranging from 15% in monkeys to 34% in dogs. The permeability of dasatinib in the Caco-2 cell model is 102 nm/sec at pH 7.4, suggesting that it has the potential for good (>50%) oral absorption in humans. The agent is highly bound to serum proteins (>91%) and has extensive extravascular distribution. Dasatinib is principally eliminated by hepatic metabolism and excreted in feces. The agent is primarily metabolized by the CYP3A4 enzyme to three hydroxylated isomers, a bisoxygenated metabolite, an N-dealkylated metabolite, a carboxylic acid, a dehydrogenation product, and glucuronide, sulfate and taurine conjugates. The value of phospho-Src as a biomarker of dasatinib efficacy has been explored in nonclinical studies.(23) In nude mice bearing subcutaneous PC-3 tumors (human prostate), measurement of phospho-Src by western blot in tumor and peripheral blood mononuclear cells (PBMCs) following treatment with a single dose of dasatinib (15 or 50 mg/kg) produced similar results in both tissues. Levels of phospho-Src were maximally inhibited at 3 hours post dose, then recovered partially between 7 and 17 hours and returned to the basal level by 24 hours after agent administration. These results were quantitated by image scanning and compared to efficacy results when the agent was administered PO BID at 15-50 mg/kg/dose for 14 days on a 5-days-on/2-days-off schedule. Efficacy and phosphoSrc inhibition appeared to correlate, and this pharmacodynamic model permitted the authors to predict that the plasma concentration of dasatinib required to produce 90% inhibition of phospho-Src would be 164 nM and 91 nM in PC-3 tumor and PBMCs, respectively. Studies to evaluate the clinical utility of phospho-Src as a biomarker are ongoing. Toxicology A range of toxicology studies have been conducted to support the oral administration of dasatinib in humans. The oral studies indicated that dasatinib induced reversible toxicities of the gastrointestinal (GI) and lymphoid systems in rats and monkeys, and of the hematopoietic system in rats. Embryofetal 4 development studies in rats and rabbits indicated that dasatinib caused embryolethality or skeletal malformations at doses that did not cause maternal toxicity, suggesting that it is a selective developmental toxicant. An in vitro cytogenetics study in CHO cells indicated that it was clastogenic at concentrations >5 μg/mL, a level not achievable in vivo. The agent is nongenotoxic and did not show significant potential for undesirable functional activity in in vitro receptor/ion channel binding and enzyme assays. In vitro potassium channel current (HERG/IKr) and Purkinje fiber assays suggested that dasatinib could potentially prolong cardiac ventricular repolarization (QT interval), and a single-dose cardiovascular study in monkeys demonstrated that the agent at a dose of 10 mg/kg caused a minimal increase in blood pressure for approximately 2 hours post dose. There were no drug-related neurologic observations in rats or monkeys. Dasatinib was found to be phototoxic in an in vitro assay in mouse fibroblasts. Clinical Experience Over two thousand subjects have received dasatinib, a number with CML refractory or intolerant to imatinib but many also with solid tumours such as advanced breast cancer and prostate cancer.(8) Studies conducted in healthy volunteers include the following: PK; formulation comparisons; the effect of food; drug interactions; and supportive care. Pharmacokinetics Pharmacokinetic studies were conducted using a single 100 mg dose of dasatinib administered to healthy volunteers in four different formulations: 50 mg clinical tablets x 2, 5 mg clinical tablets x 20, 20 mg commercial tablets x 5, and 50 mg commercial tablets x 2. The PK profile of the agent was similar in all four formulations. The PK profile of dasatinib was also assessed in CML and Ph+ ALL patients providing data which showed that the PK parameters in the patient population appear to be similar to that in the healthy volunteers. The agent was absorbed rapidly following oral administration; peak plasma concentrations were achieved in 0.5-3 hours and dose-related increases in plasma concentrations were observed. The mean terminal half-life (t1/2) of dasatinib was 4 hours. Dosing interval exposures and t1/2 values were comparable regardless of whether the agent was administered on a once daily or twice daily (BID) 5-day-on/2-day-off schedule, or BID continuously. Efficacy in Solid Tumor - Prostate Cancer CA180085 CA180085 is an open-label Phase 2 study to estimate the response rate of adding dasatinib treatment to ongoing androgen deprivation with LHRH treatment or surgical castration in men with metastatic prostate cancer. Ninety-five subjects were treated with dasatinib at 100 mg BID, 70 mg BID, or 100 mg QD. The median duration of therapy was determined to be 2.96 months (range 0.03 - 17.08). Sixty- 5 one of the 95 subjects discontinued treatment due to disease progression. At the time of this report, 8 subjects were continuing on therapy. Of the 95 treated subjects, 25 subjects were responders based on the composite endpoint. Confirmed prostate-specific antigen (PSA) response was observed in 2 subjects, 1 in each the QD and BID groups. Stabilization of visceral/nodal disease as evaluated by RECIST was observed in 10 subjects in the QD group and 12 subjects in the BID group, and a partial response was observed in 1 (1.1%) subject (QD group). One subject (BID group) had a confirmed bone scan improvement and 49 subjects (52%) had stabilization of bone as evaluated by bone scan. Reduction in bone turnover as evaluated by uNTX (urinary N-telopeptide) and BAP (bone-specific alkaline phosphatase) was also observed in a large proportion of the patients while on treatment. uNTX and BAP are bone resorption markers representative of osteoclastic and osteoblastic activity, respectively. Daily dosing with dasatinib at 100 mg/QD led to fewer and less severe side-effects compared with BID dosing with either 70 mg or 100 mg.(24-26) CA180086 CA180086 is an ongoing open label Phase 1/2 study to assess the MTD and recommended Phase 2 dose of each drug in the combination of oral dasatinib and intravenous docetaxel in subjects with metastatic castration-resistant (hormonerefractory) prostate cancer (CRPC). Docetaxel dose levels were 60 mg/m2 and 75 mg/m2. Dasatinib dose levels investigated were 50 mg, 70 mg, 100 mg, and 120 mg. Forty-six subjects were treated with 12 still receiving treatment at data cutoff (17Aug-2009) (Appendix 6). Twenty-two of the 46 treated subjects discontinued treatment due to disease progression. Currently, the median duration of therapy was 6.2 months (range 0.1 - 11.5). Of the 46 treated subjects, at the time of this interim analysis one unconfirmed complete response, 17 partial responses of visceral/nodal disease as evaluated by RECIST were observed and stabilization of disease (SD >/= 18 weeks) was observed in 5 subjects. Confirmed PSA response was observed in 26 subjects and bone scan improvement was seen in 13 subjects. Reduction in bone turnover as evaluated by uNTX and BAP was also observed in a large proportion of the patients while on treatment. No pharmacokinetic interaction was observed between dasatinib and docetaxel when administered in combination.(27, 28) CA180227 This is an ongoing double-blind, placebo-controlled, phase 3 study designed to compare overall survival for dasatinib plus docetaxel and prednisone versus placebo plus docetaxel and prednisone in subjects with metastatic CRPC. A total of 1380 subjects are to be randomized to received full dose docetaxel (75 mg/m2) and prednisone plus dasatanib, 100mg orally daily and continuously or docetaxel, 6 prednisone and placebo. The first review of the DMC after 100 subjects received two cycles or more recommended to continue enrolment without modification.(8) Based on results from phase 1 and 2 studies, a daily, continuous dose of 100 mg appears well tolerated in subjects with advanced solid tumors and will be used for this study. Safety Please consult the most recent version of the Investigator’s Brochure for more details on the following studies.(8) In Phase 1 clinical pharmacology studies, dasatinib has been administered to 464 subjects (322 normal healthy volunteers, 109 subjects with leukemia, 18 subjects with advanced solid tumors, and 15 subjects with hepatic impairment). In Phase 1, 2, and 3 clinical efficacy and safety studies, a total of 3,666 subjects have been treated with dasatinib. Dasatinib’s activity has been investigated in eight Phase 1 studies (CA180009, CA180016, CA180019, CA180020, CA180022, CA180032, CA180037, and CA180002) and five Phase 2 studies (CA180005, CA180006, CA180013, CA180015, and CA180017) that supported the approved indication and initial dosage of dasatinib at 70 mg BID in subjects with CML or Ph+ ALL. Two Phase 3 studies (CA1800034 and CA180035) were designed to compare alternate doses and administration schedules in imatinib resistant or intolerant subjects with chronic, accelerated, or blast phase CML or Ph+ ALL. Data from CA180034 supported the approval of dasatinib at 100 mg administered QD in subjects with chronic phase CML. As a result of similar efficacy and improved safety in study CA180035, the approved dose was changed from 70 mg BID to 140 mg QD in advanced disease CML and in Ph+ ALL. In the dasatinib hematology program, two Phase 2 (CA180040 and CA180072) and two Phase 3 studies (CA180056 and CA180216) in newly diagnosed chronic phase CML are ongoing. Recently completed studies in CML include Phase 1/Phase 2 studies in Japan (CA180031, CA180036, and CA180138) and a Phase 2 study in China (CA180160). Pediatric studies in CML and Ph+ ALL are completed (CA180038 - also includes solid tumor), ongoing (CA180018, CA180226, CA180204), or planned (CA180Q36). Studies of dasatinib treatment in new indications include CA180180 and CA180181 (Phase 1 studies in multiple myeloma) and CA180267 (systemic sclerosis). The dasatinib solid tumor clinical program is designed to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamic profile of dasatinib in subjects with solid tumor (breast, glioblastoma and prostate) and to assess antitumor activity. The solid tumor program currently comprises four Phase 1 (CA180003, CA180021, CA180004, CA180086 [Phase 1/2]), four Phase 2 studies 7 (CA180059, CA180088, CA180085, CA180261), and one Phase 3 study (CA180227); results from some of these studies are summarized in the Investigator’s Brochure. The clinical safety and tolerability of dasatinib administered at 70 mg BID with 2 years of follow-up was demonstrated in subjects with chronic and advanced phase CML and Ph+ ALL in one Phase 1 study (CA180002) and five pivotal Phase 2 studies (CA180005, CA180006, CA180013, CA180015, CA180017). Besides the expected cytopenias in these disease populations, fluid retention, in particular pleural effusion, was a common side effect that required medical management with dose interruptions and dose reductions. In an attempt to control these adverse events (AEs) while maintaining dasatinib’s efficacy, two Phase 3 studies (CA180034 and CA180035) were designed to assess the safety and efficacy of different dosing schedules and to investigate the optimal dose and schedule of dasatinib. As a result of comparable efficacy and improved safety reported in studies CA180034 and CA180035, the recommended dose was changed from 70 mg BID to 100 mg QD in subjects with chronic phase CML and from 70 mg BID to 140 mg QD in subjects with advanced phase CML and Ph+ ALL. Overall, the median duration of therapy was 15 months (range 0.03 - 36 months). Dasatinib continues to show a safe and tolerable safety profile. Incidence rates of fluid retention-related events (including pleural effusion, congestive heart failure, pericardial effusion, pulmonary edema) and of cytopenias (including neutropenia, thrombocytopenia, and anemia) continue to be of special interest. Safety in Solid Cancers The MTD on the 5D2 schedule was 240 mg TDD, with 1 of 6 evaluable subjects reporting DLT (Grade 3 tumor lysis syndrome). The 240-mg dose was 1 level below the MAD of 320 mg, at which 3 of 4 evaluable subjects had DLT (recurrent Grade 2 rash; Grade 3 lethargy; and 1 subject with Grade 3 prolonged bleeding time and Grade 3 hypocalcemia). The MTD on the CDD schedule was 140 mg TDD, at which no subjects reported DLT. Treatment on this schedule was initiated at 140 mg and escalated to the maximum administered dose (MAD) of 240 mg, at which 3 of 4 evaluable subjects reported DLT (Grade 3 nausea, Grade 3 fatigue, and Grade 2 proteinuria and Grade 3 rash, respectively). All but 1 of the 67 subjects (98.5%) reported at least 1 AE during the study. The most frequent AEs (regardless of relationship) were nausea, anorexia, and fatigue. A total of 64/67 subjects (95%) had at least 1 AE that was considered drug-related by the investigator. Of the 18 deaths, all but 1 of these deaths were due to disease progression; 1 subject died due to gastrointestinal bleeding that the investigator considered most likely due to disease progression, but could not rule out a possible contribution by study drug. 8 Unlike dasatinib treatment in subjects with leukemia, Grade 3 to 4 myelosuppression in subjects with solid tumors was infrequent. This comparison suggests a minimal direct myelosuppressive effect of dasatinib in normal hemapoietic progenitor cells, which are not driven by the ABL kinase. Solid Tumor - Prostate Cancer CA180085 Eight subjects remain on treatment. Of the 87 subjects off-treatment, 61 discontinued treatment due to disease progression. Four subjects died, 2 in the 100 mg BID group and 2 in the 100 mg QD group. Both of the subjects in the QD group died within 30 days of the last dose of treatment (1 due to disease progression and 1 unknown). Deaths in the100 mg BID group were due to prostate cancer. In general, fewer subjects in the QD group reported drug-related AEs compared with either of the BID groups. The majority of drug-related AEs were Grade 1/2. The most common AEs were nausea, fatigue, asthenia, pleural effusions, rash, nausea, headaches and diarrhea. Most on-treatment AEs were manageable by dose reductions and dose interruptions. A total of 20 out of 95 subjects reported SAEs (any relationship or grade). CA180086 Twenty-two of the 46 treated subjects discontinued treatment due to disease progression. Dose reductions were required in 4 treated subjects, but only following the DLT observation period. Dose interruptions were reported in the 50 mg/60 mg/m2 (n = 3), 50 mg/75 mg/m2 (n = 2), 100 mg/75 mg/m2 (n = 21), and 120 mg/75 mg/m2 (n = 3) treatment groups. Two subjects died (1 each for 50 mg/60 mg/m2 and 100 mg/75 mg/m2) due to disease progression. The majority of drugrelated AEs were Grade 1/2. A total of 15 out of 46 subjects reported SAEs (any relationship or grade). Though this study is currently ongoing, preliminary data review indicates that dasatinib at doses up to 120 mg QD in combination with docetaxel up to 75 mg/m2 is safe and tolerable. Potential Drug Interactions Dasatinib is primarily metabolized by CYP3A4 and therefore, potent inhibitors of this enzyme are contra-indicated.(8) Dasatinib is also a significant inhibitor of this hepatic enzyme but a weak inhibitor of other cytochrome enzymes, and the agent does not induce CYP3A4. Thus, dasatinib may decrease the clearance of drugs that are significantly metabolized by the CYP3A4 enzyme, and caution should be used with concurrent use of such drugs or substances. In a study in cancer patients, concomitant use of a potent CYP3A4 inhibitor (ketoconazole) produced >5-fold increase in exposure to dasatinib, while healthy subjects treated concurrently with dasatinib and a potent CYP3A4 inducer experienced a 5-fold decrease in dasatinib exposure. When the CYP3A4 substrate simvastatin was studied in combination with 9 dasatinib, increased simvastatin exposure resulted, indicating the necessity of caution when dasatinib is administered with CYP3A4 substrates with a narrow therapeutic margin (e.g., cyclosporine). A list of prohibited agents as well as a list of medications to be used with caution in patients receiving dasatinib is in Appendix A. 10 2.3. Cediranib (AZD2171) Cediranib, an orally available small molecule, is a potent inhibitor of receptor tyrosine kinases (RTKs) which influence the effects of a key angiogenic factor, vascular endothelial growth factor-A (VEGF). VEGF is implicated in tumor blood vessel formation and in disease progression in a wide range of solid tumor malignancies. Expression of this factor is increased by diverse stimuli which include proto-oncogene activation and hypoxia, with the hypoxic state frequently occurring in solid tumors because of inadequate perfusion. In addition to its angiogenic role, VEGF also profoundly increases the permeability of the vasculature and thereby potentially contributes to tumor progression – a leaky tumor endothelium enhances nutrient and catabolite exchange and represents less of a barrier to tumor cell migration during metastasis. With the goal of suppressing neovascularization and thus inhibiting tumor growth and metastasis, numerous antiangiogenic agents have been developed. In contrast to many of these intravenously-administered antiangiogenic agents, a recently emerging class of novel orally-administered VEGF TK inhibitors including cediranib has been developed.(29-31) Two high-affinity receptors for VEGF with associated TK activity have been identified on human vascular endothelium, KDR (kinase insert domain-containing receptor = VEGFR2) and Flt-1 (fms-like tyrosine kinase 1 = VEGFR1). Although the relative contributions of KDR and Flt-1 signaling in mediating tumor progression have not been elucidated, a number of studies suggest that KDR performs a predominant role. Cediranib is a potent inhibitor of both KDR (IC50 <0.002 M) and Flt-1 (IC50 = 0.005 M) and shows activity versus c-kit, platelet-derived growth -4 at nM concentrations, but is not selective against other serine/threonine kinases studied. It has been shown that cediranib potently and selectively inhibits VEGF-stimulated human umbilical cord vascular endothelial cell (HUVEC) proliferation with an IC50 of 4 nM.(31) These authors have also demonstrated the agent’s profound inhibitory effect on vessel area, length, and branching at subnanomolar concentrations using a modified fibroblast/endothelial cell co-culture system. Cediranib’s effects on hemodynamic parameters have been studied in an athymic rat xenograft model of human colorectal carcinoma (SW620) using perfusion-permeability dynamic contrast-enhanced magnetic resonance imaging (pp-DCE-MRI).(32) This method clearly demonstrated that in this model, cediranib significantly reduced vascular permeability by 80% (P<0.005) and vascular volume by 68% (P<0.05). Nonclinical Studies Nonclinical Efficacy The effect of cediranib was studied in athymic nu/nu mice bearing established subcutaneous human tumor xenografts of diverse histologies [SW620 (colon), PC-3 (prostate), Calu-6 (lung), SKOV-3 (ovarian), and MDA-MB-231 (breast)]. Animals 11 were administered cediranib orally (PO) at doses from 0.75 to 6 mg/kg/day (2.2518 mg/m2/day) in a constant volume of 0.1 mL/10 g body weight for 24-28 days. Cediranib produced a statistically significant inhibition of tumor growth in all human tumor types examined when dosed at 1.5 mg/kg/day (4.5 mg/m2/day) or higher. The murine renal cell carcinoma (RENCA) model, which rapidly (generally within 10 days) metastasizes to the lung and abdominal lymph nodes, has also been used for cediranib efficacy studies.(33) In experiments incorporating a vehicle control, cediranib (at a dose of 6.3 mg/kg/day PO) reduced primary tumor growth, metastasis, and microvessel density more potently than any other previouslystudied VEGF RTK inhibitor reported in the literature. Using a transgenic mouse model in which multiple mammary tumors spontaneously develop after two pregnancies, investigators studied the temporal effects of cediranib administration.(34) When dosed with cediranib (0.75 to 6 mg/kg/day PO) at the time early lesions start to develop, the number of tumor foci was not affected, but their growth was inhibited. When tumors were well-established before cediranib was given (at doses of 3 and 6 mg/kg/day), dose-dependent growth inhibition occurred as well as tumor regression. Further details of the non-clinical efficacy of cediranib can be found in Section 4.1 of the investigator’s brochure. Nonclinical Pharmacology and Toxicology Nonclinical pharmacology and toxicology company-sponsored cediranib studies have been conducted in rats, dogs, and cynomolgus monkeys. In rats and dogs, oral bioavailability is high, but absorption is relatively slow, with peak plasma concentration (Cmax) of the agent seen 4-6 hours after PO dosing. Plasma concentrations and exposure are generally linear over the dose ranges studied in rats. Cediranib is excreted in the feces (>70% of the dose) of rats, dogs, and cynomolgus monkey after both PO and intravenous administration. Fecal excretion was the predominant route of elimination (>70% of the dose) in both rat, dog and cynomolgus monkey after both oral and intravenous administration. Elimination was rapid in rats and monkeys with over 75% of the dose being recovered in the first 48 hours; in dogs excretion was slightly slower but again substantially complete by 7 days. Over the dose ranges examined in the rat, plasma concentrations and exposure generally increased in proportion to dose; however, in monkeys, plasma cediranib concentration-time profiles obtained following a single oral dose indicated that systemic exposure increased in a greater than dose-proportional manner over the dose range 0.05 to 2.5 mg/kg. 12 Protein binding of cediranib (90 to 95%) was relatively high across all species examined and was independent of concentration (range: 0.03 to 10 g/mL) and gender. Cediranib was approximately 95% bound to human plasma proteins, with human serum albumin and α1-acid glycoprotein accounting for most of this binding. VEGF has three major biological activities in endothelial cells of rats and primates of the age groups used in the nonclinical studies. It is an important angiogenic factor, a potent physiological mediator of vascular tone (specifically of vasodilation), and a potent modulator of capillary permeability inducing endothelial cell fenestrations. VEGF receptor inhibition was therefore considered to be the cause of many of the pathophysiological changes encountered. Vascular (myocarditis, choroid plexus) and renal (glomerulosclerosis and tubular degeneration) pathologies have been seen in rat, dog, and primate dosed with cediranib which are considered to be consistent with lesions induced by hypertension, although a direct effect by cediranib on these tissues cannot be excluded. Pathological findings were also seen in the adrenal glands (degenerative cortical changes), pancreas (acinar epithelial cell necrosis), thyroid (follicular epithelial cell atrophy), liver (hepatocyte necrosis), and biliary system (cholangitis and bile duct proliferation and bile duct cholangitis) of the rat. In addition in the primate, changes were seen in the gallbladder (mucosal hypertrophy) and bile duct (hyperplasia/hypertrophy). Cediranib did not induce rat hepatic microsomal P450 activity but caused a 40 to 60% reduction in CYP1A activity at the 2.5 mg/kg dose level. Inhibition studies in vitro using human hepatic microsomal protein gave IC50 values for cediranib against CYP2D6, CYP3A4 testosterone, and CYP3A4 midazolam of 32.9, 16.2, and 21.4 mcg/mL, respectively. For CYP1A2, CYP2A6, CYP2C8, CYP2C9, CYP2C19, and CYP2E1, the IC50 values were outside the concentration range of cediranib examined. As the clinically relevant plasma concentration of cediranib has not yet been determined, any possible effect on compound clearance and drug interaction is currently unknown. A list of prohibited agents as well as a list of medications to be used with caution in patients receiving cediranib is in Appendix A. Further details of the nonclinical pharmacology and toxicity of cediranib can be found in Sections 4.2 and 4.3 of the investigator’s brochure, respectively. Clinical Experience Clinical Studies In a phase I study with cediranib the recommended dose for further phase II studies was 45 mg once daily.(35) In this study eighty-three patients received cediranib, which was generally well tolerated at doses of 45 mg/d or less. The most frequently 13 reported dose-related adverse events were diarrhea, dysphonia, and hypertension. The most common DLT was hypertension (n = 7), which occurred at cediranib doses of 20 mg and higher. In other phase I trials where cediranib was combined with other chemotherapy regimens the dose varied between 20 and 45 mg daily. For instance, in advanced non-small cell lung cancer cediranib in combination with Carboplatin and Paclitaxel was administered at a dose of 30 mg daily,(36) and this dose of cediranib was initially selected for further phase II/III evaluation. However, the phase II/III trial (BR.24) has since been terminated based on an interim analysis of progression-free survival and accumulated toxicity data, and this trial has restarted with a similar comparison but uses cediranib 20 mg instead of 30 mg. In a phase I trial in prostate cancer the selected cediranib dose for further studies was 20 mg daily.(37) In this study a total of twenty-four patients received cediranib monotherapy treatment at once-daily oral doses of 1, 2.5, 5, 10 (all n = 3), 20 (n = 10) and 30 mg (n = 2). In the 20 and 30 mg cohorts, grade 3 adverse events considered by the investigator to be possibly drug-related were hypertension (n = 2), fatigue, muscular weakness, myalgia and transient ischemic attack (n = 1 each). The 20 mg dose was tested in a phase II trial in docetaxel resistant, CRPC patients.(38) In this ongoing study, 13 of 23 evaluable patients had tumor shrinkage and 4 have met the criteria for partial response. Decreases in lymph node metastases as well as in lung, liver and bone lesions have occurred. PSA levels have not corresponded well with imaging responses.(38, 39) In another phase I trial of cediranib given in combination with gefitinib in solid tumors, no unexpected toxicities were observed for cediranib doses between 20 mg and 45 mg.(40) Reversible Posterior Leukoencephalopathy Syndrome (RPLS) or Other Leukoencephalopthy Syndromes RPLS or clinical syndromes related to vasogenic edema of the white matter have been rarely reported in association with cediranib therapy (<3%). Clinical presentations are variable and may include altered mental status, seizure and cortical visual deficit. Hypertension is a common risk factor and was present in most (though not all) patients on cediranib who developed RPLS. MRI scans are key to diagnosis and typically demonstrate vasogenic edema (hyperintensity in T2 and FLAIR images and hypointensity in T1 images) predominantly in the white matter of the posterior parietal and occipital lobes; less frequently, the anterior distributions and the gray matter may also be involved. RPLS should be in the differential diagnosis in patients presenting with unexplained mental status change, visual disturbance, seizure or other CNS findings. RPLS is potentially reversible, but timely correction of the underlying causes, including control of blood pressure and interruption of the offending drug, is important in order to prevent progression to irreversible tissue damage. Certain physiologic processes other than endothelial cell growth are dependent on VEGF signaling, so inhibition of that growth factor may have implications for use of cediranib in selected patient populations. Cediranib interferes with normal reproductive processes and completely prevents fetal development in rats at a dose 14 of 2.5 mg/kg/day. For this reason, women of childbearing potential should have a negative pregnancy test before treatment with cediranib is initiated. In rat studies, cediranib significantly inhibited endochondral ossification and corpora lutea formation.(31) 2.4. Rationale for Combining Cediranib and Dasatinib in CRPC Several pathways have been linked to the development of CRPC, such as mutations in the androgen receptor or non-physiological activation of signaling pathways controlling cell survival, differentiation, progression and angiogenesis such as VEGFR, epithelial growth factor receptor (EGFR) or platelet-derived growth factor receptor (PDGFR).(6) The role of VEGF/VEGFR activation has been well studied in prostate cancer. Elevation of VEGF has been correlated with poor prognosis and progression(41) and inhibition of VEGF/VEGFR pathway in experimental models induces an anti-tumor effect. These findings support the rationale for the development of antiangiogenic agents in prostate cancer. Cediranib is an antiangiogenic agent that inhibits several tyrosine kinase receptors involved in the angiogenic process including VEGFR1, 2 and 3. Preclinically, cediranib inhibits the tumor volume in prostate cancer models using xenograft mice.(31) In a recent phase II study of cediranib monotherapy in docetaxel resistant CRPC patients, stable disease/partial response have been observed in 13 of 23 (57%) evaluable patients.(38, 39) Similarly, activation of EGFR and downstream pathways have been associated with the development of CRPC.(6) The nonreceptor tyrosine kinase Src has been implicated in the transduction of intracellular signaling mediated by upstream receptors. Furthermore, activation of Src in tumors from prostate cancer patients is associated with a worse prognosis.(18) In the same context, treatment of CRPC cells with a Src inhibitor provoked a reduction in migration and proliferation.(18) From a clinical perspective, a phase II trial in 47 chemo naive CRPC patients, treatment with dasatinib at 70 mg p.o. BID (initial dose was 100 mg BID) showed promising activity. In this study, 28% (13 of 47) of the treated patients responded or had tumor stabilization (composite endpoint): one patient had a confirmed PSA response, 12 patients had RECIST-criteria stable disease, and no patient had a confirmed improved bone scan.(24, 26) A phase II trial in another 47 chemo naive CRPC patients, dasatinib was given at 100 mg p.o. daily. The composite response rate of PSA responses, bone scans and disease control was 17% (8 of 47). Of 11 patients evaluable by RECIST, 64% achieved stable disease. Of 22 patients with bone scans, 50% were stable at 12 weeks and 33% were stable at 24 weeks. A prolonged PSA doubling time was observed in 32 of 39 patients (82%), including one patient with a PSA response. Grade 3 or 4 adverse events were experienced by 13% of patients including diarrhea, asthenia and pleural effusion.(25) A phase II trial of another Src inhibitor, saracatinib, at 175 mg p.o. daily in 28 patients with CRPC, of which 9 (32%) had prior docetaxel therapy, yielded a median progression- 15 free survival of 8 weeks with 5 patients experiencing a transient PSA reduction but not meeting PSA response criteria. Treatment was well tolerated with one grade 3 occurrence each of ALT elevation, AST elevation, nausea, vomiting and lymphopenia.(42) Recent biological findings suggest that therapeutic targeting with drug combinations could increase the antitumor activity compared with single agent treatment.(43) This concept is also supported by experimental findings in androgen-independent models which indicate that inhibition of receptor tyrosine kinase signaling may restore androgen-dependence or sensitivity to cytotoxic treatment.(44, 45) A phase I study of cediranib and the Src inhibitor saracatinib was performed by Trarbach et al. in patients with advanced solid tumors.(46) When combined with saracatinib at a fixed dose of 175 mg daily, no dose-limiting toxicities were observed in either the cediranib 20 mg or 30 mg cohorts, while 1 dose-limiting toxicity of grade 3 hypertension was observed in the cediranib 45 mg cohort. While all three doses of cediranib (20 mg, 30 mg and 45 mg) were well tolerated when combined with saracatinib at 175 mg daily, the data suggest that the cediranib 20 mg and 30 mg doses were more sustainable than the cediranib 45 mg dose. The most common adverse events were hypertension, diarrhea, dysphonia and fatigue. There was no evidence to suggest that saracatinib had a clinically significant effect on cediranib pharmacokinetics or vice versa. Overall, 22/39 patients (56%) achieved a best overall response of stable disease. The recommended doses of cediranib for future studies, in combination with full dose saracatanib are 20 mg and 30 mg.(46) Based on these preclinical and clinical data we consider that the concomitant administration of the Src inhibitor dasatinib with the VEGFR inhibitor cediranib could be of interest, especially in docetaxel resistant CRPC where there is an unmet need and where the combination may enhance antitumor activity. In this context, the combination of both drug is likely to be safe at doses of dasatinib of 100 mg and of cediranib of 45 mg or less. The most common adverse events most likely to be observed are hypertension, diarrhea, nausea, pleural effusion, rash, dysphonia and fatigue. 2.5 Correlative Studies Background Bone Resorption Markers for Src Inhibition While responsive to androgen ablation in its early stages, prostate cancer eventually becomes castration resistant and metastasizes preferentially to bone. Increasing evidence has shown a ubiquitous role for Src in bone-signalling processes involved in prostate tumor progression, driving proliferation, survival, migration and transition to androgen-independent growth. Src is implicated in diseases associated with increased bone resorption, such as osteoporosis and metastatic bone disease.(47) In short-term in vitro studies, dasatinib was a potent inhibitor of bone resorption. In addition, in preclinical models of cancer-related hypercalcemic 16 syndromes, dasatinib inhibited PTH-stimulated release of [45calcium] and, at 5 nM, completely blocked PTH-stimulated bone resorption in thyro-parathyroidectomized rats.(8) In a preclinical evaluation of the Src inhibitor saracatinib in the prostate cancer osteolytic cell line PC-3, saracatinib inhibited PC-3 growth in a dosedependent manner with inhibition of phosphorylation of Src, focal adhesion kinase, paxillin and P130cas at the nanomolar magnitude. For in vivo study, PC-3 cells were injected into the tibia of 12 control SCID mice and 12 SCID mice receiving 25 mg/kg/day saracatinib. At 5 weeks from surgery, 9 of 12 control mice showed osteolytic lesions, compared to only 4 of 12 in the treatment group. This data suggest the ability of Src inhibitors to retard osteolytic lesions in prostate cancer.(48) In the phase II study of dasatinib given at 100 mg daily, 20 of 41 (49%) patients had a > 35% decrease in urine n-telopeptide and 21 of 42 (50%) had a decrease from baseline in bone alkaline phosphatase. As a secondary objective, we plan to measure bone resorption markers at baseline and every 4 weeks in this study. These markers include urine c-telopeptide and bone alkaline phosphatase. We postulate that these biomarkers will decrease as a result of treatment in both arms, but a more pronounced decrease will be observed in the combination arm of cediranib and dasatinib compared to cediranib alone. 17 3. PATIENT SELECTION 3.1 Eligibility Criteria 3.1.1 Patients must have histologically or cytologically confirmed prostate cancer. 3.1.2 Patients must have measurable or non-measurable disease. Measurable disease is defined (per RECIST) as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded) as >20 mm with conventional techniques or as >10 mm with spiral CT scan. All other lesions (or sites of disease), including small lesions (longest diameter <20 mm with conventional techniques or <10 mm using spiral CT scan), are considered nonmeasurable disease. According to PCWG2 criteria, lymph nodes will only be included for measurable disease if >20 mm. Bone lesions, leptomeningeal disease, ascites, lymphangitis cutis/pulmonis, inflammatory breast disease, abdominal masses (not followed by CT or MRI), and cystic lesions are all nonmeasurable. See Section 11 for the evaluation of measurable and nonmeasurable disease. Patients with elevation of PSA alone without measurable or non-measurable disease are not eligible. 3.1.3 Patients must have been treated with prior hormonal therapy. 3.1.3.1 This must include either medical (LHRH agonist) or surgical (orchiectomy) castration. If patients have been treated with LHRH agonists in the past, this therapy should be continued or re-started. All patients must have a castration level of testosterone (<50 ng/dL). A baseline testosterone measurement is not required for patients who have had surgical castration. 3.1.3.2 Anti-androgens must have been stopped for at least 4 weeks prior to Day 1 of treatment. 3.1.4 Patients must have a clinical and/or radiographic evidence of progression on or after docetaxel therapy. 3.1.5 Concurrent therapy: 3.1.5.1 Supportive measures such as zoledronic acid can be continued as long as patients had been receiving it prior to starting study treatment. Low dose corticosteroid (equivalent of 20 mg of prednisone or less daily) and appropriate analgesics/narcotics are also permitted. 3.1.6 Prior therapy: 18 3.1.6.1 Chemotherapy for metastatic disease: Patients may have had any number of other regimens of chemotherapy following docetaxel. A minimum of 4 weeks must have elapsed since the last dose of chemotherapy and Day 1 of treatment. 3.1.6.2 Hormonal therapy: There is no limit on the number of prior hormonal therapy. Prior abiraterone is permitted. A minimum of 4 weeks must have elapsed since the last dose of hormonal therapy or abiraterone and Day 1 of treatment. 3.1.6.3 Radioisotopes: Prior radioisotopes are permitted provided a minimum of 3 weeks has elapsed since the last dose of radioisotope therapy and Day 1 of treatment. 3.1.6.4 Radiation: Prior radiation is permitted provided a minimum of 3 weeks must have elapsed since the last dose of radiation and Day 1 of treatment. Exceptions may be made, however, for low dose, non-myelosuppressive radiotherapy (Contact PMH Phase I Consortium Central Office 416-9464616 if questions arise about interpretation of this criterion). Patients must have recovered from the toxic effects of radiation. 3.1.6.5 Targeted therapy: Patients may not have had prior therapy with angiogenesis or Src or FAK inhibitors. Prior treatment with agents such as COX-2 inhibitors in standard dose is not considered antiangiogenic therapy. Prior treatment with a targeted agent that is not an angiogenesis, Src or FAK inhibitor is permitted but a minimum of 4 weeks must have elapsed since the last dose of targeted therapy and Day 1 of treatment. 3.1.6.6 Surgery: Prior surgery is permitted provided that wound healing has occurred and at least 3 weeks have elapsed (for major surgery). 3.1.7 Age >18 years. 3.1.8 Life expectancy of greater than 3 months. 3.1.9 ECOG performance status ≤ 2 (Karnofsky >60%; see Appendix B). 3.1.10 Patients must have adequate organ and marrow function as defined below: Absolute neutrophil count Hb > 90 g/L (or > 9 g/dL) Platelets ≥100 x 109/L INR ≤1.3 ≥ 1.5 x 109/L 19 Total bilirubin ≤ 1.25 X institutional upper limit of normal AST(SGOT)/ALT(SGPT) ≤ 2 X institutional upper limit of normal (< 5 X institutional upper limit of normal if clearly attributable to liver metastasis) LVEF by ECHO/MUGA within institutional normal range Creatinine ≤ institutional upper limit of normal AND calculated creatinine clearance ( ≥ 60 mL/min/1.73 m2 for patients with creatinine levels above institutional normal) Urine dipstick for protein of less than +1; for dipsticks of +1 or more, 24-hour urine for protein is necessary and should be < 1 g/24 hours 3.1.11 Eligibility of patients receiving any medications or substances known to affect or with the potential to affect the activity or pharmacokinetics of cediranib and dasatinib will be determined following review of their case by the Principal Investigator or Co-Investigator (see Appendix A for further information). 3.1.12 The effects of cediranib and dasatinib on the developing human fetus are unknown. However, teratogenic effects and reduced fetal body weight have been seen in pregnant rats and/or rabbits given both compounds. For this reason and because antiangiogenic agents are known to be teratogenic, if it is appropriate men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the entire duration of study participation. 3.1.13 Ability to understand and the willingness to sign a written informed consent document. 3.2 Exclusion Criteria 3.2.1 History of any malignancy in the last 5 years. Patients with prior history of in situ cancer, or non-metastatic basal or squamous cell skin cancer are eligible. Patients with other malignancies are eligible if they were cured by definitive primary therapy alone and have been continuously disease free for at least 5 years. 3.2.2 Patients with any condition (e.g., gastrointestinal tract disease resulting in an inability to take oral medication or a requirement for IV alimentation, active peptic ulcer disease, short gut syndrome, malabsorption syndrome of any type, total or partial bowel obstruction or inability to tolerate oral medications) that potentially impairs their ability to swallow or absorb are excluded. 3.2.3 Use of specifically prohibited CYP3A4-active agents or substances is not permitted during protocol treatment, and patients who must continue treatment with these agents are not eligible. A list of prohibited CYP3A4-active agents as well as a list of medications to be used with caution is provided in Appendix A. 20 Prohibited drugs should be discontinued fourteen (14) days prior to the administration of the first dose of cediranib and dasatinib and for 14 days following discontinuation of cediranib and dasatinib (unless otherwise specified in Appendix A). 3.2.4 Patients may not be concurrently receiving any other investigational agents. 3.2.5 Unresolved toxicity > CTC grade 2 (except alopecia) from previous anticancer therapy. 3.2.6 Patients with a history of allergic reactions attributed to compounds of similar chemical or biologic composition to cediranib or dasatinib are excluded. 3.2.7 Patients with resting BP consistently higher than, systolic > 150 mmHg and/or diastolic > 100 mmHg (in the presence or absence of a stable dose of antihypertensive medication) or poorly controlled hypertension, history of labile hypertension or poor compliance with anti-hypertensive medication. 3.2.8 Patients with QTc prolongation (defined as a QTc interval greater than or equal to 480 msec by Fridericia correction) or other significant ECG abnormalities (i.e. clinically significant arrhythmias requiring medication, conduction delays such as 2nd or 3rd degree atrioventricular blocks, etc) are ineligible. 3.2.9 Patients with any meningeal metastases or untreated known brain metastases should be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events. Patients with treated brain metastasis with radiologic and clinical evidence of stability, with no evidence of cavitation or hemorrhage in the brain lesions, are eligible providing that they are asymptomatic and do not require corticosteroids (must have discontinued steroids at least 1 week prior to randomization). 3.2.10 Patients with any of the following conditions are excluded: 3.2.10.1 Serious or non-healing wound, ulcer, or bone fracture. 3.2.10.2 History of abdominal fistula, gastrointestinal perforation, or intraabdominal abscess within 28 days of treatment. 3.2.10.3 Any history of cerebrovascular accident (CVA) within the last 6 months. 3.2.10.4 Prophylactic low-dose warfarin is permitted, but close monitoring of INR must be performed. Baseline INR must meet the inclusion criteria (Section 3.1.10). Note: Low molecular weight heparin is permitted. 21 3.2.10.5 History of symptomatic cardiac dysfunction within the last 12 months including unstable angina, congestive heart failure (Class III or IV heart failure as defined by the NYHA functional classification system (see Appendix C)), myocardial infarction or ventricular tachyarrhythmia within 6 months, major conduction abnormality (unless a cardiac pacemaker is present), cardiac angioplasty or stenting or bypass. Patients with a significant cardiac history, even if controlled, should have a LVEF of > institutional normal range by ECHO or MUGA prior to study entry. Patients with any cardiopulmonary symptoms of unknown cause (e.g. shortness of breath, chest pain, etc.) should be evaluated by a baseline echocardiogram with or without stress test as needed in addition to electrocardiogram (EKG) to rule out QTc prolongation. The patient may be referred to a cardiologist at the discretion of the principal investigator. Patients with underlying cardiopulmonary dysfunction should be excluded from the study. 3.2.10.6 Patients who have an active pleural or pericardial effusion of any grade should be excluded. 3.2.10.7 Patients with active or uncontrolled infections, or with serious illness or medical conditions which would not permit the patient to be managed according to the protocol. 3.2.10.8 Patients with known immunodeficiency syndrome. 3.2.11 HIV-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with cediranib or dasatinib. In addition, these patients are at increased risk of lethal infections when treated with marrow-suppressive therapy. Appropriate studies will be undertaken in patients receiving combination antiretroviral therapy when indicated. 3.2.12 Any clinical or radiological evidence of severe or uncontrolled interstitial lung disease (bilateral, diffuse, parenchymal lung disease) or current unstable or uncompensated respiratory conditions. Patients with current or history of idiopathic pulmonary fibrosis are not eligible. 22 3.3 Inclusion of Minorities Men of all races and ethnic groups are eligible for this trial. This study is designed to include minorities as appropriate. However, the trial is not designed to measure differences in intervention effects. The population of Southern Ontario is ethnically diverse and the proportions of different ethnic groups in the community is provided in the table below. Universal access to health care will ensure that there is no discrimination on the basis of race or gender (Guide to Canadian Human Rights Act: www.chrc-ccdp.ca/public/guidechra.pdf ). Individual hospital registries and databases do not routinely collect racial data, under the direction of the Canadian Human Rights Code. The population demographics and distribution of minorities in Canada is included in the following table: Table: Visible minority population by Consortium Provinces (2001 Census) British Columbia Alberta Ontario Nova Scotia Total Total population of province 3,868,870 2,941,150 11,285,550 897,570 18,993,140 Populatio Populatio Visible Minorities n % n % Population % Population % Population % Black 25,465 Asian 1% 31,390 1% 411,095 4% 19,670 2% 768,435 20% 268,660 9% 1,513,825 13% 12,630 1% 487,620 3% 2,563,550 13% Latin American (Hispanic) Visible minority, not included elsewhere 23,880 1% 18,745 1% 106,835 1% 520 0% 149,980 1% 4,195 0% 4,220 0% 78,915 1% 1,170 0% 88,500 0% Multiple visible minority Total Visible minority population 14,465 0% 6,910 0% 42,375 0% 535 0% 64,285 0% 836,440 22% 329,925 11% 2,153,045 19% 34,525 4% 3,353,936 18% Source: Statistics Canada, Census of Population. We have compiled some data from our consortium of representation of minorities on previous clinical trials, and the distribution is as follows: Accrual Targets Sex/Gender Ethnic Category Females Males Total Hispanic or Latino 0 + 8 = 8 Not Hispanic or Latino 0 + 42 = 42 Ethnic Category: Total of all subjects 0 +(A1) = 50 23 50 (B1) (C1) Racial Category American Indian or Alaskan Native 0 + 1 = 1 Asian 0 + 4 = 4 Black or African American 0 + 8 = 8 Native Hawaiian or other Pacific Islander 0 + 0 = 0 White 0 + 37 = 37 Racial Category: Total of all subjects 0 +(A2) (A1 = A2) Accrual Rate: 3 Projected Start Date of Study: pts/month 50 (B2) = 50 (B1 = B2) Total Expected Accrual: 45 (C2) (C1 = C2) Min 50 Max October 2010 Table: Population Percentage of Minority entering PMHC Trials 2002 2003 2004 Visible Minorities Black Asian 3.6 7.2 0 9.0 2.8 8.4 Hispanic Total 2.4 13.2 3.0 12 1.7 12.9 4. REGISTRATION PROCEDURES 4.1 General Guidelines Following registration, patients should begin protocol treatment within 3 days. Issues that would cause treatment delays should be discussed with the Principal Investigator. If a patient does not receive protocol therapy following registration, the patient’s registration on the study may be canceled. The Central Office Study Coordinator should be notified of cancellations as soon as possible. Patients can be registered and agent may be shipped only after the initial IRB approval for the participating site has been forwarded by the Coordinating Center to the CTEP PIO ([email protected]). 24 4.2 Registration Process Prior to registering a patient, each institution must have submitted all necessary regulatory documentation to the PMH Phase I Consortium Central Office. The eligibility checklist CRF will only be sent once this has been received. No patient can receive protocol treatment until registration with the Central Office has taken place. All eligibility criteria must be met at the time of registration. There will be no exceptions. Any questions should be addressed with the Central Office prior to registration. The eligibility checklist must be completed, and signed by the investigator prior to registration. Sites will fax in the signed, completed eligibility checklist and signed deidentified patient consent form to the central office at 416-946-4607. The central office will then review the checklist and once eligibility has been confirmed fax or email back a confirmation sheet indicating the unique study number for the subject and confirmation of entry into the trial. Only after this confirmation sheet has been received back from central office, can the patient receive the study drug. To ensure immediate attention is given to the faxed checklist, each site is advised to also call the study coordinator listed on the front sheet or call Robin Cheiken in the Central Office at 416-946-4616 or 416-357-9852 (Blackberry). Patient registration will be accepted between the hours of 9 am to 5 pm EST Monday to Friday, excluding Canadian statutory holidays when the central office will be closed. 4.3 Randomization and Stratifications Patients will be randomly assigned 1:1 to cediranib/dasatinib or cediranib alone. Patients will be stratified according to the presence of soft tissue (visceral, nodal) or bones only disease. Patients will be assigned to each arm by a computer-based system. Random assignment will be made to treatment versus control arms using SAS (version 9.2) software by the biostatistician. 25 5. TREATMENT PLAN 5.1. Cediranib (AZD2171) and Dasatinib (BMS-34825) Administration Treatment will be administered on an outpatient basis. Reported adverse events and potential risks are described in Section 7. Appropriate dose modifications for cediranib and dasatinib are described in Section 6. No investigational or commercial agents or therapies other than those described below may be administered with the intent to treat the patient’s malignancy. Patients will receive cediranib with or without dasatinib on an outpatient basis. Treatment will start on Cycle 1 Day 1 and each 28-day period will be considered 1 cycle. Given this study is the first combination of dasatinib and cediranib, a safety review, involving a PI conference call, will be performed after entry of the first 10 patients (either arm) and after entry of first 20 patients (either arm). At the safety reviews, if > 33% of patients in the combination arm are found to have > Grade 3 toxicity that is at least possibly related to study drug, an amendment for dose adjustments of the study drugs will be considered. Otherwise, the study recruitment will continue as per normal. 5.1.1 Arm A: Cediranib (AZD2171) Alone Patients randomized to Arm A will receive cediranib at a dose of 20 mg orally once daily. A cycle will be defined as 28 days of treatment. Cediranib will be administered at 20 mg (one 20-mg tablet) by mouth once per day continuously at approximately the same time each day. Tablets should be swallowed whole. While in an upright position, the patient should swallow the cediranib tablet with approximately 1 cup (250 mL or 8 oz.) of water. Tablets are to be taken either 1 hour before or 2 hours after meals at approximately the same time each day. The tablets must not be chewed, crushed, or broken. Agent Dose Route Schedule 20 mg Cediranib (1 * 20 mg) PO 26 Once daily in a 28 day cycle In the absence of unmanageable toxicity, treatment will continue until disease progression. Imaging of measurable disease will be repeated every 3 cycles [12 weeks]. Patients will be assessed in clinic at least every 4 weeks. Patients will be provided with a pill diary (Appendix D), instructed in its use, and asked to bring it with them to each appointment. A new copy of the pill diary will be given to patients with each new cycle. 5.1.2 Arm B: Cediranib (AZD2171) and Dasatinib (BMS-354825) Patients randomized to Arm B will receive cediranib at a dose of 20 mg orally once daily and dasatinib at a dose of 100 mg orally once daily. A cycle will be defined as 28 days of treatment. Cediranib will be administered at 20 mg (one 20-mg tablet) by mouth once per day continuously at approximately the same time each day. Tablets should be swallowed whole. Dasatinib will be administered at 100 mg (two 50-mg tablets) by mouth once per day continuously at approximately the same time each day. Tablets should be swallowed whole. While in an upright position, the patient should swallow the cediranib and dasatinib tablets with approximately 1 cup (250 mL or 8 oz.) of water. Tablets are to be taken either 1 hour before or 2 hours after meals at approximately the same time each day. The tablets must not be chewed, crushed, or broken. Agent Dose Route Schedule PO Once daily in a 28 day cycle PO Once daily in a 28 day cycle 20 mg Cediranib (1 * 20 mg) 100 mg Dasatinib (2 * 50 mg) In the absence of unmanageable toxicity, treatment will continue until disease progression. Imaging of measurable disease will be repeated every 3 cycles [12 weeks]. Patients will be assessed in clinic at least every 4 weeks. 27 Patients will be provided with a pill diary (Appendix D), instructed in its use, and asked to bring it with them to each appointment. A new copy of the pill diary will be given to patients with each new cycle. 5.2 General Concomitant Medication and Supportive Care Guidelines Supportive Care Measures Routine supportive measures for cancer patients such as erythropoietin, analgesics, blood transfusions, antibiotics, bisphosphonates, haematopoietic colony stimulating factors (CSFs) for treatment of cytopenias are permitted. Their use must be in accordance with the accepted standards such as the American Society of Clinical Oncology (ASCO) Guidelines and Cancer Care Ontario Practice Guideline Initiative (CCO-PGI). If used it should be recorded as a concomitant medication on the case report forms. The dose modification scheme must be followed even if CSFs are used i.e. CSF cannot substitute for a required dose reduction. The administration of other anticancer therapies or other investigational agents is not permitted. Radiation Therapy If radiation therapy is required to the sole site of measurable disease, the patient should be considered as having failed treatment and be removed from the study since they will no longer be evaluable for the treatment effect. In addition, the need for radiation for progressively symptomatic disease (even if not a sole site) may be an indicator of treatment failure and the investigator should consider whether continued therapy is warranted. Patients who develop urgent local complications in previously documented sites of disease may receive palliative radiation therapy. Continuation on protocol therapy, if medically appropriate, will be determined by discussion with the Principal Investigator (via the PMH Phase I Consortium Central Office 416-946-4616). Blood Pressure Frequent blood pressure monitoring is important in patients receiving cediranib. Experience to date suggests that increases in blood pressure may occur following dosing with cediranib for a number of weeks and that these increases may occur relatively quickly. Patients will be provided with a blood pressure monitoring device and a diary in which to record their twice daily blood pressure readings for the first cycle [and may be extended depending on clinical indication (Appendix E). If two successive systolic readings are >140 mmHg OR two successive diastolic readings are >90 mmHg OR any combination of elevated systolic and diastolic blood pressure are observed, patients will be instructed to contact their physician as soon as possible. Patients should seek medical advice if their BP exceeds 180 mmHg (systolic) or 105 mmHg (diastolic) at any time 28 and should also be encouraged to contact their physician if they are concerned about any symptoms that may be associated with high blood pressure (e.g., headache). Section 6 includes specific guidelines on the management and, if appropriate, dose modifications for treatment-emergent hypertension. Blood pressure monitors can be ordered by contacting: Robin Cheiken Drug Development Program 610 University Ave. Room 4-743 Toronto, ON M5G 2M9 Tel: 416-946-4616 Fax: 416-946-4607 Email: [email protected] Renal Function Renal function (creatinine and urinary protein) should be frequently monitored as suggested by the pathologic changes noted in animal studies and evidence from studies of other antiangiogenic agents. Specific guidelines for management of proteinuria are presented in Section 6.3.2. Cardiac Function Patients with NYHA functional classification system Class II despite being controlled with treatment and those with prior central thoracic radiation therapy including radiotherapy to the heart are at risk for compromised LVEF, and require increased monitoring for cardiac abnormalities (see Study Calendar, Section 10). Adrenal Function Adrenal gland damage is a potential toxicity of dasatinib. If patients develop symptoms consist with hypoadrenalism, their physicians should consider adrenal function testing to rule out this possibility. Rash The acneiform rash associated with dasatinib that is seen in some patients appears to be treatable with standard acne therapies, including topical and oral antibiotics used to treat acne. Anecdotal reports of improvement have occurred with any of the following: minocycline, topical tetracycline, topical clindamycin, topical silver sulfadiazine, diphenhydramine, and oral prednisone (short course). Nausea, Vomiting and Diarrhea The nausea, vomiting, and diarrhea that may occur with dasatinib administration can generally be managed through the use of appropriate supportive measures (anti-emetics e.g. 5-HT3 antagonists, benzodiazepines, and 29 prochlorperazine and anti-diarrheal medications e.g. loperamide). These measures should be instituted promptly at the first instance of loose stools. Concomitant Medications Because there is a potential for interaction of cediranib and dasatinib with strong inhibitors and inducers of CYP3A4, these agents are prohibited during cediranib with or without dasatinib treatment. See Appendix A for a list of prohibited agents as well as a list of medications to be used with caution in patients receiving cediranib with or without dasatinib. Prohibited drugs should be discontinued fourteen (14) days prior to the administration of the first dose of cediranib and dasatinib and for 14 days following discontinuation of cediranib and dasatinib (unless otherwise specified in Appendix A). The concomitant use of H2 blockers and proton pump inhibitors with dasatinib is not recommended (e.g. famotidine, omeprazole). The use of antiacids should be considered in place of H2 blockers or proton pump inhibitors in patients receiving dasatinib therapy. If antiacid therapy is needed, the antiacid dose should be administered two hours before or after the dose of dasatinib. The Principal Investigator should be alerted if the patient is taking any agent known to affect or with the potential to affect CYP3A4. The case report form must capture the concurrent use of all other drugs, over-the-counter medications, or alternative therapies. 5.2.1 Risk Mitigation for Pulmonary Arterial Hypertension (PAH) Patients should be evaluated for signs and symptoms of underlying cardiopulmonary disease prior to initiating dasatinib and during treatment. Symptoms of pulmonary arterial hypertension (PAH) include dyspnea, fatigue, hypoxia, and edema. Since other medical conditions may also cause these symptoms, non-invasive procedures (including echocardiogram) should be done first to rule out more the common etiologies of these symptoms, such as pleural effusion, pulmonary edema, anemia, and lung infiltration. Right heart catherization can confirm the diagnosis of PAH. Hypertension is “pre-capillary” and not a consequence of left heart failure or chronic lung disease if there is normal pulmonary capillary wedge pressure (<15 mm Hg) but elevated pulmonary artery pressure (mean pulmonary artery pressure >25 mm Hg). Since PAH may be reversible upon discontinuation of dasatinib, a diagnostic approach of interruption of dasatinib treatment may be considered at the discreation of the treating physician; however, if PAH is confirmed, dasatinib should be permanently discontinued. 5.3 Duration of Therapy 30 In the absence of treatment delays due to adverse event(s), treatment may continue indefinitely or until one of the following criteria applies: Disease progression as defined by Progression of bone lesions on bone scan (defined in section 11.1) confirmed by a second bone scan 3 or more weeks later Progression of target lesions as per RECIST criteria (defined in section 11.1) Clinical deterioration due to increase in burden of disease NOTE: PSA progression (defined in section 11.1) alone will not constitute disease progression and patients can remain on study. However, PSA progression will be recorded as an event and is still an endpoint as per PCWG2 definition. Intercurrent illness that prevents further administration of treatment Unacceptable adverse event(s) Patient decides to withdraw from the study General or specific changes in the patient’s condition render the patient unacceptable for further treatment in the judgment of the investigator For patients who achieve CR, PR or stable disease on study, study treatment may continue until disease progression. As of December 31, 2012, Cediranib supply will be permanently discontinued and Cediranib will no longer be manufactured. Patients in the combination Cediranib plus Dasatinib arm (ARM B) who are felt by the Principal Investigator to be deriving clinical benefit may remain on Dasatinib alone. Patients on Cediranib alone (ARM A) will be taken off study on December 31, 2012. 5.4 Duration of Follow Up Patients will be followed for 4 weeks after removal from study or until death, whichever occurs first. Patients removed from study for unacceptable adverse events will be followed until resolution or stabilization of the adverse event. 6. DOSING DELAYS/DOSE MODIFICATIONS 6.1. Criteria for Continuing Treatment 31 Patients will be evaluated at each clinic visit during the treatment period to determine if continued treatment is appropriate. If, at any time during treatment the evaluation criteria are not met, cediranib and/or dasatinib will be held or the dose adjusted according to the dose modification criteria stated in Section 6.2. To begin a new cycle of therapy, subjects must meet the following criteria: Absolute neutrophil count (ANC) ≥ 1,000/mm3 (1 x 109/L) Platelet count ≥ 75,000/mm3 (75 x 109/L) Blood pressure, if elevated, should be controlled with antihypertensive medication(s). Urine dipstick less than 1+ protein or 24-hour urine for protein < 1 g/24 hours No clinically significant non-hematologic toxicity > intolerable grade 2 6.2. Dose Modifications 6.2.1 Arm A or B: Cediranib and Dasatinib The dose levels and the general approach to dose modification for Arms A and B are shown below. AEs should be treated with the appropriate maximum supportive care, and dose reductions should be clearly documented in the case report form. If more than one dose reduction of cediranib, the patient must come off protocol therapy. If more than one dose reduction of dasatinib is required for toxicity, the patient may continue on cediranib monotherapy alone. Patients are taken off protocol therapy if cediranib or dasatinib is held for more than 21 days (exceptions include dose holding for asymptomatic reductions in LVEF, as described in 6.3.3). Patients requiring dose reductions should not have the dose re-escalated with subsequent treatments. If a patient experiences several toxicities and there are conflicting recommendations, please use the recommended dose adjustment that reduces the dose to the lowest dose level. Dose level dasatinib dose cediranib dose -1 70 mg (one 50 mg tablet and one 20 mg tablet) daily 15 mg (one 15 mg tablet) daily 1 100 mg (two 50 mg tablets) daily 20 mg (one 20 mg tablet) daily General Management of Adverse Events: cediranib 32 Observation Action Maintain dose level Grade 1-2 AE resolves promptly with supportive care Upon recovery to Intolerable grade 2, grade 3 or higher (nontolerable grade 2 or hematologic) AE at least possibly related to better, may restart at the cediranib same dose or reduce 1 Grade 4 (hematologic) AE at least possibly related to dose level cediranib For specific toxicities specified below in Section 6.3 (e.g. hypertension, proteinuria, etc.), please follow guidelines specified in Section 6.3. General Management of Adverse Events: dasatinib Observation Grade 1-2 AE resolves promptly with supportive care Intolerable grade 2, grade 3 or higher (nonhematologic) AE at least possibly related to dasatinib Grade 4 (hematologic) AE at least possibly related to dasatinib Any occurrence of interstitial lung disease confirmed by HRCT QTc > 530 ms Action Maintain dose level Upon recovery to tolerable grade 2 or better, may restart at the same dose or reduce 1 dose level Permanently discontinue dasatinib Permanently discontinue dasatinib For specific toxicities specified below in Section 6.3 (e.g. hypertension, proteinuria, etc.), please foll 6.3 Management of Selected Adverse Events 6.3.1 Management of Hypertension (For cediranib only) Increases in blood pressure and cases of hypertension (BP) have been associated with many drugs acting on the VEGF pathway. The proposed mechanism for this increase is through inhibition of VEGF-induced peripheral vasodilation. Hypertension following cediranib treatment has been seen in animal studies as well as clinical trials. Specific guidance for management of this adverse event is provided below. Management of Hypertension 33 Adverse event Hypertension NCI CTCAE v.4 grade Management Cediranib administration Grade 1 - Consider increased BP No change Systolic 120-139 mmHg monitoring or diastolic 80-89 mmHg Grade 2 - Start/ add long acting DHP CCB (Table 1). Gradually increase dose to control BP up to maximum dose. Stage 1 hypertension (systolic 140-159 mmHg or diastolic 9099 mmHg); medical intervention indicated; recurrent or persistent > 24 hrs); symptomatic increase by > 20 mmHg (diastolic) or to > 140/90 mmHg if previously WNL; monotherapy indicated - If partial or no control and still moderate hypertension, add an additional drug and increase dose until BP control up to maximum dose. Restart cediranib at one lower dose level (when controlled). 34 First occurrence: Continue cediranib at full dose or decrease dose by one level Second occurrence: Decrease cediranib dose by one level Adverse event NCI CTCAE v.4 grade Management Grade 3 - If asymptomatic: Hold cediranib and start immediate antihypertensive therapy with 2 drug combination including at least a DHP CCB. o Increase dose until BP control up to maximum dose of both agents. If control to mild hypertension range, restart cediranib at one dose level lower. o If partial or no BP control, add another drug and increase dose until BP control up to maximum dose. If partial or no control, stop cediranib. Stage 2 hypertension (systolic > 160 mmHg or diastolic > 100 mmHg); medical intervention indicated; more than one drug or more intensive therapy than previously used indicated Cediranib administration First occurrence: Hold cediranib until diastolic BP < 100 mmHg and decrease dose by one level Second occurrence: Hold cediranib until diastolic BP < 100 mmHg and stop cediranib permanently - If symptomatic: stop cediranib, hospitalize with aggressive IV therapy as per hypertensive crisis management Grade 4 Life-threatening consequences (e.g. malignant hypertension, transient or permanent neurological deficit, hypertensive crisis); urgent intervention indicated - Stop cediranib, hospitalize with aggressive IV therapy as per hypertensive crisis management. Stop cediranib permanently Notes: Hypertension should be grade according to NCI CTCAE Version 4.0 and recorded on CRFs Patients requiring a delay of > 3 weeks of cediranib should stop cediranib permanently Patients requiring > 1 dose reduction of cediranib should stop cediranib permanently 35 Patients may have up to 2 antihypertensive medications before cediranib dose reduction These are guidelines only and clinical investigators should use them at their own discretion 24-48 hrs are suggested as elapse time between decision steps suggested in the algorithm unless persistent severe hypertension occurred For centres outside of Canada please follow the recommendations using comparable drugs locally available. Table 1. Dihydropyridine calcium-channel blockers (DHP CCB) Agent Nifedipine XL Amlodipine Felodipine Initial dose 30 mg po qd 2.5 mg po qd 2.5 mg po qd Intermediate dose 60 mg po qd 5 mg po qd 5 mg po qd Maximum dose 90 mg po qd 10 mg po qd 10 mg po qd Hepatic metabolism? CYP 3A4 substrate CYP 3A4 substrate CYP 3A4 substrate + inhibitor Table 2: Selective blockers (BB) Agent Metoprolol Atenolol Acebutolol Bisoprolol Initial dose 25 mg po bid 25 mg po qd Intermediate dose 50 mg po bid 50 mg po qd 200mg-300 mg po 100 mg po bid bid 2.5 mg po qd 5-10 mg po bid Maximum dose Hepatic metabolism? 100 mg po bid CYP 2D6 substrate 100 mg po qd No 400 mg po bid Yes (possibly cyp 450) 20 mg po qd Yes (possibly cyp 450) Table 3. Angiotensin Converting Enzyme Inhibitors (ACEIs) Agent Initial dose Captopril Enalapril Ramipril Lisinopril Fosinopril Rarely used: Perindopril Quinapril 12.5 po tid 5 mg po qd 2.5 mg po qd 5 mg po qd 10 mg po qd Intermediate dose 25 mg po tid 10-20 mg po qd 5 mg po qd 10-20 mg po qd 20 mg po qd 4 mg po qd 10 mg po qd none 20 mg po qd Maximum dose Hepatic metabolism? 50 mg po tid 40 mg po qd 10 mg po qd 40 mg po qd 40 mg po qd CYP 2D6 substrate CYP 3A4 substrate Yes (possibly cyp 450) No Yes (possibly cyp 450) 8 mg po qd 40 mg po /qd Yes But Not Cyp-450 No Table 4. Angiotensin II Receptors Blockers (ARBs) Agent Losartan Candesartan Irbesartan Telmisartan Valsartan Initial dose 25 mg po qd 4 mg po qd 75mg po qd 40 mg po qd 80 mg po qd Intermediate dose 50 mg po qd 8-16 mg po qd 150 mg po qd none none 36 Maximum dose 100 mg po qd 32 mg po qd 300 mg po qd 80 mg po qd 160mg po qd Hepatic metabolism? CYP 3A4 substrate CYP 2C9 substrate CYP 2C9 substrate Yes but not per cyp-450 Yes but not per cyp-450 Table 5. and blocker Agent Initial dose Intermediate dose Labetolol 100 mg po bid 200 mg po bid Maximum dose 400 mg po bid Hepatic metabolism? CYP 2D6 substrate and inhibitor NB. Agents in bold characters are suggested as optimal choices to avoid or minimize potential drug-interactions with antiangiogenic inhibitors through cyp-450. 6.3.2 Management of Proteinuria (For cediranib only) Although patients with 24-hour urine for protein > 1 g/24 hours at entry are ineligible, increases in proteinuria may occur during treatment of cediranib and should be managed as follows: Proteinuria Value Urine dipstick 1+ or higher Management of Proteinuria Monitoring Dose Modification for cediranib Perform the following tests: Continue dosing until results of 24h urine 24-hour urine collection for total collection known, then protein and creatinine follow table below Based on results of the 24-hour urine collection: <1g protein (24hour collection) Continue dipstick or equivalent routine laboratory analysis Continue planned dose >1g but <2g protein (24 hour collection) Perform 24 –hour urine collection (total protein, creatinine) prior to day 1 of each subsequent cycle of therapy (q4w) until total protein is <1g/24 hours. Perform 24-hour urine collection (total protein, creatinine) weekly until proteinuria is <1g. Decrease cediranib by one dose level; continue treatment >2g protein (24hour collection) 37 Hold cediranib When protein is <1g/24 hours, resume cediranib at one lower dose level Proteinuria Value Monitoring Perform 24-hour urine collection (total protein, creatinine) prior to day 1 of each subsequent cycle of therapy (q4w). Dose Modification for cediranib Continue until patient is off study 6.3.3 Management of Asymptomatic Decrease in LVEF (For cediranib and dasatinib) The decision to continue or hold cediranib and dasatinib is based on the LVEF as it relates to the institutions lower limit of normal (LLN) and change in ejection fraction from screening (LVEF as measured at registration) according to the following table: LVEF Relation to LLN Normal 1-5% points below LLN > 6% points below LLN LVEF decrease (absolute change) <10% points 10-15% points >16% points Continue Continue Continue Repeat MUGA/ECHO (1-2 cycles) Continue Repeat MUGA/ECHO (1-2 cycles) Continue Repeat MUGA/ECHO (1-2 cycles) Hold Repeat MUGA/ECHO (1-2 cycles) Continue Repeat MUGA/ECHO (1-2 cycles) Hold Repeat MUGA/ECHO (1-2 cycles) Hold Repeat MUGA/ECHO (1-2 cycles) Discontinue cediranib and dasatinib if: Two consecutive HOLD categories occur Three intermittent HOLD categories occur (at the discretion of the investigator, cediranib may also be permanently discontinued prior to the occurrence of 3 intermittent HOLD categories.) If LVEF is maintained at a “Continue and repeat MUGA/ECHO” or improves from a hold to a “Continue and repeat MUGA/ECHO” category, additional MUGA scans/ echocardiograms prior to the next scheduled MUGA/ECHO will be at the discretion of the investigator. 38 6.3.4 Management of Symptomatic Cardiac Events (For cediranib and dasatinib) Discontinue cediranib and dasatinib both if: A patient has symptoms of congestive heart failure (CHF) and a diagnosis of CHF is confirmed. A patient has a myocardial infarction. 6.3.5 Management of Reversible Posterior Leukoencephalopathy Syndrome (RPLS) (For cediranib and dasatinib) Cediranib and dasatinib should be held in patients with symptoms/signs suggestive of RPLS, pending work-up and management, including control of blood pressure. Cediranib and dasatinib should be discontinued upon diagnosis or RPLS. After consultation with the Principal Investigator and the NCI Senior Investigator, consideration of restarting the study may be evaluated in light of any clinical benefit. 39 7. ADVERSE EVENTS: LIST AND REPORTING REQUIREMENTS Adverse event (AE) monitoring and reporting is a routine part of every clinical trial. The following list of AEs (Section 7.1) and the characteristics of an observed AE (Section 7.2) will determine whether the event requires expedited (via AdEERS) reporting in addition to routine reporting. 7.1 Comprehensive Adverse Events and Potential Risks List (CAEPR) Comprehensive Adverse Events and Potential Risks list (CAEPR) for Cediranib (AZD2171, NSC 732208) The Comprehensive Adverse Event and Potential Risks list (CAEPR) provides a single list of reported and/or potential adverse events (AE) associated with an agent using a uniform presentation of events by body system. In addition to the comprehensive list, a subset, the Specific Protocol Exceptions to Expedited Reporting (SPEER), appears in a separate column and is identified with bold and italicized text. This subset of AEs (SPEER) is a list of events that are protocol specific exceptions to expedited reporting to NCI via AdEERS (except as noted below). Refer to the 'CTEP, NCI Guidelines: Adverse Event Reporting Requirements' http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguidelines.pdf for further clarification. Frequency is provided based on 895 patients. Below is the CAEPR for cediranib (AZD2171). NOTE: Report AEs on the SPEER ONLY IF they exceed the grade noted in parentheses next to the AE in the SPEER. If this CAEPR is part of a combination protocol using multiple investigational agents and has an AE listed on different SPEERs, use the lower of the grades to determine if expedited reporting is required. Version 2.11, November 10, 20111 Adverse Events with Possible Relationship to Cediranib (AZD2171) (CTCAE 4.0 Term) [n= 895] Specific Protocol Exceptions to Expedited Reporting (SPEER) (formerly known as ASAEL) Likely (>20%) CARDIAC DISORDERS Less Likely (<=20%) Rare but Serious (<3%) Left ventricular systolic dysfunction ENDOCRINE DISORDERS Hyperthyroidism Hypothyroidism Hypothyroidism (Gr 2) GASTROINTESTINAL DISORDERS Abdominal pain Anal mucositis Constipation Diarrhea Dry mouth Dysphagia Mucositis oral Nausea Rectal mucositis Small intestinal mucositis Vomiting Abdominal pain (Gr 3) Anal mucositis (Gr 2) Constipation (Gr 3) Diarrhea (Gr 3) Dry mouth (Gr 2) Dysphagia (Gr 2) Mucositis oral (Gr 3) Nausea (Gr 3) Rectal mucositis (Gr 2) Small intestinal mucositis (Gr 2) Vomiting (Gr 3) GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS Fatigue Fatigue (Gr 3) INVESTIGATIONS Alanine aminotransferase increased 40 Alanine aminotransferase increased (Gr 3) Aspartate aminotransferase increased Investigations - Other (increased blood erythropoietin) Investigations - Other (increased thyroid stimulating hormone) Weight loss Aspartate aminotransferase increased (Gr 3) Investigations - Other (increased thyroid stimulating hormone) (Gr 2) Weight loss (Gr 2) METABOLISM AND NUTRITION DISORDERS Anorexia Dehydration Hypophosphatemia Anorexia (Gr 2) Dehydration (Gr 3) Hypophosphatemia (Gr 2) NERVOUS SYSTEM DISORDERS Dizziness Headache Dizziness (Gr 2) Headache (Gr 3) Leukoencephalopathy Reversible posterior leukoencephalopathy syndrome Seizure RENAL AND URINARY DISORDERS Proteinuria RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS Cough Dyspnea Laryngeal mucositis Pharyngeal mucositis Tracheal mucositis Voice alteration Cough (Gr 2) Dyspnea (Gr 3) Laryngeal mucositis (Gr 2) Pharyngeal mucositis (Gr 2) Tracheal mucositis (Gr 2) Voice alteration (Gr 2) SKIN AND SUBCUTANEOUS TISSUE DISORDERS Palmar-plantar erythrodysesthesia syndrome Palmar-plantar erythrodysesthesia syndrome (Gr 2) Thromboembolic event Hypertension (Gr 3) Thromboembolic event (Gr 4) VASCULAR DISORDERS Hypertension Vascular disorders - Other (arterial thrombosis) This table will be updated as the toxicity profile of the agent is revised. Updates will be distributed to all Principal Investigators at the time of revision. The current version can be obtained by contacting [email protected] . Your name, the name of the investigator, the protocol and the agent should be included in the e-mail. 1 2Infection includes all 75 sites of infection under the INFECTIONS AND INFESTATIONS SOC. Also reported on cediranib (AZD2171) trials but with the relationship to cediranib (AZD2171) still undetermined: BLOOD AND LYMPHATIC SYSTEM DISORDERS - Anemia CARDIAC DISORDERS - Acute coronary syndrome; Cardiac arrest; Chest pain - cardiac; Heart failure; Myocardial infarction EAR AND LABYRINTH DISORDERS - Ear and labyrinth disorders - Other (viral labyrinthitis); Tinnitus GASTROINTESTINAL DISORDERS - Abdominal distension; Ascites; Colitis; Colonic perforation; Dyspepsia; Enterocolitis; Esophagitis; Flatulence; Gastric perforation; Gastric ulcer; Gastrointestinal disorders - Other (abdominal abscess); Ileal perforation; Ileus; Oral pain; Rectal hemorrhage; Rectal pain GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Edema limbs; Fever; Non-cardiac chest pain; Pain 41 HEPATOBILIARY DISORDERS - Gallbladder obstruction; Hepatic failure; Hepatic hemorrhage; Hepatic pain; Hepatobiliary disorders - Other (bile duct obstruction); Hepatobiliary disorders - Other (jaundice cholestatic) IMMUNE SYSTEM DISORDERS - Anaphylaxis INFECTIONS AND INFESTATIONS – Infection2 INJURY, POISONING AND PROCEDURAL COMPLICATIONS - Bruising; Fracture; Injury, poisoning and procedural complications - Other (tracheostomy malfunction) INVESTIGATIONS - Alkaline phosphatase increased; Blood bilirubin increased; CPK increased; Cardiac troponin T increased; Cholesterol high; Creatinine increased; Electrocardiogram QT corrected interval prolonged; GGT increased; Investigations - Other (elevated LDH); Lipase increased; Lymphocyte count decreased; Neutrophil count decreased; Platelet count decreased; White blood cell decreased METABOLISM AND NUTRITION DISORDERS - Hypercalcemia; Hyperglycemia; Hyperkalemia; Hypertriglyceridemia; Hypoalbuminemia; Hypocalcemia; Hypoglycemia; Hypokalemia; Hyponatremia MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Arthralgia; Back pain; Bone pain; Chest wall pain; Generalized muscle weakness; Muscle weakness lower limb; Myalgia; Pain in extremity NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND POLYPS) - Tumor pain NERVOUS SYSTEM DISORDERS - Cognitive disturbance; Depressed level of consciousness; Dysgeusia; Dysphasia; Encephalopathy; Intracranial hemorrhage; Lethargy; Memory impairment; Nervous system disorders - Other (spinal cord compression); Peripheral motor neuropathy; Peripheral sensory neuropathy; Somnolence; Transient ischemic attacks PSYCHIATRIC DISORDERS - Confusion; Insomnia; Suicide attempt RENAL AND URINARY DISORDERS - Acute kidney injury; Hematuria; Renal and urinary disorders Other (nephrotic syndrome); Urinary retention REPRODUCTIVE SYSTEM AND BREAST DISORDERS - Irregular menstruation RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Bronchopulmonary hemorrhage; Epistaxis; Hypoxia; Pharyngolaryngeal pain; Pleural effusion; Pneumonitis; Pneumothorax SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Dry skin; Hyperhidrosis; Nail loss; Pruritus; Purpura; Rash maculo-papular; Skin ulceration VASCULAR DISORDERS - Hypotension Note: Cediranib (AZD2171) in combination with other agents could cause an exacerbation of any adverse event currently known to be caused by the other agent, or the combination may result in events never previously associated with either agent. Comprehensive Adverse Events and Potential Risks list (CAEPR) for Dasatinib (BMS-354825, NSC 732517) The Comprehensive Adverse Event and Potential Risks list (CAEPR) provides a single list of reported and/or potential adverse events (AE) associated with an agent using a uniform presentation of events by body system. In addition to the comprehensive list, a subset, the Specific Protocol Exceptions to Expedited Reporting (SPEER), appears in a separate column and is identified with bold and italicized text. This subset of AEs (SPEER) is a list of events that are protocol specific exceptions to expedited reporting to NCI via AdEERS (except as noted below). Refer to the 'CTEP, NCI Guidelines: Adverse Event Reporting Requirements' http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguidelines.pdf for further clarification. Frequency is provided based on 2937 patients. Below is the CAEPR for dasatinib (BMS-354825). NOTE: Report AEs on the SPEER ONLY IF they exceed the grade noted in parentheses next to the AE in the SPEER. If this CAEPR is part of a combination protocol using multiple investigational agents and has an AE listed on different SPEERs, use the lower of the grades to determine if expedited reporting is required. Version 2.4, October 31, 20111 42 Adverse Events with Possible Relationship to Dasatinib (BMS-354825) (CTCAE 4.0 Term) [n= 2937] Likely (>20%) Less Likely (<=20%) BLOOD AND LYMPHATIC SYSTEM DISORDERS Specific Protocol Exceptions to Expedited Reporting (SPEER) (formerly known as ASAEL) Rare but Serious (<3%) Anemia Anemia (Gr 3) Febrile neutropenia CARDIAC DISORDERS Heart failure Left ventricular systolic dysfunction Myocardial infarction Pericardial effusion GASTROINTESTINAL DISORDERS Abdominal distension Abdominal pain Anal mucositis Constipation Abdominal pain (Gr 2) Diarrhea Diarrhea (Gr 3) Dyspepsia Gastrointestinal hemorrhage2 Mucositis oral Nausea Nausea (Gr 3) Rectal mucositis Small intestinal mucositis Vomiting Vomiting (Gr 3) GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS Edema limbs Fatigue Fatigue (Gr 3) Fever (Gr 2) Fever General disorders and administration site conditions - Other (generalized edema) General disorders and administration site conditions - Other (superficial edema) Non-cardiac chest pain Pain General disorders and administration site conditions - Other (superficial edema) (Gr 2) INFECTIONS AND INFESTATIONS Infection3 Infection3 (Gr 3) INVESTIGATIONS Alanine aminotransferase increased Aspartate aminotransferase increased Electrocardiogram QT corrected interval prolonged Neutrophil count decreased Platelet count decreased Neutrophil count decreased (Gr 3) Platelet count decreased (Gr 4) Weight gain Weight loss White blood cell decreased White blood cell decreased Gr 3) METABOLISM AND NUTRITION DISORDERS 43 Anorexia Hypocalcemia Hypokalemia Hypophosphatemia Anorexia (Gr 3) Hypophosphatemia (Gr 3) Tumor lysis syndrome MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS Arthralgia Myalgia Myalgia (Gr 2) NERVOUS SYSTEM DISORDERS Dizziness Headache Headache (Gr 3) Intracranial hemorrhage Leukoencephalopathy Reversible posterior leukoencephalopathy syndrome RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS Cough Dyspnea Dyspnea (Gr 3) Laryngeal mucositis Pharyngeal mucositis Pleural effusion Pleural effusion (Gr 3) Pneumonitis Pulmonary hypertension Tracheal mucositis SKIN AND SUBCUTANEOUS TISSUE DISORDERS Alopecia Pruritus Rash acneiform Rash maculo-papular Rash maculo-papular (Gr 2) VASCULAR DISORDERS Flushing 1This table will be updated as the toxicity profile of the agent is revised. Updates will be distributed to all Principal Investigators at the time of revision. The current version can be obtained by contacting [email protected]. Your name, the name of the investigator, the protocol and the agent should be included in the e-mail. 2Gastrointestinal hemorrhage includes Anal hemorrhage, Cecal hemorrhage, Colonic hemorrhage, Duodenal hemorrhage, Esophageal hemorrhage, Esophageal varices hemorrhage, Gastric hemorrhage, Hemorrhoidal hemorrhage, Ileal hemorrhage, Intra-abdominal hemorrhage, Jejunal hemorrhage, Lower gastrointestinal hemorrhage, Oral hemorrhage, Pancreatic hemorrhage, Rectal hemorrhage, Retroperitoneal hemorrhage, and Upper gastrointestinal hemorrhage under the GASTROINTESTINAL DISORDERS SOC. 3Infection includes all 75 sites of infection under the INFECTIONS AND INFESTATIONS SOC. 4Gastrointestinal ulcer includes Anal ulcer, Colonic ulcer, Duodenal ulcer, Esophageal ulcer, Gastric ulcer, Ileal ulcer, Jejunal ulcer, Rectal ulcer, and Small intestine ulcer under the GASTROINTESTINAL DISORDERS SOC. Also reported on dasatinib (BMS-354825) trials but with the relationship to dasatinib (BMS354825) still undetermined: CARDIAC DISORDERS - Acute coronary syndrome; Atrial fibrillation; Cardiac disorders - Other (cardiomegaly); Cardiac disorders - Other (heart rate increased); Chest pain - cardiac; Myocarditis; Palpitations; Pericarditis; Sinus tachycardia; Ventricular tachycardia CONGENITAL, FAMILIAL AND GENETIC DISORDERS - Congenital, familial and genetic disorders - Other (Keratosis follicular) EAR AND LABYRINTH DISORDERS - Ear pain; Middle ear inflammation; Tinnitus; Vertigo 44 EYE DISORDERS - Blurred vision; Conjunctivitis; Dry eye; Eye disorders - Other (optic nerve neuritis) GASTROINTESTINAL DISORDERS - Ascites; Colitis; Dry mouth; Dysphagia; Enterocolitis; Esophagitis; Flatulence; Gastritis; Gastrointestinal disorders - Other (anal fissure); Gastrointestinal disorders - Other (hematemesis); Gastrointestinal disorders - Other (mouth ulceration); Gastrointestinal disorders - Other (oral soft tissue disorder); Gastrointestinal disorders - Other (oropharyngeal pain); Gastrointestinal disorders - Other (tongue eruption); Gastrointestinal ulcer4; Ileus; Oral pain; Pancreatitis; Periodontal disease; Stomach pain GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Chills; Edema face; Edema trunk; Flu like symptoms; Gait disturbance; General disorders and administration site conditions - Other (temperature intolerance); Localized edema; Malaise HEPATOBILIARY DISORDERS - Cholecystitis; Hepatobiliary disorders - Other (cholestasis) IMMUNE SYSTEM DISORDERS - Anaphylaxis INFECTIONS AND INFESTATIONS - Infections and infestations - Other (herpes virus infection) INJURY, POISONING AND PROCEDURAL COMPLICATIONS - Bruising INVESTIGATIONS - Alkaline phosphatase increased; Blood bilirubin increased; Cardiac troponin T increased; CD4 lymphocytes decreased; CPK increased; Creatinine increased; GGT increased; Investigations - Other (bone densitometry); Investigations - Other (EKG T-wave inversion); Investigations - Other (pancytopenia); Investigations - Other (thermometry abnormal); Lymphocyte count decreased; Lymphocyte count increased METABOLISM AND NUTRITION DISORDERS - Dehydration; Hyperkalemia; Hyperuricemia; Hypoalbuminemia; Hypomagnesemia; Hyponatremia MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Arthritis; Back pain; Bone pain; Chest wall pain; Generalized muscle weakness; Musculoskeletal and connective tissue disorder - Other (epiphyses delayed fusion); Musculoskeletal and connective tissue disorder - Other (muscle spasm); Musculoskeletal and connective tissue disorder - Other (muscle stiffness); Musculoskeletal and connective tissue disorder - Other (nuchal rigidity); Musculoskeletal and connective tissue disorder Other (rhabdomyolysis); Musculoskeletal and connective tissue disorder - Other (tendonitis); Myositis; Osteoporosis; Pain in extremity NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND POLYPS) - Neoplasms benign, malignant and unspecified (incl cysts and polyps) - Other (hemangiomatosis) NERVOUS SYSTEM DISORDERS - Acoustic nerve disorder NOS; Amnesia; Cognitive disturbance; Concentration impairment; Dysarthria; Dysgeusia; Ischemia cerebrovascular; Lethargy; Peripheral motor neuropathy; Peripheral sensory neuropathy; Seizure; Somnolence; Syncope; Transient ischemic attacks; Tremor PSYCHIATRIC DISORDERS - Anxiety; Confusion; Depression; Insomnia; Libido decreased; Suicidal ideation RENAL AND URINARY DISORDERS - Acute kidney injury; Proteinuria; Urinary frequency REPRODUCTIVE SYSTEM AND BREAST DISORDERS - Gynecomastia; Irregular menstruation RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Adult respiratory distress syndrome; Bronchospasm; Epistaxis; Hypoxia; Pulmonary edema; Sore throat SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Bullous dermatitis; Dry skin; Hyperhidrosis; Nail loss; Pain of skin; Palmar-plantar erythrodysesthesia syndrome; Periorbital edema; Photosensitivity; Purpura; Skin and subcutaneous tissue disorders - Other (acute febrile neutrophilic dermatosis); Skin and subcutaneous tissue disorders - Other (hair color changes); Skin and subcutaneous tissue disorders Other (panniculitis); Skin ulceration; Urticaria VASCULAR DISORDERS - Hematoma; Hot flashes; Hypertension; Hypotension; Phlebitis; Superficial thrombophlebitis; Thromboembolic event; Vasculitis 45 Note: Dasatinib (BMS-354825) in combination with other agents could cause an exacerbation of any adverse event currently known to be caused by the other agent, or the combination may result in events never previously associated with either agent 46 7.2 Adverse Event Characteristics CTCAE term (AE description) and grade: The descriptions and grading scales found in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be utilized for AE reporting. All appropriate treatment areas should have access to a copy of the CTCAE version 4.0. A copy of the CTCAE version 4.0 can be downloaded from the CTEP web site (http://ctep.cancer.gov). 7.3 “Expectedness”: AEs can be “Expected” (see in Section 7.1 above) or unexpected. Bold and italicized terms in Sect. 7.1 identify expected events. Attribution of the AE: - Definite – The AE is clearly related to the study treatment. - Probable – The AE is likely related to the study treatment. - Possible – The AE may be related to the study treatment. - Unlikely – The AE is doubtfully related to the study treatment. - Unrelated – The AE is clearly NOT related to the study treatment. Expedited Adverse Event Reporting 7.3.1 Expedited AE reporting for this study is via AdEERS (Adverse Event Expedited Reporting System) accessed via the secure CTEP web site https://webapps.ctep.nci.nih.gov/openapps/plsql/gadeers_main$.startup). The reporting procedures to be followed are presented in the “NCI Guidelines: Expedited Adverse Event Reporting Requirements for NCI Investigational Agents” which can be downloaded from the CTEP web site (http://ctep.cancer.gov/reporting/adeers.html). 7.3.2 In the rare event when Internet connectivity is disrupted a 24-hour notification is to be made to NCI by telephone at: 301-897-7497, or 301-897-7402 for CIP studies. An electronic report MUST be submitted immediately upon re-establishment of internet connection. Please note that all paper AdEERS forms have been removed from the CTEP website and will NO LONGER be accepted. 7.3.3 AEs that require notification to the Investigational Drug Branch (IDB) within 24 hours should be made via the AdEERS web site: https://webapps.ctep.nci.nih.gov/openapps/plsql/gadeers_main$.startup. 7.3.4 A central processing system has been set up for AdEERS reports. Each site will submit the electronic version of the AdEERS report to the Lead Group Coordinators (PMH Phase I Consortium Central Office, Program Manager and Study Coordinator - e-mail addresses are on the front sheet). Once review by the lead group coordinators has taken place the report will be forwarded to NCI. Expedited Reporting Guidelines – – AdEERS Reporting Requirements for Adverse Events that occur within 30 Days1 of the Last Dose of the Investigational Agent on Phase 2 and 3 Trials 47 Phase 2 and 3 Trials Grade 1 Grade 2 Unexpected and Expected Unexpected Unrelated Unlikely Not Required Not Required Not Required 10 Calendar Days Not Required 10 Calendar Days Possible Probable Definite Not Required 10 Calendar Days Not Required 10 Calendar Days 10 Calendar Days 10 Calendar Days 1 2 Grade 2 Grades 4 & 52 Grades 4 & 52 Unexpected Expected Not Required 10 Calendar Days 10 Calendar Days Not Required 24-Hour; 5 Calendar Days 10 Calendar Days Grade 3 Grade 3 Unexpected Expected with without with without Expected Hospitali- Hospitali- Hospitali- Hospitalization zation zation zation Adverse events with attribution of possible, probable, or definite that occur greater than 30 days after the last dose of treatment with an agent under a CTEP IND require reporting as follows: AdEERS 24-hour notification followed by complete report within 5 calendar days for: Grade 4 and Grade 5 unexpected events AdEERS 10 calendar day report: Grade 3 unexpected events with hospitalization or prolongation of hospitalization Grade 5 expected events Although an AdEERS 24-hour notification is not required for death clearly related to progressive disease, a full report is required as outlined in the table. December 15, 2004 Note: All deaths on study require both routine and expedited reporting regardless of causality. Attribution to treatment or other cause must be provided. Expedited AE reporting timelines defined: “24 hours; 5 calendar days” – The investigator must initially report the AE via AdEERS within 24 hours of learning of the event followed by a complete AdEERS report within 5 calendar days of the initial 24-hour report. “10 calendar days” - A complete AdEERS report on the AE must be submitted within 10 calendar days of the investigator learning of the event. Any medical event equivalent to CTCAE grade 3, 4, or 5 that precipitates hospitalization (or prolongation of existing hospitalization) must be reported regardless of attribution and designation as expected or unexpected with the exception of any events identified as protocolspecific expedited adverse event reporting exclusions. Any event that results in persistent or significant disabilities/incapacities, congenital anomalies, or birth defects must be reported via AdEERS if the event occurs following treatment with an agent under a CTEP IND. Use the NCI protocol number and the protocol-specific patient ID provided during trial registration on all reports. In order to ensure the timely fulfillment of both US and Canadian IND regulatory reporting requirements, all AdEERS reports must be sent to the PMH Phase I Consortium Central Office within 3 working days from the date the event was known to the investigator. In the unlikely event that an adverse event occurs that does not meet the reporting requirements for AdEERS, but does meet the definition of a Serious Adverse Event, an AdEERS report must still be completed and sent to the Central Office within 3 working days 48 of the event being known to the investigator. The event must be telephoned or e-mailed to Central Office within 1 working day. A Serious Adverse Event is any untoward medical occurrence that meets one or more of the following criteria: Results in death Is life threatening Requires inpatient hospitalization or prolongation of existing hospitalization Results in persistent or significant disability/incapacity Is a congenital anomaly/birth defect Is a medically significant event for any reason The PMH Phase I Consortium Central Office will be responsible for reporting to Canadian regulatory authorities all Serious Adverse Events that are both unexpected and related to study drug. The Central Office will notify all Investigators of all Serious Adverse Events that are reportable to regulatory authorities in Canada from this trial or from other clinical trials as reported to the Central Office by the NCI U.S. Investigators must notify their local Research Ethics Boards (REB/IRBs) of all AdEERS or SAE reports from their center and file the report in their regulatory study binder. In addition, all reports sent out to centres by the PMH Phase I Consortium Central Office must be sent to local REB/IRBs. Documentation from the REB/IRB of receipt of these reportable events must be kept on file in each institution's regulatory binder. 7.4 Events that are clearly consequences of the “main” event (e.g., hypokalemia associated with diarrhea or the arrhythmias, hypotension, hypoxia, etc. that are known to occur concurrently with sepsis) may be noted in the Description of Event in the AdEERS report, and do not require separate AdEERS reports. The possibility of the contribution of comorbid conditions to the event should be considered when reporting AEs. Examples include hyperglycemia in patients with diabetes or headaches and seizures in patients with brain tumors. Routine Adverse Event Reporting Those AEs that do not require expedited reporting must be reported in routine (CTMS or CDUS; see Section 12.1) study data submissions. AEs reported through AdEERS must also be reported in routine study data submissions. 7.5 Secondary AML/MDS reporting In addition to all routine AE reporting mechanisms and Cooperative Group-specific second/secondary malignancy reporting requirements, all new malignant tumors must be reported through AdEERS whether or not they are thought to be related to previous or current treatment. All new malignancies should be reported including solid tumors, skin malignancies, hematologic malignancies, AML/MDS, and in situ-tumors. If no other cause is evident, an attribution to new primary tumor may be made. In CTCAE v4.0, the event(s) may be reported as either: 1) Leukemia secondary to oncology chemotherapy, 2) Myelodysplastic syndrome, 3) Treatment-related secondary malignancy, or 49 4) Neoplasm-other. These events should be reported for as long as the study participants are followed. 50 8. PHARMACEUTICAL INFORMATION 8.1 Cediranib (AZD2171) (NSC 732208) (CTEP IND #72,740) AZD2171 (NSC 732208) Chemical Name: 4-[(4-Fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxy-7-(3-pyrrolidin 1- ylpropoxy) quinazoline maleate Other Names: Cediranib, AZD2171 maleate, Recentin™ CAS Registry Number: 288383-20-0 (for the free base) Molecular Formula: C25H27FN4O3 · C4H4O4 Molecular Weight: 566.59 as maleate salt (450.52 as free base) Approximate Solubility: The aqueous solubility of AZD2171 has been measured as 0.0006 mg/mL for the free base (distilled water, pH 8.1 at 25°C) and 1.9 mg/mL for the maleate salt (distilled water, pH 4.4 at 25°C). Mode of Action: AZD2171 is a highly potent inhibitor of vascular endothelial growth factor receptor (VEGFR) tyrosine kinase activity, which may inhibit vascular endothelial growth factor-A (VEGF) driven angiogenesis and, as a consequence, constrain solid tumor growth. How Supplied: AZD2171 is available as beige film-coated tablets containing 15 mg and 20 mg of AZD2171 free base. The 15 mg and 20 mg tablets are 7 mm and 8 mm in diameter, respectively. Each bottle contains 35 tablets. In addition to the active ingredient, the tablets contain mannitol, dibasic calcium phosphate anhydrous, sodium starch glycolate, microcrystalline cellulose, and magnesium stearate with a film coat coating hypromellose 2910, polyethylene glycol 400, red iron oxide, yellow iron oxide, black iron oxide, and titanium dioxide. Availability: Cediranib is an investigational agent supplied to investigators by the Division of Cancer Treatment and Diagnosis (DCTD) and is provided to the NCI under a Collaborative Agreement between Pharmaceutical Collaborator and the DCTD, NCI (see Section 12.3). Storage: Store intact bottles at controlled room temperature [20°C-25°C, (68-77°F)] and protect from light. Stability: Stability studies are ongoing. Route of Administration: Oral. AZD2171 tablets should be taken either 1 hour before or 2 hours after meals. 8.2 Dasatinib (BMS-354825) (NSC 732517) (CTEP IND #73,969) 51 BMS-354825 NSC 732517 Other name: Dasatinib, Sprycel® Chemical Name: N-(2-Chloro-6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl)-1-piperazinyl]-2 methyl4-pyrimidinyl]amino]-5-thiazolecarboxamide, monohydrate Mechanism of Action: BMS-354825 is a potent, broad spectrum ATP-competitive inhibitor of 5 critical oncogenic tyrosine kinase families: BCR-ABL, SRC family kinases, c-KIT, ephrin (EP) receptor kinases, and PDGFβ receptor. Each of these protein kinases has been strongly linked to multiple forms of human malignancies. Molecular Formula: C22H26CIN7O2S· H20 Molecular Weight: BMS-354825 monohydrate: 506.02 daltons Approximate Solubility: BMS-354825 is slightly soluble in ethanol (USP), methanol, polyethylene glycol 400, and propylene glycol. It is very slightly soluble in acetone and acetonitrile, practically insoluble in corn oil, and insoluble in water. How Supplied: BMS-354825 is available as 50 mg and 20 mg tablets. The 50 mg biconvex oval, white to offwhite film-coated tablets contain 30 tablets per bottle. The tablet is debossed with 50 on one side and 528 on the other side (or BMS on one side and 528 on the other side). The 20 mg biconvex round, white to off-white film-coated tablets contain 30 tablets per bottle. The tablet is debossed with “20” on one side and “527” on the other side. Inactive ingredients include lactose, microcrystalline cellulose, croscarmellose sodium, hydroxypropyl cellulose, magnesium stearate, hydroxypropyl methylcellulose, titanium dioxide, and polyethylene glycol. Availability: Dasatinib is an investigational agent supplied to investigators by the Division of Cancer Treatment and Diagnosis (DCTD) and is provided to the NCI under a Collaborative Agreement between Pharmaceutical Collaborator and the DCTD, NCI (see Section 12.3). Storage: Store the intact bottles at controlled room temperature (15°C-25°C) and protect from light. Excursions are permitted up to 30 °C. Stability: Stability studies are ongoing. Route of Administration: Orally with or without food. Tablets should be swallowed whole and cannot be crushed or broken. Potential Drug Interactions: 52 Potent CYP3A4 inducers and inhibitors are prohibited on BMS-354825 trials. BMS-354825 is primarily metabolized by the human CYP3A4 enzyme. CYP3A4 substrates known to have a narrow therapeutic index should be administered with caution in patients receiving BMS-354825. Systemic antacids (both H2 receptor antagonists and proton pump inhibitors) are prohibited on BMS354825 trials. Locally acting antacids can be given up to 2 hours prior or 2 hours following BMS-354825 administration. BMS-354825 may prolong the QT/QTc interval. Use caution when administering BMS-354825 with other potential QTc-prolonging medications. Due to the possibility of CNS, gastrointestinal, cardiac, and cutaneous hemorrhage, avoid using medications that inhibit platelet function or anticoagulants with BMS-354825. Special Handling: BMS-354825 tablets consist of a core tablet (containing the active drug) surrounded by a film coating to prevent exposure to the active drug substance. If tablets are accidentally crushed or broken, caregivers should wear disposable chemotherapy gloves. Pregnant women should avoid exposure to crushed and/or broken tablets. 8.3 Agent Ordering, Accountability, and Returns 8.3.1 NCI supplied agents may be requested by the Principal Investigator (or their authorized designee) at each participating institution. Pharmaceutical Management Branch (PMB) policy requires that agent be shipped directly to the institution where the patient is to be treated. PMB does not permit the transfer of agents between institutions (unless prior approval from PMB is obtained.) The CTEP assigned protocol number must be used for ordering all CTEP supplied investigational agents. The responsible investigator at each participating institution must be registered with CTEP, DCTD through an annual submission of FDA form 1572 (Statement of Investigator), Curriculum Vitae, Supplemental Investigator Data Form (IDF), and Financial Disclosure Form (FDF). If there are several participating investigators at one institution, CTEP supplied investigational agents for the study should be ordered under the name of one lead investigator at that institution. Agent may be requested by completing a Clinical Drug Request (NIH-986) and faxing it to the Pharmaceutical Management Branch at (301) 480-4612. For questions about drug orders, transfers, returns, or accountability call (301) 496-5725 Monday through Friday between 8:30 am and 4:30 pm (ET) or email [email protected]. anytime. 8.3.2 Agent Inventory Records - The investigator, or a responsible party designated by the investigator, must maintain a careful record of the inventory and disposition of all agents received from DCTD using the NCI Drug Accountability Record Form (DARF). (See the NCI Investigator’s Handbook for Procedures for Drug Accountability and Storage.) 53 8.3.3 Drug Returns: Only undispensed clinical supplies should be returned to the PMB. When it is necessary to return study drug (e.g., sealed bottles remaining when a patient permanently discontinues protocol treatment, expired bottles recalled by the PMB), investigators should return the study drug to the PMB using the NCI Return Drug List available on the CTEP home page (http://ctep.cancer.gov). Compliance: Patients will be required to return all bottles of study medication at the end of each cycle. The number of tablets remaining should be documented and recorded on the Patient’s Pill Diary (see Appendix D). 54 9. CORRELATIVE/SPECIAL STUDIES 9.1 Archival Specimens Archival tumor specimens will be obtained on all patients for pathology review. The specimens will also be analyzed for c-Src protein expression and activity. We hypothesize that sensitivity to dasatinib will depend on the levels of c-Src protein expression and activity in the pretreatment biopsy samples. To measure these, we will use a combined immunofluorescence staining protocol labeling total c-Src, Y419 phosphorylated c-Src, and the endogenous src inhibitor c-terminal src kinase (Csk). Based on the three interrelated markers, we will develop a scoring system to assign tumors into low and high c-Src activity. Additional biomarkers for VEGF/VEGFR and Src pathways. Paraffin embedded archival blocks are preferred. However if blocks cannot be released, 10 unstained slides 4-5 microns each mounted on positively charged slides are also acceptable. Please note that if blocks are provided, they will be returned to the sender at the end of the study. Archival Specimens should be shipped to: Anne Eisenhauer Correlative Studies Manager Drug Development Program Princess Margaret Hospital 610 University Avenue 9-718 Toronto, Ontario M5G 2M9 Canada Tel: (416) 946-4501 ext 5788 Fax: (416) 946-2016 Email: [email protected] Note: Before shipping, fax Archival Tumor Tissue Specimen Requisition to Anne Eisenhauer @ 416 946 2016 9.2 Bone Resorption Markers As a secondary objective, we plan to measure bone resorption markers at baseline and then at the end of cycles 1 and 3 in this study, including serum C-telopeptide and bone alkaline phosphatase, and we postulate that these biomarkers will decrease as a result of treatment in both arms, but more pronounced decrease will be observed in the combination arm of cediranib and dasatinib compared to cediranib alone. 55 To avoid variations in C-telopeptide measurements (influenced by both food intake and circadian rhythms) blood will be obtained early morning from fasting subjects with the serum separated and frozen. These specimens will be analyzed for both Ctelopeptide and bone-specific alkaline phosphate on commercial clinical assays. Blood should be collected in red top BD Vacutainer (1 tube 10 mL volume - PLEASE ALLOW 1 HOUR TO CLOT BEFORE CENTRIFUGATION) with serum aliquoted equally in 3 orange top cyrovials (2mL each). The cryovials (labelled) should be frozen (at -20C) and sent for long-term storage in liquid nitrogen (vapor phase 150C) before bone turnover marker analysis. Bone resportion markers specimens should be sent to: Clinical Research and Clinical Trials Laboratory Hamilton Health Sciences 237 Barton St. E, Hamilton, ON L8L 2X2 Canada Attn: Mrs. Kim Hall, Manager (Dr. P. Kavsak – Biochemist) Tel: (905) 527-4322 ext 46149 Fax: (905) 577-1476 Email: [email protected] 9.3 Quality of Life Questionnaires and Pain Assessment Quality of life and pain assessment will be evaluated at baseline and every 4 weeks in this study, using the Functional Assessment of Cancer Therapy-Prostate (FACT-P) questionnaire (Appendix F) and the Present Pain Intensity (PPI) scale from the McGill-Melzack questionnaire (Appendix G). FACT-P is a multidimensional, selfreport quality of life instrument specifically designed for use with prostate cancer patients.(49) It consists of 27 core items which assess patient function in four domains: Physical, Social/Family, Emotional, and Functional well-being, which is further supplemented by 12 site-specific items to assess for prostate related symptoms. It is a validated questionnaire to measure quality of life in men undergoing therapy for prostate cancer. Pain assessment will be performed using the PPI from the McGill-Melzack questionnaire,(50), which is a 5-point scale, asking about the current pain level the patient is experiencing. 56 10. STUDY CALENDAR Baseline evaluations are to be conducted within 1 week prior to administration of protocol therapy. Scans (CT and MUGA) and x-rays must be done 28 days prior to registration. In the event that the patient’s condition is deteriorating, laboratory evaluations should be repeated within 48 hours prior to initiation of the next cycle of therapy. Pre-study physical examination, performance status and laboratory tests should be done within 7 days prior to start of treatment. A minus 1 day time window for On Treatment study assessments is permitted. Evaluation of response will follow the Prostate Cancer Clinical Trials Working Group 2 (PCWG2) criteria as described in section 11. The timing and scheduling for each of the investigations is described below: 57 PreStudy Cediriniaba +/ - dasatinibb C1D1 C1 D8 C1 D15 C1 D21 C2 D1 C2 D8 C2 D15 C2 C3D 1 D21 C3 D8 C3 D15 C3 D21 C4 D1 X----------------------------------------------------------------------------------------------------------X Informed consent X Demographics X Medical history X Concurrent meds X Physical exam (including vital signs BP, pulse, RR, temp) X Patient twice daily BP recording X----------------------------------------------------------------------------------------------------------X X X X X X X X X X Weight X X X X X Performance status X X X X X CBC w/diff, plts; INR, Biochemistryc X X X X Urine dipstick for proteind X X X X PSA X X X X ECGe X X X X Adverse event evaluation TSH, Free T3, Free T4f `ECHO/MUGAg X X----------------------------------------------------------------------------------------------------------X X X X As clinically indicated Height Tumor measurements including CT/MRI and bone scan Off Studyj Tumor measurements are repeated every 12 weeks. Documentation (radiologic) must be provided for patients removed from study for progressive disease. X X X X X X X X X X X Bone resorption markers X Archival tumor specimensh X Testosteronei X FACT-P and PPI X X X X X X a: cediranib (AZD2171): Dose as assigned. Administered orally, daily at a fixed dose. Please keep a pill diary (Appendix D). Cycles = 28 days. b: dasatinib (BMS-354825): Dose as assigned. Administered orally, daily at a fixed dose. Please keep a pill diary (Appendix D). Cycles = 28 days. c: Albumin, alkaline phosphatase, total bilirubin, bicarbonate, BUN, calcium, chloride, creatinine, glucose, LDH, phosphorus, potassium, total protein, SGOT[AST], SGPT[ALT], sodium, magnesium. d: If patient has significant protein on dipstick (+1 or higher), then obtain a 24 hour urine for protein. e: ECG should be done at baseline, Day 1 of each cycle and as clinically indicated. f: TSH, free T3, free T4, should be obtained at baseline, end of cycle 1, end of cycle 2 and then if clinically indicated. g: ECHO/MUGA should be done in all patients prior to treatment start and repeated if clinically indicated. Patients with a cardiac history 58 and patients with NYHA functional classification system Class II despite being controlled with treatment and those with prior central thoracic radiation therapy including radiotherapy to the heart, should have ECHO/MUGA repeated every other cycle or more frequently if clinically indicated h: Archival tumor tissue and samples for markers of bone turnover will be obtained on all patients as outlined in Section 9. i: required at baseline within 7 days prior to start of treatment for patients who are medically castrated. Not required for patients who have had surgical castration j:Off-study visits: 1) end of study visit and 2) follow-up visit about 30 days after the last dose of study drug(s). Radiological examinations only need to be repeated if study subject has not had tumor assessment within the last 8 weeks 11. MEASUREMENT OF EFFECT 11.1 Antitumor Effect – Solid Tumors Progression will be evaluated in this study using The Prostate Cancer Clinical Trials Working Goup 2 (PCWG2) criteria(1), which is a composite endpoint of PSA, bone scan, and CT scan assessments, as define as follow: PSA: Progression is defined as an increase in PSA >25% and > 2ng/mL above the nadir value which is confirmed by a second value 3 or more weeks later after the first 12 weeks on study. Ignore early rises (prior to 12 weeks) in determining PSA response. Target Lesions: Measurable lesions are not required for considering progression. The new international criteria proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1) [Eur J Ca 45:228-247, 2009] (see Section 11.1.1 to11.1.4 below) will be used to record soft tissue lesions (nodal and visceral soft tissue sites should be recorded separately). Only lymph nodes > 2 cm in diameter should be used to assess for a change in size. Primary tumor site: Presence of disease should be confirmed with directed pelvic imaging (e.g. CT, MRI). Bone lesions: Progression is defined as the appearance of > 2 new lesions. Ambiguous results should be confirmed by other imaging modalities. For the purposes of this study, patients should be re-evaluated for response every 12 weeks. In addition to a baseline scan, confirmatory scans should also be obtained 4 to 8 (not less than 4) weeks following initial documentation of objective response. 11.1.1 Definitions Evaluable for toxicity. All patients will be evaluable for toxicity from the time of their first treatment with cediranib +/- dasatinib. 59 Evaluable for objective response. Only those patients who have measurable disease present at baseline, have received at least one cycle of therapy, and have had their disease re-evaluated will be considered evaluable for response. These patients will have their response classified according to the definitions stated below. (Note: Patients who exhibit objective disease progression prior to the end of cycle 1 will also be considered evaluable.) Evaluable Non-Target Disease Response. Patients who have lesions present at baseline that are evaluable but do not meet the definitions of measurable disease, have received at least one cycle of therapy, and have had their disease re-evaluated will be considered evaluable for non-target disease. The response assessment is based on the presence, absence, or unequivocal progression of the lesions. 11.1.2 Disease Parameters Measurable disease. Measurable lesions are defined as those that can be accurately measured in at least one dimension (longest diameter to be recorded) as >20 mm by chest x-ray, as >10 mm with CT scan, or >10 mm with calipers by clinical exam. All tumor measurements must be recorded in millimeters (or decimal fractions of centimeters). Note: Tumor lesions that are situated in a previously irradiated area might or might not be considered measurable. Malignant lymph nodes. As per PCWG2 criteria, to be considered pathologically enlarged and measurable, a lymph node must be >20 mm in diameter when assessed by spiral CT scan. Non-measurable disease. All other lesions (or sites of disease), including small lesions (longest diameter <10 mm or pathological lymph nodes with <20 mm in diameter are considered non-measurable disease. Bone lesions, leptomeningeal disease, ascites, pleural/pericardial effusions, lymphangitis cutis/pulmonitis and abdominal masses (not followed by CT or MRI), are considered as non-measurable. Note: Cystic lesions that meet the criteria for radiographically defined simple cysts should not be considered as malignant lesions (neither measurable nor non-measurable) since they are, by definition, simple cysts. ‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable lesions, if they meet the definition of measurability described above. However, if non-cystic lesions are present in the same patient, these are preferred for selection as target lesions. 60 Target lesions. All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in total, representative of all involved organs, should be identified as target lesions and recorded and measured at baseline. Target lesions should be selected on the basis of their size (lesions with the longest diameter), be representative of all involved organs, but in addition should be those that lend themselves to reproducible repeated measurements. It may be the case that, on occasion, the largest lesion does not lend itself to reproducible measurement in which circumstance the next largest lesion which can be measured reproducibly should be selected. A sum of the diameters (longest for non-nodal lesions and nodal lesions) for all target lesions will be calculated and reported as the baseline sum diameters. The baseline sum diameters will be used as reference to further characterize any objective tumor regression in the measurable dimension of the disease. Non-target lesions. All other lesions (or sites of disease) including any measurable lesions over and above the 5 target lesions should be identified as non-target lesions and should also be recorded at baseline. Measurements of these lesions are not required, but the presence, absence, or in rare cases unequivocal progression of each should be noted throughout follow-up. 11.1.3 Methods for Evaluation of Measurable Disease All measurements should be taken and recorded in metric notation using a ruler or calipers. All baseline evaluations should be performed as closely as possible to the beginning of treatment and never more than 4 weeks before the beginning of the treatment. The same method of assessment and the same technique should be used to characterize each identified and reported lesion at baseline and during follow-up. Imaging-based evaluation is preferred to evaluation by clinical examination unless the lesion(s) being followed cannot be imaged but are assessable by clinical exam. Clinical lesions Clinical lesions will only be considered measurable when they are superficial (e.g., skin nodules and palpable lymph nodes) and 10 mm diameter as assessed using calipers (e.g., skin nodules). In the case of skin lesions, documentation by color photography, including a ruler to estimate the size of the lesion, is recommended. Chest x-ray Lesions on chest x-ray are acceptable as measurable lesions when they are clearly defined and surrounded by aerated lung. However, CT is preferable. Conventional CT and MRI This guideline has defined measurability of lesions on 61 CT scan based on the assumption that CT slice thickness is 5 mm or less. If CT scans have slice thickness greater than 5 mm, the minimum size for a measurable lesion should be twice the slice thickness. MRI is also acceptable in certain situations (e.g. for body scans). Use of MRI remains a complex issue. MRI has excellent contrast, spatial, and temporal resolution; however, there are many image acquisition variables involved in MRI, which greatly impact image quality, lesion conspicuity, and measurement. Furthermore, the availability of MRI is variable globally. As with CT, if an MRI is performed, the technical specifications of the scanning sequences used should be optimized for the evaluation of the type and site of disease. Furthermore, as with CT, the modality used at follow-up should be the same as was used at baseline and the lesions should be measured/assessed on the same pulse sequence. It is beyond the scope of the RECIST guidelines to prescribe specific MRI pulse sequence parameters for all scanners, body parts, and diseases. Ideally, the same type of scanner should be used and the image acquisition protocol should be followed as closely as possible to prior scans. Body scans should be performed with breath-hold scanning techniques, if possible. PET-CT At present, the low dose or attenuation correction CT portion of a combined PET-CT is not always of optimal diagnostic CT quality for use with RECIST measurements. However, if the site can document that the CT performed as part of a PET-CT is of identical diagnostic quality to a diagnostic CT (with IV and oral contrast), then the CT portion of the PET-CT can be used for RECIST measurements and can be used interchangeably with conventional CT in accurately measuring cancer lesions over time. Note, however, that the PET portion of the CT introduces additional data which may bias an investigator if it is not routinely or serially performed. Ultrasound Ultrasound is not useful in assessment of lesion size and should not be used as a method of measurement. Ultrasound examinations cannot be reproduced in their entirety for independent review at a later date and, because they are operator dependent, it cannot be guaranteed that the same technique and measurements will be taken from one assessment to the next. If new lesions are identified by ultrasound in the course of the study, confirmation by CT or MRI is advised. If there is concern about radiation exposure at CT, MRI may be used instead of CT in selected instances. Endoscopy, Laparoscopy The utilization of these techniques for objective tumor evaluation is not advised. However, such techniques may be useful to confirm complete pathological response when biopsies are obtained or to determine relapse in trials where recurrence following complete response (CR) or surgical resection is an endpoint. 62 Tumor markers Tumor markers alone cannot be used to assess response. If markers are initially above the upper normal limit, they must normalize for a patient to be considered in complete clinical response. Specific guidelines for PSA response (in recurrent prostate cancer) have been published [J Clin Oncol 26:1148-1159, 2008]. Cytology, Histology These techniques can be used to differentiate between partial responses (PR) and complete responses (CR) in rare cases (e.g., residual lesions in tumor types, such as germ cell tumors, where known residual benign tumors can remain). The cytological confirmation of the neoplastic origin of any effusion that appears or worsens during treatment when the measurable tumor has met criteria for response or stable disease is mandatory to differentiate between response or stable disease (an effusion may be a side effect of the treatment) and progressive disease. FDG-PET While FDG-PET response assessments need additional study, it is sometimes reasonable to incorporate the use of FDG-PET scanning to complement CT scanning in assessment of progression (particularly possible 'new' disease). New lesions on the basis of FDG-PET imaging can be identified according to the following algorithm: a. Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of PD based on a new lesion. b. No FDG-PET at baseline and a positive FDG-PET at follow-up: If the positive FDG-PET at follow-up corresponds to a new site of disease confirmed by CT, this is PD. If the positive FDG-PET at follow-up is not confirmed as a new site of disease on CT, additional follow-up CT scans are needed to determine if there is truly progression occurring at that site (if so, the date of PD will be the date of the initial abnormal FDG-PET scan). If the positive FDG-PET at follow-up corresponds to a pre-existing site of disease on CT that is not progressing on the basis of the anatomic images, this is not PD. c. FDG-PET may be used to upgrade a response to a CR in a manner similar to a biopsy in cases where a residual radiographic abnormality is thought to represent fibrosis or scarring. The use of FDG-PET in this circumstance should be prospectively described in the protocol and supported by disease-specific medical literature for the indication. However, it must be acknowledged that both approaches may lead to false positive CR due to limitations of FDG-PET and biopsy resolution/sensitivity. Note: A ‘positive’ FDG-PET scan lesion means one which is FDG avid with an uptake greater than twice that of the surrounding tissue on the attenuation corrected image. 63 11.1.4 Response Criteria 11.1.4.1 11.1.4.2 Evaluation of Target Lesions Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. Partial Response (PR): At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters Progressive Disease (PD): At least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered progressions). Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study Evaluation of Non-Target Lesions Complete Response (CR): Disappearance of all non-target lesions and normalization of tumor marker level. All lymph nodes must be non-pathological in size (<10 mm short axis) Note: If tumor markers are initially above the upper normal limit, they must normalize for a patient to be considered in complete clinical response. 64 Non-CR/Non-PD: Persistence of one or more non-target lesion(s) and/or maintenance of tumor marker level above the normal limits Progressive Disease (PD): Appearance of one or more new lesions and/or unequivocal progression of existing non-target lesions. Unequivocal progression should not normally trump target lesion status. It must be representative of overall disease status change, not a single lesion increase. Although a clear progression of “non-target” lesions only is exceptional, the opinion of the treating physician should prevail in such circumstances, and the progression status should be confirmed at a later time by the review panel (or Principal Investigator). 11.1.4.3 Evaluation of Best Overall Response The best overall response is the best response recorded from the start of the treatment until disease progression/recurrence (taking as reference for progressive disease the smallest measurements recorded since the treatment started). The patient's best response assignment will depend on the achievement of both measurement and confirmation criteria. For Patients with Measurable Disease (i.e., Target Disease) Target Lesions Non-Target Lesions New Lesions Overall Response CR CR CR NonCR/Non-PD Not evaluated NonCR/NonPD/not evaluated NonCR/NonPD/not evaluated Any PD*** Any No No CR PR CR PR SD PD Any Any * Best Overall Response when Confirmation is Required* >4 wks. Confirmation** >4 wks. Confirmation** No PR No PR No SD Yes or No Yes or No Yes PD PD PD documented at least once >4 wks. from baseline** no prior SD, PR or CR See RECIST 1.1 manuscript for further details on what is evidence of a new lesion. 65 ** Only for non-randomized trials with response as primary endpoint. *** In exceptional circumstances, unequivocal progression in non-target lesions may be accepted as disease progression. Note: Patients with a global deterioration of health status requiring discontinuation of treatment without objective evidence of disease progression at that time should be reported as “symptomatic deterioration.” Every effort should be made to document the objective progression even after discontinuation of treatment. For Patients with Non-Measurable Disease (i.e., Non-Target Disease) Non-Target Lesions New Lesions Overall Response CR No CR Non-CR/non-PD No Non-CR/non-PD* Not all evaluated No not evaluated Unequivocal PD Yes or No PD Any Yes PD * ‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since SD is increasingly used as an endpoint for assessment of efficacy in some trials so to assign this category when no lesions can be measured is not advised 66 11.1.5 Duration of Response Duration of overall response: The duration of overall response is measured from the time measurement criteria are met for CR or PR (whichever is first recorded) until the first date that recurrent or progressive disease is objectively documented (taking as reference for progressive disease the smallest measurements recorded since the treatment started). The duration of overall CR is measured from the time measurement criteria are first met for CR until the first date that progressive disease is objectively documented. Duration of stable disease: Stable disease is measured from the start of the treatment until the criteria for progression are met, taking as reference the smallest measurements recorded since the treatment started, including the baseline measurements. 11.1.6 Progression-Free Survival Progression free survival (PFS) is defined as the duration of time from start of treatment to progression (as defined above), death or last contact, or last tumor assessment before the start of further antitumor therapy. PFS is primary endpoint of this study 11.1.7 Response Review All objective response will independently be reviewed centrally at PMH, using images free of marks that might obscure the lesions or bias the evaluation of the reviewer. 12. DATA REPORTING / REGULATORY REQUIREMENTS Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 7.0 (Adverse Events: List and Reporting Requirements). 12.1 Data Reporting 12.1.1 Method This study will be monitored by the Clinical Data Update System (CDUS). Cumulative CDUS data will be submitted quarterly to CTEP by electronic means. Reports are due January 31, April 30, July 31, and October 31. Instructions for submitting data using the CDUS can be found on the CTEP web site (http://ctep.cancer.gov/reporting/cdus.html). 67 12.1.2 Responsibility for Submissions Study participants are responsible for submitting CDUS data and/or data forms to the Coordinating Center quarterly by January 31, April 30, July 31, and October 31 to allow time for Coordinating Center compilation, Principal Investigator review, and timely submission to CTEP (see Section 12.1.1.). Please refer to Appendix H, Data Management Guidelines, for further details regarding data submission requirements. The Coordinating Center is responsible for compiling and submitting CDUS data to CTEP for all participants and for providing the data to the Principal Investigator for review. 12.2 CTEP Multicenter Guidelines This protocol will adhere to the policies and requirements of the CTEP Multicenter Guidelines. The specific responsibilities of the Principal Investigator and the Coordinating Center (Study Coordinator) and the procedures for auditing are presented in Appendix I. 12.3 The Principal Investigator/Coordinating Center is responsible for distributing all IND Action Letters or Safety Reports received from CTEP to all participating institutions for submission to their individual IRBs for action as required. Except in very unusual circumstances, each participating institution will order DCTD-supplied agents directly from CTEP. Agents may be ordered by a participating site only after the initial IRB approval for the site has been forwarded by the Coordinating Center to the CTEP PIO ([email protected]) except for Group studies. Cooperative Research and Development Agreement (CRADA)/Clinical Trials Agreement (CTA) The agent(s) supplied by CTEP, DCTD, NCI used in this protocol is/are provided to the NCI under a Collaborative Agreement (CRADA, Agent-CRADA, CTA, CSA) between the Pharmaceutical Company(ies) (hereinafter referred to as a “Collaborator(s)”) and the NCI Division of Cancer Treatment and Diagnosis. Therefore, the following obligations/guidelines, in addition to the provisions in the “Intellectual Property Option to Collaborator” (http://ctep.cancer.gov/industryCollaborations2/default.htm) contained within the terms of award, apply to the use of the Agent(s) in this study: 68 1. Agent(s) may not be used for any purpose outside the scope of this protocol, nor can Agent(s) be transferred or licensed to any party not participating in the clinical study. Collaborator(s) data for Agent(s) are confidential and proprietary to Collaborator(s) and shall be maintained as such by the investigators. The protocol documents for studies utilizing investigational agents contain confidential information and should not be shared or distributed without the permission of the NCI. If a copy of this protocol is requested by a patient participating on the study or patient’s family member, the individual should sign a confidentiality agreement. A suitable model agreement can be downloaded from http://ctep.cancer.gov. 2. For a clinical protocol where there is an investigational Agent used in combination with (an)other investigational Agent(s), each the subject of different collaborative agreements, the access to and use of data by each Collaborator shall be as follows (data pertaining to such combination use shall hereinafter be referred to as "Multi-Party Data”.): a. NCI must provide all Collaborators with prior written notice regarding the existence and nature of any agreements governing their collaboration with NIH, the design of the proposed combination protocol, and the existence of any obligations that would tend to restrict NCI's participation in the proposed combination protocol. b. Each Collaborator shall agree to permit use of the Multi-Party Data from the clinical trial by any other Collaborator solely to the extent necessary to allow said other Collaborator to develop, obtain regulatory approval, or commercialize its own investigational agent. c. Any Collaborator having the right to use the Multi-Party Data from these trials must agree in writing prior to the commencement of the trials that it will use the Multi-Party Data solely for development, regulatory approval, and commercialization of its own investigational agent. 3. Clinical Trial Data and Results and Raw Data developed under a Collaborative Agreement will be made available exclusively to Collaborator(s), the NCI, and the FDA, as appropriate and unless additional disclosure is required by law or court order. Additionally, all Clinical Data and Results and Raw Data will be collected , used and disclosed consistent with all applicable federal statutes and regulations for the protection of human subjects, including, if applicable, the Standards for Privacy of Individually Identifiable Health Information set forth in 45 C.F.R. Part 164. 4. When a Collaborator wishes to initiate a data request, the request should first be sent to the NCI, who will then notify the appropriate investigators (Group 69 Chair for Cooperative Group studies, or PI for other studies) of Collaborator's wish to contact them. 5. Any data provided to Collaborator(s) for phase 3 studies must be in accordance with the guidelines and policies of the responsible Data Monitoring Committee (DMC), if there is a DMC for this clinical trial. 6. Any manuscripts reporting the results of this clinical trial must be provided to CTEP for immediate delivery to Collaborator(s) for advisory review and comment prior to submission for publication. Collaborator(s) will have 30 days from the date of receipt for review. Collaborator shall have the right to request that publication be delayed for up to an additional 30 days in order to ensure that Collaborator’s confidential and proprietary data, in addition to Collaborator(s)’s intellectual property rights, are protected. Copies of abstracts must be provided to CTEP for forwarding to Collaborator(s) for courtesy review as soon as possible and preferably at least three (3) days prior to submission, but in any case, prior to presentation at the meeting or publication in the proceedings. Press releases and other media presentations must also be forwarded to CTEP prior to release. Copies of any manuscript, abstract, and/or press release/ media presentation should be sent to: Regulatory Affairs Branch, CTEP, DCTD, NCI 6130 Executive Boulevard, Suite 7111 Rockville, MD 20852 FAX 301-402-1584 E-mail: [email protected]. The Regulatory Affairs Branch will then distribute them to Collaborator(s). No publication, manuscript or other form of public disclosure shall contain any of Collaborator’s confidential/proprietary information. 70 13. STATISTICAL CONSIDERATIONS 13.1 Study Design/Endpoints This is a multicenter, randomized, phase II study. The primary endpoint is the efficacy of cediranib versus cediranib plus dasatinib in the treatment of docetaxel-resistant, castration resistant prostate cancer using progression free survival (PFS) as per the Prostate Cancer Clinical Trials Working Group (PCWG2) which is a composite endpoint of PSA, bone scan, and CT scan assessments.(1) The control arm (i.e. cediranib alone) is assumed to have a 30% 3-month probability of PFS as determined by the composite endpoint. The experimental arm (i.e. cediranib plus dasatinib) will be postulated to have a 60% 3-month PFS. With 25 patients in each arm, an alpha rate of 0.15 (one-sided), the power would be 80%. Total sample size = 50 evaluable patients. For analysis of the primary endpoint, i.e. PFS rate at 3 months will be compared between the two arms using Z test. This will be performed three months after the last patient is randomized. 13.2 Sample Size/Accrual Rate The anticipated accrual rate is 3 patients per month. 13.3 Stratification Factors Patients will be stratified according to the presence of soft tissue (visceral, nodal) or bones only disease. 13.4 Analysis of Secondary Endpoints safety and tolerability of cediranib with or without dasatinib symptom assessment using the FACT-P questionnaire and PPI scale laboratory-based biomarkers: bone resorption markers (e.g. c-telopeptide and bone alkaline phosphatase) Standard descriptive statistics, such as the mean, median, range and proportion, will be used to summarize the patient sample and to estimate parameters of interest. Ninety-five percent confidence intervals will be provided for estimates of interest where possible. Correlative markers will be investigated for potential associations with clinical outcomes. 71 It is noted that the number of patients are small and this study is powered to detect potential differences in the primary endpoint only. It is possible that statistical testing of secondary endpoints may be statistically significant due to chance, even if no association exists. Likewise, there is insufficient power to detect a significant difference if a true, but small, difference exists. All secondary analyses will be considered exploratory in nature, and are not powered to draw definitive conclusions. For instance, ANCOVA of change from baseline at 4 weeks and at 12 weeks in CTC will be evaluated. Since these analyses are exploratory, no primary hypothesis has been set a priori. No statistical adjustment of p-values will occur and a p-value of 0.05 or less will be considered statistically significant. 13.5 Reporting and Exclusions 13.5.1 Evaluation of toxicity. All patients will be evaluable for toxicity from the time of their first treatment with cediranib with or without dasatinib 13.5.2 Evaluation of response. All patients included in the study must be assessed for response to treatment, even if there are major protocol treatment deviations or if they are ineligible. Each patient will be assigned one of the following categories: 1) complete response, 2) partial response, 3) stable disease, 4) progressive disease, 5) early death from malignant disease, 6) early death from toxicity, 7) early death because of other cause, or 9) unknown (not assessable, insufficient data). [Note: By arbitrary convention, category 9 usually designates the “unknown” status of any type of data in a clinical database.] All of the patients who met the eligibility criteria (with the possible exception of those who received no study medication) should be included in the main analysis of the response rate. 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Trarbach T, Drevs J, Strumberg D, Gauler TC, Schneider V, Eberhardt WE, et al. A phase I, open-label, multicenter study of cediranib and AZD530 in patients with advanced solid tumors. J Clin Oncol. 2008;26:(May 20 suppl; abstract 3592). 47. Boyce BF, Xing L, Yao Z, Yamashita T, Shakespeare WC, Wang Y, et al. SRC inhibitors in metastatic bone disease. Clin Cancer Res. 2006;12(20 Pt 2):6291s-5s. Epub 2006/10/26. 48. Evans CP, Bai L, Kung H, Yang JC. Effect of the specific Src kinase inhibitor AZD0530 on osteobytic lesionis in prostate cancer. Proc ASCO Genitourinary Cancers Symposium. 2008:Abstr 170. 49. Esper P, Mo F, Chodak G, Sinner M, Cella D, Pienta KJ. Measuring quality of life in men with prostate cancer using the functional assessment of cancer therapy-prostate instrument. Urology. 1997;50(6):920-8. Epub 1998/01/14. 50. Melzack R. The McGill Pain Questionnaire: major properties and scoring methods. Pain. 1975;1(3):277-99. Epub 1975/09/01. 77 Sample Consent Study Title : A Phase 2 Randomized Study of Cediranib (AZD2171) Alone Compared with the Combination of Cediranib (AZD2171) plus BMS354825 (dasatinib, Sprycel) in Docetaxel Resistant, Castration Resistant Prostate Cancer NCI Protocol #: 8476 Local Protocol # PJC-002 This is a clinical trial, a type of research study. Your study doctor will explain the clinical trial to you. Clinical trials include only people who choose to take part. Please take your time to make your decision about taking part. You may discuss your decision with your friends and family. You can also discuss it with your health care team. If you have any questions, you can ask your study doctor for more explanation. You are being asked to take part in this study because you have prostate cancer that has progressed despite the continued use of hormone treatment and chemotherapy with docetaxel. Why is this study being done? Cediranib (AZD2171) is an investigational or experimental anti-cancer agent that has not yet been approved by the Health Canada or the US Food and Drug Administration for use in any cancer. Cediranib (AZD2171) inhibits blood vessel growth in cancers (called “angiogenesis”) which may be important in the development and growth of castration resistant prostate cancer. Dasatinib (BMS-354825) is also an investigational or experimental anti-cancer agent that has not yet been approved by Health Canada or the US Food and Drug Administration for use in your cancer but is approved to treat certain types of blood cancers. Dasatinib (BMS-354825) inhibits a protein involved in cancer proliferation and migration termed Src which may be important in the development and growth of castration resistant prostate cancer. Laboratory studies on cancer cells suggest that the combination of both drugs, may work better than either treatment alone. However the anti-cancer effect in humans of the combination is unknown. 78 The purpose of this study is to find out the potential beneficial effects that the administration of cediranib (AZD2171) alone or in combination with dasatinib (BMS-354825) has on you and your prostate cancer. How many people will take part in the study? About 50 people will take part in this study. Half will receive cediranib (AZD2171) alone and the other half will receive cediranib (AZD2171) with dasatinib (BMS-354825). What will happen if I take part in this research study? Before you begin the study … You will need to have the following exams, tests or procedures to find out if you can be in the study. These exams, tests or procedures are part of regular cancer care and may be done even if you do not join the study. If you have had some of them recently, they may not need to be repeated. Usually the amount of blood required is around 10 mL (about twothirds of a tablespoon). This will be up to your study doctor. Review of your medical history, including when you first found out you had cancer, and the kinds of treatments that you may have received for cancer Physical examination including your vital signs (blood pressure, heart rate, breathing rate, temperature), height, weight, and how well you are able to do your day to day activities (performance status) Blood tests to evaluate the electrolytes in your blood and to assess your bone marrow, kidney and liver function Blood test to measure PSA (Prostate Specific Antigen) which is often elevated in prostate cancer An ECG (electrocardiogram which is a tracing of the electrical activity of your heart performed by placing sensors on your skin) Urine tests CT scans (to evaluate if there is spread of the cancer to lungs, liver and other organs) Bone scan (to evaluate if there is spread of the cancer to the bones) If the tests and procedures show that you are not eligible to receive cediranib (AZD2171) and dasatinib (BMS-354825), you will not be able to continue in this research study. During the study … If the exams, tests and procedures show that you can be in the study, and you choose to take part, you will be "randomized" into one of the study groups described below. Randomization means that you are put into a group by chance. A computer program will 79 place you in one of the study groups. Neither you nor your doctor can choose the group you will be in. You will have an equal chance of being placed in either group. If you are in group 1 (also called "Arm A"), you will receive cediranib (AZD2171) at a dose of 20 mg (1 tablet) orally once daily. This drug may be decreased if you have bad side effects from taking it. While in an upright position, you should swallow the tablet with approximately 1 cup (250 mL) of water. The tablet should be taken either 1 hour before or 2 hours after meals at approximately the same time each day. If you are in group 2 (also called "Arm B"), you will receive cediranib (AZD2171) at a dose of 20 mg (1 tablet) orally once daily and dasatinib (BMS-354825) at a dose of 100 mg (2 tablets) orally once daily. Either drug may be decreased if you have bad side effects from them. While in an upright position, you should swallow the tablets with approximately 1 cup (250 mL) of water. Tablets should be taken either 1 hour before or 2 hours after meals at approximately the same time each day. It does not matter which tablets, cediranib (AZD2171) or dasatinib (BMS-354825), are taken first. You will receive study drug(s) continuously without break, and every 4 weeks (= 28 days) is called a cycle. The cycle will be repeated indefinitely until your cancer grows or you have other problems that necessitate stopping the treatment. Each cycle is numbered in order. You will be asked to maintain a medication diary for cediranib and dasatinib, and bring it with you to each visit. Cycle 1 and beyond. You will be seen at least every 4 weeks by your study doctors. At each visit the following will be performed: History and physical exam Vital signs Blood tests to evaluate the electrolytes (minerals which regulate how our body functions) in your blood and to assess your bone marrow, kidney and liver function (about 10 mL or 2/3 tablespoon each time) Blood test to measure PSA (Prostate Specific Antigen) An ECG (electrocardiogram which is a tracing of the electrical activity of your heart performed by placing sensors on your skin) In addition, CT scans and bone scan will be done every 12 weeks to assess your response to treatment. 80 If you have had bad side effects from cediranib (AZD2171) or dasatinib (BMS-354825) at the time you finish taking the medications, your doctor will follow you until those side effects have resolved. Research-related tests The following tests are not part of regular care but are being done because you are taking part in this study: Urine tests to assess if there is any spillage of protein in your urine due to the study drugs (every 4 weeks) Blood test to assess thyroid function (before you start the study and at the end of 4 weeks and at the end of 8 weeks, and as needed) Echocardiogram or MUGA scan to assess how well your heart chambers fill with blood and pump it to the rest of the body (before you start the study, and as needed) Blood test to evaluate bone resorption markers (the effect of the medications on what is happening in your bones) (the test will be done before you start the study and at the end of 4 weeks and at the end of 12 weeks). The amount of blood required is about 1 tablespoon. Tumor samples that were removed previously by biopsy or by surgery so that research studies can be done to better understand the nature of cancer and how patients respond to the study treatment (before you start the study) Questionnaires to evaluate your quality of life and pain status (before you start the study and then every 4 weeks) How long will I be in the study? You will be asked to take cediranib (AZD2171) with or without dasatinib (BMS354825) for as long as your prostate cancer does not progress. You will also be seen four weeks after the treatment has ended. The researcher may decide to take you off this study if: your cancer grows despite the treatment you are not able to tolerate the treatment or its side-effects new information becomes available and the treatment is no longer in your best interest your doctor no longer feels that this is the best treatment for you Can I stop being in the study? Yes. You can decide to stop at any time. Tell the study doctor if you are thinking about stopping or decide to stop. He or she will tell you how to stop safely. 81 It is important to tell the study doctor if you are thinking about stopping so any risks from cediranib (AZD2171) and/or dasatinib (BMS-354825) can be evaluated by your doctor. Another reason to tell your doctor that you are thinking about stopping is to discuss what follow-up care and testing could be most helpful for you. The study doctor may stop you from taking part in this study at any time if he/she believes it is in your best interest; if you do not follow the study rules; or if the study is stopped. What side effects or risks can I expect from being in the study? You may have side effects while on the study. Everyone taking part in the study will be watched carefully for any side effects. However, doctors don’t know all the side effects that may happen. Side effects could range from mild to moderate but could also be severe and life-threatening or even fatal. . Your health care team may give you medicines to help lessen side effects. Many side effects go away soon after you stop taking cediranib (AZD2171) or dasatinib (BMS-354825). In some cases, side effects can be serious, long lasting, or may never go away. You should talk to your study doctor about any side effects that you have while taking part in the study. Since cediranib (AZD2171) and dasatinib (BMS-354825) are both experimental drugs, all the side effects are not known. Long-term effects of these study drugs are also unknown. If you experience any symptoms that require treatment between regular clinic/hospital visits, it is important that you make every effort to return to the clinic/hospital where these drugs were given. If you need immediate treatment and are unable to return to the clinic/hospital where the study drugs were given, it is important that you contact your doctor as soon as possible and seek emergency room care as needed. There are many drugs (prescription and over the counter medications) and dietary supplements (including “complementary” or “alternative” medicines), which may interact with the experimental drugs. Your doctor will review all of the medications and supplements you are currently taking before starting these experimental drugs. You should not take any new medications or dietary supplements without discussing it with your doctor first. You will be given a list of medications you should not take while you are participating in this study. Risks and side effects related to cediranib (AZD2171) include: Common (greater than 20% of patients): Diarrhea Fatigue or tiredness High blood pressure 82 Less Common (less than or equal to 20% of patients): Abnormally high level of thyroid gland hormone Abnormally low level of thyroid gland hormone Belly pain Irritation or sores in the lining of the anus Constipation Dry mouth Difficulty swallowing Irritation or sores in the lining of the mouth Nausea or the urge to vomit Irritation or sores in the lining of the rectum Irritation or sores in the lining of the small bowel Vomiting Increased blood level of a liver enzyme (ALT/SGPT) Increased blood level of a liver enzyme (AST/SGOT) Increased levels of a substance involved in the production of red blood cells Increased levels of a substance (thyroid stimulating hormone) involved in the function of the thyroid gland, which indicates an underactive thyroid Weight loss Loss of appetite Dehydration (when your body does not have as much water and fluid as it should) Decreased blood level of phosphate Dizziness (or sensation of lightheadedness, unsteadiness, giddiness, spinning or rocking) Headache or head pain Convulsion or seizure More protein in the urine than usual, often a sign of kidney disease Cough Shortness of breath Irritation or sores in the lining of the voice box Irritation or sores in the lining of the throat Irritation or sores in the lining of the windpipe Voice change Swelling and redness of the skin on the palms of the hands and soles of the feet Formation of a blood clot that plugs the blood vessel; blood clots may break loose and travel to another place, such as the lung Rare but Serious (less than 3% of patients): Decreased in heart’s ability to pump blood during “active” phase of the heartbeat (systole) Progressive necrosis (tissue death) of a part (the white matter) of the brain without 83 inflammation (swelling and redness) Abnormal changes in the brain that can cause a collection of symptoms including headache, confusion, seizures, and vision loss associated with MRI imaging findings (RPLS) Blood clot in a blood vessel (artery) Frequent blood pressure (BP) monitoring is important when receiving treatment with cediranib (AZD2171). Experience to date suggests that increases in blood pressure may occur following dosing with cediranib (AZD2171) for a number of weeks and that these increases may occur over a relatively short time frame. You will be provided with a blood pressure monitoring device and a diary in which to record blood pressure readings twice per day. If two successive systolic readings are > (more or equal to) 140 mmHg OR two successive diastolic readings are > (more or equal to) 90 mmHg, you should contact your physician as soon as possible. The systolic number is the top number and is higher than the bottom or diastolic number. You should contact your physician if you are concerned about any symptoms that may be associated with high blood pressure (e.g., headache). Due to the rare but serious risk of decrease in the hearts ability to pump, you will be asked to under go extra tests - echocardiogram or MUGA (tests that evaluate how well your heart chambers fill with blood and pump it to the rest of the body) – before you start the study and then as clinically indicated. Risks reported on cediranib (AZD-2171) trials but the relationship to cediranib (AZD-2171) still undetermined: Low levels of iron in the blood, changes in heart rhythm, cardiac arrest, chest pain, heart failure, decreased blood flow to the heart (heart attack), inflammation of the inner ear possibly causing difficulties with balance, ringing in the ears, abdominal swelling, fluid collection in the belly, inflammation in the lining of the bowel, perforated (formation of a hole) colon or small intestine, inflammation of the small intestines of the bowel, heartburn, inflammation to the esophagus (the tube that carries food from the mouth to the stomach), flatulence (gas), gastric perforation (formation of a hole in the stomach), stomach ulcer, abdominal abscess (pus inside the belly), abnormally slow bowel contractions (constipation or lack of bowel movements), mouth pain, bleeding in the rectum, rectal pain, swelling of the legs and arms, fever, non-cardiac chest pain, generalized pain, obstruction (blockage) in the gallbladder or bile duct, liver failure, bleeding in the liver, liver pain, yellowing of skin and eyes (jaundice), anaphylaxis (life-threatening allergic reaction), infection, bruising, fracture, tracheostomy malfunction (malfunction of the tube inserted into the windpipe to help with breathing), increased levels of liver and kidney blood tests, increase in blood tests to measure tissue damage (CPK, LDH), increase in cardiac blood tests that show heart damage, cholesterol high, increased lipase (an increase in the amount of an enzyme that measures pancreas damage), decreased number of white blood cells which can lead to infection, decreased number of a type of blood cell that helps to clot blood (platelet), changes in laboratory values (high and low potassium, high and low blood 84 sugar, high triglycerides, high and low calcium, low sodium), joint pain, bone pain, back pain, chest wall pain, generalized muscle weakness, muscle weakness in legs, muscle pain, leg or arm pain, tumor pain, difficulty thinking or concentrating, decreased level of consciousness or alertness, taste changes, difficulty speaking, abnormal change in brain function, bleeding in the brain or spinal cord, lethargy or sluggishness, memory impairment (forgetfulness), spinal cord compression, weakness or loss of function caused by nerve damage, numbness or tingling, sleepiness, change in blood flow to the brain (ministroke), confusion, insomnia or difficulty sleeping, suicide attempt, kidney damage or failure, blood in the urine, urinary retention (inability or difficulty urinating), irregular menstrual periods, bleeding in the respiratory tract, nosebleed, decreased oxygen supply to a tissue, neck/throat pain, fluid in the chest cavity, inflammation of the lungs, collection of air around the lungs, dry skin, excessive sweating, nail changes or loss, itchiness, bruises or broken blood vessels in the skin, skin rash with the presence of macules (flat discolored area) and papules (raised bump), skin ulcers (sores on the skin), low blood pressure. Depending on the side effect and how severe it is, it may be managed by stopping cediranib (AZD2171) temporarily, by reducing the dose and/or require other treatment, possibly in the hospital. It is possible that a new side effect or risk may be seen that would be serious, long lasting, permanent or even fatal. Risks and side effects related to dasatinib (BMS-354825) include: Some side effects have been seen in patients who already have received dasatinib (BMS-354825) on other ongoing research studies. These side effects, which may or may not have been related to dasatinib (BMS-354825), include: Likely (greater than 20% of patients): Lack of enough red blood cells (anemia) Diarrhea Nausea or the urge to vomit Fatigue or tiredness Decreased number of a type of white blood cell (neutrophil/granulocyte) Decreased number of a type of blood cell that help to clot blood (platelet) Muscle Pain Headache or head pain Shortness of breath Build up of a large amount of fluid between the layers of tissue that line the lungs and chest cavity Skin rash with the presence of macules (flat discolored area) and papules (raised bump) Less Likely (less than or equal to 20% of patients): 85 Fever associated with dangerously low levels of a type of white blood cell (neutrophils) Fluid in the sac around the heart Swelling or feeling of fullness and tightness in the abdomen (belly) Belly pain Irritation or sores in the lining of the anus Constipation Heartburn Bleeding in some organ(s) of the digestive tract Irritation or sores in the lining of the mouth Irritation or sores in the lining of the rectum Irritation or sores in the lining of the small bowel Vomiting Swelling of the arms and/or legs Fever Swelling of soft tissues in more than one part of the body Swelling of parts of the body that are visible Chest pain not heart-related Pain Infection Increased blood level of a liver enzyme (ALT/SGPT) Increased blood level of a liver enzyme (AST/SGOT) Weight gain Weight loss Decrease in the total number of white blood cells (leukocytes) Loss of appetite Decreased blood level of calcium Decreased blood level of potassium Decreased blood level of phosphate Joint pain Dizziness (or sensation of lightheadedness, unsteadiness, giddiness) Cough Irritation or sores in the lining of the voice box Irritation or sores in the lining of the throat Inflammation of the lungs that may cause difficulty breathing and can be lifethreatening Irritation or sores in the lining of the windpipe Hair loss Itching Acne Sudden reddening of the face and/or neck Rare but Serious (less than 3% of patients): 86 Heart failure or inability of the heart to adequately pump blood to supply oxygen to the body Decrease in heart’s ability to pump blood during the “active” phase of the heartbeat (systole) Heart attack caused by a blockage or decreased blood supply to the heart Abnormal electrical conduction within the heart Group of signs and symptoms due to rapid breakdown of tumor that can occur after treatment of cancer has started that causes increased levels of blood potassium, uric acid, and phosphate, decreased levels of blood calcium, and kidney failure Bleeding in the brain Progressive necrosis (tissue death) of a part (the white matter) of the brain without inflammation (swelling and redness) Abnormal changes in the brain that can cause a collection of symptoms including headache, confusion, seizures, and vision loss associated with MRI findings (RPLS) High blood pressure of the blood vessels in the lungs Risks reported on dasatinib (BMS-354825) trials but the relationship to dasatinib (BMS-354825) still undetermined: Inflammation of blood vessels, decrease in the number of a type of white blood cells (CD4 and lymphocytes), increased lymphocytes which can be a sign of infection, condition resulting from decreased oxygen in the heart, irregular heart beat (atrial fibrillation), an enlarged heart (cardiomegaly), fast heart beat, chest pain, inflammation of the heart muscle (myocarditis) or fluid surrounding the heart (pericarditis), heart palpitations, abnormally fast heart rate, changes in heart rhythms on EKGs, decrease in the number of blood cells (red blood cells, white blood cells and platelets), high blood pressure, low blood pressure, increase in cardiac blood tests that show heart damage (cardiac troponin T), lifethreatening damage to the lungs which can lead to fluid in the lungs (ARDS), irritation of the small airways (bronchospasm) or wheezing, nosebleeds, build up of fluid in the lung, sore throat, insomnia or difficulty sleeping, sweating, bruising, dry skin, nail loss, irritation or destruction of skin or other body tissues, blisters on the skin, skin pain, blisters and swelling on the hands and feet, swelling or puffiness around the eyes, sensitive to light, bruises or broken blood vessels in the skin, skin disease characterized by fever, increased white blood cell count and tender, skin with papules (raised bump), hair color changes, inflammation of the fatty layer under the skin, hives/ welts, ear pain, inflammation of the middle ear, ringing in the ears, dizziness or a spinning sensation, fluid collection in the abdomen, inflammation of the colon, infection of the colon, dehydration, dry mouth, difficulty swallowing, inflammation of the stomach, esophagus and small bowel, flatulence (gas), a tear in the tissue lining the rectum, vomiting of blood, ulcers in the mouth, mouth disorders, mouth or throat pain, breakout or bumps on the tongue, stomach ulcers, blockage in the intestines, pain in the mouth and stomach, inflammation of the pancreas, gum disease, taste changes, chills, swelling of the head/ neck area, swelling of the trunk of the body or genitals, localized swelling, flu like symptoms, difficulty walking, inability to be comfortable with temperature changes, general feeling of discomfort or tiredness, inflammation of the gall bladder, obstruction (blockage) in the bile duct, anaphylaxis (life 87 threatening allergic reaction), increased levels of liver and kidney blood tests, increase in blood tests to measure tissue damage (CPK), changes in laboratory values (high potassium, high uric acid, low magnesium, low albumin, low sodium), protein in the urine, muscle weakness, muscle inflammation, neck stiffness, anxiety, abnormal function of the nerve responsible for hearing and balance, depression, confusion, convulsion or seizure, sleepiness or decreased level of consciousness/ alertness, decreased sexual desire, suicidal thoughts, disturbed or lost memory (amnesia), disturbances in thinking patterns, difficulty thinking or concentrating, voice changes or hoarseness, decrease in blood flow to the brain, lethargy or sluggishness, weakness or loss of function caused by nerve damage, condition of the nervous system that causes numbness, tingling or burning, fainting, tremor, ministroke or stroke-like symptoms (TIA), infection of the lining of the inner surface of the eyelid and the eyeball (conjunctivitis), dry eyes, blurred vision, inflammation of the optic nerve that may cause a complete or partial loss of vision (optic nerve neuritis), back pain, bone pain, chest wall pain, arthritis, delayed growth of the leg bone during puberty, muscle spasm, muscle stiffness, breakdown of muscle tissue resulting in muscle damage, arm/ leg pain, inflammation of the tendons, decreased bone density that may lead to fracture (osteoporosis), build-up of blood vessels in the skin or organs (hemangioma), decrease in the oxygen supply to a tissue, kidney failure, increased need to urinate, increase of dilated blood vessels, inflammation of a vein due to a blood clot that may occur under the skin that may result in redness and swelling, blood clots (in a tissue, organ, artery or vein), disorder characterized by dark crusty patches on the skin (keratosis follicular), infection caused by herpes virus causing blisters in the skin, mouth, lips or genitals, abnormal bone density scans, abnormal body temperatures, enlarged breasts in males, irregular menstrual periods, blood clot in tissue, and hot flashes. You should avoid grapefruit juice, starfruit, and St. John’s wort while you are taking dasatinib (BMS-354825). You will be provided a list of medications that should be avoided while you are on the study. Tests and Procedure risks: Risks of Blood Tests: For most people, needle punctures for blood draws do not cause any serious problems. However, they may cause bleeding, bruising, discomfort, infections or pain at the needle site, or dizziness. ECG/EKG: When you have your heart monitored, you may have itching or get bruising of the skin where the machine patches are placed. CT Scan Risks: During a CT scan, a dye is injected into the veins. This creates sharper images. There is a small amount of discomfort due to the needle used to inject the dye. Small risks associated with the dye include: an allergic reaction around the time the contrast dye is given into the veins and decreased kidney function, which will be monitored using regular blood tests. The amount of radiation from a CT scan is equivalent to approximately 400 chest x-rays or 3.6 years of 88 background radiation; this does not cause any symptoms. The images produced from the CT scan outweigh the risks, which are minimal, from the radiation dose. Bone Scan risks: During a bone scan a radioactive tracer substance is injected into the vein. Later on a special camera (gamma) takes pictures of the tracer in the bones. Small risks associated with this procedure include discomfort due to the needle used to inject the tracer or in very rare occasions an allergic reaction. MUGA scan: a special radioactive dye is injected into your blood vessel to study the pumping action of your heart. Small risks associated with this procedure include discomfort due to the needle used to inject the tracer or in very rare occasions an allergic reaction. ECHO: does not involve any injections. A technologist will look at your heart (left side of your chest) with a special scanner. No significant risks are associated with this procedure. Reproductive risks: You should not father a baby while on this study because the drug in this study can affect an unborn baby. It is important that you and your partner use an adequate birth control method while on this study and for 8 weeks after you stop taking the study medications (i.e. birth control pills, condoms, approved contraceptive implant, intrauterine device). Check with your study doctor about what kind of birth control methods to use and how long to use them. Some methods might not be approved for use in this study. You must notify your study doctor immediately if your partner becomes pregnant. If you have any questions about the risks and side effects, please ask your study doctor. Are there benefits to taking part in the study? Taking part in this study may or may not make your health better. While doctors hope cediranib (AZD2171) alone or the combination with dasatinib (BMS-354825) will be more useful against cancer compared to the usual treatment, there is no proof of this yet. We do know that the information from this study will help doctors learn more about cediranib (AZD2171) or dasatinib (BMS-354825) as a treatment for cancer. This information could help future cancer patients. What other choices do I have if I do not take part in this study? Your other choices may include: Getting treatment or care for your cancer without being in a study. Taking part in another study Getting no treatment 89 Getting comfort care, also called palliative care. This type of care helps reduce pain, tiredness, appetite problems and other problems caused by the cancer. It does not treat the cancer directly, but instead tries to improve how you feel. Comfort care tries to keep you as active and comfortable as possible. Talk to your doctor about your choices before you decide if you will take part in this study. What About Confidentiality? We will do our best to make sure that the personal information in your medical record will be kept private. However, we cannot guarantee total privacy. Your personal information may be given out if required by law. If information from this study is published or presented at scientific meetings, your name and other personal information will not be used. Organizations that may look at and/or copy your medical records for research, quality assurance, and data analysis include: Princess Margaret Hospital Phase I Consortium Health Canada (because it oversees the use of new drugs in Canada) U.S. Food and Drug Administration (because it oversees the use of new drugs in the U.S.) The research ethics board for your hospital (because it oversees the conduct of this study at this hospital) The National Cancer Institute (US) because it is sponsoring the study and supplying the study drug Pharmaceutical Collaborators, because they are the manufacturers of cediranib (AZD2171) and dasatinib (BMS-354825) This information may include test results, reports of operations, and x-rays or other body scan reports. The organizations listed above will keep information about you confidential in the following manner: your name will not be given to anyone except the researchers doing the study your name will not be used in any reports about the study you will be identified only by a study code and initials, identifying information will be kept behind locked doors What are the costs of taking part in this study? The NCI, will supply cediranib (AZD2171) and/ or dasatinib (BMS-354825) to you at no charge while you take part in this study. The NCI does not cover the cost of getting cediranib (AZD2171) and/ or dasatinib (BMS-354825) ready and giving it to you, so you or your insurance company may have to pay for these. After December 31, 2012, the study drug Cediranib will no longer be made or supplied by AstraZeneca. Although the drug is being discontinued, there are no safety or activity 90 concerns for the drug. The study doctors feel that the study you are participating in is still appropriate and scientifically relevant. On December 31, 2012, all study patients will stop taking the study drug Cediranib. If you are randomized to the combination Cediranib and Dasatinib arm (ARM B) and receiving benefit from the study medications, your study doctor will talk to you prior to this date about your options. It may be possible to continue taking Dasatinib alone on study for as long as it is felt to be helping you. If you are randomized to Cediranib alone (ARM A), you will stop taking the study drug Cediranib on December 31, 2012. Your study doctor will talk to you before this date about treatment options which may be available to you. If you become ill or are physically injured as a result of participation in this study, medical treatment will be provided by your doctor or you will be referred for appropriate medical care. In no way does signing this consent form waive your legal rights nor does it relieve the investigators, sponsors or involved institutions from their legal and professional responsibilities. You will receive no payment for taking part in this study. Taking part in this study may result in added costs to you (for example: parking, medications for side effects). What happens if I am injured because I took part in this study? It is important that you tell your study doctor, __________________ [investigator’s name(s)], if you feel that you have been injured because of taking part in this study. You can tell the doctor in person or call him/her at __________________ [telephone number]. What are my rights if I take part in this study? Taking part in this study is your choice. You may choose either to take part or not to take part in the study. If you decide to take part in this study, you may leave the study at any time. No matter what decision you make, there will be no penalty to you and you will not lose any of your regular benefits. Leaving the study will not affect your medical care. You can still get your medical care from our institution. You will be told about new information or changes in the study that may affect your health or your willingness to continue in the study. In the case of injury resulting from this study, you do not lose any of your legal rights to seek payment by signing this form. 91 Who can answer my questions about the study? You can talk to your study doctor about any questions or concerns you have about this study. Contact your study doctor __________________ [name(s)] at __________________ [telephone number]. For questions about your rights or if you feel you have been injured as a result of taking part in this study, call the ________________________ [name of center] Institutional Review Board (a group of people who review the research to protect your rights) at __________________ (telephone number). [Note to Local Investigator: Contact information for patient representatives or other individuals in a local institution who are not on the IRB or research team but take calls regarding clinical trial questions can be listed here.] *You may also call the Operations Office of the NCI Central Institutional Review Board (CIRB) at 888-657-3711 (from the continental US only). [*Only applies to sites using the CIRB.] Where can I get more information? You may call the National Cancer Institute's Cancer Information Service at: 1-800-4-CANCER (1-800-422-6237) or TTY: 1-800-332-8615 You may also visit the NCI Web site at http://cancer.gov/ For NCI’s clinical trials information, go to: http://cancer.gov/clinicaltrials/ For NCI’s general information about cancer, go to http://cancer.gov/cancerinfo/ You will get a signed copy of this form. If you want more information about this study, ask your study doctor. SIGNATURES My signature on this consent form means the following: The study has been fully explained to me and all of my questions have been answered. I understand the requirements and the risks of the study I allow access to my medical records as explained in this consent form and I agree to take part in this study. __________________________ Printed Name of Patient ________________________ _________________ Signature of Patient 92 Date __________________________ Printed Name of Person Obtaining Consent ________________________ _________________ Signature of Person Obtaining Consent __________________________ Printed Name of Doctor ________________________ _________________ Signature of Doctor Date Date If this consent process has been done in a language other than that on this written from, with the assistance of a translator, please indicate: (language)_______________________ __________________________ Printed Name of Translator ________________________ _________________ Signature of Translator 93 Date APPENDIX A Drugs Known to be Metabolized by Selected CYP450 Isoenzymes 94 Agents and Substances Prohibited During Dasatinib and Cediranib Administration Prohibited agents cannot be used during treatment or for 2 weeks after termination of drug administration. CYP3A4 SUBSTRATES Generic Name Trade Name Anti-neoplastics: e.g. Docetaxel Taxotere Gefitinib Iressa Irinotecan Camptosar Anti-virals: e.g. Amprenivir Agenerase Rifampin Rifadin Anxiolytics: e.g. Diazepam Sertraline Valium Zoloft Cyclosporine Anti-infectives: e.g. Erythromycin Tetracycline Steroids: e.g. Estrogens, conjugated Estradiol Progesterone Haloperidol Cardiovascular agents: e.g. Digitoxin Quinidine Anti-hypertensives: e.g. Nicardipine Verapamil Anesthetics: e.g. Ketamine Lidocaine Nefazodone Sandimmune Erythrocin Sumycin Premarin Climara Crinone Haldol Cyclosporine Antibiotics: e.g. Ciprofloxacin Clarithromycin Doxycycline Enoxacin Isoniazid Telithromycin Imatinib Sandimmune Haloperidol Diclofenac Haldol Cataflam, Voltaren INDUCERS Generic Name Trade Name Aminoglutethimide Cytadren Antibiotics: e.g. Rifabutin Rifampin Rifadin Mycobutin Anticonvulsants: e.g. Carbamazapine Phenytoin Pentobarbital Phenobarbital Hypericum perforatum (2) Tegretol Dilantin Nembutal Luminal St. John’s Wort Cipro, Ciloxan Biaxin Adoxa, Periostat Penetrex Nydrazid, INH Ketek Gleevec Crystodigin Cardioquin Cardene Calan, Chronovera Xylocaine Diprivan Serzone Cocaine Ketoconazole Sildenafil Albuterol Carbamazapine Lovastatin INHIBITORS Generic Name Trade Name Anti-arrhythmics: e.g. Amiodarone Cordarone, Pacerone Diltiazem Cardizem, Dilacor XR Quinidine Cardioquin Anti-virals: e.g. Amprenavir Agenerase Indinavir Crixivan Nelfinavir Viracept Ritonavir Norvir Cimetadine Tagamet Nizoral Viagra Ventolin Tegretol Mevacor Vasodilators: e.g. Nicardipine Verapamil Anesthetics: e.g. Lidocaine Propofol Anti-depressants: e.g. Nefazodone Sertraline Anti-fungals: e.g. Fluconazole Itraconazole Ketoconazole Miconazole Cardene Calan, Chronovera Xylocaine Diprivan Serzone Zoloft Sporanox Nizoral Lotrimin, Monistat Grapefruit juice (1) When drugs classified as ‘substrates’ are co-administered with Dasatinib and Cediranib, there is the potential for higher concentrations of the ‘substrate’. When Dasatinib and Cediranib is co-administered with compounds classified as ‘inhibitors’, increased plasma concentration of Dasatinib and Cediranib is the potential outcome. The coadministration of ‘inducers’ would potentially lower plasma Dasatinib and Cediranib concentrations. 96 Comprehensive List of Drugs That Can Potentially Interact with Dasatinib and Cediranib Use with Caution During Dasatinib and Cediranib Administration CYP3A4 Substrates Alfentanil Alprazolam Amlodipine Aprepitant Aripiprazole Atazanavir Atorvastatin Benzphetamine Bisoprolol Bortezomib Bosentan Bromazepam Bromocriptine Buprenorphine Buspirone Busulfan Cerivastatin Chlordiazepoxide Chloroquine Chlorpheniramine Cisapride Citalopram Clobazam Clonazepam Clorazepate Colchicine Cyclophosphamide Cyclosporine Dantrolene Dapsone Delavirdine Dihydroergotamine Disopyramide Doxepin Doxorubicin Efavirenz Eletriptan Enalapril Eplerenone Ergoloid mesylates Ergonovine Ergotamine Escitalopram Estrone Estropipate Ethinyl estradiol Ethosuximide Etoposide Felbamate Felodipine Fentanyl Flurazepam Flutamide Fosamprenavir Fulvestrant Halofantrine Ifosfamide Isosorbide dinitrate Isosorbide mononitrate Isradipine Itraconazole Lansoprazole Letrozole Levomethadyl acetate hydrochloride Levonorgestrel Losartan Medroxyprogesterone Mefloquine Mestranol Methadone Methylergonovine Methysergide Miconazole Midazolam Miglustat Mirtazapine Modafinil Montelukast Moricizine Nateglinide Nevirapine Nifedipine Nimodipine Nisoldipine Nitrendipine Norethindrone Norgestrel Ondansetron Paclitaxel Pergolide Phencyclidine Pimozide Pioglitazone Primaquine Quetiapine Rabeprazole Repaglinide Rifabutin Saquinavir Sibutramine Simvastatin Sirolimus Sufentanil Tacrolimus Tamoxifen Tamsulosin Teniposide Terbinafine Theophylline Tiagabine Ticlopidine Tolterodine Toremifene Trazodone Triazolam Trimethoprim Trimipramine Troleandomycin Vardenafil Venlafaxine Vinblastine Vincristine Vinorelbine Zolpidem Zonisamide Zopiclone 97 Comprehensive List of Drugs That Can Potentially Interact with Dasatinib and Cediranib, continued Use with Caution During Dasatinib and Cediranib Administration CYP3A4 Inhibitors Acetominophen Acetazolamide Amlodipine Anastrozole Aprepitant Atazanavir Atorvastatin Azelastine Azithromycin Betamethasone Bortezomib Bromocriptine Cerivastatin Chloramphenicol Chlorzoxazone Cisapride Clemastine Clofazimine Clotrimazole Clozapine Cocaine Cyclophosphamide Danazol Delavirdine Desipramine Dexmedetomidine Diazepam Dihydroergotamine Lovastatin Mefloquine Mestranol Methadone Methimazole Methoxsalen Methylprednisolone Metronidazole Midazolam Mifepristone Mirtazapine Mitoxantrone Modafinil Nevirapine Nifedipine Nisoldipine Nitrendipine Nizatidine Norfloxacin Olanzapine Omeprazole Orphenadrine Oxybutynin Paroxetine Pentamidine Pergolide Phencyclidine Pilocarpine Pimozide Pravastatin Prednisolone Primaquine Disulfiram Docetaxel Doxorubicin Doxycycline Drospirenone Efavirenz Entacapone Ergotamine Erythromycin Ethinyl estradiol Etoposide Felodipine Fentanyl Fluconazole Fluoxetine Fluvastatin Fluvoxamine Fosamprenavir Glyburide Hydralazine Ifosfamide Irbesartan Isradapine Lansoprazole Lomustine Losartan Progesterone Propoxyphene Quinine Quinupristin Rabeprazole Risperidone Saquinavir Selegiline Sildenafil Sirolimus Sulconazole Tacrolimus Tamoxifen Teniposide Testosterone Tetracycline Ticlopidine Tranylcypromine Trazodone Troleandomycin Valproic acid Venlafaxine Vinblastine Vincristine Vinorelbine Zafirlukast Ziprasidone CYP3A4 Inducers Fosphenytoin Nevirapine Oxcarbazepine Primidone Rifapentine (Adapted from Cytochrome P-450 Enzymes and Drug metabolism. In: Lacy CF, Armstrong LL, Goldman MP, Lance LL eds. Drug Information Handbook 12TH ed. Hudson, OH; LexiComp Inc. 2004: 1619-1631.) (1) Malhorta et al. (2000). Clin Pharmacol Ther. 69:14-23 (2) Mathijssen et al. (2002). J Natl Cancer Inst. 94:1247-1249 Frye et al. (2004). Clin Pharmacol Ther. 76:323-329 98 APPENDIX B: PERFORMANCE STATUS CRITERIA ECOG Performance Status Scale Karnofsky Performance Scale Grade Percen t Descriptions 100 0 1 2 3 4 5 Normal activity. Fully active, able to carry on all pre-disease performance without restriction. 90 Symptoms, but ambulatory. Restricted in physically strenuous activity, but ambulatory and able to carry out work of a light or sedentary nature (e.g., light housework, office work). In bed <50% of the time. Ambulatory and capable of all self-care, but unable to carry out any work activities. Up and about more than 50% of waking hours. In bed >50% of the time. Capable of only limited self-care, confined to bed or chair more than 50% of waking hours. 100% bedridden. Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair. Dead. Description Normal, no complaints, no evidence of disease. Able to carry on normal activity; minor signs or symptoms of disease. 80 Normal activity with effort; some signs or symptoms of disease. 70 Cares for self, unable to carry on normal activity or to do active work. 60 50 40 30 20 10 0 Requires occasional assistance, but is able to care for most of his/her needs. Requires considerable assistance and frequent medical care. Disabled, requires special care and assistance. Severely disabled, hospitalization indicated. Death not imminent. Very sick, hospitalization indicated. Death not imminent. Moribund, fatal processes progressing rapidly. Dead. 99 APPENDIX C: NYHA CARDIOVASCULAR DISABILITY CLASSIFICATION 100 CTEP-assigned Protocol #___________ APPENDIX D: PATIENT’S PILL DIARY Local Protocol # ___________________ (Cediranib (AZD2171) alone) Today’s date _______________________________________ Patient Initials________________________________ Cycle # _________________________ Patient Study ID __________________ INSTRUCTIONS TO THE PATIENT: 1. Complete one form for each month. 2. You will take ___ pills of cediranib (AZD2171). You may take the pill one hour before or 2 hours after eating, as you prefer, with 1 cup of water. 3. The pill must be swallowed whole and should NOT be chewed, crushed or broken. 4. Record the date, the number of pill you took, and when you took it. If you skipped or missed drug dose(s), please record it on the diary. 5. If you have any comments or notice any side effects, please record them in the Comments column. 6. Please bring your pill bottle and this form to your physician when you go for your next appointment. 7 Do not eat grapefruit or drink grapefruit juice, and do not share your supply of cediranib (AZD2171). Date Day AZD2171 # of __mg pills taken Time taken and Comments Date Day 1 17 2 18 3 19 4 20 5 21 6 22 7 23 8 24 9 25 10 26 11 27 12 28 AZD2171 # of __mg pills taken Time taken and Comments 13 14 15 16 101 Patient’s Signature: _______________________________ Date: ____________________________________ Physician’s Office will complete this section: 1. Date patient started protocol treatment________________ Date patient was removed from study _____________________ 2. Patient’s planned daily dose________________________ Total number of pills taken this month ____________________ Physician/Nurse/Data Manager’s Signature ____________________________________________________________________ 102 CTEP-assigned Protocol #___________ APPENDIX D: PATIENT’S PILL DIARY Local Protocol # ___________________ (Cediranib (AZD2171) and Dasatinib (BMS-354825) Today’s date _______________________________________ Patient Initials________________________________ Cycle # _________________________ Patient Study ID __________________ INSTRUCTIONS TO THE PATIENT: 1. Complete one form for each month. 4. You will take ___ pills of cediranib (AZD2171) and ___ pills of dasatinib (BMS-354825) each day. You may take the pill(s) one hour before or 2 hours after eating, as you prefer, with 1 cup of water. 5. The pills must be swallowed whole and should NOT be chewed, crushed or broken. 4. Record the date, the number of pills you took, and when you took them. If you skipped or missed drug dose(s), please record it on the diary. 5. If you have any comments or notice any side effects, please record them in the Comments column. 6. Please bring your pill bottle and this form to your physician when you go for your next appointment. 7 Do not eat grapefruit or drink grapefruit juice, and do not share your supply of cediranib (AZD2171) or dasatinib (BMS354825) Date Day BMS354825 # of __ mg pills taken AZD2171 # of __ mg pills taken Time taken and Comments Date Day 1 17 2 18 3 19 4 20 5 21 6 22 7 23 8 24 9 25 10 26 11 27 12 28 BMS-354825 AZD2171 # of __ mg pills taken # of __ mg pills taken Time taken and Comments 13 14 15 16 103 Patient’s Signature: _____________________________________________ Date: ______________________________________ Physician’s Office will complete this section: 1. Date patient started protocol treatment________________ Date patient was removed from study _____________________ 2. Patient’s planned daily dose________________________ Total number of pills taken this month ____________________ Physician/Nurse/Data Manager’s Signature ____________________________________________________________________ 104 APPENDIX E: PATIENT’S BLOOD PRESSURE DIARY Today’s date ________________________________ Patient Initials________________________________ Patient Study ID ________________ INSTRUCTIONS TO THE PATIENT: 1. Your blood pressure readings have two numbers. The first number is the pressure in your blood vessels during a heart beat (systolic), and the second number is the pressure in the vessels when the heart rests in between beats (diastolic). These numbers are usually written with a slash in between them (for example, normal blood pressure is 120/80). 2. Record the date, then record your blood pressure twice each day using a home blood pressure monitor: each morning while you are resting or reading (not while you are active: dressing, making breakfast, etc.) each evening at bedtime or while you are relaxing during the evening 3. If you take your blood pressure at other times of the day, please record the numbers and time under “Other readings.” 4. If your systolic pressure is greater than 140 or your diastolic blood pressure is greater than 90 twice in a row measured several hours apart, please contact your doctor’s office at _______________________________ for instructions. 5. Please bring this form to every clinic visit or appointment. Date AM reading s PM reading s / Other readings (include time of day) Date AM reading s PM readin gs / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / Other readings (include time of day) 105 / / / / Patient’s Signature: _____________________________________________ Date: _____________________________ Physician’s Office will complete this section: _________________________________ Date of this clinic visit __________________________________________________ Physician/Nurse/Data Manager’s Signature 106 Appendix F: FACT-P Questionnaire (version 4) 107 108 109 Appendix G: Present Pain Intensity (PPI) Questionnaire 110 APPENDIX H: DATA MANAGEMENT GUIDELINES Case Report Form Submission Schedule Data required for the study will be collected in Case Report Forms provided by the PMH Phase 1 Consortium Central Office. The site will be required to complete a paper Eligibility Checklist case report form (CRF) at the time of patient registration. All other data will be collected on electronic case report forms (eCRFs) in the Medidata Rave system. Site staff access to Medidata Rave will be initiated at the time of site activation. The form submission schedule is outlined below. Case Report Form Eligibility Checklist Submission Schedule At the time of registration Baseline Form On Treatment Form Within 3 weeks of on study date Within 3 weeks of the end of each cycle of treatment Within 3 weeks of the patient coming off-study Within 3 weeks of the patient coming to clinic. Within 3 weeks of the patient's death being known to the investigator unless this constitutes a reportable adverse event when it should be reported according to AdEERS guidelines Off Treatment Form Short Follow-up Form Final Report Form Case Report Form Completion The paper Eligibility Checklist CRF must be completed using black ink. Any errors must be crossed out so that the original entry is still visible, the correction clearly indicated and then initialed and dated by the individual making the correction. eCRFs will be completed according to the schedule noted above and all relevant supporting documentation such as scans, progress notes, nursing notes, blood work, pathology reports, etc., will be submitted to the PMHC Phase 1 Consortium Central Office for review. All patient names or other identifying information will be removed prior to being sent to the Central Office and the documents labeled with patient initials, study number and the protocol number. eCRF completion guidelines are available for all sites. Monitoring Central data monitoring will take place throughout the trial at the Central Office. Onsite monitoring will be performed at least once a year at some participating sites 111 during which a subset of PMHC studies will be picked for on-site monitoring. Data in the Medidata Rave eCRFs will be monitored on a regular basis and quality assurance measures will be performed. Electronic data queries as well as paper query letters may be issued to the site prior to the quarterly submission of data to CDUS. Patient Registration Refer to Section 4 of the protocol Regulatory Requirements Please submit all required documents to the PMH Phase 1 Consortium Central Office. Canadian Principal investigators must submit a completed Qualified Investigator Undertaking. All investigators must have a current NCI investigator number on file with the PMH Phase 1 Consortium Central Office. All investigators must have an up-to-date CV on file with the PMH Phase 1 Consortium Central Office. Laboratory certification/accreditation and normal ranges are required Confirmation of all investigators having undergone training in the Protection of Human Research Subjects is required. It is preferred that other staff involved in the trial also undergo such training. Investigators and site staff are required to complete Medidata eCRF training modules depending on delegated tasks OPRR assurance numbers for each institution are required Consent forms must be reviewed by the Central Office before submission to the local ethics regulatory board (REB/IRB) and must include a statement that 1. information will be sent to and 2. medical records will be reviewed by the PMH Phase 1 Consortium Central Office. A Membership list of the local ethics board is required. A copy of the initial approval letter from the ethics board must be submitted to the PMH Phase I Consortium Central Office. A completed Site Participant List/Training Log is required and must be submitted to the PMH Phase I Consortium Central Office. Continuing approval will be obtained at least yearly until follow-up on patients is completed and no further data is being obtained for research purposes. Data Safety A Data Safety and Monitoring Board, an independent group of experts, will be reviewing the data from this research throughout the study to see if there are unexpected or more serious side effects than described in the consent. 112 APPENDIX I CTEP MULTICENTER GUIDELINES If an institution wishes to collaborate with other participating institutions in performing a CTEP sponsored research protocol, then the following guidelines must be followed. Responsibility of the Protocol Chair The Protocol Chair will be the single liaison with the CTEP Protocol and Information Office (PIO). The Protocol Chair is responsible for the coordination, development, submission, and approval of the protocol as well as its subsequent amendments. The protocol must not be rewritten or modified by anyone other than the Protocol Chair. There will be only one version of the protocol, and each participating institution will use that document. The Protocol Chair is responsible for assuring that all participating institutions are using the correct version of the protocol. The Protocol Chair is responsible for the overall conduct of the study at all participating institutions and for monitoring its progress. All reporting requirements to CTEP are the responsibility of the Protocol Chair. The Protocol Chair is responsible for the timely review of Adverse Events (AE) to assure safety of the patients. The Protocol Chair will be responsible for the review of and timely submission of data for study analysis. Responsibilities of the Coordinating Center Each participating institution will have an appropriate assurance on file with the Office for Human Research Protection (OHRP), NIH. The Coordinating Center is responsible for assuring that each participating institution has an OHRP assurance and must maintain copies of IRB approvals from each participating site. Prior to the activation of the protocol at each participating institution, an OHRP form 310 (documentation of IRB approval) must be submitted to the CTEP PIO. The Coordinating Center is responsible for central patient registration. The Coordinating Center is responsible for assuring that IRB approval has been obtained at each participating site prior to the first patient registration from that site. The Coordinating Center is responsible for the preparation of all submitted data for review by the Protocol Chair. The Coordinating Center will maintain documentation of AE reports. There are two options for AE reporting: (1) participating institutions may report directly to CTEP with a copy to the Coordinating Center, or (2) participating institutions report to the Coordinating Center who in turn report to CTEP. The Coordinating Center will submit AE reports to the Protocol Chair for timely review. Audits may be accomplished in one of two ways: (1) source documents and research records for selected patients are brought from participating sites to the 113 Coordinating Center for audit, or (2) selected patient records may be audited onsite at participating sites. If the NCI chooses to have an audit at the Coordinating Center, then the Coordinating Center is responsible for having all source documents, research records, all IRB approval documents, NCI Drug Accountability Record forms, patient registration lists, response assessments scans, x-rays, etc. available for the audit. Inclusion of Multicenter Guidelines in the Protocol The protocol must include the following minimum information: The title page must include the name and address of each participating institution and the name, telephone number and e-mail address of the responsible investigator at each participating institution. The Coordinating Center must be designated on the title page. Central registration of patients is required. The procedures for registration must be stated in the protocol. Data collection forms should be of a common format. Sample forms should be submitted with the protocol. The frequency and timing of data submission forms to the Coordinating Center should be stated. Describe how AEs will be reported from the participating institutions, either directly to CTEP or through the Coordinating Center. Describe how Safety Reports and Action Letters from CTEP will be distributed to participating institutions. Agent Ordering Except in very unusual circumstances, each participating institution will order DCTD-supplied investigational agents directly from CTEP. Investigational agents may be ordered by a participating site only after the initial IRB approval for the site has been forwarded by the Coordinating Center to the CTEP PIO. 114 115
