Survey
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
Society of Integrative Oncology A Phase I/II Clinical Trial Assessing Safety and Efficacy of BZL101 for Metastatic Breast Cancer Alejandra Perez, MD Co-Director, Breast Cancer Center Memorial Cancer Institute SIO Nov 08 1 What is BZL101? • An oral extract of Scutellaria Barbata • Pin Yin name Ban Zhi Lian (BZL) • The aerial parts (leaves & stems) are used for BZL101 • Delivered in a packet with excipients to mask the bitter taste of the herb • Powder is mixed with liquid to make a tea SIO Nov 08 2 BZL101- A Novel Mechanism of Action Cancer Cells Normal Cells • Normal cells depend on citric acid cycle (>85%) and glycolysis (<7%) for energy production • Cancer cells depend on glycolysis (>85%) for energy production • BZL101 inhibits energy production by inhibiting glycolysis • BZL101 causes DNA damage and cancer cell death • BZL101 does NOT cause normal cell death SIO Nov 08 3 BZL101- Basis for the Selectivity Towards Cancer Cells • Tumor cells rely on glycolysis for energy production. This is associated with increased endogenous levels of ROS. Normal cells rely on oxidative phosphorylation for their energy needs. • BZL101 treatment further increases ROS levels in tumor cells leading to hyperactivation of PARP and massive oxidative DNA damage. In normal cells BZL101 treatment results only in mild increase of ROS levels and moderate DNA damage without PARP activation. • Activation of PARP depletes NAD+/NADH (substrate for synthesis of poly ADPribose) and ATP stores. • Glycolysis uses cytosolic NAD+ as a substrate to generate ATP and is inhibited by lack of NAD+. (Oxidative phosphorylation uses mitochondrial NAD+ to generate ATP and is generally not affected by PARP activation). • Depletion of NAD+ and ATP by BZL101-induced PARP activation leads to inhibition of glycolysis, further reduction in ATP levels and cell death. . Cancer Biol Ther. 2008 Jan 7;7(4) [Epub ahead of print] PMID: 18305410 SIO Nov 08 4 BZL101 Phase 1A Results 21 Treated with BZL101 Average # prior therapies 3.9 In modified RECIST evaluation, where all measurable lesions included as evaluable 16 Were on trial for ≥28 days and evaluable by RECIST 6/16 (38%) stable disease for >90 days Expected survival 90-120 days On study, average survival 327.5 days (Kaplan-Meier Survival Analysis) 3/16 5/16 (19%) stable disease for >180 days (31%) some degree of objective tumor regression 1 1mm short of a partial remission based on RECIST Criteria 1 31% reduction in the sum of the longest tumor diameter Breast Cancer Research and Treatment (2006), Rugo H, et al. 2007 Sep;105(1):17-28. Epub 2006 Nov 17. PMID: 17111207 Accepted in 5 days and highlighted as critical trial SIO Nov 08 5 BZL101 Phase 1A vs. BZL101 Phase 1B BZL-101-001 Phase 1A Dose Number of Participants Study Drug SIO Nov 08 Single Dose 12 gm – 350 ml BZL-102-002 Phase 1B Multiple Ascending Doses 10 gm – 100 ml; 20 gm – 100 ml 30 gm – 150 ml; 40 gm – 200 ml (note: 20, 30, and 40 grams were taken twice/day) 21 27 • High volume of insoluble plant fiber • Taste – bitter • Liquid form • Reduced volume of insoluble plant fiber • Taste – bitter taste has been modified and masked • Freeze-dried to be mixed with liquid 6 BZL101 Phase 1B Design Primary: To determine the maximum tolerated dose of BZL101 To provide preliminary data on safety and efficacy of BZL101 Secondary: Tumor response as defined by Response Evaluation Criteria In Solid Tumors (RECIST) Overall and progression-free survival Duration of response Change in participant-reported QOL (EORTC QLQ-C30) Main eligibility criteria: Histologically confirmed breast cancer Measurable stage IV disease No more than 3 prior chemotherapies for metastatic disease SIO Nov 08 7 BZL101 Phase 1B Summary Phase 1B 10g 20g 30g 40g • 10g/qd • 10g/bid • 15g/bid • 20g/bid • 11 Enrolled • 6 Enrolled • 3 Enrolled • 7 Enrolled • 1 DLT • 1 DLT • 0 DLT • 1 DLT • Average days on study: 55 • Average days on study: 113 • Average days on study: 66 • Average days on study: 27 Why 20 grams? Decision 20g Phase 2 • Easier to tolerate • 40g/30g many GI side effects and difficulty taking BZL101 • Average days on study longest SIO Nov 08 8 Phase 1B Baseline Characteristics Age (years) N=27 Mean (SD) 58.4 (13.9) Median (Range) 59 (32-78) Mean (SD) 5.6 (3.7) Median (Range) 5 (1-19) Prior Chemo Regimens* Race/Ethnicity White/Caucasian Prior Anticancer Therapies* N=27 (SD) 16 (59%) Black/African American 6 (22%) Hispanic 5 (19%) Baseline ECOG PS Mean (SD) 2.8 (2.4) Median (Range) 2 (0-10) Hormone Receptor Status N=27 (%) Positive (either ER or PR +) 14 (63) Negative (both ER and PR -) 10 (37) 0 16 (60%) HER2/neu Status 1 9 (33%) Positive 17 (63) 2 2 (7%) Negative 10 (37) *For metastatic disease SIO Nov 08 9 Phase 1B Summary of Study Participants Study Participants N=27 (%) Included in safety analysis 27 (100) Evaluable by RECIST criteria 17 (63) Number of participants with DLTs 3 (11) Number of active participants 1 (4) Total number discontinued Disease progression SIO Nov 08 26 (96) 18 (67) Patient choice 3 (11) Adverse event 2 (7) Serious adverse event 2 (7) Non-compliance with study procedures 1 (4) 10 Phase 1B Adverse Events Related and Experienced by ≥10% Adverse Event By CTCAE 10 g/d N (n=11) 20 g/d N (n=6) 30 g/d N (n=3) 40 g/d N (n=7) Total N (%) (n=27) 0 3 0 3 6 (22) Abdominal distension 1 2 0 0 3 (11) Anorexia 2 0 0 1 3 (11) Diarrhea 4 2 2 5 13 (48) Flatulence 1 1 0 1 3 (11) Nausea 2 2 2 5 11 (41) Vomiting 0 1 2 4 7 (26) ALT elevation 2 1 1 0 4 (15) AST elevation 2 1 0 0 3 (11) Pain-abdomen 1 1 0 1 3 (11) Headache 3 1 0 0 4 (15) Constitutional Fatigue Gastrointestinal Metabolic/Laboratory Pain SIO Nov 08 11 Phase 1B Dose Limiting Toxicities Definitions • Grade 3, 4, or 5 toxicity based on the NCI CTCAE V 3.0 that is possibly, probably, or definitely related to study medication. • Grade 2 gastrointestinal toxicity lasting for >3 weeks that is possibly, probably, or definitely related to study medication. • Baseline laboratory or medical conditions that worsen to grade 3 or above that is possibly, probably or definitely related to study medication. SIO Nov 08 12 Phase 1B Dose Limiting Toxicities ID # # Days on Study 03004 20 10g/day Grade 4 increase in AST with baseline grade 2 AST. 19 Grade 3 diarrhea and fatigue. Note that this participant had a history of chronic diarrhea and was taking cholestryramine at baseline to treat this 20g/day condition. 13 Grade 3 rib pain secondary to vomiting. This participant had bone metastasis in her rib and 40g/day baseline grade 1 rib pain. 05003 05011 SIO Nov 08 Dose Description 13 Phase 1B Summary of Adverse Events • Oral administration of BZL101 is well tolerated. The most common treatment emergent, related adverse events are: diarrhea (48%), nausea (41%), vomiting (26%) and fatigue (22%). • There were 12 serious adverse events on the study, only 1 deemed related to study medication: hospitalization for grade 3 rib pain secondary to vomiting at the 40 g/day dose. • There were 3 participants with dose limiting toxicities. SIO Nov 08 14 Phase 1B Compliance with Study Medication 10g/day N=10* 20g/day N=6 30g/day N=3 40g/day N=7 Total N=26 Mean 92% 89% 92% 85% 90% Range 73-100% 61-100% 85-100% 79-100% 61-100% Compliance *Note: compliance is unknown for 1 participant in 10g/day cohort SIO Nov 08 15 Phase 1B Preliminary Efficacy RECIST Criteria Complete Response (CR): Disappearance of all target lesions Partial Response (PR): At least 30% decrease in the sum LD of target lesions from the sum at baseline Progressive Disease (PD): 20% increase in the sum LD of target lesions or appearance of one or more new lesions Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum LD since the treatment started Evaluable participants according to RECIST: 17 of 27 6/17 (35%) stable >90 days 3/17 (18%) stable >180 days SIO Nov 08 16 Phase 1B Preliminary Efficacy ID# Dose Receptor Status ER+ 05005 PR10g/d Her2/neuER+ 05006 PR+ 20g/d Her2/neu ND ER+ 03006 PR20g/d Her2/neu- SIO Nov 08 # Days on # Days BZL Stable 54 329 130 Comments 376 Axillary tumor decreased from 25.0mm at baseline to 15.0mm at Month 1 on physical exam; breast tumor also decreased in size at Month 1 on exam. Pending independent radiology review to determine disease status. 329 Active on study. At Months 6 and 8 there was a 14% and 16% decrease in total longest diameter, respectively. 104 Despite progression noted in lung lesion at Month 4, bone scans demonstrated stable disease and patient reported complete resolution of bone pain and improved quality of life. 17 Phase 1B Preliminary Efficacy ID# Dose 03002 10g/d Receptor Status ERPRHer2/neu- # Days # Days on Stable BZL 207 Baseline Bone Scan SIO Nov 08 564 Comments Bone only disease (not evaluable by RECIST). At Month 2, the radiologist reported “Mild improvement in the patient’s bone scans with less intrusive activity noted in the left anteromedial rib and left acetabular region.” Month 2 Bone Scan 18 Phase 2 Outcome Measures • Primary Outcomes – Obtain preliminary estimate of efficacy based on tumor response rate using RECIST criteria – Adverse events assessed at each clinic visit by self-report, physical exam and lab results • Secondary Outcomes – Tumor response: clinical benefit rate, complete response, partial response, progression of disease – Duration of response and survival time: duration of overall response, complete response and partial response, overall survival, and progression-free survival – Change in participant-reported quality of life (EORTC QLQ-C30) SIO Nov 08 19 Phase 2 Enrollment N = 80 N = 40 N = 40 Hormone Receptor Positive Hormone Receptor Negative • ER+ / PR+ • ER- / PR- • ER- / PR+ • ER+ / PR- •Enrollment open December 2008 •Estimated 1 year to enroll 80 pts •17 sites across the US SIO Nov 08 20 Phase 2 Key Inclusion/Exclusion Criteria • Women 18 years or older with histologically confirmed diagnosis of breast cancer and clinical evidence of metastatic involvement • At least one measurable disease site defined by RECIST criteria • No more than 2 prior cytotoxic regimens administered for metastatic breast cancer • Life expectancy of ≥12 weeks • Eastern Cooperative Oncology Group (ECOG) performance status ≤2 • Participants are excluded from the study for clinically significant gastrointestinal abnormalities, extensive liver involvement (>50% of liver parenchyma), lymphangitic pulmonary involvement, central nervous system involvement or spinal cord compression not stabilized by therapy for >3 months and organ or marrow dysfunction SIO Nov 08 21 Summary • The Maximum Feasible Dose (MFD) reached in the Phase 1B trial was 40g/day. Phase 2 will move forward with 20g/day enrolling 80 participants (40 HR+ and 40 HR-). • BZL101 treatment leads to the inhibition of glycolysis as evident from the decrease in the enzymatic activities within the glycolytic pathway. • BZL101 invokes selective cancer cell death. • Oral administration of BZL101 is well tolerated. The most common adverse events are: diarrhea (48%), nausea (41%), vomiting (26%) and fatigue (22%). • There were 3 participants with dose limiting toxicities. SIO Nov 08 22 Summary • One SAE was attributed to BZL101; hospitalization for the grade 3 rib pain secondary to vomiting at 40g/day. • On average, compliance with study medication was 90% of prescribed doses taken. • In this heavily pre-treated population, 6/17 (35%) were stable for >90 days and 3/17 (18%) were stable for >180 days. • There has been radiographic evidence of tumor regression. • Of the 27 women enrolled, 18 discontinued due to progression, 3 due to participant choice, 2 due to an AE, 2 due to an SAE, and 1 due to noncompliance with study procedures. SIO Nov 08 23