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Welcome to the Cancer Drug Development Roundtable at Ohio State May 4, 2011 Public Session Michael Caligiuri, MD (Co-host and Panelist) OSUCCCJames Director, OSUCCC; CEO, The James Ellen Sigal, PhD (Co-host) Friends of Cancer Research Chair and Founder James Doroshow, MD (Panelist) NCI Director, Division of Cancer Treatment and Diagnosis Eric Rubin, MD (Panelist) Merck VP, Oncology Clinical Research Janet Woodcock, MD (Panelist) FDA Director, Center for Drug Evaluation & Research Robert Brueggemeier, PhD (Q&A Moderator) Ohio State Dean, College of Pharmacy The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute 2 Additional Roundtable Participants Brian Cummings Ohio State VP, Technology Commercialization Anthony Dennis PhD BioOhio President and CEO Richard Gaynor MD Eli Lilly and Company VP, Clinical Development & Medical Affairs, Oncology Business Unit Courtney Granville PhD, MSPH Battelle Toxicologist/Study Director OSUCCCJames Chair & Professor, Dept of Internal Medicine; Associate Dean of Medical Services; Co-Leader, Experimental Therapeutics Program Michael Grever MD The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute 3 Additional Roundtable Participants Joanne Lager MD SanofiAventis Senior Director and Oncology Drug Project Head Michael Mitchell JD Ohio State Assistant VP and Associate General Counsel Christine Poon MBA Ohio State Dean, Fisher College of Business David Roth MD Pfizer VP, Early Development, Oncology Business Unit David Schmickel JD, PhD FoxKiser Legal Counsel Allen Singer DVM Battelle VP, Center for Life Sciences Research The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute 4 Additional Roundtable Participants Ira Steinberg MD SanofiAventis Associate VP & Global Medical Affairs Leader Miguel Villalona MD OSUCCCJames Director, Division of Medical Oncology & Professor, Dept of Internal Medicine Tim Wright Signal Hill Advisors Biotech and Pharmaceutical Consultant The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute 5 Ellen Sigal, PhD Chair and Founder, Friends of Cancer Research Janet Woodcock, MD Director Center for Drug Evaluation and Research U.S. Food and Drug Administration James Doroshow, MD Director Division of Cancer Treatment and Diagnosis National Cancer Institute Developing Experimental Drug Combinations: Opportunities and Challenges James H. Doroshow, M.D. Director Division of Cancer Treatment and Diagnosis, NCI OSU Comprehensive Cancer Center Columbus, OH May 4, 2011 Challenges to Development of Combination Targeted Therapeutics • Incomplete understanding of mechanisms of action for a growing number of targeted agents available for trial Inability to assess target effect • Lack of preclinical models for combinations • Clinical trials methodology • Intellectual property & regulatory challenges to novel combinations • – – – – Lack of assays, imaging tools Lack of assay standardization Lack of commercially-available agents formulated for in vitro use Lack of available investigational agents for in vitro use – To evaluate efficacy, schedule effects, biomarker utility, toxicity – – – – Need to screen large numbers of patients? Need for tumor biopsies? Is histologic homogeneity relevant? Pharmacokinetic interactions? SD vs RR? Lack of Molecular Markers with Proven Clinical Utility Drug Biomarker Anti-estrogens ER, PR, genomic signature Trastuzumab Her2 FISH, IHC EGFR small molecule inhibitors Mutation status B-Raf, ALK inhibitors Mutation status Anti-VEGF/VEGFR agents ?? IGF-I receptor antagonists ?? Src inhibitors ?? Cdk/Cyclin D1 inhibitors ?? HDAC/DNMT inhibitors ?? Anti CTLA-4 Antibody ?? Pharmacodynamic Assay Development Concept Target Application γ-H2AX Protein (tumor) γ-H2AX Protein (tumor) Top 1 Protein DNA Damaging Agents DNA Damaging Agents TOPO Inhibitors MET TK domain and Grb2 Docking Site MET TK domain and Grb2 Docking Site PARG mRNA PARP 1 mRNA PARP 1,2 Activity (PAR levels) PARP 2 mRNA Stem Cell Proteins -ALDH 1A1 -OCT 3/4 -NANOG -CD44v6 KEY: Feasibility & Development Analytical Preclinical Specimen Validation Modeling SOPs Assay Transfer Launch Support Transfer to Clinical NCI Clinical Scientific Validation Trials Community Biopsy Assays ELISA P P l qIFA P P P P P ELISA P P P l P P P l l l l Custom Reagents P P P l RT-qPCR P P P P P P P R RT-qPCR P P P P P P P R IA P P P P P P P l RT-qPCR P P P P P P P R IFA P l H l l l l IFA Commerci Kinase Inhibitors al Reagents Kinase Inhibitors PARP Inhibitors PARP Inhibitors PARP Inhibitors PARP Inhibitors Tumor Stem Cell Inhibitors l l l Platform Feasibility Development Validation IFA In Progress P Delayed CA Commercially Available Technical Difficulty X Completed H On Hold Dropped NA/UIN Not Applicable or Uninformative R Ready l Standard 18 gauge Bx Cryobiopsy: Excise Cryobiopsy: Freeze Excisional Biopsy Challenges to Development of Combination Targeted Therapeutics • Incomplete understanding of mechanisms of action for a growing number of targeted agents available for trial Inability to assess target effect • Lack of preclinical models for combinations • Clinical trials methodology • Intellectual property & regulatory challenges to novel combinations • – – – – Lack of assays, imaging tools Lack of assay standardization Lack of commercially-available agents formulated for in vitro use Lack of available investigational agents for in vitro use – To evaluate efficacy, schedule effects, biomarker utility, toxicity – – – – Need to screen large numbers of patients? Need for tumor biopsies? Is histologic homogeneity relevant? Pharmacokinetic interactions? SD vs RR? NCI “COMBO Plates” Plated Compounds for Combination Studies • COMBO set 1 – 87 compounds of diverse mechanism – Includes many older FDA-approved anticancer agents • FDA-approved COMBO set (9/09): Molec. Cancer Ther. 9:1451-1460, 2010 Challenges to Development of Combination Targeted Therapeutics • Incomplete understanding of mechanisms of action and a growing number of targeted agents available for trial Inability to assess target effect • Lack of preclinical models for combinations • Clinical trials methodology • Intellectual property & regulatory challenges to novel combinations • – – – – Lack of assays, imaging tools Lack of assay standardization Lack of commercially-available agents formulated for in vitro use Lack of available investigational agents for in vitro/in vivo use – To evaluate efficacy, schedule effects, biomarker utility, toxicity – – – – Need to screen large numbers of patients? Need for tumor biopsies? Is histologic homogeneity relevant? Pharmacokinetic interactions? SD vs RR? Challenges to Development of Combination Targeted Therapeutics • Incomplete understanding of mechanisms of action and a growing number of targeted agents available for trial Inability to assess target effect • Lack of preclinical models for combinations • Clinical trials methodology • Intellectual property & regulatory challenges to novel combinations • – – – – Lack of assays, imaging tools Lack of assay standardization Lack of commercially-available agents formulated for in vitro use Lack of available investigational agents for in vitro/in vivo use – To evaluate efficacy, schedule effects, biomarker utility, toxicity – – – – Need to screen large numbers of patients? Need for tumor biopsies? Is histologic homogeneity relevant? Pharmacokinetic interactions? SD vs RR? Modeling Therapeutic Combinations in NCI 60 For any 2-drug combination: MALME-3M M14 MDA-MB-435 SK-MEL-2 Bars to left SK-MEL-28 SK-MEL-5 indicate loss UACC-257 of benefit relative UACC-62 IGROV1 OVCAR-3 to best singleOVCAR-4 OVCAR-5 OVCAR-8 agent results NCI/ADR-RES SK-OV-3 786-0 A498 ACHN CAKI-1 RXF-393 SN12C TK-10 UO-31 PC-3 DU-145 MCF7 Bars to right indicate overall benefit to using combo relative to best single-agent results Doxorubicin + Rapamycin -10 Cell line Cell line CCRF-CEM HL-60(TB) K-562 MOLT-4 RPMI-8226 SR A549/ATCC EKVX HOP-62 HOP-92 NCI-H226 NCI-H23 NCI-H322M NCI-H460 NCI-H522 COLO 205 HCC-2998 HCT-116 HCT-15 HT29 KM12 SW-620 SF-268 SF-295 SF-539 SNB-75 SNB-19 U251 LOX IMVI MALME-3M M14 MDA-MB-435 SK-MEL-2 SK-MEL-28 SK-MEL-5 UACC-257 UACC-62 IGROV1 OVCAR-3 OVCAR-4 OVCAR-5 OVCAR-8 NCI/ADR-RES SK-OV-3 786-0 A498 ACHN CAKI-1 RXF-393 SN12C TK-10 UO-31 PC-3 DU-145 MCF7 MDA-MB-231/ATCC HS 578T BT-549 T-47D MDA-MB-468 Bortezomib + Cladribine (2CDA) -5 0 123127_226080 5 CCRF-CEM HL-60(TB) K-562 MOLT-4 RPMI-8226 SR A549/ATCC EKVX HOP-62 HOP-92 NCI-H226 NCI-H23 NCI-H322M NCI-H460 NCI-H522 COLO 205 HCC-2998 HCT-116 HCT-15 HT29 KM12 SW-620 SF-268 SF-295 SF-539 SNB-75 SNB-19 U251 LOX IMVI MALME-3M M14 MDA-MB-435 SK-MEL-2 SK-MEL-28 SK-MEL-5 UACC-257 UACC-62 IGROV1 OVCAR-3 OVCAR-4 OVCAR-5 OVCAR-8 NCI/ADR-RES SK-OV-3 786-0 A498 ACHN CAKI-1 RXF-393 SN12C TK-10 UO-31 PC-3 DU-145 MCF7 MDA-MB-231/ATCC HS 578T BT-549 T-47D MDA-MB-468 -10 -5 0 5 10 15 681239_606869 20 25 CCRF-CEM HL-60(TB) K-562 MOLT-4 RPMI-8226 SR A549/ATCC EKVX HOP-62 HOP-92 NCI-H226 NCI-H23 NCI-H322M NCI-H460 NCI-H522 COLO 205 HCC-2998 HCT-116 HCT-15 HT29 KM12 SW-620 SF-268 SF-295 SF-539 SNB-75 SNB-19 U251 LOX IMVI MALME-3M M14 MDA-MB-435 SK-MEL-2 SK-MEL-28 SK-MEL-5 UACC-257 UACC-62 IGROV1 OVCAR-3 OVCAR-4 OVCAR-5 OVCAR-8 NCI/ADR-RES SK-OV-3 786-0 A498 ACHN CAKI-1 RXF-393 SN12C TK-10 UO-31 PC-3 DU-145 MCF7 MDA-MB-231/ATCC C HS 578T BT-549 T-47D MDA-MB-468 718781_707545 718781_45388 226080_718781 609699_718781 718781_102816 732517_718781 67574_718781 718781_105014 226080_409962 226080_221019 123127_226080 681239_105014 681239_707545 681239_606869 732517_755 732517_221019 732517_246131 83265_732517 747971_122758 747971_71423 613327_721517 123127_745750 750690_102816 19893_241240 609699_266046 609699_82151 609699_707545 613327_105014 123127_312887 266046_19893 266046_105014 cellname Challenges to Development of Combination Targeted Therapeutics • Incomplete understanding of mechanisms of action and a growing number of targeted agents available for trial Inability to assess target effect • Lack of preclinical models for combinations • Clinical trials methodology • Intellectual property & regulatory challenges to novel combinations • – – – – Lack of assays, imaging tools Lack of assay standardization Lack of commercially-available agents formulated for in vitro use Lack of available investigational agents for in vitro/in vivo use – To evaluate efficacy, schedule effects, biomarker utility, toxicity – – – – Need to screen large numbers of patients? Need for tumor biopsies? Is histologic homogeneity relevant? Pharmacokinetic interactions? SD vs RR? Principles of Combination Therapy: Then (1975) and Now (2010) Cytotoxic • • • • Targeted Drugs are each active against the • tumor in question (ORR) Drugs have different mechanisms of • action to minimize resistance Drugs have different clinical toxicities to allow full dose therapy Intermittent intensive > continuous • treatment for cytoreduction & to reduce immunosuppression • Frei, Cancer Res., 32: 2593, 1972 DeVita, Cancer, 35: 98, 1975 Agent has therapeutic effect on molecular pathway in vivo Agents have complementary effects on the same target or other targets in the same pathway or pathways that cross-talk to control tumor growth Toxicities do not overlap with cytotoxics and are moderate to allow prolonged administration Schedule chosen to maximize target inhibition: Either continuous Rx or high dose to suppress target a reasonable goal Kummar, Nat. Rev. Drug Disc., 9: 843, 2010 of Cancer Treatment DCTD Division and Diagnosis Developmental Therapeutics Jerry Collins Joe Tomaszewski Melinda Hollingshead Ralph Parchment Robert Kinders Tom Pfister Jay Ji Center for Cancer Research Yves Pommier Lee Helman Bob Wiltrout Shivaani Kummar William Bonner Accelerating Cancer Diagnosis and Drug Development DCTD Jason Cristofaro Barbara Mrochowski Michael Difilippantonio CTEP Jamie Zweibel Jeff Abrams Cancer Imaging Paula Jacobs Cancer Diagnosis Barbara Conley Eric Rubin, MD Vice President Oncology Clinical Research Merck Approaches to solving the combinations problem in oncology therapeutics Eric H Rubin Merck Research Laboratories The Most Effective Treatments Involve Combinations • Probability of drug-resistant cells = 1 – e[-x(N-1)],where N is number of cells and x is the spontaneous drug resistance rate – Assuming a resistance rate of 1 of every million cells, for a 1 mm3 tumor, this probability is 0.64 • Principles of combination chemotherapy – Additive or synergistic anti-tumor activity without additive toxicity – Non-cross-resistance Combinations Problem in Oncology • • • For every 10 new drugs approved, 45 trials would be required to test each possible 2-drug combination If the trials were done separately and sequentially, this would take about 90 years This problem is amplified by a need to identify responsive subgroups (e.g. by biomarkers) The Combinations Problem in Cancer: Lung Cancer Example Standard-of-care drugs (2) –EGFRi (e.g. erlotinib) –VEGFRi (e.g. bevacizumab) New Compounds (5) – – – – – AKTi HGFi IGFRi mTORi CHK1i Biomarkers (4) – – – – RAS IGFR MET EGFR Possible drug doublets = (7 x 6)/2 -1 (SOC doublet) = 20 possible all comer ph2 trials Possible biomarker groups (if independent) = 24 = 16 possible patient subgroups Possible drug doublet-biomarker groups = 20 x 16 = 320 possible enrichment ph2 trials Solutions to the Combinations Problem 1. Identify most promising combinations from preclinical studies and combine them early in the clinic – IGF1Ri + mTORi – AKTi + MEKi – Caveat is that the historical success rate of preclinical prediction is low 2. Use branched adaptive trials – BATTLE – lung cancer – I-SPY – breast cancer Enhancer Screen for IGF1R inhibition IGF1Ritreated cell lines (dalotuzumab) siRNA Library Candidate Enhancers Untreated Cell lines Rationale for Combined mTOR and IGFR1 Targeting Dalotuzumab Enhancer Screen mTOR shRNA • • Anti-proliferative effect shRNA=small hairpin RNA mTOR is top hit in dalotuzumab enhancer screen IGF1R is top hit in ridaforolimus enhancer screen Rationale for Combined mTOR and IGFR1 Targeting DALOTUZUMAB IGFR-1 Feedback activation of AKT following mTOR inhibition by rapalogs IRS PI3K PTEN PDK1 Akt pAKT-S473 staining PIP3 Tumor sample of a patient on treatment with everolimus pre-therapy on-therapy Tuberin Co-treatment with IGFR1 inhibitor prevents feedback activation of AKT by mTOR inhibition in preclinical models Rheb RIDAFOROLIMUS TORC1 S6K S6 4EBP1 Tabernero, et al., J Clin Oncol. 2008 Ridaforolimus (Rida) + Dalotuzumab (Dalo): Phase I Design Part B - 2 dose cohorts Part A 5 dose levels 37 patients • Cohort 1 12 patients Cohort 2 13 patients Presented at oral session ASCO 2010 – DiCosimo et al, abstract # 3008 • Serena Di Cosimo, Johanna Bendell, Andres Cervantes-Ruiperez, Desamparados. Roda, Ludmilla Prudkin, Mark Stein, Ann LeightonSwayze, Yang Song, Scot Ebbinghaus, and José Baselga 36 Example of a Partial Response to Ridaforolimus + Dalotuzumab • 56 year-old female – Stage IV breast cancer • • • ER+/PR+/HER2 neg, Ki67 20% Adjuvant chemotherapy 4 prior chemotherapy regimens – Cyclophosphamide + doxorubicin, docetaxel + vinorelbine, paclitaxel + gemcitabine, capecitabine • 3 prior hormone therapies 2 cycles – Tamoxifen, fulvestrant, anastrazole • Patient remained on study treatment for 9 months before progression 37 Summary of Efficacy Signals in Breast Cancer • Overall, 10 of 23 breast cancer patients had objective evidence of anti-tumor activity – 6 of 11 (54%) patients with ER+/high proliferation breast tumors – 0 of 5 patients with ER+/low proliferation breast tumors Breast Cancer Subpopulation N FDG-PET PR (EORTC) n % PFS > 6 months n % Tumor Marker n % RECIST PR n ER+ 18 2 4 7 3 ER+/high proliferation 11 2 4 5 3 ER+/low proliferation 5 0 0 0 0 HER2+ 3 3 0 2 0 All breast cancer 23 5 22 4 17 8 35 3 % 13.0 PR=partial response; PFS = progression-free survival; tumor marker decline > 25% for CA-125, CA15.3 or CA27.29 Inter-Company 2 NME Combination • • Allosteric AKT inhibitor (MK-2206) + allosteric MEK inhibitor (AZD6244) Collaboration signed June 2009 – First example of two companies collaborating on combining 2 NMEs in early development • • • First patient dosed in phase 1 trial December 2009 Results to be presented at ASCO 2011 Combination also to be studied in BATTLE2 Acknowledgements • Merck – – – – – – • Gary Gilliland Stephen Friend Pearl Huang Keaven Anderson Li Yan David Mauro Astra Zeneca – – – – – Alan Barge Paul Smith Ian Smith Grahme Smith Victoria Zazulina • MD Anderson Cancer Center – – – – Roy Herbst Vali Papadimitrakopoulou J Jack Lee Don Berry Michael Caligiuri, MD Director, The Ohio State University Comprehensive Cancer Center CEO, James Cancer Hospital and Solove Research Institute Success with New Trials at The James Developed nude rat model of human primary CNS EBV+ lymphoma (PCNSL) NCI R01 funded in 1997 Rat model of PCNSL: Identified tumor upregulation of viral thymidine kinase by XRT & cytotoxicity with high dose AZT & GCV Phase I clinical trial developed 1st Patient: cured of fatal EBV+ PCNSL (10 years disease-free survival) The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute 42 Success with New Trials at The James The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute 43 An Astonishing Range of Molecular Interactions Occurs in Cancer Cells Biochemical pathways control cancer-cell growth and survival of cancer cells The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute 44 Drugs Designed to Target Key Molecules In Biomedical Pathways Turns on protective genes that the cancer process has turned off Blocks PI3K, which drives growth The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute 45 Preclinical Evidence: Targeted Agents In Combination Will Improve Patient Outcomes They cripple several key pathways simultaneously As a result, they may slow development of resistance and extend patient lives The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute 46 Dr. Bhuvaneswari Ramaswamy Assistant Professor of Medical Oncology The Ohio State University School of Medicine and Public Health A link to the full video will be sent to those participating virtually following the session. The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute 47 Major Stakeholders Need to Develop COOPERATIVE Policies and Procedures Patient advocacy groups Pharmaceutical industry Regulatory agencies Academia National Cancer Institute The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute 48 Great First Step by FDA The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute 49 CCCs & Academic Institutions Can Help Basic research Patients The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute 50 CCCs & Academic Institutions Can Help Basic research Patients Science-based combination strategies Pre-clinical studies The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute 51 CCCs & Academic Institutions Can Help Basic research Patients Science-based combination strategies Pre-clinical studies Bring stakeholders together Academic expertise in intellectual property CCCs can file investigational new drug (IND) applications The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute 52 Today’s Roundtable Battelle Merck BioOhio NCI Eli Lilly and Company Ohio State FDA OSUCCC-James FoxKiser Pfizer Friends of Cancer Research Sanofi-Aventis Signal Hill Advisors The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute 53 Solve Critical Business and Legal Issues: Co-developing Agents in Combination Define roles Financing the science Intellectual property Concentrated effort on broad coalition Profits Prices Experimental combinations Adverse Effects Commercialization Patent protection Draw up agreements Create workable template The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute 54 The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute 55 Question and Answer Session Thank you for attending. To view related material, please visit cancer.osu.edu/go/CancerDrugRoundtable.