Welcome to the Cancer Drug Development Roundtable at Ohio State. May 4, 2011

Transcription

1 Welcome to the Cancer Drug Development Roundtable at Ohio State May 4, 2011

2 Public Session Michael Caligiuri, MD (Co-host and Panelist) Ellen Sigal, PhD (Co-host) James Doroshow, MD (Panelist) OSUCCC- James Friends of Cancer Research NCI Director, OSUCCC; CEO, The James Chair and Founder 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

3 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 Michael Grever MD Battelle OSUCCC- James Toxicologist/Study Director Chair & Professor, Dept of Internal Medicine; Associate Dean of Medical Services; Co-Leader, Experimental Therapeutics Program The Ohio State University Comprehensive Cancer Center Arthur G. James Cancer Hospital and Richard J. Solove Research Institute 3

4 Additional Roundtable Participants Joanne Lager MD Michael Mitchell JD Sanofi- Aventis Ohio State Senior Director and Oncology Drug Project Head 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

5 Additional Roundtable Participants Ira Steinberg MD Miguel Villalona MD Tim Wright Sanofi- Aventis OSUCCC- James Signal Hill Advisors Associate VP & Global Medical Affairs Leader Director, Division of Medical Oncology & Professor, Dept of Internal Medicine Biotech and Pharmaceutical Consultant The Ohio State University Comprehensive Cancer Center Arthur G. James Cancer Hospital and Richard J. Solove Research Institute 5

6 Ellen Sigal, PhD Chair and Founder, Friends of Cancer Research

7 Janet Woodcock, MD Director Center for Drug Evaluation and Research U.S. Food and Drug Administration

8 James Doroshow, MD Director Division of Cancer Treatment and Diagnosis National Cancer Institute

9 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

10 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 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 Lack of preclinical models for combinations To evaluate efficacy, schedule effects, biomarker utility, toxicity Clinical trials methodology Need to screen large numbers of patients? Need for tumor biopsies? Is histologic homogeneity relevant? Pharmacokinetic interactions? SD vs RR? Intellectual property & regulatory challenges to novel combinations

11 Lack of Molecular Markers with Proven Clinical Utility Drug Anti-estrogens Trastuzumab EGFR small molecule inhibitors Biomarker ER, PR, genomic signature Her2 FISH, IHC 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??

12 Pharmacodynamic Assay Development Concept Feasibility & Development Validation Launch Target Application Platform Feasibility Development γ-h2ax Protein (tumor) γ-h2ax Protein (tumor) DNA Damaging Agents DNA Damaging Agents Analytical Validation Biopsy Assays ELISA P P Preclinical Modeling Specimen SOPs Assay Transfer Clinical Validation qifa P P P P P Top 1 Protein TOPO Inhibitors ELISA P P P P 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 Kinase Inhibitors Kinase Inhibitors PARP Inhibitors PARP Inhibitors PARP Inhibitors PARP Inhibitors Tumor Stem Cell Inhibitors IFA Commerci al Reagents IFA Custom Reagents P P P P P RT-qPCR P P P P P P P R RT-qPCR P P P P P P P R Support Transfer to NCI Clinical Scientific Trials Community IA P P P P P P P RT-qPCR P P P P P P P R IFA P H KEY: In Progress P Completed X Dropped Delayed CA Commercially Available NA/UIN Not Applicable or Uninformative Technical Difficulty H On Hold R Ready

13 Standard 18 gauge Bx Cryobiopsy: Freeze Cryobiopsy: Excise Excisional Biopsy

14 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 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 Lack of preclinical models for combinations To evaluate efficacy, schedule effects, biomarker utility, toxicity Clinical trials methodology Need to screen large numbers of patients? Need for tumor biopsies? Is histologic homogeneity relevant? Pharmacokinetic interactions? SD vs RR? Intellectual property & regulatory challenges to novel combinations

15 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: , 2010

16 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 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 Lack of preclinical models for combinations To evaluate efficacy, schedule effects, biomarker utility, toxicity Clinical trials methodology Need to screen large numbers of patients? Need for tumor biopsies? Is histologic homogeneity relevant? Pharmacokinetic interactions? SD vs RR? Intellectual property & regulatory challenges to novel combinations

17 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 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 Lack of preclinical models for combinations To evaluate efficacy, schedule effects, biomarker utility, toxicity Clinical trials methodology Need to screen large numbers of patients? Need for tumor biopsies? Is histologic homogeneity relevant? Pharmacokinetic interactions? SD vs RR? Intellectual property & regulatory challenges to novel combinations

18 Modeling Therapeutic Combinations in NCI 60 For any 2-drug combination: Bars to left indicate loss of benefit relative to best singleagent results 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 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

19 Doxorubicin + Rapamycin Bortezomib + Cladribine (2CDA) CCRF-CEM HL-60(TB) K-562 MOLT-4 RPMI-8226 A549/ATCC SR 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 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 Cell line _ Cell line CCRF-CEM HL-60(TB) K-562 MOLT-4 RPMI-8226 A549/ATCC SR 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 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 _606869

20 cellname 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 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 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 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 cellname C _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _105014

21 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 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 Lack of preclinical models for combinations To evaluate efficacy, schedule effects, biomarker utility, toxicity Clinical trials methodology Need to screen large numbers of patients? Need for tumor biopsies? Is histologic homogeneity relevant? Pharmacokinetic interactions? SD vs RR? Intellectual property & regulatory challenges to novel combinations

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25 Principles of Combination Therapy: Then (1975) and Now (2010) Cytotoxic 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 Targeted 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

26 DCTD Division of Cancer Treatment 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

27 Eric Rubin, MD Vice President Oncology Clinical Research Merck

28 Approaches to solving the combinations problem in oncology therapeutics Eric H Rubin Merck Research Laboratories

29 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 mm 3 tumor, this probability is 0.64 Principles of combination chemotherapy Additive or synergistic anti-tumor activity without additive toxicity Non-cross-resistance

30 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)

31 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) = 2 4 = 16 possible patient subgroups Possible drug doublet-biomarker groups = 20 x 16 = 320 possible enrichment ph2 trials

32 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

33 Enhancer Screen for IGF1R inhibition IGF1Ritreated cell lines (dalotuzumab) sirna Library Untreated Cell lines Candidate Enhancers

34 Rationale for Combined mtor and IGFR1 Targeting Dalotuzumab Enhancer Screen mtor shrna mtor is top hit in dalotuzumab enhancer screen IGF1R is top hit in ridaforolimus enhancer screen Anti-proliferative effect shrna=small hairpin RNA

35 Rationale for Combined mtor and IGFR1 Targeting IGFR-1 DALOTUZUMAB IRS Feedback activation of AKT following mtor inhibition by rapalogs PI3K Tumor sample of a patient on treatment with everolimus PIP 3 PTEN Akt PDK1 pakt-s473 staining Tuberin Rheb RIDAFOROLIMUS pre-therapy on-therapy Co-treatment with IGFR1 inhibitor prevents feedback activation of AKT by mtor inhibition in preclinical models TORC1 S6 S6K 4EBP1 Tabernero, et al., J Clin Oncol. 2008

36 Ridaforolimus (Rida) + Dalotuzumab (Dalo): Phase I Design Part A 5 dose levels 37 patients Part B - 2 dose cohorts 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 Leighton- Swayze, Yang Song, Scot Ebbinghaus, and José Baselga 36

37 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 Tamoxifen, fulvestrant, anastrazole Patient remained on study treatment for 9 months before progression 2 cycles 37

38 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) PFS > 6 months Tumor Marker RECIST PR n % n % n % n % ER ER+/high proliferation ER+/low proliferation HER All breast cancer PR=partial response; PFS = progression-free survival; tumor marker decline > 25% for CA-125, CA15.3 or CA27.29

39 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

40 Acknowledgements Merck Gary Gilliland Stephen Friend Pearl Huang Keaven Anderson Li Yan David Mauro MD Anderson Cancer Center Roy Herbst Vali Papadimitrakopoulou J Jack Lee Don Berry Astra Zeneca Alan Barge Paul Smith Ian Smith Grahme Smith Victoria Zazulina

41 Michael Caligiuri, MD Director, The Ohio State University Comprehensive Cancer Center CEO, James Cancer Hospital and Solove Research Institute

42 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 1 st 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

43 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

44 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

45 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

46 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

47 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

48 Major Stakeholders Need to Develop COOPERATIVE Policies and Procedures Patient advocacy groups Pharmaceutical industry Academia Regulatory agencies National Cancer Institute The Ohio State University Comprehensive Cancer Center Arthur G. James Cancer Hospital and Richard J. Solove Research Institute 48

49 Great First Step by FDA The Ohio State University Comprehensive Cancer Center Arthur G. James Cancer Hospital and Richard J. Solove Research Institute 49

50 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

51 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

52 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

53 Today s Roundtable Battelle BioOhio Eli Lilly and Company FDA FoxKiser Friends of Cancer Research Merck NCI Ohio State OSUCCC-James Pfizer Sanofi-Aventis Signal Hill Advisors The Ohio State University Comprehensive Cancer Center Arthur G. James Cancer Hospital and Richard J. Solove Research Institute 53

54 Solve Critical Business and Legal Issues: Co-developing Agents in Combination Financing the science Define roles Intellectual property Concentrated effort on broad coalition Prices Profits Adverse Effects Experimental combinations Patent protection Draw up agreements Create workable template Commercialization The Ohio State University Comprehensive Cancer Center Arthur G. James Cancer Hospital and Richard J. Solove Research Institute 54

55 The Ohio State University Comprehensive Cancer Center Arthur G. James Cancer Hospital and Richard J. Solove Research Institute 55

56 Question and Answer Session Thank you for attending. To view related material, please visit cancer.osu.edu/go/cancerdrugroundtable.