1. The Preclinical Pathway to a Phase 0 Clinical Trial Accelerating Cancer Diagnosis and Drug Development DCTD Division of Cancer Treatment and Diagnosis Joseph E. Tomaszewski, PhD Deputy Director, DCTD, NCI September 5, 2007 Joseph E. Tomaszewski, PhD Deputy Director, DCTD, NCI September 5, 2007 DCTD Phase 0 Workshop

2. Can A New Path For Cancer Drug Development Be Charted? (Nov 2003)   Toward an initial clinical experience / development paradigm NOT driven by toxicity   Instead by predefined / predictable -pharmacological endpoints (plasma concentrations) in humans -pharmacodynamic endpoints (in surrogate or tumor tissue)   Goal: Preclinical studies shift from causing toxicity to assessing PK / PD relationships

3. Drive for drugs leads to baby clinical trials. Nature 2006, 440:406-407. Slow Start to Phase 0 as Researchers Debate Value. JNCI 2006 98: 804-806. January 2006 Pharmacology/Toxicology

4. 3. Clinical Studies of Mechanism of Action (MOA) Related to Efficacy  FDA will accept alternative, or modified, pharmacologic and toxicological studies  Short-term modified toxicity or safety studies in 2 species to achieve a clinical PD endpoint  Incorporate PD endpoints in toxicity studies  Possible use of single, relevant species  Doses based on efficacy, MED and safe BEDs, not MTDs

5. Compressing Drug Development Timelines In Oncology Using Phase ‘0’ Trials NATURE REVIEWS | CANCER VOLUME 7 | FEBRUARY 2007 | 131-139 Shivaani Kummar, Robert Kinders, Larry Rubinstein, Ralph E. Parchment, Anthony J. Murgo, Jerry Collins, Oxana Pickeral, Jennifer Low, Seth M. Steinberg, Martin Gutierrez, Sherry Yang, Lee Helman, Robert Wiltrout, Joseph E. Tomaszewski and James H. Doroshow Abstract | The optimal evaluation of molecularly targeted anticancer agents requires the integration of pharmacodynamic assays into early clinical investigations. Phase ‘0’ trials conducted under the new Exploratory Investigational New Drug Guidance from the US Food and Drug Administration can provide a platform to establish the feasibility of assays for target modulation in human samples, evaluate biomarkers for drug effects and provide pharmacokinetic data. Phase 0 trials could facilitate rational drug selection, identify therapeutic failures early, and might compress timelines for anticancer drug development. We expect that such trials will become a routine part of early-phase oncological drug development in the future.

6. What Does a Phase 0 Trial Involve? Pre-Clinical to Clinical Transition  Assay development in vitro and in vivo  Development of pre-clinical system on which to model tissue acquisition, handling, and processing  Demonstration of drug target or biomarker effect and PK-PD relationships in vivo  Drug biodistribution and binding using novel imaging technologies  Innovative statistical designs ¬Limited sample size ¬PD and PK as primary endpoints, rather than MTD

7. How Can Phase 0 Trials Improve Efficiency and Success of Subsequent Trials?  Eliminating an agent very early in clinical development because of poor PD or PK properties ¬e.g., lack of target effect, poor bioavail., rapid clearance ¬“Fail Fast, Fail Early”  By informing subsequent trials ¬Validating a PD assay for assessing target modulation ¬Developing a reliable SOP for tissue acquisition, handling, and processing ¬Determining dose and time course that yields a required target effect ¬Intensively evaluating PK, providing a closer approximation to a safe, but potentially effective starting dose and support for limited sampling in subsequent trials

8. Summary: PD Assay Development Before Initiation of Phase 0 Clinical Trials

9. REGULATORY AGENCY CLINICAL LABORATORY Trial Monitor IND Sponsor National Cancer Institute Pharmaceutical Industry Investigator Laboratory for Pharmacodynamic (PD) Analysis Laboratory for Tissue Handling and Processing Laboratory for Pharmakinetic (PK) Analysis Interventional Radiology Drug Development Clinic Research Imaging Bioethics Schedule tumor biopsies: coordinate with times for drug administration Review imaging studies, determine feasibility of obtaining biopsies Research Nursing Medical Oncologists Clinical Nursing Data Managers Social Workers Patient Education Documentation of patient understanding of the nature of the clinical trials Pathology Laboratory Repository Integrated Phase 0 Research Team

10. NCI’s First Phase 0 Study Abbott Laboratories PARP Inhibitor, ABT-888

11. Poly (ADP- Ribose) Polymerase (PARP) Ratnam K, et al. Clin Cancer Res. 2007;13:1383-1388. Copyright ©2007 American Association for Cancer Research

12. ABT-888 History with NCI  July 2004: CTEP brings in Abbott’s PARP inhibitor for development  Early 2005: PK/Toxicology issues identified with lead development candidate  August 2005: Abbott decides to pursue development of back-up molecule (ABT-888) ¬IND filing delayed until late 2006/early 2007 ¬CTEP & Phase 0 team selects ABT-888 for first Phase 0 trial

13. Rationale for ABT-888 Phase 0  Exploratory IND candidate ¬No anticipated toxicity at low doses ¬Pharmacodynamic marker studies possible ¬CMC, Non-GLP pharm/tox studies available ¬Phase 1 IND filing delayed  Phase 0 candidate ¬PD assay required optimization ¬Assay development would support Phase 1 studies ¬PK and PD data from Phase 0 would accelerate Phase 1 combination studies

14. ABT-888 ± TMZ (U87MG Glioma Xenograft): Pre-clinical Starting Point for Choosing Dose and Schedule for Clinical Protocol 28 Days of Dosing  ABT-888 Treatment Schedule C P : C Tumor PD1, PD2, PD3 Data supplied by Abbott Labs

15. Copyright ©2007 American Association for Cancer Research Donawho, C. K. et al. Clin Cancer Res 2007;13:2728-2737 Efficacy and PARP Inhibition: (ABT-888, bidx5, Oral, 2Hr Post Dose) TMZ

16. ABT-888 p.o., b.i.d.x5 * ** p < 0.05 PAR Inhibition: (ABT-888 alone, bidx5, Oral, 2Hr Post Dose) PAR Data supplied by Abbott Labs B16F10 syngeneic melanoma in mice

17. C P = 570nM C P = 210 nM PAR Inhibition: (ABT-888, Dx1, Oral, 2Hr Post Dose) Human Equiv Dose 60-70 mg 30-35 mg PAR VEH 12.5mg/kg 6.25mg/kg 3.13mg/kg 1.56mg/kg 0.78mg/kg Data supplied by Abbott Labs Veh vs 12.5 and 6.25 mg/kg only 12.5 and 6.25 vs 3.13

18. Therapeutic Window for ABT-888 Predicted human C max Steady state (OMP) concentration required for efficacy Animal Toxicity Therapeutic Window 7.3 – 12.8 x Time (hours) Plasma Concentration 01224

19. First Phase 0 – How Did We Get There?  Efficacy – Work backward 1.Schedule: 28 Day, ip, combination. PAR inhibition related to tumor regression, stasis 2.Reduced schedule to Dx5, po, bid; PAR inhibition at p <0.05 level for 5 dose levels 3.Reduced schedule to Dx1, po; PAR inhibition at p <0.05 level for 2 top dose levels 4.Determined C P and C T in all studies to establish target levels for clinical study  Pharmacology 1.Developed and validated PK assay 2.Developed and qualified PD assay

20. New Model Summary  Perform studies in animal models prior to initiating clinical trials to:  Select appropriate endpoints to evaluate in man  Interrogate and validate PD target or biomarker assay  Simulate human tissue acquisition, handling, processing and storage  Demonstrate drug target or biomarker effect in tumor and/or surrogate tissues/samples  Determine PK-PD relationships  Evaluate drug biodistribution and binding using imaging technologies  Enable conducting Phase 0 clinical trials

21. The Next Speaker is: Dr. Shivaani Kummar