1. 1 Phase 0 Trials Role in Radiation Mitigation Agent Development? Anthony J. Murgo, M.D., M.S. Office of Oncology Drug Products Center for Drug Evaluation and Research Food and Drug Administration Jan 25, 2010

2. 2 Outline Description of Phase 0 trials Phase 0 vs. traditional first-in-human Phase 1 trials Types of agents appropriate for Phase 0 testing Ways Phase 0 may improve efficiency of drug development

3. 3 Disclosure

4. 4 What is a Phase 0 trial? A what???

5. 5 What is a Phase 0 trial?

6. 6 Basic Features of Phase 0 trials First-in-human trial conducted prior to traditional Phase 1 study Small number of subjects (≈10-15) Limited drug exposure –Low, non-toxic doses –Short duration (≈ ≤7 days) –One course only No therapeutic intent Phase 0 trials are not definitive studies

7. 7 Phase 0 trials can start earlier than Phase 1 Conceived under FDA’s “Critical Path” initiative to help sponsors identify promising candidate drugs more quickly Toxicology evaluation less extensive than for traditional IND because of reduced dosing and limited exposure.

8. 8 How do Phase 0 Trials Differ from Traditional First-In- Human Phase 1 Trials?

9. 9 Phase 0 vs. FIH Phase 1 Oncology Trials VariablePhase 1 TrialPhase 0 Trial Preclinical toxFull IND-directed Less required; sufficient to support ExpIND Pre-clinical target/biomarker validation studies Not consistently performed; assays rarely validated in preclinical models Target/biomarker analytical assays validated in preclinical models

10. 10 Phase 0 vs. FIH Phase 1 Oncology Trials VariablePhase 1 TrialPhase 0 Trial Primary objective & dose-escalation scheme Establish dose-limiting toxicities and MTD Establish a dose- range that modulates target, for use in subsequent Phase 1 (or 2 trials) Duration of dosing Repetitive; multiple cycles until disease progression or unacceptable toxicity Limited dosing (e.g., 1-7 days); one cycle only Evaluation for therapeutic benefit Tumor response routinely evaluated None Tumor Biopsies Almost always optional Required (pre- and post) to evaluate drug effect

11. 11 Phase 0 vs. FIH Phase 1 Oncology Trials (cont.) VariablePhase 1 TrialPhase 0 Trial PD/target effect assays Not consistently performed; commonly use assay methods that are not validated or standardized Integrated into the trial to establish MOA and target/biomarker analytical assay validation in subject tissue samples SOP’s for tissue acquisition, handling, and processing Generally not validated or standardized SOP’s validated first in in vivo preclinical models and applied to Phase 0 human samples PK/PD analysis Samples usually batched and analyzed at a later time point, generally after completion of the trial Performed in “real-time”

12. 12 Murgo, A. J. et al. Clin Cancer Res 2008;14:3675-3682 Phase 0 Trials

13. 13 Types of Phase 0/Expl IND trials Pharmacologically relevant doses Micro-dose studies

14. 14 Various Goals of Phase 0/Expl IND trials Pharmacologically relevant doses Explore mechanism of action in humans –MOA defined in non-clinical models can be observed in humans –Agent binds to or inhibits its alleged target Refine a biomarker assay using human tumor tissue and/or surrogate tissue Provide human PK-PD relationship data prior to definitive single-agent or combination Phase 1 testing Select most promising candidate for further development –Evaluate human PD of two or more analogs directed at same target and possessing practically the same preclinical properties

15. 15 Various Goals of Phase 0/Expl IND trials (2) Micro-dose studies Less than 1/100th of the dose calculated (based on animal data) to yield a pharmacologic effect (max dose of <100 micrograms (≤30 nanomoles, protein products) Evaluate in humans an agent’s biodistribution, binding characteristics and target effects Develop novel imaging probes Evaluate human PK (e.g., bioavailability) to select most promising candidate for further development

16. 16 Phase 0 – Small Sample Size Demonstration target modulation requires: –Precise and reproducible assay methods –Robust drug effect –Limited intra-patient variability –Limited inter-patient variability –Innovative, rational statistical designs

17. 17 Why conduct Phase 0 trials?

18. 18 Kola & Landis; Nat Rev Drug Disc 2004 Ma & Zemmel; Nat Rev Drug Disc 2002 Unfavorable PK currently plays less of a role compared to early 1990’s Lack of efficacy continues to play a major role Lack of predictive animal models Why drugs fail

19. 19 Phase 0 trials Can Improve Efficiency and Success of Subsequent Trials Informing subsequent trials –Establishing MOA and drug hits its target in human subjects –Refining target/biomarker PD analytical assay with human biopsy samples –Developing reliable SOP for human tissue acquisition, handling, and processing –Determining dose and time-course that yields desired target effect –Exploring PK-PD relationships Approximation of safe, efficacious starting dose for studies in different populations and settings: –Use in otherwise healthy subjects –In combination with other drugs or radiation Support limited sampling in subsequent trials

20. 20 Phase 0 trials Can Improve Efficiency and Success of Subsequent Trials (cont.) Selecting a candidate agent with most favorable properties for further clinical testing Eliminating “bad” agents early in clinical development because of poor PD or PK properties e.g., lack of target effect, poor bioavail., very rapid clearance “Fail fast, fail early”

21. 21 What Makes an Agent a Good Candidate for a Phase 0 PD Trial Credentialed target (modulation yields desired effect) Wide therapeutic window (e.g., biomodulators) PD modulation expected at low doses and short duration of exposure (e.g. ≤7 days) Drug target effect evaluable with a relatively small sample size (≤10-15 patients) –Robust drug effect –Precise analytical assay –Target expressed in majority of study subjects

22. 22

23. 23 Kummar, S., et al. Phase 0 Clinical Trial of the Poly (ADP-Ribose) Polymerase Inhibitor ABT-888 in Patients With Advanced Malignancies. J Clin Oncol; 27:2705-11, 2009 Kinders, R., et al. Phase 0 trials in cancer drug development. Mol Interventions; 7:327-34, 2007 Jacobson-Kram D, Mills G. Leveraging exploratory investigational new drug studies to accelerate drug development. Clin Cancer Res;14:3670–4, 2008 Murgo AJ, et al. Designing phase 0 cancer clinical trials. Clin Cancer Res; 14:3675-82, 2008 Doroshow, JH, Parchment, RE. Oncologic Phase 0 Trials: Incorporating Clinical Pharmacodynamics from Concept to Patient. Clin Cancer Res 14:3658-63, 2008 Gutierrez, M, Collyar, D. Patient perspectives on phase 0 clinical trials. Clin Cancer Res 14:3689–91, 2008 Abdoler E, et. al. The ethics of phase 0 oncology trials. Clin Cancer Res 2008;14:3692–7 Kummar, S, et al. Compressing drug development timelines in oncology using phase ‘0’ trials. Nature Reviews Cancer 7:131-9, 2007 Rubinstein, LV, et al. The Statistics of Phase 0 Trials. Statistics in Med; in press. Suggested Reading

24. 24 Back-up Slides

25. 25 Phase 0 – Patient Recruitment and Ethical Considerations Challenging, but not insurmountable Potential barriers to patient enrollment –No therapeutic intent or chance of benefit –Pre- and post-treatment tissue biopsies –Delay or exclusion from other trials or therapies External concerns about ethics and availability of patients for study Institutional Ethics committee review and input IRB approval Informed Consent Process –Clearly explain the rationale for the study –Clearly describe the limited treatment and follow up period –Clearly state that there is absolutely no anticipated clinical benefit to the participant –More straightforward than Phase 1 – but low risk – avoid if possible – washout period for phase 0 shorter

26. 26 Murgo, A. J. et al. Clin Cancer Res 2008;14:3675-3682 Statistical Methodology for Phase 0 Trials

27. 27 Murgo, A. J. et al. Clin Cancer Res 2008;14:3675-3682