1. APPLYING PRE-CLINICAL DATA TO CLINICAL STUDIES-I Edward A. Sausville, M.D., Ph.D. Developmental Therapeutics Program National Cancer Institute October 17, 2002

2. GOALS OF PRECLINICAL DRUG STUDIES IND = “Investigational New Drug” application = approval by FDA to conduct human studies; main criterion : SAFETY AND LIKELY REVERSIBLE TOXICITY = allows start of Phase I trials Pediatric Phase I Oncology Drugs: Special Issues *Few (thankfully) patients; many agents *Unmet medical need; ethical concerns *Prior Rx ; Concomitant meds *Unique pediatric biology (tumor and host) vs. value of adult data in study design Regulatory framework

3. PEDIATRIC PHASE I STUDIES: “CLASSICAL” NCI RECOMMENDATIONS Begin in pediatric patients with solid tumors and leukemias at 80% of max tol dose (MTD) in adults with solid tumors Solid tumor and leukemia pts at each level Escalate in 20% increments; distinguish myelosuppressive tox (desired in leukemia) vs non myeloid tox In absence ofnon-myelo tox, escalate beyond solid tumor MTD in leukemia patients. Marsoni et al. Cancer Treatment Reports 69, 1263, 1985

4. PEDIATRIC PHASE I STUDIES: BASIS FOR RECONSIDERATION OF CLASSICAL PRACTICE BIOLOGY: Pediatric tumors may have targets intrinsically different from adults; therefore adult data will never be available for drugs directd to those targets. PHARMACOLOGY: Past practice weighted toward “cytotoxics” ; ? Relevance to “targeted” agents. TIMING: Many new agents; delay in completing adult studies before application in peds neoplasms therefore exacerbate unmet need.

5. COMPONENTS OF AN IND “Form 1571” Table of Contents Intro Statement / Plan Investigator Brochure Clinical Protocol Chemistry, Manufacture, Control The goal of the pre-clinical process Pharmacology/ Toxicology Prior Human Experience Additional Info - Data monitoring, Quality Assurance

6. HOW ARE PHASE I DOSE AND SCHEDULE FIXED IN ADULTS ? Animal (usually mouse) model studies define likely active schedules in animals bearing human-derived tumors *Likelihood of human activity stochastic: more models with activity, greater likelihood of human activity *Limitations: difference between animal / human metabolism *Drug concentrations OR effect on target provide important ancillary info. Toxicology according to NCI guidelines / FDA requirements Starting dose a fraction of dose causing no or minimal reversible toxic effect; escalate dose in steps likely to capture reversible toxic effect

7. PROBLEMS WITH “MTD” DRIVEN ENDPOINTS Drugs regulating pathways important in oncogenesis are effective by combining with high affinity binding sites; therefore must distinguish “targeted” vs “non-targeted” toxicity related to these binding sites Whether dosing beyond effect on desired target “buys” therapeutic value not clear Therefore must define in pre-clinical studies “BIOLOGICALLY EFFECTIVE DOSE” and “MAXIMUM TOLERATED DOSE” Use BIOLOGIC rather than TOXIC endpoints in PhaseI?

8. REGULATORY CONSIDERATIONS FOR PRE- CLINICAL DEVELOPMENT OF ANTICANCER DRUGS [DeGeorge, et al, CCP (1998) 41: 173-185] “… The types of preclinical studies expected for support of clinical trials and marketing of a new drug depends on both the intended use of the drug and the population of patients being studied and treated. In situations where potential benefits are greatest (Advanced, life- threatening disease), greater risks of treatment toxicity can be accepted and the required preclinical testing can be minimal. …”

9. FDA PRECLINICAL PHARMACOLOGY & TOXICOLOGY REQUIREMENTS DRUGS – Two Species - Rodent & Non-rodent – Clinical Route & Schedule Follow NCI Guidelines – Pharmacokinetics - Optional BIOLOGICALS – Most Relevant Species – Clinical Route & Schedule

10. OBJECTIVES OF PRECLINICAL TOXICOLOGY STUDIES FOR ANTI-NEOPLASTIC DRUGS DETERMINE IN APPROPRIATE ANIMAL MODELS: –The Maximum Tolerated Dose (MTD) –Dose Limiting Toxicities ( DLT ) –Schedule-Dependent Toxicity –Reversibility of Adverse Effects –A Safe Clinical Starting Dose

11. NCI STANDARDIZED PRECLINICAL TOXICOLOGY PROTOCOLS FOR ANTI-NEOPLASTIC AGENTS (1980 - 1988) Mouse Lethality Studies Dog Toxicity Studies Rodent (Rat) Toxicity Studies Determine LD 10 on Dx1 & Dx5 Schedules Assess safety of 1/10 LD 10 ; Determine DLTs on Dx1 & Dx5 Schedules.

12. CURRENT NCI TOX PHILOSOPHY Agent-Directed Studies Pharmacologically- Guided Integrate With Preclinical Efficacy Data & the Proposed Clinical Protocol Rational Evaluation of Role of Schedule Dependence, Pharmacokinetics & Metabolism in the Development of Toxicity Relate Plasma Drug LeveLs and/or AUC to Safety and to Occurrence & Severity of Toxicity Extrapolate Toxic Effects Across Species

13. AGENT-DIRECTED versus STANDARD PROTOCOL DRUG DEVELOPMENT Greater Scientific Basis for Development Permits Greater Flexibility Data Rich IND Submission to Support Phase I Preclinical Potential … Less Expensive Permits PK-Guided Dose Escalation in Phase I Clinical Trial Potential … Shorter, Less Expensive Optimal Schedule … Greater Chance of Success? Patients … Greater Chance of Effective Therapy?

17. BENZOYLPHENYLUREA PRECLINICAL MTD & DLTs Bone Marrow, GI Tract Bone Marrow GI Tract DLT > 150 < 240 mg/m 2 360 mg/m 2 MTD (Total Dose) DOGRAT Schedule q4Dx3, po Starting Dose: 24 mg/m 2

18. ADDITIONAL AGENT-DIRECTED TOXICOLOGY STUDY REQUIREMENTS Attain Efficacious Drug Levels in Plasma In Vivo Correlate Drug Plasma Levels and/or AUC with Toxicity and Safety Across Species Ameliorate Toxicity by Change in Route/Schedule Compare Toxicity with Accepted Clinical Agents as Necessary

19. SCHEDULE and ROUTE versus TOXICITY Pyrazoloacridine:Bolus ivNeurotoxicity 1 Hr civBone Marrow Penclomedine:Bolus ivNeurotoxicity 1 Hr Dx5BM (& Neuro) 5 Hr civNeuro & Death OralBM O 6 –Benzylguanine:BolusCNS, HR  InfusionNeutrophilia

20. HOW PREDICTIVE OF HUMAN EXPERIENCE ARE THESE SAFETY-TESTING ALGORITHMS? NCI data Predictive power varies with endpoint desired: - 97% safe starting dose if 2-3 species (rodent plus dog) - 83% mouse only (Smith, A.C. Proc AACR 35: 459) BUT: Human MTD accurately predicted by: -mouse in 36% -rat in 19% -dog in 44% NO in vitro or silico methodology has yet emerged to predict human toxicity or dosing scheme (?marrow)

21. CONCLUSIONS FROM ILSI HUMAN TOXICITY PROJECT DATA SOT.BiomarkersSymposium; Regul. Toxicol. 32: 56, 2000 71% (151/214) human toxicities(HTs) associated with toxicities in animals - 63% in non-rodents - 36% in rodent plus non-rodent combinations - 43% in rodents 29% of human toxicities not predicted for by animals (8HTs insufficient animal data) Two species best predictor; for single species non-rodent (dog and/or primate) better than rodent (mainly rat)

22. CONSIDERATIONS IN APPLYING DATA TO PEDS POPULATIONS How closely do adult / peds MTDs correspond? *cytotoxics? *noncytotoxics Are “classical” MTDs still relevant? “Age” / maturity / nature of tox species relevant if adult human phase I data not to drive peds dosing? Importance of efficacy model PK / PD? Chronicity / reversibility / age-relatedness of target related tox’s (e.g.s): *bone growth and anti-VEGFRs? *skin (anti-EGFR)

23. ACKNOWLEDGEMENTS J. Covey M. Hollingshead A. Smith J. Tomaszewski S. Decker