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

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

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

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.

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

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

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?

REGULATORY CONSIDERATIONS FOR PRE- CLINICAL DEVELOPMENT OF ANTICANCER DRUGS [DeGeorge, et al, CCP (1998) 41: ] “… 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. …”

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

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

NCI STANDARDIZED PRECLINICAL TOXICOLOGY PROTOCOLS FOR ANTI-NEOPLASTIC AGENTS ( ) 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.

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

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?

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

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

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

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)

CONCLUSIONS FROM ILSI HUMAN TOXICITY PROJECT DATA SOT.BiomarkersSymposium; Regul. Toxicol. 32: 56, % (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)

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)

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