Rationale for Developing New Drugs 25% of children with cancer will not survive 5 years25% of children with cancer will not survive 5 years The acute toxicity of dose-intensive chemotherapy is life-threateningThe acute toxicity of dose-intensive chemotherapy is life-threatening The long-term effects of cancer therapy can be debilitating or life-threateningThe long-term effects of cancer therapy can be debilitating or life-threatening –Growth delay –Cognitive effects –Hormonal/reproductive problems –Permanent tissue/organ damage –Second cancers

Toxicity in IRS-III Worst Degree of Any Toxicity (n=1062) No. of Patients Severity of Toxicity

Clinical Drug Development

Separate Pediatric Clinical Trials Developmental changes affect:Developmental changes affect: –Drug disposition (pharmacokinetics) –Tissue/organ sensitivity (pharmacodynamics) Childhood cancers differ from adult cancersChildhood cancers differ from adult cancers –Tissue of origin –Pathogenesis (genetic alterations) –Disease manifestations –Drug sensitivity

Pediatric vs. Adult MTD (1970s) % Difference between Pediatric and Adult MTD MTDs in mg/m 2

Pediatric vs. Adult MTD (1990s) % Difference between Pediatric and Adult MTD

Clinical Anticancer Drug Development DRUGS PATIENTS Phase I Phase III Phase II NewlyDiagnosed Relapsed Relapsed Cured New Agent Too Toxic Not Efficacious Inactive Approved Drug

Docetaxel Phase I Trials * 7 days was considered dose-limiting

Determinants of Chemotherapy Selection of front line treatment regimenSelection of front line treatment regimen –Tumor histology –Stage of cancer –Prognostic characteristics Studying activity of new agentsStudying activity of new agents –Stratified by tumor histology

Molecularly-Targeted Drugs Specific for molecular target (e.g., mutant ras) rather than histologySpecific for molecular target (e.g., mutant ras) rather than histology –Patient treated based on presence of molecular lesion rather than tumor histology –Phase II trials not stratified by histology Molecular pathogenesis of adult and childhood cancers differentMolecular pathogenesis of adult and childhood cancers different Endpoint of dose finding (phase I) trials may be blocking target rather than toxicityEndpoint of dose finding (phase I) trials may be blocking target rather than toxicity Toxicity profile and dose-limiting toxicity may be different than for cytotoxic agentsToxicity profile and dose-limiting toxicity may be different than for cytotoxic agents