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Rationale for Developing New Drugs

Rationale for Developing New Drugs. 25% of children with cancer will not survive 5 years The acute toxicity of dose-intensive chemotherapy is life-threatening The long-term effects of cancer therapy can be debilitating or life-threatening Growth delay Cognitive effects

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Rationale for Developing New Drugs

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  1. Rationale for Developing New Drugs • 25% of children with cancer will not survive 5 years • The acute toxicity of dose-intensive chemotherapy is life-threatening • The 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

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

  3. Clinical Drug Development

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

  5. Pediatric vs. Adult MTD (1970s) MTDs in mg/m2 % Difference between Pediatric and Adult MTD

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

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

  8. Docetaxel Phase I Trials * <500/µL for >7 days was considered dose-limiting

  9. Determinants of Chemotherapy • Selection of front line treatment regimen • Tumor histology • Stage of cancer • Prognostic characteristics • Studying activity of new agents • Stratified by tumor histology

  10. Molecularly-Targeted Drugs • Specific 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 different • Endpoint 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 agents

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