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ONCOLOGY Drug Development Fadi Sami Farhat , MD Hematology Oncology drfadi@drfadi

ONCOLOGY Drug Development Fadi Sami Farhat , MD Hematology Oncology drfadi@drfadi.org. Toxicology Pharmacology Biochemistry. ONCOLOGY Drug development. Steps in cancer drug development. Identify Candidate Compounds Screening Preclinical Evaluation Production and Formulation

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ONCOLOGY Drug Development Fadi Sami Farhat , MD Hematology Oncology drfadi@drfadi

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  1. ONCOLOGYDrug DevelopmentFadi Sami Farhat, MDHematology Oncologydrfadi@drfadi.org

  2. Toxicology Pharmacology Biochemistry ONCOLOGYDrug development Steps in cancer drug development Identify Candidate Compounds Screening Preclinical Evaluation Production and Formulation Phase I, II, III, IV Clinical Trials General Medical Practice

  3. Drug Type Source Antitumor antibiotic (daunorubicin, doxorubicin) Streptomyces fungus Vinca alkyloid (vincristine, vinblastine) Vinca rosea plant Taxane Yew tree Camptothecin (topotecan, CPT-11) Camptotheca accuminata tree Podophyllin (etoposide, teniposide) Podophyllum peltatum plant Bryostatin, dolastatin, halichondrin Marine organisms ONCOLOGYDrug development Identification of candidate compounds: Natural products Chu E, et al. Cancer: Principles & Practice of Oncology. 6th ed. 2001;345-356.Haskell CM. Cancer Treatment. 1995;35-36.

  4. ONCOLOGYDrug development Identification of candidate compounds: Molecular-targeted screening • Computer-aided construction of molecules • Mutant oncogenes (BCR-ABL) • Aberrant tumor suppressor genes (RB) • Protein kinases • Transcription activators Chu E, et al. Cancer: Principles & Practice of Oncology. 6th ed. 2001;345-356.

  5. ONCOLOGYDrug development Screening for anticancer activity IN VITRO HUMAN TUMOR CELL LINE PANELS Prostate Lung Colon Breast CNS Melanoma Ovarian “Nonspecific” antitumor activity “Highly specific” antitumor activity In Vivo “tumor panel” human tumor xenograft studies Targeted preclinical development Preclinical development followed by broad-based clinical trials Specific “disease-oriented” Phase I/II trials Adapted from NCI drug screening strategy,1985.

  6. ONCOLOGYDrug development Preclinical evaluation of cytotoxic agents  Target level  Maximum tolerated dose  Spectrum of activity  Cellular level  Dose-limiting toxicities  Schedule dependency  Efficacy  Route of administration  Cross resistance  Combination therapies IN VITRO IN VIVO Mechanism of action Stage I Stage II

  7. ONCOLOGYDrug development Use of animal models in evaluation of cytotoxic agents • Preclinical studies in mice, rats, and dogs provide an important bridge from in vitro studies to clinical studies • Objectives • Define major toxicities • Identify initial safe starting dose for clinical trials

  8. Study Phase Objectives Patient Population Phase I Identify maximum tolerated dose  Small (3-6 patients/dose level) Define key toxicities  Various tumor types Phase II Evaluate tumor response  Larger than Phase I (10-50 Determine whether drug patients/treatment group) warrants Phase III study  More uniform disease characteristics Phase III Compare new treatment with  Larger than Phase II (100s of standard patients/treatment group) Support marketing approval  Same tumor type Broader patient pool Phase IV Integrate clinical study experience  Very large cohorts (100s-1000s) into general clinical practice  Represent general patient Monitor safety after approval population ONCOLOGYDrug development Clinical evaluation of cytotoxic agents

  9. ONCOLOGYDrug development Clinical trials: Efficacy endpoints • Response rate • Survival • Disease-free survival • Time to disease progression • Duration of response • Quality of life • Pharmacoeconomics

  10. ONCOLOGYDrug development Clinical endpoints: Complete remission Primary Tumor Nodes Metastases Treatment Disappearance of all clinical, radiologic and biologic signs of tumor Adapted from World Health Organization, 1980.

  11. ONCOLOGYDrug development Clinical endpoints: Partial remission Treatment Decrease of the multiple of two tumor diameters by at least 50% Adapted from World Health Organization, 1980.

  12. ONCOLOGYDrug development Clinical endpoints: Disease progression Treatment Increase of the multiple of two tumor diameters by at least 25% Adapted from World Health Organization, 1980.

  13. ONCOLOGYDrug development Clinical trials: Safety analyses • Major toxicities • Adverse effects • Need for dose/schedule modifications • Discontinuation of therapy during study

  14. PREPARATION OF DOCUMENTS CLINICAL SUPPLIES ETHICS COMMITTEE INVESTIGATOR PATIENTS MONITORING WRITTEN ACCOUNTS DATA ON ADVERSE EVENTS DATA PROCESSING STUDY REPORT ONCOLOGYDrug development Summary of organization and reporting of clinical studies

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