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

2. Identify Candidate Compounds Screening Preclinical Evaluation Production and Formulation Phase I, II, III, IV Clinical Trials General Medical Practice ToxicologyPharmacologyBiochemistry ONCOLOGY Drug development Steps in cancer drug development

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

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

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

6. ONCOLOGY Drug development IN VITRO IN VIVO Preclinical evaluation of cytotoxic agents Mechanism of actionStage IStage II Target level Maximum tolerated dose Spectrum of activity Cellular level Dose-limiting toxicities Schedule dependency Efficacy Route of administration Cross resistance Combination therapies

7. ONCOLOGY Drug development 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 Use of animal models in evaluation of cytotoxic agents

8. Study Phase Objectives Patient Population Phase I Phase I Identify maximum tolerated dose Small (3-6 patients/dose level) Define key toxicities Various tumor types Phase II 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 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 Phase IV Integrate clinical study experience Very large cohorts (100s-1000s) into general clinical practice Represent general patient Monitor safety after approval population ONCOLOGY Drug development Clinical evaluation of cytotoxic agents

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

10. Adapted from World Health Organization, 1980. Clinical endpoints: Complete remission ONCOLOGY Drug development PrimaryTumorNodesMetastases Disappearance of all clinical, radiologic and biologic signs of tumor Treatment

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

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

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

14. ETHICSCOMMITTEEINVESTIGATORPATIENTS PREPARATIONOFDOCUMENTS CLINICALSUPPLIES DATA ON ADVERSEEVENTS DATAPROCESSING WRITTENACCOUNTS MONITORING STUDY REPORT ONCOLOGY Drug development Summary of organization and reporting of clinical studies