ONCOLOGY Drug Development Fadi Sami Farhat, MD Hematology Oncology [e-mail]

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ONCOLOGYDrug DevelopmentFadi Sami Farhat,
MDHematology Oncologydrfadi_at_drfadi.org
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ONCOLOGYDrug development
Steps in cancer drug development
Identify Candidate Compounds Screening Preclinic
al Evaluation Production and Formulation Phase
I, II, III, IV Clinical Trials General Medical
Practice
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ONCOLOGYDrug development
Identification of candidate compounds Natural
products
Chu E, et al. Cancer Principles Practice of
Oncology. 6th ed. 2001345-356.Haskell CM.
Cancer Treatment. 199535-36.
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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. 2001345-356.
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ONCOLOGYDrug development
Screening for anticancer activity
IN VITRO HUMAN TUMOR CELL LINE PANELS
Prostate
Ovarian
Melanoma
CNS
Breast
Colon
Lung
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.
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ONCOLOGYDrug development
Preclinical evaluation of cytotoxic agents
IN VITRO
IN VIVO
Mechanism of action Stage I Stage II

• ? Target level ? Maximum tolerated dose ?
  Spectrum of activity
• ? Cellular level ? Dose-limiting toxicities ?
  Schedule dependency
• ? Efficacy ? Route of administration
• ? Cross resistance
• ? Combination therapies

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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

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ONCOLOGYDrug development
Clinical evaluation of cytotoxic agents
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ONCOLOGYDrug development
Clinical trials Efficacy endpoints

• Response rate
• Survival
• Disease-free survival
• Time to disease progression
• Duration of response
• Quality of life
• Pharmacoeconomics

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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.
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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.
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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.
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ONCOLOGYDrug development
Clinical trials Safety analyses

• Major toxicities
• Adverse effects
• Need for dose/schedule modifications
• Discontinuation of therapy during study

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ONCOLOGYDrug development
Summary of organization and reporting of clinical
studies