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ONCOLOGY
Drug Development
ONCOLOGY
Drug development
Steps in cancer drug development
Identify Candidate Compounds
Screening
Preclinical Evaluation
Production and Formulation
Toxicology
Pharmacology
Phase I, II, III, IV Clinical Trials
General Medical Practice
Biochemistry
ONCOLOGY
Drug development
Identification of candidate compounds: Natural products
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
Chu E, et al. Cancer: Principles & Practice of Oncology. 6th ed. 2001;345-356.
Haskell CM. Cancer Treatment. 1995;35-36.
ONCOLOGY
Drug 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.
ONCOLOGY
Drug development
Screening for anticancer activity
IN VITRO HUMAN TUMOR CELL LINE PANELS
Lung
Colon
Breast
“Nonspecific” antitumor activity
CNS
Melanoma
Ovarian
Prostate
“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.
ONCOLOGY
Drug 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
ONCOLOGY
Drug 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
ONCOLOGY
Drug development
Clinical evaluation of cytotoxic agents
Study Phase
Objectives
Patient Population
Phase I
 Identify maximum tolerated dose
 Small (3-6 patients/dose level)
 Define key toxicities
 Various tumor types
 Evaluate tumor response
 Larger than Phase I (10-50
 Determine whether drug
patients/treatment group)
 More uniform disease characteristics
Phase II
warrants Phase III study
Phase III
Phase IV
 Compare new treatment with
 Larger than Phase II (100s of
standard
 Support marketing approval
patients/treatment group)
 Same tumor type
 Broader patient pool
 Integrate clinical study experience
 Very large cohorts (100s-1000s)
into general clinical practice
 Monitor safety after approval
 Represent general patient
population
ONCOLOGY
Drug development
Clinical trials: Efficacy endpoints

Response rate

Survival

Disease-free survival

Time to disease progression

Duration of response

Quality of life

Pharmacoeconomics
ONCOLOGY
Drug development
Clinical endpoints: Complete remission
Primary
Tumor
Nodes
Treatment
Metastases
Disappearance of all clinical,
radiologic and biologic
signs of tumor
Adapted from World Health Organization, 1980.
ONCOLOGY
Drug development
Clinical endpoints: Partial remission
Treatment
Decrease of the multiple of two
tumor diameters by at least 50%
Adapted from World Health Organization, 1980.
ONCOLOGY
Drug development
Clinical endpoints: Disease progression
Treatment
Increase of the multiple of two
tumor diameters by at least 25%
Adapted from World Health Organization, 1980.
ONCOLOGY
Drug development
Clinical trials: Safety analyses

Major toxicities
– Adverse effects
– Need for dose/schedule modifications
– Discontinuation of therapy during study
ONCOLOGY
Drug development
Summary of organization and reporting of clinical studies
PREPARATION
OF
DOCUMENTS
CLINICAL
SUPPLIES
ETHICS
COMMITTEE
MONITORING
WRITTEN
ACCOUNTS
INVESTIGATOR
PATIENTS
DATA
PROCESSING
DATA ON
ADVERSE
EVENTS
STUDY REPORT