ONCOLOGYONCOLOGYDrug DevelopmentDrug Development

Fadi Sami Farhat, MDFadi Sami Farhat, MDHematology Oncology

drfadi@drfadi.org

Identify Candidate CompoundsIdentify Candidate Compounds

ScreeningScreening

Preclinical EvaluationPreclinical Evaluation

Production and FormulationProduction and Formulation

Phase I, II, III, IV Clinical TrialsPhase I, II, III, IV Clinical Trials

General Medical PracticeGeneral Medical Practice

ToxicologyToxicology PharmacologyPharmacology BiochemistryBiochemistry

ONCOLOGYONCOLOGYDrug developmentDrug developmentSteps in cancer drug developmentSteps in cancer drug development

ONCOLOGYONCOLOGYDrug developmentDrug developmentIdentification of candidate compounds: Natural productsIdentification of candidate compounds: Natural products

Drug TypeDrug Type SourceSource

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.

Chu E, et al. Cancer: Principles & Practice of Oncology. 6th ed. 2001;345-356.

Identification of candidate compounds: Molecular-targeted screeningIdentification of candidate compounds: Molecular-targeted screening

ONCOLOGYONCOLOGYDrug developmentDrug development

Computer-aided construction of molecules

Mutant oncogenes (BCR-ABL)

Aberrant tumor suppressor genes (RB)

Protein kinases

Transcription activators

ProstateProstate

IN VITROIN VITRO HUMAN TUMOR CELL LINE PANELS HUMAN TUMOR CELL LINE PANELS

OvarianOvarianMelanomaMelanomaCNSCNSBreastBreastColonColonLungLung

Preclinical developmentPreclinical developmentfollowed by broad-based clinical trialsfollowed by broad-based clinical trials

In VivoIn Vivo “tumor panel” “tumor panel”human tumor xenograft studieshuman tumor xenograft studies

Specific “disease-oriented”Specific “disease-oriented”Phase I/II trialsPhase I/II trials

Targeted preclinical developmentTargeted preclinical development

““Nonspecific” antitumor activityNonspecific” antitumor activity “Highly specific” antitumor activity“Highly specific” antitumor activity

Adapted from NCI drug screening strategy,1985.

ONCOLOGYONCOLOGYDrug developmentDrug developmentScreening for anticancer activityScreening for anticancer activity

ONCOLOGYONCOLOGYDrug developmentDrug development

IN VITROIN VITRO IN VIVOIN VIVO

Preclinical evaluation of cytotoxic agentsPreclinical evaluation of cytotoxic agents

Mechanism of actionMechanism of action Stage IStage I Stage IIStage II

Target level Maximum tolerated dose Spectrum of activity

Cellular level Dose-limiting toxicities Schedule dependency

Efficacy Route of administration

Cross resistance

Combination therapies

ONCOLOGYONCOLOGYDrug developmentDrug 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 agentsUse of animal models in evaluation of cytotoxic agents

Study PhaseStudy Phase ObjectivesObjectives Patient PopulationPatient Population

Phase IPhase I Identify maximum tolerated dose Small (3-6 patients/dose level)

Define key toxicities Various tumor types

Phase IIPhase 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 IIIPhase 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 IVPhase IV Integrate clinical study experience Very large cohorts (100s-1000s)

into general clinical practice Represent general patient

Monitor safety after approval population

ONCOLOGYONCOLOGYDrug developmentDrug developmentClinical evaluation of cytotoxic agentsClinical evaluation of cytotoxic agents

ONCOLOGYONCOLOGYDrug developmentDrug development

Response rate

Survival

Disease-free survival

Time to disease progression

Duration of response

Quality of life

Pharmacoeconomics

Clinical trials: Efficacy endpointsClinical trials: Efficacy endpoints

Adapted from World Health Organization, 1980.

Clinical endpoints: Complete remissionClinical endpoints: Complete remission

ONCOLOGYONCOLOGYDrug developmentDrug development

PrimaryPrimaryTumorTumor

NodesNodes

MetastasesMetastases

Disappearance of all clinical,Disappearance of all clinical,radiologic and biologicradiologic and biologic

signs of tumorsigns of tumor

TreatmentTreatment

TreatmentTreatment

Decrease of the multiple of twoDecrease of the multiple of twotumor diameters by at least 50%tumor diameters by at least 50%

ONCOLOGYONCOLOGYDrug developmentDrug developmentClinical endpoints: Partial remissionClinical endpoints: Partial remission

Adapted from World Health Organization, 1980.

Increase of the multiple of twoIncrease of the multiple of twotumor diameters by at least 25%tumor diameters by at least 25%

ONCOLOGYONCOLOGYDrug developmentDrug developmentClinical endpoints: Disease progressionClinical endpoints: Disease progression

Adapted from World Health Organization, 1980.

TreatmentTreatment

ONCOLOGYONCOLOGYDrug developmentDrug development

Major toxicities

– Adverse effects

– Need for dose/schedule modifications

– Discontinuation of therapy during study

Clinical trials: Safety analysesClinical trials: Safety analyses

ETHICSETHICSCOMMITTEECOMMITTEE

INVESTIGATORINVESTIGATOR

PATIENTSPATIENTS

PREPARATIONPREPARATIONOFOF

DOCUMENTSDOCUMENTS

CLINICALCLINICALSUPPLIESSUPPLIES

DATA ONDATA ONADVERSEADVERSEEVENTSEVENTS

DATADATAPROCESSINGPROCESSING

WRITTENWRITTENACCOUNTSACCOUNTS

MONITORINGMONITORING

STUDY REPORTSTUDY REPORT

ONCOLOGYONCOLOGYDrug developmentDrug developmentSummary of organization and reporting of clinical studiesSummary of organization and reporting of clinical studies