Development of a New

Cancer Drug
 Overview

• Scope of the problem

• Source of new agents
• Requirements for approval
• Preclinical development
• Phase I, II, III trials
• Post-marketing trials, extension of registration
 Where do new drugs come from?

• Serendipity (cisplatin)
• Natural product screen (Vinca alkaloids)
• Derivatives of older agents (oxaliplatin,
vinorelbine, many others)
• Rational design based upon putative targets
(methotrexate, 5FU, estramustine, tamoxifen,
Iressa, C225)
 Cancer Drugs:
How Do We Know We Have a Winner?
Treatment A
- PHASE III CLINICAL TRIAL
%
= WINNER Alive Treatment B or no Rx

Time
- PHASE II
= POTENTIAL
WINNER ; Time?

Rx

- PRECLINICAL MODEL Rx Untreated

(e.g., mouse or rat) Cytostatic
Tumor
Size Cytotoxic

Time
 Six Essential Alterations
in Cell Physiology in Malignancy
Self-sufficiency in
Hanahan & Weinberg,
growth signals
Cell 100:57 (2000)
Evading Insensitivity to
apoptosis anti-growth signals

Targets for
classical drugs?

Targets for
novel drugs?
Sustained Tissue invasion
angiogenesis & metastasis

Limitless replicative
potential
 SITES OF ACTION OF CYTOTOXIC
AGENTS
PURINE SYNTHESIS PYRIMIDINE SYNTHESIS

6-MERCAPTOPURINE
6-THIOGUANINE
RIBONUCLEOTIDES
METHOTREXATE
5-FLUOROURACIL
HYDROXYUREA
DEOXYRIBONUCLEOTIDES

CYTARABINE
ALKYLATING AGENTS
ANTIBIOTICS
DNA

ETOPOSIDE

RNA

L-ASPARAGINASE
PROTEINS
VINCA ALKALOIDS
ENZYMES MICROTUBULES
TAXOIDS
 DRUG RESISTANCE
EXTRACELLULAR INTRACELLULAR
PGP170 ATP

Drug

ATP

Drug

Plasma
Membrane
 “Rational” Drug Discovery
MOLECULAR TARGET SCREEN PHARMACOLOGY
Biochemical (to affect target)
Engineered cell
Animal (yeast/worm/fish)
CHEMISTRY

TARGET-DEPENDENT IN VIVO MODEL

IND DIRECTED TOX/FORM

PHASE I: DOSE/SCHEDULE: HUMAN PHARM/TOX;

? AFFECT TARGET

PHASE II: ACTIVITY = ? AFFECT TARGET

PHASE III: SURVIVAL/TIME TO PROGRESSION

 Requirements for FDA Approval

• Drug must be proven to be “safe and

effective”
• Efficacy must be demonstrated in a “defined
patient population”
– What is efficacy?
 Definitions of Patient Benefit

• Survival
• Decreased requirement for supportive care e.g.
transfusions, pain medication
• Improved quality of life
• ? Response
Phases of Drug Development

• Preclinical
• Phase I
• Phase II
• Phase III
 Preclinical Development

• Identification of “lead compound”

– Able to be produced in adequate quantities
– Favorable properties for administration
• In vitro activity
• In vivo activity: animal models
 Problems with animal models

• Mice are not men

• Transplanted human tumors behave very
differently
• Uniformity of models: important for
reproducibility, but inherently different from
natural system
 Investigational New Drug
Application (INDA)

• Allows drug to be administered to humans

• Drug must be manufactured according to GMP
 Clinical Trials
• Requires review by institutional review board
(IRB)
• IRB must be constituted appropriately
• May require independent data safety
monitoring (DSMB)
 Phase I Development

• Dosage and schedule based upon animal data

– Not always correct e.g. UCN-01
• Traditional Phase I designs
• New Phase I designs
• Phase I based upon target inhibition
• Very limited numbers of patients (e.g. 15)
 Phase II Trials

• Typically several trials of the agent in diseases

likely to be affected.
• Endpoint: “efficacy”
• Two-stage design
 Problems with Phase II design

• May underestimate activity

– Unknown heterogenity
• May overestimate activity
– Referral population
– Unknown heterogenity
 Phase III Study

• Definitive comparison with “standard of care”

• Superiority assumption
• Equivalence assumption
 Approval of a New Drug

• New drug application (NDA)

• Patient benefit demonstrated
• Ability to manufacture the drug
• Oncology Drug Advisory Committee (ODAC)
 Post-marketing testing

• Registration of an agent is only the beginning

• Many drugs may have much broader use than
their registration
• No drug has ever been registered for use with
radiation
• Adjuvant use
 Summary
• Many sources for new anticancer drugs
• While in vitro and animal in vivo models are helpful
for identifying active agents and beginning
evaluation, they are insufficient for determining
actual toxicity of efficacy (tdk pas utk menentukan
toksisitas)
• Several phases of development: agents may fail at
any point
• Registration is only the beginning of a drugs life.
• Very expensive process