ODAC Meeting

1
ODAC Meeting

• Pediatric Subcommittee
• November 28, 2001

2
Challenges in Pediatric Cancer Drug Development

• Phase 1 Design
• Efficacy extrapolation
• Need for combination trials
• Role of phase 2 window
• Prioritization
• Invoking the rule

3
Phase 1 Design Optimum Biologic Dose

• Tissue acquisition
• Procedure must be minimal risk to be acceptable
• Is it the correct endpoint?
• Specificity of drug
• AUC as surrogate
• Independent of drug specificity
• Correlation with target tissue exposure

4
Phase 1 Design Starting Dose

• Optimum biologic dose may differ between adult
  and pediatric tumors
• Pre-clinical data required
• OBD may not be known following adult phase 1 or 2
  trials
• Increased lag time to initiate pediatric trials

5
Phase 1 Trial Design Pharmacology

• Phenotype matters
• Defining phenotype is more challenging than
  defining genotype
• Phase 1 trials define phenotype
• Obtaining genotype data must be considered
• Phase 1 PK/PD data sets stage for phase 2 3
  investigations
• Need for genotyping/phenotyping in phase 2 3
  trials

6
Challenges in Pediatric Cancer Drug Development

• Phase 1 Design
• Efficacy extrapolation
• Need for combination trials
• Role of phase 2 window
• Prioritization
• Invoking the rule

7
Efficacy Extrapolation

• Limited situations
• Phase 1 and 2 Trials required
• If pediatric phase 2 data consistent with adult
  phase 2 data, consider sufficient to extend
  labeling

8
Challenges in Pediatric Cancer Drug Development

• Phase 1 Design
• Efficacy extrapolation
• Need for combination trials
• Role of phase 2 window
• Prioritization

9
Combination Studies

• If single agent has no prospect for direct
  benefit AND is greater than minimal risk, cannot
  perform single agent study
• Single agent window
• Start with new agent
• Determine acute toxicity
• Define pharmacokinetics
• Continue with combination

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Combination Studies

• RMP-7/Carboplatin
• Genasense/Cyclphosphamide-Doxorubicin

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RMP-7/Carboplatin Phase I Trial
Cycle 1
Cycle 2-12
Cereport
Carboplatin
Day 1 2 3 1 2
12
Genasense Phase 1 Trial
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Challenges in Pediatric Cancer Drug Development

• Phase 1 Design
• Efficacy extrapolation
• Need for combination trials
• Role of phase 2 window
• Prioritization
• Invoking the rule

14
Challenges in Pediatric Cancer Drug Development

• Phase 1 Design
• Efficacy extrapolation
• Need for combination trials
• Role of phase 2 window
• Prioritization
• Invoking the rule

15
Prioritization

• With FDAMA and the Final Rule, we are faced with
  the situation whereby it may be easier to
  administer a new drug to a child with cancer than
  it will be to administer the new drug to a mouse

mouse model of pediatric tumor
16
Pre-clinical Models

• Obtaining novel agents in a timely manner to
  study in pre-clinical models of childhood cancer
  is essential to guide prioritization of new
  agents for children with cancer

17
Challenges in Pediatric Cancer Drug Development

• Phase 1 Design
• Efficacy extrapolation
• Need for combination trials
• Role of phase 2 window
• Prioritization
• Invoking the rule