Challenges in early phase development oncology 17 nov2013
1. Challenges in Early Cancer Drug
Development
Q: What are the biggest challenges you see facing early
development oncology and how could you become part of
the solution?
2. Increasing Complexity
Then (1991)
• Nonselective cytotoxics
• Simple administration &
schedule (eg, IV Q3W)
• Single arm early phase trials
Now (2013)
• Molecularly targeted
• IV or oral, multiple
schedules
• More complex trials in
targeted populations
3. Phase 1 Studies
Nonselective Cytotoxic
Targeted Agent
•
•
Standard 3+3 design
– Determine MTD
• Toxicity drives RPIID
selection
– “All comers” advanced,
refractory disease
– Limited BA assay development
– IV administration, simple
schedule (eg, IV Q3W)
Standard 3+3 design
– Determine MTD?
• Non- or less toxic agents
• PK/PD may drive RPIID
selection
– Targeted or “enriched” tumor
subtypes?
– Companion diagnostic, Robust PD
assay(s)
– IV or oral, QD, BID, Intermittent,
etc.
• Real time PK and preclinical
models may help to suggest
the right schedule
4. Phase 2 Studies
•
Cytotoxic
• ORR
•
•
•
S R Brown, W M Gregory, C J Twelves, et al.
British Journal of Cancer (2011) 105, 194–199
More randomized studies
– Time to event
endpoints
– Combination
treatments
– Dose selection (high
vs. low dose)
Patient selection based
on marker expression
Central pathology and
radiology reviews
Population PK and
PD/Biomarker analyses
– Collection of
tumor/surrogate
tissue samples for
correlative analyses
5. Phase 2 Studies
45%
40%
35%
30%
25%
20%
15%
10%
5%
0%
Phase 2 Cancer Trial Publications
(PubMed)
% Randomized
% Randomized
Industry Sponsored Phase 2
Interventional Cancer Trials in Adults
and Seniors - Clinicaltrials.gov
45%
40%
35%
30%
25%
20%
15%
10%
5%
0%
8. Managing Complexity
•
More pre-clinical data before Phase 1 can be helpful
– Guide dose schedule (not just starting dose)
– Identify tumor types more likely to respond or harbor marker of interest
• Initiate companion diagnostic and PD assay development early
• Establish go/no-go criteria for Phase 2
– Acceptable safety profile, Target blood levels, Indications of drug activity
• Prepare Clinical Development Plan early
– Next study can be developed during FIM Phase 1 study
• Consider how increased clinical trial complexity affects study execution
– More PK/PD sampling = more lab kits, more coordination, more data
– Phase 1 development may be more extensive if multiple schedules or
combinations need to be explored
– Randomized Phase 2 trials require more time to plan and resources to
conduct
– High quality data (Safety, Efficacy, PK, PD) are needed for decision
making
9. Managing Complexity
• Successful drug development has always been an endeavor involving
capable individuals working together collaboratively in teams.