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?
Nov 27, 2014
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?
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
Phase 1 Studies
Nonselective Cytotoxic• 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)
Targeted Agent• 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
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
Phase 2 Studies
20012002
20032004
20052006
20072008
20092010
20112012
20130%
5%
10%
15%
20%
25%
30%
35%
40%
45%
Industry Sponsored Phase 2 Interven-tional Cancer Trials in Adults and Seniors
- Clinicaltrials.gov
% R
ando
mize
d
19931995
19971999
20012003
20052007
20092011
20130%
5%
10%
15%
20%
25%
30%
35%
40%
45%
Phase 2 Cancer Trial Publications (PubMed)
% R
ando
mize
d
Increasing Complexity
Increasing Complexity
• Better science. • Better medicines. • Better trials.
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
Managing Complexity• Successful drug development has always been an endeavor involving
capable individuals working together collaboratively in teams.