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

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Industry Sponsored Phase 2 Interven-tional Cancer Trials in Adults and Seniors

- Clinicaltrials.gov

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Phase 2 Cancer Trial Publications (PubMed)

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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.