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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%
- 7. Increasing Complexity • Better science. • Better medicines. • Better trials.
- 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.