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Dose escalation trial designs based on a molecularly targeted endpoint.
Sally Hunsberger1, Lawrence V Rubinstein, Janet Dancey
1Biometrics Research Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. sallyh@ctep.nci.nih.gov
Statistics in Medicine
|May 24, 2005
Summary
New phase I study designs for molecularly targeted agents use binary target response rates for dose escalation, moving beyond traditional toxicity assessments. These novel designs aim to optimize dose finding for targeted therapies with minimal side effects.
Area of Science:
- Oncology
- Clinical Pharmacology
- Biostatistics
Background:
- Traditional Phase I studies rely on toxicity for dose escalation, which is unsuitable for molecularly targeted agents (MTAs) with low toxicity.
- The development of MTAs necessitates new dose-finding strategies for early-phase clinical trials.
Purpose of the Study:
- To propose and evaluate two novel Phase I study designs for MTAs based on molecular target response.
- To compare these designs against traditional toxicity-based escalation methods.
Main Methods:
- Two distinct dose-escalation designs utilizing binary molecular target response rates were developed.
- A simulation study was conducted to compare the proposed designs based on final dose level and patient numbers.
Main Results:
- One design ensures escalation when target response is low and stops when high.
- The second design escalates as long as response rates increase, stopping at plateaus or decreases.
- Simulations evaluated dose levels and patient accrual for each design.
Conclusions:
- Novel Phase I designs based on molecular target engagement offer a viable alternative to toxicity-based escalation for MTAs.
- These designs address the unique challenges posed by targeted therapies with favorable safety profiles.
- Further evaluation is warranted to optimize dose-finding for molecularly targeted agents.