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Abstract:
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Phase I dose-escalation in oncology has seen a dramatic uptake of innovative design usage over the past decade. Many companies are adopting a model-based approach versus traditional 3+3 designs, but even these improved methods cannot dramatically increase precision of MTD finding due to their limited sample size and restrictive dose exploration. There is added on complexity of evaluating multiple drugs (combinations), multiple grades of toxicity or simultaneous assessment of target engagement and toxicity in a single study. In other words, Phase 1 oncology trials of today are very different from small, MTD-focused studies of a single drug with dichotomous endpoint of the past. They are larger, often include substantial expansion cohorts, and their objectives are more complex than simple MTD determination as a single dose to take forward. Such goals are better addressed by incorporating a seamless Phase 2-like extension into initial dose-escalation phase and using combined data along with quantitative decision making to improve the probability of success in further development.
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