Evaluation of safety in biomarker driven multiple agent phase IB trial

Tyner and colleagues in the Center for Hematological Malignancies, Knight Cancer Institute, at the Oregon Health & Science University have recently developed a novel kinase-inhibitor assay and rapid mutation screening to identify molecularly targeted drugs to which patient leukemic cells are sensitive. As a proof of concept and feasibility trial, they proposed a phase IB trial focusing on feasibility and safety of an assay-based kinase-inhibitor treatment assignment in combination with the standard induction chemotherapy among newly diagnosed acute myeloid leukemia patients. Because each patient receives one of five kinase inhibitors in combination with standard chemotherapy, the sample size for each kinase inhibitor group is varied and limited. In addition, there is a different toxicity profile associated with each inhibitor, making safety assessment challenging. We will discuss a continuous toxicity monitoring plan in biomarker driven, multiple agent feasibility and safety trials, and evaluate its operating characteristics in a simulation study.