Phase I cancer clinical trial designs for cell therapies

Cell therapies comprise one of the most important advances in oncology. One of the biggest challenges in the early development of cell therapies is to recommend a dose that is both feasible and safe to carry forward to middle development. The treatment involves extracting cells from a patient, expanding the cells, and infusing the cells back into the patient. Each dose level being studied is defined by the number of cells infused into the trial participant. A common problem arises when the assigned dose exceeds the ability of the patient’s cell manufacturing process to generate that dose level, leading to a dose- feasibility issue for that patient. The primary design challenge is to efficiently use accumu- lated data from participants treated away from their assigned doses to efficiently allocate future trial participants and recommend a feasible maximum tolerated dose (FMTD) for all patients at the study conclusion. Currently, there are few available options for design- ing and implementing Phase I trials of cell therapies that can incorporate a dose-feasibility endpoint. Moreover, the application of these designs is limited to a traditional dose-finding framework where a single drug is evaluated, for a homogeneous patient population with toxicity outcomes determined in early cycles of therapy. This dissertation presents novel statistical methodology to implement three phase I designs for cell therapy trials. The first design simultaneously accounts for dose-feasibility and late-onset toxicities in a single drug dose-escalation framework. The second design simultaneously accounts for dose- feasibility and late-onset toxicities in a dual drug dose-escalation framework. The third design accounts for dose-feasibility and patient group heterogeneity. Each design was motivated by a proposed clinical trial or one that has been completed. If our designs are implemented we hope that they can improve clinical results and facilitate more efficient drug development and approval.