Dose-finding based on feasibility and late-onset toxicity in adoptive cell therapy trials.

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 safe and feasible doses 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. The manufacturing process may not generate enough cells for a given patient to receive their assigned dose level, making it infeasible to administer their intended dose. The primary design challenge is to efficiently use accumulated data from participants treated away from their assigned dose to efficiently allocate future trial participants and recommend a feasible maximum tolerated dose (FMTD) at the study conclusion. Currently, there are few available options for designing 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 the dose-limiting toxicity (DLT) endpoint is observed in early cycles of therapy. This paper presents a novel phase I trial design for adoptive cell therapy that simultaneously accounts for dose feasibility and late-onset toxicities. We apply our design to a phase I dose-escalation trial of Rituximab-based bispecific activated T-cells combined with a fixed dose of Nivolumab. Our simulation results demonstrate that our proposed method can reduce trial duration without significantly hindering trial accuracy.

Impact of dose feasibility on the conduct of phase I trials of adoptive cell therapy.

BACKGROUND: /Aims: In early-phase cell therapy trials, each dose level being studied is defined by the number of cells infused into the trial participant. The issue of dose feasibility presents itself when the desired number of cells is not reached in the expansion process. Consequently, dose assignments for some patients may deviate from the planned dose according to the chosen design. Widely used algorithmic designs aren't flexible enough to handle this complication and can lead to the exclusion of safety data from the dose assignment algorithm. This article studies the impact of dose feasibility challenges on the behavior of the 3 + 3 decision rule. METHODS: We conducted a simulation study across six dose-feasibility and dose-toxicity scenarios. Trials are simulated using the 3 + 3 algorithm. We present a novel algorithm for random feasibility curve generation. We used this algorithm to conduct a large-scale simulation study across 100 random scenarios. RESULTS: We found that the 3 + 3 has problematic characteristics due to the exclusion of safety data from the algorithm. Ignoring toxicity data can complicate the allocation of subsequent patients in the trial and can bias the final maximum tolerated dose recommendation for the next phase of drug development. CONCLUSION: Our study demonstrates that excluding safety data from the 3 + 3 algorithm can be detrimental to trial conduct. Furthermore, there are existing methods that are flexible enough to include data that is observed away from the planned dose. We recommend that these methods be used in conducting phase I cell therapy trials.