Determining a maximum-tolerated schedule of a cytotoxic agent.

Most phase I clinical trials are designed to determine a maximum-tolerated dose (MTD) for one initial administration or treatment course of a cytotoxic experimental agent. Toxicity usually is defined as the indicator of whether one or more particular adverse events occur within a short time period from the start of therapy. However, physicians often administer an agent to the patient repeatedly and monitor long-term toxicity due to cumulative effects. We propose a new method for such settings. It is based on the time to toxicity rather than a binary outcome, and the goal is to determine a maximum-tolerated schedule (MTS) rather than a conventional MTD. The model and method account for a patient's entire sequence of administrations, with the overall hazard of toxicity modeled as the sum of a sequence of hazards, each associated with one administration. Data monitoring and decision making are done continuously throughout the trial. We illustrate the method with an allogeneic bone marrow transplantation (BMT) trial to determine how long a recombinant human growth factor can be administered as prophylaxis for acute graft-versus-host disease (aGVHD), and we present a simulation study in the context of this trial.