A new approach to integrate toxicity grade and repeated treatment cycles in the analysis and reporting of phase I dose-finding trials

Abstract

 More than 50% of phase I adverse drug reactions occur after the first cycle of treatment and moderate toxicities are an important source of information to investigate increasing probability of toxicity over time. Appropriate statistical modelling can be used to evaluate per cycle probability of moderate or severe toxicity, and cumulative probability of severe toxicity. Three situations were identified: Constant probability of toxicity over time and numerous repeated cycles provide a major gain in the precision of the estimate of the risk of toxicity at the RPD2. Increased risk of toxicity with time and numerous repeated cycles support reassessment of the RP2D that would be safe over the treatment period.

Background Safety assessment beyond the dose-limiting toxicity evaluation period provides relevant information to define the recommended phase II dose (RP2D) of a new treatment. We retrospectively analyzed three phase I trials to illustrate two indicators: per cycle probability of graded toxicity and cumulative probability of severe toxicity over the treatment period.

Patients and methods Data were collected from two continual reassessment method (CRM) trials (T1: aviscumine in solid tumors with short time on treatment; T2: erlotinib+radiotherapy in brainstem gliomas with longer time on treatment) and one 3+3 design (T3: liposomal doxorubicin+cyclophosphamide combination in ovarian carcinoma). The probability of severe and moderate or severe toxicity per cycle was estimated at each dose level
with mixed proportional odds model. The cumulative probability of severe toxicity was also estimated with the time-to-event CRM.

Results 83 patients were included in the three trials; 94, 96 and 72 treatment cycles were administered, in T1, T2 and T3, respectively. Moderate toxicities were at least twice as frequent as severe toxicities. An increased probability of toxicity over time was detected in T3 (per cycle probability of severe toxicity: 27% (cycle 1) to 59% (cycle 6) at the RP2D). At the RP2D, 37% of patients experienced at least one severe toxicity over the first six cycles in T2, and 78% in T3.

Conclusions Dedicated methods can be used to analyze toxicities from all cycles of treatment. They do not delay accrual and should be integrated in the analysis and reporting of phase I dose-finding trials.