A new approach to integrate toxicity grade and repeated treatment cycles in the analysis and reporting of phase I dose-finding trials
Abstract
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: Eighty-three 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 [P = 0.04; 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.