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.

• Authors: A Doussau, R Thiébaut, B Geoerger, P Schöffski, A Floquet, M C Le Deley, S Mathoulin-Pélissier, E Rizzo, P Fumoleau, C Le Tourneau, X Paoletti
• Journal: Annals of oncology : official journal of the European Society for Medical Oncology (Ann Oncol) Vol. 26 Issue 2 Pg. 422-8 (Feb 2015) ISSN: 1569-8041 [Electronic] England
• PMID: 25403589 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © The Author 2014. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected].

Chemical References

• Antineoplastic Agents

Topics

• Antineoplastic Agents (adverse effects)
• Clinical Trials, Phase I as Topic (standards)
• Female
• Humans
• Male
• Maximum Tolerated Dose
• Models, Statistical
• Neoplasms (drug therapy)