This article considers the problem of designing Phase I-II clinical trials with delayed toxicity and efficacy outcomes. The proposed design is motivated by a Phase I-II study evaluating all-trans retinoic acid (ATRA) in combination with a fixed dose of daratumumab in the treatment of relapsed or refractory multiple myeloma. The primary objective of the study is to identify a dose that maximizes efficacy and has an acceptable level of toxicity. The toxicity endpoint is observed in one cycle of therapy (i.e., 4 weeks) while the efficacy endpoint is assessed after 8 weeks of treatment. The difference in endpoint observation windows causes logistical challenges in conducting the trial, since it is not practical to wait until both outcomes for each patient have been fully observed before sequentially assigning the dose of a newly eligible patient. In order to avoid delays in treatment for newly enrolled patients and to accelerate trial progress, we generalize the time-to-event continual reassessment method (TITE-CRM) to bivariate outcomes. Simulation studies are conducted to evaluate the proposed method, and we found that the proposed design is able to accurately select doses that maximize efficacy and have acceptable toxicity, while using all available information in allocating patients at the time of dose assignment. We compare the proposed methodology to two existing methods in the area.
|Number of pages||13|
|Journal||Journal of Biopharmaceutical Statistics|
|State||Published - Jul 4 2019|
Bibliographical noteFunding Information:
This work was supported by the National Cancer Institute [K25CA181638]. Dr. Wages is supported by the National Institute of Health grant K25CA181638. The authors would like to thank the Editor and two reviewers for their comments that lead to an improved manuscript.
This work was supported by the National Cancer Institute [K25CA181638].
Dr. Wages is supported by the National Institute of Health grant K25CA181638. The authors would like to thank the Editor and two reviewers for their comments that lead to an improved manuscript.
© 2019, © 2019 Taylor & Francis Group, LLC.
- continual reassessment method
- dose finding
- molecularly targeted agent
- optimal dose
ASJC Scopus subject areas
- Statistics and Probability
- Pharmacology (medical)