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Adapting isotonic dose-finding to a dynamic set of drug combinations with application to a phase I leukemia trial
- Source :
- Clin Trials
- Publication Year :
- 2021
- Publisher :
- SAGE Publications, 2021.
-
Abstract
- Background/aims This article describes the proposed design of a phase I study evaluating the safety of ceramide nanoliposome and vinblastine among an initial set of 19 possible dose combinations in patients with relapsed/refractory acute myeloid leukemia and patients with untreated acute myeloid leukemia who are not candidates for intensive induction chemotherapy. Methods Extensive collaboration between statisticians and clinical investigators revealed the need to incorporate several adaptive features into the design, including the flexibility of adding or eliminating certain dose combinations based on safety criteria applied to multiple dose pairs. During the design stage, additional dose levels of vinblastine were added, increasing the dimension of the drug combination space and thus the complexity of the problem. Increased complexity made application of existing drug combination dose-finding methods unsuitable in their current form. Results Our solution to these challenges was to adapt a method based on isotonic regression to meet the research objectives of the study. Application of this adapted method is described herein, and a simulation study of the design’s operating characteristics is conducted. Conclusion The aim of this article is to bring to light examples of novel design applications as a means of augmenting the implementation of innovative designs in the future and to demonstrate the flexibility of adaptive designs in satisfying changing design conditions.
- Subjects :
- Drug
Maximum Tolerated Dose
media_common.quotation_subject
Pharmacology
Article
Set (abstract data type)
Dose finding
Phase (matter)
Isotonic
medicine
Humans
Computer Simulation
media_common
Clinical Trials, Phase I as Topic
Dose-Response Relationship, Drug
Adaptive Clinical Trials as Topic
Chemistry
General Medicine
medicine.disease
Vinblastine
Phase i study
Drug Combinations
Leukemia, Myeloid, Acute
Leukemia
Research Design
medicine.drug
Subjects
Details
- ISSN :
- 17407753 and 17407745
- Volume :
- 18
- Database :
- OpenAIRE
- Journal :
- Clinical Trials
- Accession number :
- edsair.doi.dedup.....e80a8926d517d6f429e4365bc5558c73