Model-based adaptive phase I trial design of post-transplant decitabine maintenance in myelodysplastic syndrome. Issue 1 (December 2015)

• Record Type: Journal Article
• Authors: Han, Seunghoon; Kim, Yoo-Jin; Lee, Jongtae; Jeon, Sangil; Hong, Taegon; Park, Gab-jin; Yoon, Jae-Ho; Yahng, Seung-Ah; Shin, Seung-Hwan; Lee, Sung-Eun; Eom, Ki-Seong; Kim, Hee-Je; Min, Chang-Ki; Lee, Seok; Yim, Dong-Seok
• Is Part Of: Journal of hematology & oncology. Volume 8:Issue 1(2015)
• Page Start: 1
• Page End: 9
• Publication Date: 2015-12
• Subjects: Model-based drug development -- Adaptive design -- Myelodysplastic syndrome -- Population pharmacokinetics-pharmacodynamics -- Phase I clinical trial; Hematology -- Periodicals; Oncology -- Periodicals; Blood -- Diseases -- Periodicals; 616.994
• DOI: 10.1186/s13045-015-0208-3
• Languages: English
• ISSNs: 1756-8722

Abstract

Abstract Background This report focuses on the adaptive phase I trial design aimed to find the clinically applicable dose for decitabine maintenance treatment after allogeneic hematopoietic stem cell transplantation in patients with higher-risk myelodysplastic syndrome and secondary acute myeloid leukemia. Methods The first cohort (three patients) was given the same initial daily dose of decitabine (5 mg/m2 /day, five consecutive days with 4-week intervals). In all cohorts, the doses for Cycles 2 to 4 were individualized using pharmacokinetic-pharmacodynamic modeling and simulations. The goal of dose individualization was to determine the maximum dose for each patient at which the occurrence of grade 4 (CTC-AE) toxicities for both platelet and neutrophil counts could be avoided. The initial doses for the following cohorts were also estimated with the data from the previous cohorts in the same manner. Results In all but one patient (14 out of 15), neutrophil count was the dose-limiting factor throughout the cycles. In cycles where doses were individualized, the median neutrophil nadir observed was 1100/mm3 (grade 2) and grade 4 toxicity occurred in 5.1 % of all cycles (while it occurred in 36.8 % where doses were not individualized). The initial doses estimated for cohorts 2 to 5 were 4, 5, 5.5, and 5 mg/m2 /day, respectively. The median maintenance dose was 7 mg/m2 /day. Conclusions We determined the acceptable starting dose and individualized the maintenance dose for each patient, while minimizing the toxicity using the adaptive approach. Currently, 5 mg/m2 /day is considered to be the most appropriate starting dose for the regimen studied. Trial registration Clinicaltrials.govNCT01277484