Model-based adaptive phase I trial design of post-transplant decitabine maintenance in myelodysplastic syndrome

Journal of Hematology & Oncology

Dong-Seok Yim²  Seok Lee¹  Chang-Ki Min¹  Hee-Je Kim¹  Ki-Seong Eom¹  Sung-Eun Lee¹  Seung-Hwan Shin¹  Seung-Ah Yahng¹  Jae-Ho Yoon¹  Gab-jin Park²  Taegon Hong²  Sangil Jeon²  Jongtae Lee²  Yoo-Jin Kim¹  Seunghoon Han² 

[1] Catholic Blood and Marrow Transplantation Center, Seoul St. Mary’s Hospital, The Catholic University of Korea, 222 Banpo-Daero, Seochogu, Seoul, Republic of Korea;PIPET (Pharmacometrics Institute for Practical Education and Training), 222 Banpo-Daero, Seochogu, Seoul, Republic of Korea

关键词: Phase I clinical trial;    Population pharmacokinetics-pharmacodynamics;    Myelodysplastic syndrome;    Adaptive design;    Model-based drug development;   

Others  :  1233273
DOI  :  10.1186/s13045-015-0208-3

 received in 2015-08-13, accepted in 2015-09-28,  发布年份 2015

【 摘 要 】

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/m ² /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/mm ³(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/m ² /day, respectively. The median maintenance dose was 7 mg/m ² /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/m ² /day is considered to be the most appropriate starting dose for the regimen studied.

Trial registration

Clinicaltrials.gov NCT01277484

【 授权许可】

   
2015 Han et al.

【 图 表 】

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