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


BACKGROUND
Clinicaltrials.gov NCT01277484.
Department of Pharmacology, College of Medicine, The Catholic University of Korea, 222 Banpo-Daero, Seochogu, Seoul, Republic of Korea. waystolove@catholic.ac.kr.|PIPET (Pharmacometrics Institute for Practical Education and Training), 222 Banpo-Daero, Seochogu, Seoul, Republic of Korea. waystolove@catholic.ac.kr.
Seunghoon
S
Han
Catholic Blood and Marrow Transplantation Center, Seoul St. Mary's Hospital, The Catholic University of Korea, 222 Banpo-Daero, Seochogu, Seoul, Republic of Korea. yoojink@catholic.ac.kr.
Yoo-Jin
YJ
Kim
Department of Pharmacology, College of Medicine, The Catholic University of Korea, 222 Banpo-Daero, Seochogu, Seoul, Republic of Korea. massive2@catholic.ac.kr.|PIPET (Pharmacometrics Institute for Practical Education and Training), 222 Banpo-Daero, Seochogu, Seoul, Republic of Korea. massive2@catholic.ac.kr.
Jongtae
J
Lee
Department of Pharmacology, College of Medicine, The Catholic University of Korea, 222 Banpo-Daero, Seochogu, Seoul, Republic of Korea. gainsay98@catholic.ac.kr.|PIPET (Pharmacometrics Institute for Practical Education and Training), 222 Banpo-Daero, Seochogu, Seoul, Republic of Korea. gainsay98@catholic.ac.kr.
Sangil
S
Jeon
Department of Pharmacology, College of Medicine, The Catholic University of Korea, 222 Banpo-Daero, Seochogu, Seoul, Republic of Korea. tg_cpt.hong@samsung.com.|PIPET (Pharmacometrics Institute for Practical Education and Training), 222 Banpo-Daero, Seochogu, Seoul, Republic of Korea. tg_cpt.hong@samsung.com.
Taegon
T
Hong
Department of Pharmacology, College of Medicine, The Catholic University of Korea, 222 Banpo-Daero, Seochogu, Seoul, Republic of Korea. oopsmr@catholic.ac.kr.|PIPET (Pharmacometrics Institute for Practical Education and Training), 222 Banpo-Daero, Seochogu, Seoul, Republic of Korea. oopsmr@catholic.ac.kr.
Gab-Jin
GJ
Park
Catholic Blood and Marrow Transplantation Center, Seoul St. Mary's Hospital, The Catholic University of Korea, 222 Banpo-Daero, Seochogu, Seoul, Republic of Korea. royoon@catholic.ac.kr.
Jae-Ho
JH
Yoon
Catholic Blood and Marrow Transplantation Center, Seoul St. Mary's Hospital, The Catholic University of Korea, 222 Banpo-Daero, Seochogu, Seoul, Republic of Korea. saymd@catholic.ac.kr.
Seung-Ah
SA
Yahng
Catholic Blood and Marrow Transplantation Center, Seoul St. Mary's Hospital, The Catholic University of Korea, 222 Banpo-Daero, Seochogu, Seoul, Republic of Korea. chironhmt@catholic.ac.kr.
Seung-Hwan
SH
Shin
Catholic Blood and Marrow Transplantation Center, Seoul St. Mary's Hospital, The Catholic University of Korea, 222 Banpo-Daero, Seochogu, Seoul, Republic of Korea. lee86@catholic.ac.kr.
Sung-Eun
SE
Lee
Catholic Blood and Marrow Transplantation Center, Seoul St. Mary's Hospital, The Catholic University of Korea, 222 Banpo-Daero, Seochogu, Seoul, Republic of Korea. dreom@catholic.ac.kr.
Ki-Seong
KS
Eom
Catholic Blood and Marrow Transplantation Center, Seoul St. Mary's Hospital, The Catholic University of Korea, 222 Banpo-Daero, Seochogu, Seoul, Republic of Korea. cumckim@catholic.ac.kr.
Hee-Je
HJ
Kim
Catholic Blood and Marrow Transplantation Center, Seoul St. Mary's Hospital, The Catholic University of Korea, 222 Banpo-Daero, Seochogu, Seoul, Republic of Korea. ckmin@catholic.ac.kr.
Chang-Ki
CK
Min
Catholic Blood and Marrow Transplantation Center, Seoul St. Mary's Hospital, The Catholic University of Korea, 222 Banpo-Daero, Seochogu, Seoul, Republic of Korea. leeseok@catholic.ac.kr.
Seok
S
Lee
Department of Pharmacology, College of Medicine, The Catholic University of Korea, 222 Banpo-Daero, Seochogu, Seoul, Republic of Korea. yimds@catholic.ac.kr.|PIPET (Pharmacometrics Institute for Practical Education and Training), 222 Banpo-Daero, Seochogu, Seoul, Republic of Korea. yimds@catholic.ac.kr.
Dong-Seok
DS
Yim
D000328:Adult; D000368:Aged; D000964:Antimetabolites, Antineoplastic / Q000493:pharmacokinetics / Q000627:therapeutic use; D001374:Azacitidine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D003131:Combined Modality Therapy; D000077209:Decitabine; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D018380:Hematopoietic Stem Cell Transplantation / Q000379:methods*; D006801:Humans; D060046:Maintenance Chemotherapy / Q000379:methods; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D009190:Myelodysplastic Syndromes / Q000628:therapy*; D012107:Research Design; D014184:Transplantation, Homologous; D016896:Treatment Outcome; D055815:Young Adult
D000964:Antimetabolites, Antineoplastic; D000077209:Decitabine; D001374:Azacitidine