Pharmacokinetics and safety of ixazomib plus lenalidomide-dexamethasone in Asian patients with relapsed/refractory myeloma: a phase 1 study.
BACKGROUND
The oral proteasome inhibitor ixazomib is under phase 3 clinical investigation in multiple myeloma (MM) in combination with lenalidomide-dexamethasone. This study was conducted to investigate the pharmacokinetic and safety profiles of ixazomib, administered with lenalidomide-dexamethasone, in East Asian patients with relapsed/refractory MM.


METHODS
Adult patients with measurable disease who had received 1-3 prior lines of therapy received oral ixazomib on days 1, 8, and 15, lenalidomide (25 mg) on days 1-21, and dexamethasone (40 mg) on days 1, 8, 15, and 22, in 28-day cycles. Primary objectives were to characterize ixazomib plasma pharmacokinetics, determine the recommended phase 2/3 dose, and evaluate safety and tolerability.


RESULTS
Forty-three patients were enrolled. No dose-limiting toxicities were reported for the first six patients receiving ixazomib (4.0 mg), confirming this as the recommended phase 2/3 dose. Ixazomib was rapidly absorbed with a median T max of 1.5 h on day 1 and 2.0 h on day 15 of cycle 1 and had a geometric mean terminal half-life of 6.1 days. Twenty-one (49%) patients had at least one drug-related grade ≥3 adverse event (AE); the most common were neutropenia (19%), diarrhea (14%), and thrombocytopenia (12%). Twenty-eight of 43 (65%) response-evaluable patients had at least a partial response. The recommended phase 2/3 dose for ixazomib was determined to be 4.0 mg.


CONCLUSIONS
The all-oral combination of ixazomib plus lenalidomide-dexamethasone appeared active and well tolerated at 4.0 mg. Consequently, East Asian patients enrolled in phase 3 studies are receiving the same ixazomib dose as patients in other regions.


BACKGROUND
This study is registered at NCT01645930.
Clinical Pharmacology, Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited, Cambridge, MA, USA. Neeraj.Gupta@takeda.com.
Neeraj
N
Gupta
Singapore General Hospital, Singapore, Singapore. goh.yeow.tee@sgh.com.sg.
Yeow Tee
YT
Goh
Seoul St Mary's Hospital, Seoul, South Korea. ckmin@catholic.ac.kr.
Chang-Ki
CK
Min
Gachon University Gil Medical Center, Incheon, South Korea. jhlee@gilhospital.com.
Jae Hoon
JH
Lee
Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea. kihyunkimk@gmail.com.
Kihyun
K
Kim
Department of Medicine and Therapeutics, Prince of Wales Hospital, Sir Y. K. Pao Centre for Cancer, The Chinese University of Hong Kong, Hong Kong, China. raymondwong@cuhk.edu.hk.
Raymond S M
RS
Wong
Queen Mary Hospital, Hong Kong, China. jcschim@hku.hk.
Chor Sang
CS
Chim
Clinical Pharmacology, Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited, Cambridge, MA, USA. Michael.Hanley@takeda.com.
Michael J
MJ
Hanley
Biostatistics, Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited, Cambridge, MA, USA. Huyuan.Yang@takeda.com.
Huyuan
H
Yang
Clinical Pharmacology, Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited, Cambridge, MA, USA. Karthik.Venkatakrishnan@takeda.com.
Karthik
K
Venkatakrishnan
Oncology Clinical Research, Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited, Cambridge, MA, USA. ai-min.hui@takeda.com.
Ai-Min
AM
Hui
Oncology Clinical Research, Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited, Cambridge, MA, USA. Dixie-Lee.Esseltine@takeda.com.
Dixie-Lee
DL
Esseltine
Cancer Science Institute, National University of Singapore, Singapore, Republic of Singapore. mdccwj@nus.edu.sg.|National University Cancer Institute, National University Health System, Singapore, Republic of Singapore. mdccwj@nus.edu.sg.
Wee Joo
WJ
Chng
D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001208:Asia; D001896:Boron Compounds / Q000493:pharmacokinetics / Q000627:therapeutic use*; D003907:Dexamethasone / Q000493:pharmacokinetics / Q000627:therapeutic use*; D005260:Female; D005998:Glycine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D006801:Humans; D000077269:Lenalidomide; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma / Q000188:drug therapy*; D012008:Recurrence; D013792:Thalidomide / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use
D000970:Antineoplastic Agents; D001896:Boron Compounds; D013792:Thalidomide; C548400:ixazomib; D003907:Dexamethasone; D000077269:Lenalidomide; D005998:Glycine