• Neeraj Gupta, Yeow Tee Goh, Chang-Ki Min, Jae Hoon Lee, Kihyun Kim, Raymond S M Wong, Chor Sang Chim, Michael J Hanley, Huyuan Yang, Karthik Venkatakrishnan, Ai-Min Hui, Dixie-Lee Esseltine, and Wee Joo Chng.
• Clinical Pharmacology, Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited, Cambridge, MA, USA. Neeraj.Gupta@takeda.com.
• J Hematol Oncol. 2015 Sep 4; 8: 103.

BackgroundThe 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.MethodsAdult 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.ResultsForty-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.ConclusionsThe 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.Trial RegistrationThis study is registered at NCT01645930.

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