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01.12.2015 | Research Article | Ausgabe 1/2015 Open Access

Journal of Hematology & Oncology 1/2015

Pharmacokinetics and safety of ixazomib plus lenalidomide–dexamethasone in Asian patients with relapsed/refractory myeloma: a phase 1 study

Zeitschrift:
Journal of Hematology & Oncology > Ausgabe 1/2015
Autoren:
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, Wee Joo Chng
Wichtige Hinweise

Electronic supplementary material

The online version of this article (doi:10.​1186/​s13045-015-0198-1) contains supplementary material, which is available to authorized users.

Competing interests

NG, MJH, HY, KV, AMH, and DLE are employees of Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited. YTG received honoraria (Novartis, Janssen, Roche, Gilead Sciences, Bristol Myers Squibb) and research funding (Novartis, Janssen). RW received honoraria (Janssen, Novartis, Amgen, Boehringer Ingelheim, GlaxoSmithKline, Sanofi, Bayer) and research funding (Roche, Merck, Novartis, Amgen, Janssen, Boehringer Ingelheim, Bayer, GlaxoSmithKline, Biogen-Idec, Pfizer, Takeda). CSC received honoraria (Takeda). WJC received honoraria (Janssen, Celgene, Takeda, Novartis, Roche, Amgen) and research funding (Roche, Merck, Takeda). The other authors declare that they have no competing interest.

Authors’ contributions

NG, KV, AMH, and DLE designed the research. NG, YTG, CKM, JHL, KK, RSMW, CSC, MJH, HY, KV, and WJC performed the research. NG, MJH, YTG, CKM, JHL, KK, RSMW, CSC, and WJC collected the data. NG, MJH, and HY performed the statistical analysis. NG, MJH, HY, KV, AMH, and DLE analyzed and interpreted the data. NG, MJH, HY, and KV wrote the manuscript. All authors reviewed the draft and approved the final version of the manuscript for submission.

Abstract

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.

Trial registration

This study is registered at NCT01645930.

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Zusatzmaterial
Additional file 1: Figure S1. Waterfall plot of the best percent change in M-protein from baseline. Figure S2. Flowchart for ixazomib dose determination during cycle 1.
13045_2015_198_MOESM1_ESM.docx
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