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Clinical Trial
. 2015 Sep 4:8:103.
doi: 10.1186/s13045-015-0198-1.

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

Neeraj Gupta  1 , Yeow Tee Goh  2 , Chang-Ki Min  3 , Jae Hoon Lee  4 , Kihyun Kim  5 , Raymond S M Wong  6 , Chor Sang Chim  7 , Michael J Hanley  8 , Huyuan Yang  9 , Karthik Venkatakrishnan  10 , Ai-Min Hui  11 , Dixie-Lee Esseltine  12 , Wee Joo Chng  13   14
Affiliations
Clinical Trial

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

Neeraj Gupta et al. J Hematol Oncol. .

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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Figures

Fig. 1
Fig. 1
Mean plasma concentration–time profiles of ixazomib in combination with lenalidomide–dexamethasone on a day 1 and b day 15 of cycle 1 (safety population)
Fig. 2
Fig. 2
Ixazomib dose-normalized AUC0–168 on day 1 (a) and day 15 (b) of cycle 1 in East Asian and Western patients. Box plots represent the 25th, 50th, and 75th percentiles; whiskers denote the 10th and 90th percentiles. East Asian patients received ixazomib in combination with lenalidomide–dexamethasone. Western patients received ixazomib as a single agent or in combination with lenalidomide–dexamethasone
See this image and copyright information in PMC

References

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