Dataset Information

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

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.

SUBMITTER: Gupta N

PROVIDER: S-EPMC4559079 | biostudies-literature | 2015 Sep

REPOSITORIES: biostudies-literature

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

Gupta Neeraj N Goh Yeow Tee YT Min Chang-Ki CK Lee Jae Hoon JH Kim Kihyun K Wong Raymond S M RS Chim Chor Sang CS Hanley Michael J MJ Yang Huyuan H Venkatakrishnan Karthik K Hui Ai-Min AM Esseltine Dixie-Lee DL Chng Wee Joo WJ

Journal of hematology & oncology 20150904

<h4>Background</h4>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.<h4>Methods</h4>Adult patients with measurable disease who had received 1-3 prior lines of therapy received oral ixazomib on days 1, 8, and ...[more]

PMID: 26337806

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Project description:BackgroundWe have performed a head to head comparison of all-oral triplet combination of ixazomib, lenalidomide and dexamethasone (IRD) versus lenalidomide and dexamethasone (RD) in patients with relapsed and refractory multiple myeloma (RRMM) in the routine clinical practice.MethodsA total of 344 patients treated with IRD (N = 127) or RD (N = 217) were selected for analysis from the Czech Registry of Monoclonal Gammopathies (RMG). Descriptive statistics were used to assess patient's characteristics associated with the respective therapy. The primary endpoint was progression free survival (PFS), secondary end points included response rates and overall survival (OS). Survival endpoints were plotted using Kaplan-Meier methodology at 95% Greenwood confidence interval. Univariable and multivariable Cox proportional hazards models were used to evaluate the effect of treatment regimens and the significance of uneven variables. Statistical tests were performed at significance level 0.05.ResultsIn the whole cohort, median PFS for IRD was 17.5 and for RD was 11.5 months favoring the all-oral triplet, p = 0.005; in patients within relapse 1-3, the median PFS was 23.1 vs 11.6 months, p = 0.001. The hazard ratio for PFS was 0.67 (95% confidence interval [CI] 0.51-0.89, p = 0.006). The PFS advantage translated into improved OS for patients treated with IRD, median 36.6 months vs 26.0 months (p = 0.008). The overall response rate (ORR) was 73.0% in the IRD group vs 66.2% in the RD group with a complete response rate (CR) of 11.1% vs 8.8%, and very good partial response (VGPR) 22.2% vs 13.9%, IRD vs RD respectively. The IRD regimen was most beneficial in patients ≤75 years with ISS I, II, and in the first and second relapse. Patients with the presence of extramedullary disease did not benefit from IRD treatment (median PFS 6.5 months). Both regimens were well tolerated, and the incidence of total as well as grade 3/4 toxicities was comparable.ConclusionsOur analysis confirms the results of the TOURMALINE-MM1 study and shows benefit of all-oral triplet IRD treatment versus RD doublet. It demonstrates that the addition of ixazomib to RD improves key survival endpoints in patients with RRMM in a routine clinical setting.

Dataset Information

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

Publications

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

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