A phase 1/2 study of the oral proteasome inhibitor ixazomib in relapsed or refractory AL amyloidosis

Abstract

This phase 1/2 study assessed the safety, tolerability, and preliminary efficacy of the oral proteasome inhibitor (PI) ixazomib in patients with relapsed/refractory immunoglobulin light chain (AL) amyloidosis. Ixazomib was administered to adult patients with relapsed/refractory AL amyloidosis after 1 or more prior lines of therapy (including bortezomib) on days 1, 8, and 15 of 28-day cycles, for up to 12 cycles. Patients with less than partial response after 3 cycles received oral dexamethasone (40 mg, days 1-4) from cycle 4. A 3+3 dose-escalation phase was followed by 2 expansion cohorts (PI-naive and PI-exposed patients) at the maximum tolerated dose (MTD). Twenty-seven patients were enrolled: 11 during dose escalation (6 at 4.0 mg and 5 at 5.5 mg) and 16 during dose expansion (4.0 mg). Three patients experienced dose-limiting toxicities: 1 at 4.0 mg and 2 at 5.5 mg; the MTD was determined as 4.0 mg. Most common adverse events (AEs) included nausea, skin and subcutaneous tissue disorders (SSTD), diarrhea, and fatigue; grade 3 or higher AEs included dyspnea, fatigue, and SSTD. Overall, the hematologic response rate was 52% in patients treated at the MTD (n = 21). Organ responses were seen in 56% of patients (5 cardiac, 5 renal). Median hematologic progression-free survival was 14.8 months; 1-year progression-free and overall survival rates were 60% and 85%, respectively (median follow-up, 16.9 months). Weekly oral ixazomib appears to be active in patients with relapsed/refractory AL amyloidosis, with a generally manageable safety profile. The study was registered at clinicaltrials.gov as #NCT01318902 A phase 3 study is ongoing (#NCT01659658).

Conflict of interest statement

Conflict-of-interest disclosure: V.S. received research support from Celgene; Millennium Pharmaceuticals Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited; Onyx; and Prothena Biosciences, Inc. G.P. received honoraria and travel grants from Prothena Biosciences, Inc.; travel grants from Celgene; and advisory board for Janssen-Cilag. V.K. received honoraria from Celgene, Lundbeck, and Amgen. J.A.Z. received research support from Celgene and Millennium Pharmaceuticals Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited; consultancy for Millennium Pharmaceuticals Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited, and BMS, Janssen, Amgen, Prothena Biosciences, Inc., and Seattle Genetics. A.D.C. received honoraria and membership on the board of directors or advisory committee for Celgene, BMS, and Onyx. A.D. received research funding from Celgene; Millennium Pharmaceuticals Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited; and Janssen Research & Development. A.J. received research funding from Celgene; honoraria from Millennium Pharmaceuticals Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited; Janssen; and Celgene. S.O.S. received research funding from Celgene and Janssen and honoraria from Janssen, Prothena Biosciences, Inc., GlaxoSmithKline, and Celgene. D.B., H.Y., N.G., and A.-M.H. are employed by Millennium Pharmaceuticals Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited. R.L.C. had a consultancy and membership on board of directors or advisory committee for Millennium Pharmaceuticals Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited, and received research funding from Millennium Pharmaceuticals Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited. G.M. had a consultancy from Millennium Pharmaceuticals Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited; Pfizer; Janssen; and Prothena Biosciences, Inc.

© 2017 by The American Society of Hematology.

Figures

Figure 1.

Waterfall plot of percentage reduction in dFLC for all hematologic response-evaluable patients (n = 21).

Figure 2.

Survival in patients who received ixazomib 4.0 mg (n = 22). (A) PFS; (B) overall survival.