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).

Immunoglobulin light chain amyloidosis: 2020 update on diagnosis, prognosis, and treatment

“…Unfortunately, neuropathy was reported in 44% 145 . The non‐neurotoxic proteosome inhibitor, Ixazomib, in relapse‐refractory AL produced hematologic response in 52%, and organ response in 56%, at a dose of 4 mg by mouth weekly 146 . Ixazomib, with dexamethasone, in a phase 3 trial compared with standard of care demonstrated superior time to organ failure or death 147 .…”

Daratumumab proves safe and highly effective in AL amyloidosis

“…Treatment is more variable for relapsed disease. IMiDs as well as the proteasome inhibitor, ixazomib, are used in this setting, with response rates ranging between 40% to 60% in small prospective studies (Dispenzieri et al , ; Sanchorawala et al , ). Each of these drugs is associated with myelosuppression, and IMiDs are associated with cardiac side effects in AL Comenzo et al , .…”

Novel pharmacotherapies for cardiac amyloidosis

“…In a phase 1/2 study of relapsed/refractory AL patients, ixazomib, a potent oral proteasome inhibitor, had a hematologic response rate of 52% with diarrhea, nausea, fatigue, and soft tissue disorders as the most common adverse effects (Sanchorawala et al, 2017). Ixazomib is currently being studied in a phase 3 trial of ixazomib plus dexamethasone in patients with relapsed or refractory AL amyloidosis ( TOURMALINE-AL1 , NCT01659658 ).…”