Phase 1 study of twice-weekly ixazomib, an oral proteasome inhibitor, in relapsed/refractory multiple myeloma patients

Abstract

Key Points Twice-weekly oral ixazomib appears tolerable, with no severe neuropathy seen to date, in heavily pretreated multiple myeloma patients. These phase 1 data suggest clinical activity including 76% stable disease or better, with durable responses and sustained disease control.

Phase 1 study of weekly dosing with the investigational oral proteasome inhibitor ixazomib in relapsed/refractory multiple myeloma

“…Nausea, vomiting, and diarrhea were among the most common toxicities with bortezomib in the phase 3 Assessment of Proteasome Inhibition for Extending Remissions (APEX) trial of bortezomib versus dexamethasone. 17 Similarly, in the current study and in the twice-weekly dosing study of ixazomib, 38 gastrointestinal toxicity was among the most common AEs. Fatigue, one of the most common toxicities observed in the current study, was also reported commonly with bortezomib.…”

“…17 The overall rate of drug-related skin toxicity (all AEs within the MedDRA system organ class) was 22% in the current study, including 3% grade 3 events: 1 of the 3 DLTs was grade 3 skin rash, albeit at the highest ixazomib dose level (above the MTD), and 1 patient in the MTD expansion cohorts had grade 3 papular rash. Importantly, rash was reported as a DLT in the parallel trial of twice-weekly ixazomib 38 as well as in a phase 1/2 study of weekly ixazomib in combination with lenalidomide and dexamethasone, for which rash is an overlapping toxicity with lenalidomide. 39 Given the relatively low overall frequency of this AE, it is possible that the development of rash is a dosedependent effect.…”

“…In the current study, we determined the MTD of weekly ixazomib to be 2.97 mg/m 2 , which contrasts with the MTD of 2.0 mg/m 2 determined for twice-weekly ixazomib. 38 Moreover, less frequent dosing may favorably affect the toxicity profile, given the differences observed between the 2 phase 1 trials evaluating the weekly and twice-weekly dosing schedules. However, accommodating for cycle-length differences with the 2 schedules, the weekly planned doses of ixazomib were similar, at 2.25 and 2.67 mg/m 2 for the weekly and twice-weekly schedules, respectively, resulting in the delivery of similar cumulative doses.…”

A pharmacokinetics and safety phase 1/1b study of oral ixazomib in patients with multiple myeloma and severe renal impairment or end‐stage renal disease requiring haemodialysis

“…The safety, tolerability, pharmacokinetics (PK), pharmacodynamics and clinical activity of the oral proteasome inhibitor ixazomib have been assessed previously in phase 1 and phase 1–3 studies in relapsed and/or refractory MM (RRMM) and newly diagnosed MM, relapsed or refractory systemic light‐chain amyloidosis (RRAL), lymphoma and solid tumours (Assouline et al , 2014; Kumar et al , 2014a,b; Merlini et al , 2014; Richardson et al , 2014; Gupta et al , 2015a; Moreau et al , 2015a; Smith et al , 2015). Among these cancer types, the efficacy of ixazomib has been particularly noted in MM.…”

Selective Toxicity of Investigational Ixazomib for Human Leukemia Cells Expressing Mutant Cytoplasmic NPM1: Role of Reactive Oxygen Species

“…Its substantial oral bioavailability and weekly or twice-weekly scheduling (13) are additional attractive properties for a disease, such as AML, which primarily affects an elderly population that may not tolerate intensive treatment regimens. In addition, ixazomib has significantly less neurotoxicity than bortezomib and has displayed a manageable safety profile in early-phase clinical trials in refractory and heavily pretreated myeloma populations (14,15). This improved tolerability profile positions ixazomib as a promising antileukemic agent for maintenance therapy or for combination therapy with other antileukemic drugs in the treatment of AML.…”