Phase 1 Study of the Investigational Proteasome Inhibitor Ixazomib Alone or in Combination with Lenalidomide–Dexamethasone (Rd) in Japanese Patients (Pts) with Relapsed and/or Refractory Multiple Myeloma (RRMM)

Background

Ixazomib is the first oral proteasome inhibitor to be investigated clinically for the treatment of MM. Phase 1 studies have shown single-agent activity and manageable toxicities in RRMM (Kumar et al. Blood 2014) and phase 1/2 studies have suggested the feasibility and activity of weekly oral ixazomib plus Rd in previously untreated MM (Kumar et al. ASH 2012; Richardson et al. ASH 2013). These findings have led to ongoing phase 3 trials of weekly ixazomib 4 mg + Rd in RRMM and previously untreated MM. However, the early-phase studies were conducted in Western pts. This phase 1, open-label multicenter study aimed to determine the safety, tolerability, and pharmacokinetics (PK) of weekly ixazomib alone or with Rd in Japanese pts with RRMM (Japic Clinical Trials Information no. 121822).

Methods

Primary objectives were to evaluate the safety and tolerability, including dose-limiting toxicities (DLTs) and adverse events (AEs), and the PK of ixazomib alone or with Rd. A secondary objective was evaluation of antitumor activity. Japanese pts aged ≥20 years with RRMM who had received at least 2 prior regimens, which must have included bortezomib, thalidomide or lenalidomide, and corticosteroids, were eligible. All had measurable disease and ECOG performance status of 0–2. Pts with grade ≥2 peripheral neuropathy or grade ≥2 diarrhea at study entry were excluded. Pts received ixazomib 4 mg on days 1, 8, and 15 of 28-day cycles, alone or with Rd (lenalidomide 25 mg on days 1–21, dexamethasone 40 mg on days 1, 8, 15, and 22), per the regimen used in the ongoing phase 3 trials. AEs were graded per NCI-CTCAE v4.03. Blood samples for PK analysis were taken at multiple time points prior to and after dosing on days 1 and 15 of cycle 1. Responses were assessed per IMWG uniform response criteria.

Results

Fourteen pts were enrolled; 8 (57%) were male, median age was 62.5 yrs (range 53–71), 4 pts were aged ≥65 yrs, median number of prior therapies was 7. Seven pts received single-agent ixazomib and 7 received ixazomib + Rd. One pt in each cohort was excluded from the DLT-evaluable population. Two patients experienced DLTs in cycle 1: 1 pt receiving single-agent ixazomib had grade 4 thrombocytopenia and grade 3 diarrhea, hypertension, hypokalemia, hyponatremia, and nausea; 1 pt in the ixazomib + Rd cohort had grade 4 thrombocytopenia and neutropenia. All events were considered treatment-related. At data cut-off (Jan 6 2014), 6 pts remained on treatment and 8 had discontinued due to: progressive disease (PD; n=3), AEs (n=3), symptomatic deterioration, and protocol violation (each n=1). At data cut-off, pts (n=14) had received a median of 6 cycles of ixazomib (range 1–21); the 7 pts in the ixazomib + Rd cohort had received a median of 4 cycles (range 1–12) of ixazomib + Rd. Thirteen (93%) pts experienced treatment-related AEs; the most common were neutropenia (71%), thrombocytopenia (71%), leukopenia (64%), lymphopenia (57%), and diarrhea (50%). There were no cases of peripheral neuropathy. Nine (64%) pts had grade ≥3 AEs; the most common were lymphopenia (50%), neutropenia (43%), and thrombocytopenia (36%). Two (14%) pts (single-agent cohort) had serious AEs (grade 2 bronchitis in 1 pt, and grade 4 thrombocytopenia and grade 3 hypokalemia in 1 pt). Three pts discontinued due to AEs; 1 due to diarrhea in the single-agent cohort, and 1 due to neutropenia and 1 due to thrombocytopenia in the ixazomib + Rd cohort. There were no deaths. PK data showed ixazomib was rapidly absorbed with a T_max at 1.08–1.83 hrs. Terminal half-life (geometric mean) was 5.7 days for single-agent ixazomib and 5.2 days for ixazomib + Rd. There were no substantial differences in the ixazomib PK profile between the two cohorts. Thirteen pts were response-evaluable. One pt (ixazomib + Rd cohort) had a partial response; at data cut-off, this pt remained in response with a 100% M-protein reduction (unconfirmed VGPR) and duration of response of ~10.8 months. Seven pts had stable disease (including 3 with M-protein reductions of 25–50%), 2 had PD, and 3 were not assessable.

Conclusions

These data suggest that ixazomib 4 mg alone or with Rd is feasible and tolerable in Japanese pts with RRMM. The AEs were manageable, reflecting the AE profile seen in Western populations, supporting the use of this dose and schedule in Japanese pts.