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ASH 2011: Dr. Richardson - Investigational Agent MLN9708, An Oral Proteasome Inhibitor, in Patients (Pts) with Relapsed and/or Refractory Multiple Myeloma (MM): Results From the Expansion Cohorts of a Phase 1 Dose-Escalation Study
Paul G. Richardson, MD
Dana-Farber Cancer Institute
Boston, Massachusetts, USA
12.07.11

Background: The investigational agent MLN9708 is the first oral proteasome inhibitor (PI) to enter clinical investigation in MM pts. MLN9708 has shown antitumor activity in solid tumor and hematologic malignancy xenograft models, including in vivo models of MM. The primary objectives of this study (NCT00932698) were to determine safety/tolerability, maximum tolerated dose (MTD), and recommended phase 2 dose of oral MLN9708 in pts with relapsed and/or refractory MM. Secondary objectives included evaluation of response rate and characterization of pharmacokinetics (PK, of MLN2238, the biologically active hydrolysis product) and pharmacodynamics (20S proteasome inhibition in blood).

Methods: Pts aged ≥18 years with measurable disease and no grade ≥2 peripheral neuropathy (PN) were eligible. For the dose-escalation phase (3+3 design), pts required ≥2 prior therapies, which must have included bortezomib, thalidomide or lenalidomide, and corticosteroids. Pts could have received other PIs. At the MTD, pts were enrolled to four expansion cohorts: relapsed and refractory cohort (progressive disease [PD] on therapy or <60 days after last dose of most recent prior therapy), bortezomib-relapsed cohort (relapsed after previous bortezomib but not refractory), PI-naïve cohort (relapsed after ≥1 therapy, including thalidomide or lenalidomide and corticosteroids), and prior carfilzomib cohort (last dose of carfilzomib 21–60 days prior to first dose of MLN9708). MLN9708 was administered orally on days 1, 4, 8, and 11 of 21-day cycles. Adverse events (AEs) were graded per NCI-CTCAE v3.0. Response was assessed per modified EBMT/IMWG uniform criteria. Blood samples were obtained at multiple time points on days 1 and 11, cycle 1, for PK and pharmacodynamic analyses; parameters were calculated using noncompartmental methods (WinNonlin software v5.3).

Results: As of June 29 2011, 53 pts have been enrolled (53% male). Median age was 66 years (range 50–86), median time since initial MM diagnosis was 4.6 years (range 1.1–24.3), and median number of prior therapies was 4 (range 1–28); 55% of pts had received stem cell transplant, 92%, 80%, 56%, and 4% had prior bortezomib, lenalidomide, thalidomide, and carfilzomib, respectively, and 47% were refractory to last therapy, including 28% who were bortezomib-refractory. During dose escalation, 27 pts received MLN9708 0.24–2.23 mg/m2; the MTD was determined as 2.0 mg/m2. To date, 32 pts have been enrolled to the expansion cohorts (including 6 from the dose-escalation phase): 17, 11, and 4 to the relapsed and refractory, bortezomib-relapsed, and PI-naïve cohorts, respectively. Overall, pts have received a median of 3 cycles (range 1–17), with 6 (11%) receiving ≥12 cycles. At data cut-off, 58% of pts had discontinued, mainly due to PD (36%). Safety profiles appeared similar between dose-escalation and expansion cohorts. Overall, 87% of pts experienced drug-related AEs, the most common being fatigue (45%), thrombocytopenia (30%), nausea (26%), diarrhea (25%), vomiting, and rash (each 23%). Only four (8%) pts had drug-related PN (three grade 1, one grade 2); all had grade 1 PN (n=3) or paresthesias (n=1) at baseline. Overall, 58% had grade ≥3 AEs, 21% had dose reductions, and 6% discontinued due to AEs (thrombocytopenia, arthralgia, hypoxia). Two pts died on study due to PD and a cardiac disorder, considered unrelated. To date, of 36 evaluable pts, six have achieved minimal response or better, including two with partial responses (in the 1.2 and 2.23 mg/m2 cohorts), with duration of disease control of up to 11.3 months; all 6 pts remain in response. Another 22 pts have achieved stable disease, which also proved durable with stabilization for up to 9.9 months. MLN9708 was rapidly absorbed with MLN2238 Tmax of 0.5–1.25 hours and terminal half-life of approximately 4–5 days after multiple MLN9708 dosing. MLN2238 plasma exposure appeared to increase proportionally with increasing MLN9708 dose from 0.8–2.23 mg/m2. Maximal 20S proteasome inhibition in blood was immediate and dose-dependent.

Conclusions: Current data suggest that single-agent MLN9708 may result in clinical activity in heavily pretreated relapsed and/or refractory MM pts, including durable disease control, and is generally well tolerated, with infrequent PN. Updated information for all cohorts, plus data from an analysis of candidate biomarkers of responsiveness to treatment with MLN9708, will be presented.


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