J Clin Oncol 31, 2013 (suppl; abstr 8514)
Shaji Kumar, William Bensinger, Todd M. Zimmerman, Craig B. Reeder, James R. Berenson, Deborah Berg, Ai-Min Hui, Neeraj Gupta, Alessandra Di Bacco, Jiang Yu, Yaping Shou, Ruben Niesvizky; Mayo Clinic, Rochester, MN; Clinical Division, Fred Hutchinson Cancer Research Center, Seattle, WA; Department of Medicine, University of Chicago, Chicago, IL; Division of Hematology/Oncology, Mayo Clinic, Scottsdale, AZ; Institute for Myeloma and Bone Cancer Research, West Hollywood, CA; Millennium Pharmaceuticals, Inc., Cambridge, MA; Center of Excellence for Lymphoma and Myeloma, Weill Medical College of Cornell University, New York Presbyterian Hospital, New York, NY
Background: MLN9708 is an investigational, orally bioavailable, potent, reversible, specific inhibitor of the 20S proteasome that has demonstrated antitumor activity in in vivo models of MM. We report safety, activity and pharmacokinetics (PK) of weekly oral MLN9708 in a phase 1 trial in patients (pts) with relapsed and/or refractory MM after full enrollment (NCT00963820).
Methods: Pts received MLN9708 (days 1, 8, 15; 28-day cycles) at 0.24–3.95 mg/m2 (dose-escalation phase) and at the MTD, 2.97 mg/m2, in relapsed and refractory (RR), bortezomib (btz)-relapsed, PI-naïve, and prior carfilzomib (CZ) expansion cohorts. Adverse events (AEs) were graded by NCI-CTCAE v3.0. Response was assessed by IMWG uniform criteria.
Results: 60 pts (33 male, median age 64 yrs [40–79]) were enrolled, 32 in the dose-escalation phase and 31 to the expansion cohorts (11 RR, 10 btz-relapsed, 6 PI-naïve, 4 CZ; 2 RR and 1 btz-relapsed pts included from MTD dose-escalation cohort). Median time from MM diagnosis was 4.9 yrs (1.5–18.8). Median number of prior regimens was 6 (2–18), including btz, lenalidomide, thalidomide, and CZ in 83%, 95%, 52%, and 13%, respectively; 76% were refractory to last therapy (17% btz-refractory). At data cut-off (Nov 29, 2012) pts had received a median of 2 cycles (1–11); 5 pts remained on treatment. All-grade/grade ≥3 drug-related AEs were seen in 83%/52% of pts; common drug-related grade ≥3 AEs were thrombocytopenia (33%), diarrhea, neutropenia (17%), decreased appetite, fatigue, and lymphopenia (8%). 6 pts (10%) had drug-related PN (no grade ≥3). 5 pts discontinued due to drug-related AEs; 1 pt died on study due to an unrelated AE. By investigator assessment in 41 evaluable pts, responses included1 VGPR, 5 PR, 1 MR, and 15 with SD. MLN9708 was rapidly absorbed, with a terminal half-life of 4–12 days (supporting weekly dosing) and a proportional increase in plasma AUC with dose (0.8–3.95 mg/m2). PK data were similar across expansion cohorts.
Conclusions: Current data suggest weekly oral MLN9708 is generally well tolerated with infrequent PN, and shows activity in this heavily pretreated population with prior exposure to immunomodulatory drugs and btz.
Clinical trial information: NCT00963820