ORAL MLN9708, AN INVESTIGATIONAL PROTEASOME INHIBITOR, IN COMBINATION WITH MELPHALAN AND PREDNISONE IN PATIENTS WITH PREVIOUSLY UNTREATED MULTIPLE MYELOMA: A PHASE 1 STUDY

Sborník

Background. MLN9708 is an investigational oral, potent, reversible, and specific 20S proteasome inhibitor undergoing clinical investigation for the treatment of hematologic malignancies and solid tumors. The proteasome inhibitor bortezomib in combination with melphalan plus prednisone (MP) is recommended for patients with previously untreated multiple myeloma (MM) that are not eligible for transplant. Here we report phase 1 results of the first study of MLN9708 in combination with MP in patients with previously untreated MM (NCT01335685). Aims. To determine the safety, maximum tolerated dose (MTD), recommended phase 2 dose (RP2D), pharmacokinetics (PK), pharmacodynamics (PD), and anti-tumor activity of MLN9708 administered once- or twice-weekly in combination with MP in patients with previously untreated MM. Methods. Adults with previously untreated MM with measurable disease but ineligible for transplant were enrolled. All patients provided informed consent. Patients received twice-weekly (TW) or weekly (W) oral MLN9708: TW schedule, MLN9708 on days 1, 4, 8, 11, 22, 25, 29, and 32, and MP (9 mg/m² and 60 mg/m², respectively) days 1-4 of 42-day cycles; W schedule, MLN9708 on days 1, 8, and 15 and MP (6 mg/m² and 60 mg/m², respectively) days 1-4 of 28-day cycles. Dose-escalation proceeded from a fixed dose of 3 mg in both schedules using a standard 3+3 schema based on the occurrence of dose-limiting toxicities (DLTs) in cycle 1. Results. At data cut-off (Jan 27, 2012), 13 patients had been enrolled and included in the safety population, 7 to the TW (3 mg and 3.7 mg dose levels), and 6 to the W (3 mg and 4 mg dose levels) schedules. Median age was 78 years (range 65-84) and 73 years (range 66- 81) for the TW and W schedules, respectively; 29% and 50% were male, and 71% and 83% had ISS stage I/II disease. Patients are ongoing on treatment, with a median duration of treatment of 2.2 cycles for the TW and 3 cycles for the W schedule at time of data cut-off. One patient receiving 3.7 mg TW experienced DLTs of subileus and grade 3 rash. The MTD for MLN9708 has not been reached for either schedule. Safety data are shown in the Table 1.

Most common drug-related grade ≥3 adverse events (AEs) were neutropenia and thrombocytopenia; neutropenia occurred in 5 patients (3 on the TW schedule and 2 on the W schedule) and thrombocytopenia in 2 patients (both on the TW schedule). Three TW patients experienced drug-related serious AEs of neutropenia, subileus, vomiting, and pneumonia; 2 patients had serious AEs with W MLN9708, both unrelated. Thus far, of 6 TW response-evaluable patients, 4 patients achieved ≥PR (2 at each dose level, including 1 CR). Of 5 W response-evaluable patients, 3 achieved a PR. Dose escalation is ongoing. Updated data, including assessment of PK interaction, will be presented. Conclusions. These preliminary phase 1 data suggest that weekly and twice-weekly MLN9708 in combination with MP is generally well tolerated with manageable toxicities. Preliminary anti-tumor activity in patients with previously untreated MM was observed.

Haematologica, 2012; 97(s1):  118