MLN0128 (INK128), an Investigational Oral Dual TORC1/2 Inhibitor, in Patients (pts) with Relapsed or Refractory Multiple Myeloma (MM), Non-Hodgkin's Lymphoma (NHL), or Waldenstrom Macroglobulinemia (WM): Preliminary Results From a Phase 1 Dose-Escalation Study

MLN0128 is an investigational, oral, potent, and selective, ATP site inhibitor of the mTOR complexes 1 and 2 (TORC1/2), and is structurally and mechanistically distinct from rapamycin and rapalogs, which primarily target TORC1. Constitutive activation of the mTOR pathway has been demonstrated in MM cell lines and primary pt samples; dual TORC1/2 inhibition has been shown to be more active than TORC1 inhibition alone. MLN0128 has been shown to inhibit proliferation and induce apoptosis in MM cell lines and pt samples (Maiso et al. Blood 2011); mTOR activation has also been seen in NHL and WM, providing the rationale for investigation of MLN0128 in these diseases. The primary objectives of this phase 1 study, the first report of TORC1/2 inhibition in MM and B cell malignancies, are to determine safety/tolerability and the maximum tolerated dose (MTD) of multiple dosing schedules of MLN0128 in relapsed/refractory MM, NHL or WM. Secondary objectives include evaluation of pharmacokinetics (PK), pharmacodynamics, and preliminary antitumor activity.

Eligible pts were aged ≥18 yrs with ECOG performance status 0–2, and included pts with relapsed/refractory MM/WM, and pts with NHL who had failed/were ineligible for standard-of-care therapy. Pts received oral MLN0128 daily (QD), or QD for 3 days on and 4 days off each week (QDx3d QW), in 28-day cycles, for ≤1 year. Dose was escalated using a modified Fibonacci schema (standard 3+3 design) based on dose-limiting toxicities (DLTs) in cycle 1. Adverse events (AE) were graded using NCI-CTCAE v4.0. Blood samples were collected at multiple timepoints for PK analysis. Response was assessed using the IMWG uniform response criteria (MM; plus EBMT criteria for minimal response [MR]), IWG revised response criteria (NHL), and updated Third International Workshop criteria (WM).

At data cut-off (June 18, 2012) 37 pts (30 MM; 4 NHL – 2 DLBCL, 1 mantle cell, 1 lymphoplasmacytic lymphoma [LL]; 3 WM) had been enrolled to 6 dose levels (Table). Median age was 60 yrs (range 46–85), 20 were male, and median number of prior systemic therapies was 2 (range 1–10) including chemotherapy in 89%, autologous transplant in 46%, and steroids in 38%. DLTs are shown in the table. The QD MTD is 6 mg; the MTD for QDx3d QW has not yet been defined. Pts have been treated for a median of 3 cycles (range 1–8); 9 (24%) received ≥4 cycles, and 3 (8%) are ongoing. Pts discontinued due to progressive disease (n=14), pt/investigator decision (n=10), AE (n=4), or multiple/other reasons (n=6). Overall, 89% of pts had ≥1drug-related AE, the most common were nausea (43%), fatigue (41%), hyperglycemia (35%), thrombocytopenia (32%), mucosal inflammation, vomiting, and anemia (each 19%). Overall, 43% of pts had drug-related grade 3/4 AEs, including thrombocytopenia (16%), fatigue (8%), mucosal inflammation, and neutropenia (each 5%); 57% had dose reductions/modifications, and 27% discontinued due to AEs. Overall, 19% of pts had serious AEs, none were considered related to MLN0128. One pt with advanced MM and multiple plasmacytomas who had had several relapses on prior therapies received two doses of 2 mg QD MLN0128 and subsequently died from a subdural hemorrhage, considered unrelated to MLN0128. The pt had a history of pneumonia and was receiving anticoagulation therapy. MLN0128 exhibited a dose-dependent increase in exposure with a plasma half-life of ∼8 hours, and did not accumulate in plasma with repeat dosing. Among 27 pts evaluable for confirmed responses, 1 MM pt (7 mg QD) achieved a MR lasting ∼2 months, and 13 MM pts (2 at 2 mg QD, 4 each at 4 mg QD and 7 mg QD, 2 at 9 mg QDx3d QW, and 1 at 12 mg QDx3d QW) and 2 WM pts (at 6 mg QD and 9 mg QDx3d QW) had stable disease.

To date, in this first study of TORC1/2 inhibition in MM and B cell malignancies, oral MLN0128 has been observed as generally well tolerated, with a limited incidence of hyperglycemia, a toxicity associated with PI3k/Akt/mTOR pathway inhibition (Busaidy et al. J Clin Oncol 2012). The preliminary antitumor activity supports further research in this pt population.

Ghobrial:Millennium pharmaceuticals Inc.: Membership on an entity's Board of Directors or advisory committees; Onyx: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Off Label Use: Use of the investigational agent MLN0128, an oral TORC1/2 inhibitor, in the treatment of relapsed and/or refractory MM, NHL, or WM. Siegel:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Millennium pharmaceuticals Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Onyx: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Vij:Millennium Pharmaceuticals Inc.: Speakers Bureau. Wolf:Millennium Pharmaceuticals, Inc.: Honoraria, Speakers Bureau. Matous:Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Millennium Pharmaceuticals, Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees. Lipman:Millennium Pharmaceuticals, Inc.: Employment, offered Takeda stock as part of company long term incentive plan Other. Patel:Millennium Pharmaceuticals, Inc.: Employment, offered Takeda stock as part of company long term incentive plan Other. Le:Intellikine, LLC.: Former employee and stockholder Other. Rommel:Intellikine, LLC.: Former employee and stockholder Other. Berk:Intellikine, LLC. : Former employee and stockholder, Former employee and stockholder Other; Millennium Pharmaceuticals, Inc.: Consultancy.