Phase 1 Study Of Investigational Agent MLN8237 (Alisertib) + Rituximab ± Vincristine In Patients (Pts) With Relapsed/Refractory (Rel/Ref) Aggressive B-Cell Lymphomas

Amplification and/or over-expression of the mitotic Aurora A kinase (AAK) have been reported in a variety of tumors. The investigational, selective, AAK inhibitor MLN8237 (alisertib) has shown signs of anti-tumor activity in pts with hematologic malignancies including aggressive non-Hodgkin lymphoma (NHL). Over-expression of AAK leads to resistance to microtubule targeted agents such as vincristine (V) and inhibiting AAK leads to synergy in the presence of these agents (Mahadevan D et al. CCR 2012). The combination of MLN8237 (M) + rituximab (R) ± V has shown synthetic lethality in pre-clinical B-NHL mouse models (ibid) supporting clinical evaluation of this combination; we report the safety and recommended phase 2 dose (RP2D) from the phase 1 clinical data of this MR ± V combination in pts with aggressive B-NHL.

Adults with CD20+ B-NHL after 1–4 prior regimens (including ASCT) and ECOG PS 0–2 were eligible. In part 1 (MR), pts received one dose level of M 50 mg BID days 1–7 + R 375 mg/m² IV day 1 in 21-day cycles (up to 8) in combination, followed by single agent M. In part 2 (MRV), M dose escalation followed a 3+3 design (M starting dose: ∼50% of MR RP2D [30mg BID] days 1–7 + R 375 mg/m² IV on day 1 + V 1.4 mg/m² [max, 2 mg] IV on days 1 and 8 of 21-day cycle). The RP2D was determined as the dose level at which <2 dose limiting toxicities (DLT) occurred in 6 pts in cycle 1. Primary objectives were safety/tolerability and determination of MR and MRV RP2Ds. Secondary objectives included M pharmacokinetics (PK), the effect of M on V PK, and anti-tumor activity.

As of 16 July 2013, 35 pts were enrolled (28 DLBCL, 1 transformed follicular, 1 Burkitt, and 5 mantle cell) with data entered for 32 pts (21 male) at time of data cut-off (part 1, n=13; part 2, n=19 [MLN8237: 30 mg, n=4; 40 mg n=12; 50 mg, n=3]). 1 pt in the MR cohort and 8 pts in the MRV cohorts continue on treatment. Pt demographics, exposure, and safety data are shown in the table. MR was well tolerated with 1 DLT; therefore M 50 mg BID x 7 d + R 375mg/m² was the recommended regimen for this doublet. For the MRV triplet the RP2D was M 40 mg BID. Common grade (G) ≥3 drug-related AEs across the cohorts included: thrombocytopenia, leukopenia, neutropenia, fatigue and anemia. To date, 26 pts have discontinued treatment (15 progressive disease [PD], 5 AEs [including 2 unrelated deaths, unrelated G4 T7 spinal cord mass and compression, G1 related pulmonary fibrosis, G2 unrelated cough and dysphagia], 3 symptomatic deterioration, 2 other, 1 withdrawal by subject). An additional unrelated, on-study death occurred in a pt who had discontinued treatment due to PD. At the MR RP2D combination, MLN8237 median T_max was 2 hr and geometric mean steady-state AUC_0-12hr was 18,960 nM*hr (n=11, CV: 61.2%), which is consistent with what was achieved in M single agent at 50 mg BID. Assessment of the effect of MLN8237 on vincristine PK is ongoing. 12 pts administered MR were response evaluable; 1 50 y male pt with DLBCL had a complete response (CR), 2 pts had partial response (PR) including one 79 y male pt with DLBCL ongoing at 29 cycles, and 5 pts had stable disease (SD) for up to 13 cycles. 8 MRV pts are currently response evaluable (M 30 mg, n=3; 40 mg, n=5); one 78 y male pt with DLBCL in the 30 mg cohort had CR; at the RP2D (40 mg BID cohort) one 71 y male with non- germinal center B-cell-like DLBCL and having progressed following prior transplant had CR; one 66 y male pt with large B-cell had PR, 5 pts had SD. Response assessments are pending for 5 pts. Enrollment continues to the MRV RP2D to complete the required number of PK-evaluable pts.

MR ± V is overall well tolerated and has shown preliminary anti-tumor activity in pts with relapsed/refractory B-cell lymphomas.

Off Label Use: Use of the investigational agent MLN8237 in combination in patients with aggressive B-cell NHL. Persky:Millennium: The Takeda Oncology Company: Research Funding. Mahadevan:Novartis: Honoraria; Millennium: The Takeda Oncology Company: Honoraria. Miller:Spectrum: Research Funding; Abbott Laboratories: Research Funding. Hayslip:Celgene: Research Funding. Park:TEVA: Research Funding; Seattle Genetics, Inc.: Research Funding. Ruan:Seattle Genetics, Inc.: Membership on an entity’s Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity’s Board of Directors or advisory committees, Research Funding. Rosen:Disney Family Cancer Center: Research Funding. Padmanabhan Iyer:Millennium: The Takeda Oncology Company: Research Funding. Zhang:Takeda Pharmaceutical Company Ltd.: Equity Ownership; Millennium: The Takeda Oncology Company: Employment. Zhou:Millennium: The Takeda Oncology Company: Employment. Dansky Ullmann:Millennium: The Takeda Oncology Company: Employment. Leonard:Millennium: The Takeda Oncology Company: Employment, Equity Ownership.