Results from a Phase 1 Study and Expanded Cohort of an Interrupted Dosing Schedule of the Aurora Kinase a Inhibitor MLN8237 Combined with Vorinostat in Lymphoid Malignancies

Abstract

BackgroundMLN8237 is an oral inhibitor of aurora kinase A (AURKA) that causes mitotic spindle defects, mitotic delay, and apoptosis in lymphoma cell lines and mouse models. Human studies have shown promising responses in hematologic malignancies. Vorinostat is an oral HDAC inhibitor that is FDA-approved for cutaneous T-cell lymphoma, and is under study in other lymphomas. AURKA inhibitors in combination with vorinostat show synergistic pro-apoptotic effects in vitro in Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL) cell lines (Kretzner 2011, Cancer Res 71:3912). Our phase I multicenter study assessed the safety and tolerability of MLN8237 combined with vorinostat in patients with lymphoid malignancies [NCT01567709] and determined the maximum tolerated dose (MTD) to be 20 mg twice daily (BID) of MLN8237 and 200 mg BID of vorinostat orally in an interrupted dosing schedule (Schedule II). We have recently completed accrual to an expanded cohort at MTD and report preliminary data on our secondary endpoints among patients treated on Schedule II of this study.MethodsEligible patients were ≥18 years old with relapsed or refractory (r/r) lymphoid malignancies (HL, B-NHL, T-NHL), measureable disease, ECOG performance status 0-2, neutrophils ≥1500/µL, platelets ≥100,000/µL, and adequate kidney and liver function. Secondary endpoints were toxicities, clinical response, pharmacokinetic (PK) analysis, and correlative studies. A 3+2 modified rolling-6 design was employed to determine the MTD. Enrollment was initiated on a continuous dosing schedule (Schedule I) that was poorly tolerated, with adverse events (AEs) on dose levels 1 and 2 leading to many dose delays primarily due to gastrointestinal intolerance and myelosuppression. The protocol was amended to the interrupted dosing Schedule II: MLN8237 escalated from 20 to 50 mg BID on days 1-3 and 8-10, and vorinostat given at 200 mg BID on days 1-5 and 8-12 of a 21-day cycle.ResultsWe treated 25 patients (11 DLBCL, 7 HL, 3 FL, 2 MCL, 1 PTCL, 1 NK/T cell) on the interrupted dosing Schedule II. Median age was 59 years (range 26-78). Mediannumber of prior therapies was 4 (range 1-10); 9 patients (36%) underwent prior stem cell transplantation. See Table for treatment summary. MTD of the combination is 20 mg BID for MLN8237 and 200 mg BID for vorinostat on the interrupted schedule. The commonest (>5%) ≥ grade 3 drug-related AEs were neutropenia (52%), thrombocytopenia (44%), leukopenia (44%), anemia (28%), lymphopenia (24%), febrile neutropenia (12%), oral mucositis (8%), diarrhea (8%), and lung infection (8%). There were no study-related deaths. 4 patients stopped treatment due to AEs and 13 due to progressive disease (PD). 2 patients achieved complete remission (CR); both had DLBCL, and both halted therapy after completing 2 further cycles of treatment post-CR. They both remain in CR (18 months and 1 month at data lock). 1 patient had a partial response (PR), and 8 patients maintained stable disease (SD). PKs demonstrated a clearance of 230 L/h (sd=495) and 2.94 L/h (sd=1.57) for vorinostat and MLN8237, respectively. Archived baseline biopsies are being analyzed to determine AURKA expression. Six fresh paired tumor biopsies were obtained before and on-treatment in the expanded cohort at MTD for correlative studies.ConclusionsMLN8237 when given in combination with vorinostat is safe and tolerable in an interrupted dosing schedule among heavily pre-treated patients with r/r lymphoid malignancies. The MTD for MLN8237 is 20 mg BID on days 1-3 and 8-10, combined with vorinostat at 200 mg BID on days 1-5 and 8-12, of 21 day cycles. The commonest AEs were hematologic and gastrointestinal. Promising responses were seen in several patients, especially those with DLBCL, which support phase 2 exploration of this therapy in patients with intermediate-high grade NHL. PK analysis suggests that combination therapy exposures are similar to single agent exposure. Correlative studies done in a 12-patient expanded cohort will be presented. [Trial supported in part by UM1CA186717]Table 1Schedule II:MLN8237 (mg)/ Vorinostat (mg)# of patients treated# of cycles completed Median (range)# of dose limiting toxicities (DLT)DLT DescriptionBest responseDose level 1 (30/200)73 (0-18)21 pt had grade 3 febrile neutropenia; 1 pt had grade 3 thrombocytopenia requiring transfusion1 CR, 3 SD, 2 PD, 1 N/ADose level -1 (20/200)182 (0-14)01 CR, 1 PR, 5 SD, 8 PD, 3 too early to assess DisclosuresSiddiqi:Kite pharma: Other: attended advisory board meeting; Seattle Genetics: Speakers Bureau; Pharmacyclics/Jannsen: Speakers Bureau. Off Label Use: Vorinostat is only FDA-approved for CTCL but in this study it is being used in conjunction with MLN8237 (not FDA-approved) for all lymphomas.. Beumer:Millenium: Other: Research support. Forman:Mustang Therapeutics: Research Funding.