Phase 1 Study of MLN8237, an Aurora KinaseA (AURKA) Inhibitor, Combined with Vorinostat, a Histone Deacetylase (HDAC) Inhibitor, in Lymphoid Malignancies

Abstract

Background: Amplification or overexpression of AURKA, a key mitotic regulator, is seen in various tumors and is associated with poor outcome in relapsed/refractory (r/r) lymphoma patients. MLN8237 is an oral inhibitor of AURKA, leading to 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 FDA-approved for cutaneous T cell lymphoma, and is under study in other lymphomas. AURKA inhibitors, MK0457 and MK5108, when combined with vorinostat and applied to Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL) cell lines, convincingly showed synergistic pro-apoptotic effects compared with the AURKA inhibitor alone (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].Methods: Patients ³18 years old with r/r mature lymphoid malignancies (HL, B-NHL, T-NHL), measureable disease, ECOG performance status 0-2, neutrophils ³1500/µL, platelets ³100,000/µL, and adequate kidney and liver functions were eligible. The primary endpoints were maximum tolerated dose (MTD) of MLN8237 when combined with vorinostat and description of adverse events (AEs). Secondary endpoints were toxicity, clinical response, pharmacokinetic (PK) analysis and correlative studies. A 3+2 modified rolling design was employed. Enrollment was initiated on Schedule I: MLN8237 escalated from 30-50 mg twice daily (BID) on days 1-7 and vorinostat given at 200 mg BID on days 1-14 of a 21-day cycle*. AEs in patients treated on Schedule I dose levels 1 and 2 led to many dose delays, primarily due to gastrointestinal intolerance and myelosuppression. The protocol was amended to the interrupted dosing Schedule II: MLN8237 escalated from 20-50 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.Results: As of August 1 2014, 23 patients have been treated (3 HL, 6 DLBCL, 7 FL, 1 MCL, 1 MZL, 2 B-CLL/SLL, 2 ALCL, 1 NK/T cell). Median age was 61 years (range 28-82). Median number of prior therapies was 4 (range 1-8); 9 patients (39%) underwent prior stem cell transplantation. See Table for treatment summary. MTD of the combination is 20mg BID for MLN8237 and 200mg BID for vorinostat in an interrupted schedule. The most common grade 1-2 AEs (>/=30%) were fatigue (78%), nausea (65%), diarrhea (65%), vomiting (56%), hypokalemia (48%), hypertension (47%), anemia (43%) high alkaline phosphatase (39%), hyponatremia (39%), thrombocytopenia (35%), anorexia (31%), alopecia (31%), constipation (30%), high ALT (30%), high AST (30%), high creatinine (30%), leukopenia (30%). Commonest (>5%) >/= grade 3 drug-related AEs were thrombocytopenia (66%), neutropenia (60%), leukopenia (52%), lymphopenia (43%), anemia (34%), febrile neutropenia (13%), and oral mucositis (8%). There were no study-related deaths. 6 patients stopped protocol treatment due to AEs/intolerance and 7 due to progressive disease (PD). Most patients (8) had stable disease (SD) and 1 patient achieved a complete remission (CR).Conclusions: MLN8237 when given in combination with vorinostat is safe and tolerable in an interrupted schedule among heavily pre-treated patients with r/r lymphoid malignancies. The MTD for MLN8237 is 20mg BID on days 1-3 and 8-10, combined with vorinostat at 200mg BID on days 1-5 and 8-12, of 21 day cycles. The commonest AEs are hematologic and gastrointestinal. PK analysis, correlative studies and response assessments are ongoing in a 12-patient expansion cohort. [Trial supported in part by UM1CA186717] Abstract 4483. TableMLN8237 (mg)/ Vorinostat (mg)# treated# completed cyclesMedian (range)# DLTsDLT DescriptionBest responsesSCHEDULE I (continuous)Dose level 1 (30/400*)62 (1-3)1Grade 3 thrombocytopenia requiring a plt transfusion2 SD, 2 PD, 2 N/ADose level 2 (20/200)32 (2-13)2Both pts had grade 4 thrombocytopenia2 SD, 1 PDSCHEDULE II (interrupted)Dose level 1 (30/200)73 (0-18)21 pt had grade 3 febrile neutropenia; 1 pt had grade 3 thrombocytopenia requiring a plt transfusion1 CR, 3 SD, 2 PD, 1 N/ADose level -1 (20/200)71 (1-3)01 SD, 2 PD, 4 too early*Initial vorinostat dosing was 400mg daily but subsequent cohorts were switched to 200mg BID for better tolerance. DisclosuresOff Label Use: MLN8237 and vorinostat have not been FDA-approved for all lymphoid malignancies..