Phase I Study of An Investigational Aurora A Kinase Inhibitor MLN8237 In Patients with Advanced Hematologic Malignancies.
Authors: Padmanabhan Swaminathan , Shea Thomas C. , Vose Julie M. , Reeder Craig B. , Berdeja Jesus G , McDonagh Kevin T. , Goy Andre , Kelly Kevin R , Zhou Xiaofei , Liu Hua , Fingert Howard , Fowler Nathan 
Published: October 2019

Abstract
Abstract 2799

Background:
Aurora A kinase (AAK) is important in a diverse set of mitotic processes and is amplified or overexpressed in a number of heme-lymphatic malignancies. MLN8237 is an investigational, orally administered, selective AAK inhibitor in clinical development for the treatment of hematologic and solid tumors. This multicenter study (NCT00697346) is the first phase 1 program to assess safety and pharmacology of MLN8237 in patients with advanced hematologic malignancies.

Methods:
Eligible patients were aged ≥18 yr, had response-evaluable, relapsed or refractory hematologic malignancies, and had ECOG performance status 0–2; there was no restriction on the number of prior therapies, but prior allogeneic transplant was excluded. Patients received escalating doses of MLN8237 as powder-in-capsule formulation in a 3+3 design. Endpoints included safety, dose-limiting toxicity (DLT), maximum tolerated dose (MTD), pharmacokinetics, and response.

Results:
Twenty-eight patients were included; median age was 62 yr (range 41–74), 50% were male, 86% were white, and 43% had prior transplant. Diagnoses were non-Hodgkin's lymphoma (68%), including diffuse large B-cell (DLBCL), mantle cell, follicular, and small lymphocytic lymphoma; multiple myeloma (29%); and chronic lymphocytic leukemia (4%). Seventy-nine percent of patients had received ≥3 prior therapies. Patients initially received a 21-day treatment schedule of MLN8237 25 or 35 mg (BID loading dose on Day 1, then QD on Days 2–21) followed by a 7-day rest period (28-day cycles). Based on results with the first two cohorts, subsequent cohorts received a 14-day treatment schedule of MLN8237 35, 45, 65, or 90 mg (BID loading dose on Day 1, then QD on Days 2–14) followed by a 14-day rest period (28-day cycles). Median number of cycles administered was 2 (range 1–14+). After escalation to 90 mg (maximum administered dose), two DLTs per cohort led to de-escalation to 65 mg and then 45 mg, which was the MTD on the 14-day schedule. The most common treatment-related adverse events (AEs) were neutropenia (46%), thrombocytopenia (36%), and asthenic conditions (32%); grade ≥3 treatment-related AEs were reported in 14 (50%) patients, and 13 (46%) had a serious AE. DLTs included grade 3–4 myelosuppression associated with infection or delay in treatment, which were generally manageable by reduction in dose or schedule. AEs were generally reversible and manageable, although 5 (18%) patients discontinued due to AEs. Three patients died, from causes (renal failure; airway obstruction; progressive large cell lymphoma) not considered related to MLN8237. Following multiple doses, an overall median Tmax of 2 hr, a mean t1/2 of 23 hr, and a peak/trough ratio of 5 were observed. The geometric mean of steady-state AUC increased from 19,534 to 30,811 nM*hr when the daily dose was increased from 25 to 65 mg. With the 14-day schedule, antitumor activity was observed in a patient with relapsed DLBCL treated with 65 mg and reduced to 45 mg, who enrolled after disease progression following ifosfamide-carboplatin-etoposide (ICE) salvage therapy. A durable PR coupled with resolution of B symptoms sustained for >1 yr was observed in a patient with post-transplant grade 3B follicular lymphoma treated with 35 mg, escalated per protocol to 45 mg and then 65 mg. Stable disease (SD; 5 months) was observed in a patient with myeloma treated at 90 mg.

Conclusions:
MLN8237 toxicities were consistent with AAK inhibition in proliferating tissue (chiefly bone marrow), and were generally manageable. The MTD was 45 mg on the 14-day schedule in these patients with advanced hematologic malignancies. Antitumor activity was observed, and repeat cycles were tolerable over 6–12 months in some patients who achieved PR or SD. The results support further investigation of MLN8237 in heme-lymphatic malignancies, and ongoing clinical development includes alternative schedules and formulations.

Disclosures:
Padmanabhan: Millennium Pharmaceuticals, Inc.: Consultancy, Research Funding. Off Label Use: Investigational agent in clinical development for the treatment of advanced hematologic malignancies. Shea:Millennium Pharmaceuticals, Inc: Consultancy, Research Funding. Vose:Millennium Pharmaceuticals, Inc.: Research Funding. Goy:Millennium Pharmaceuticals, Inc., Celgene, GSK, Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Zhou:Millennium Pharmaceuticals, Inc.: Employment. Liu:Millennium Pharmaceuticals, Inc.: Employment. Fingert:Millennium Pharmaceuticals, Inc.: Employment, Equity Ownership. Fowler:Millennium Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Honoraria, Research Funding; Cephalon: Research Funding; Genentech: Honoraria, Research Funding; Celgene: Honoraria.