Secondary Logo

Institutional members access full text with Ovid®

Phase I Study of Aurora A Kinase Inhibitor Alisertib (MLN8237) in Combination With Selective VEGFR Inhibitor Pazopanib for Therapy of Advanced Solid Tumors

Shah, Hiral A., MD*,†; Fischer, James H., PharmD; Venepalli, Neeta K., MD*; Danciu, Oana C., MD*; Christian, Sonia, MD*; Russell, Meredith J., BS§; Liu, Li C., PhD; Zacny, James P., PhD*; Dudek, Arkadiusz Z., MD, PhD*,¶

American Journal of Clinical Oncology: May 2019 - Volume 42 - Issue 5 - p 413–420
doi: 10.1097/COC.0000000000000543
Original Articles: Experimental Therapeutics
Buy
SDC

Objectives: Pazopanib is a multikinase angiogenesis inhibitor. Alisertib is a highly selective inhibitor of mitotic Aurora A kinase. There is preclinical evidence that mitosis-targeting agents exhibit antiangiogenic effects. Thus, the combination of these 2 agents may have a synergistic effect on tumor vasculature. The primary objective of this study is to determine the optimal tolerated dose (OTD) for alisertib and pazopanib.

Materials and Methods: This phase 1b study evaluated the OTD of alisertib twice a day, on days 1 to 7 with pazopanib, once a day, continuously in a 21-day cycle, both taken orally. Disease response was assessed using the Response Evaluation Criteria in Solid Tumors version 1.1 every 2 cycles. OTD cohort was expanded to assure safety and perform pharmacokinetics analysis.

Results: A total of 27 patients received treatment. Seventy-seven percent of the patients had received at least 3 prior chemotherapy regimens. Dose-limiting toxicities occurred in dose level (DL) 2+ (grade 4 thrombocytopenia and grade 3 mucositis) and DL 3 (grade 3 liver transaminases elevation and grade 3 abdominal pain). The OTD was determined to be DL 2: alisertib 20 mg twice daily and pazopanib 600 mg daily. Pharmacokinetic analysis revealed that clearance of alisertib was reduced by ∼40% in the presence of pazopanib compared with clearance in the absence of pazopanib. Fourteen patients had stable disease and 2 patients had a partial response.

Conclusions: The combination of alisertib with pazopanib demonstrates manageable safety and early clinical evidence of antitumor activity in patients with advanced malignancies (NCT01639911).

*Department of Medicine, Division of Hematology/Oncology

Department of Pharmacy Practice, College of Pharmacy

§Oncology Clinical Trials Office, University of Illinois Cancer Center

Division of Epidemiology and Biostatistics, School of Public Health, University of Illinois at Chicago

Developmental Therapeutics Program, Division of Hematology/Oncology, Feinberg School of Medicine, Chicago, IL

HealthPartners Regions Cancer Care Center, St. Paul, MN

Supported by the Millennium Pharmaceuticals and the University of Illinois Cancer Center.

A.Z.D. has received research funding from Millennium Pharmaceuticals, Merck, Eli Lilly, and consulting honoraria from Biothera. A.Z.D. serves as Chief Medical Officer for Vanquish Oncology, TTC Oncology, IGF Oncology, and Martell Diagnostic Laboratories. The remaining authors declare no conflicts of interest.

Reprints: Arkadiusz Z. Dudek, MD, PhD, HealthPartners Regions Cancer Care Center, Suite 1161 Mail Stop 11101G, 640 Jackson Street, St. Paul, MN 55101. E-mail: arkadiusz.z.dudek@healthpartners.com.

Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.