Phase 1 study of the Aurora kinase A inhibitor alisertib (MLN8237) combined with the histone deacetylase inhibitor vorinostat in lymphoid malignancies

Abstract

Alisertib, an Aurora kinase A inhibitor, was evaluated in a Phase 1 study in combination with the histone deacetylase inhibitor vorinostat, in patients with relapsed/refractory lymphoid malignancies (N = 34; NCT01567709). Patients received alisertib plus vorinostat in 21-day treatment cycles with escalating doses of alisertib following a continuous or an intermittent schedule. All dose-limiting toxicities (DLTs) were hematologic and there were no study-related deaths. The recommended phase 2 dose (RP2D) of the combination was 20 mg bid of alisertib and 200 mg bid of vorinostat on the intermittent schedule. A 13-patient expansion cohort was treated for a total of 18 patients at the RP2D. There were no DLTs at the RP2D, and toxicities were mainly hematologic. Two patients with DLBCL achieved a durable complete response, and two patients with HL achieved partial response. Alisertib plus vorinostat showed encouraging clinical activity with a manageable safety profile in heavily pretreated patients with advanced disease.

Keywords:

• Alisertib
• vorinostat
• lymphoma
• Aurora kinase
• histone deacetylase inhibitor

Acknowledgments

Alisertib was supplied by Millennium Pharmaceuticals, Inc. and distributed by the CTEP, DCTD, and NCI. Vorinostat was supplied by Merck and Co., Inc. and distributed by the CTEP, DCTD, and NCI.

The authors wish to acknowledge assistance with protocol management by Stella Khoo, M.B.A., and Diana Calcanas-Perez in the California Cancer Consortium Data Coordinating Center at City of Hope.

Disclosure statement

TS: Speaker for Pharmacyclics/Janssen and Seattle Genetics; consultant for Juno Therapeutics, Pharmacyclics, BeiGene, and Astra Zeneca. RC: Millennium Pharmaceuticals: Consultancy, Research Funding; Merck & Co., Inc.: Consultancy, Research Funding, Speakers Bureau; Genentech Inc.: Consultancy; Affimed: Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding, Speakers Bureau; Pharmacyclics: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding. KK: Speaker for Pharmacyclics/Janssen, Seattle Genetics, Bayer, Gilead, Novartis; consultant for Agios, Amgen, Teva and Jazz, research funding from Takeda (not for the current study). SA: Research funding: Pharmacyclics and Advisory Board/Consultant: Celgene, Takeda, Janssen, Amgen, Novartis. PK: Speaker for Bristol Myers Squibb and Incyte Pharmaceuticals. The other authors declare no conflict of interest in regards to the current manuscript.

Additional information

Funding

This trial was supported in part by the National Cancer Institute (UM1CA186717, UM1CA186690) and Leidos Biomedical Research Inc. (BOA 14X251-TO1). Research reported in this publication included work performed in the City of Hope Comprehensive Cancer Center Pathology Core supported by the National Cancer Institute of the National Institutes of Health under award number P30CA033572. This project used the UPMC Hillman Cancer Center Cancer Pharmacokinetics and Pharmacodynamics Facility (CPPF) and was supported in part by award P30CA047904, and R50CA211241. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.