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; Aurora kinase; histone deacetylase inhibitor; lymphoma; vorinostat.

Conflict of interest statement

Disclosure of interest

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.

Figures

Figure 1.

Duration of treatment and response – each bar represents one patient in the study. With the exception of the two patients who continue in CR without additional treatment on or off protocol (see text), the plots do not reflect survival after the patients discontinued protocol-specified treatment.