A phase I/II multicenter, open-label study of the oral histone deacetylase inhibitor abexinostat in relapsed/refractory lymphoma

Andrew M. Evens, Sriram Balasubramanian, Julie M. Vose, Wael Harb, Leo I. Gordon, Robert Langdon, Julian Sprague, Mint Sirisawad, Chitra Mani, Jeanne Yue, Ying Luan, Sharon Horton, Thorsten Graef, Nancy L. Bartlett

Research output: Contribution to journalArticlepeer-review

35 Scopus citations

Abstract

Purpose: Additional targeted therapeutics are needed for the treatment of lymphoma. Abexinostat is an oral pan-histone deacetylase inhibitor (HDACi) displaying potent activity in preclinical models.Weconducted amulticenter phase I/II study (N=55)with single-agent abexinostat in relapsed/refractory lymphoma. Experimental Design: In phase I, 25 heavily pretreated patients with any lymphoma subtype received oral abexinostat ranging from 30 to 60 mg/m2 twice daily 5 days/week for 3 weeks or 7 days/week given every other week. Phase II evaluated abexinostat at the maximum tolerated dose in 30 patients with relapsed/ refractory follicular lymphoma or mantle cell lymphoma. Results: The recommended phase II dose was 45 mg/m2 twice daily (90 mg/m2 total), 7 days/week given every other week. Of the 30 follicular lymphoma and mantle cell lymphoma patients enrolled in phase II, 25 (14 follicular lymphoma, 11 mantle cell lymphoma) were response-evaluable. Tumor size was reduced in 86% of follicular lymphoma patients with an investigatorassessed ORR of 64.3% for evaluable patients [intent-to-treat (ITT) ORR 56.3%]. Median duration of response was not reached, and median progression-free survival (PFS) was 20.5 months (1.2-22.3+). Of responding follicular lymphoma patients, 89% were on study/drug >8 months. In mantle cell lymphoma, the ORR was 27.3% for evaluable patients (ITT ORR 21.4%), and median PFS was 3.9 months (range, 0.1-11.5). Grade 3-4 treatment- related adverse events (phase II) with ≥10% incidence were thrombocytopenia (20%), fatigue (16.7%), and neutropenia (13.3%) with rare QTc prolongation and no deaths. Conclusions: The pan-HDACi, abexinostat, was overall well tolerated and had significant clinical activity in follicular lymphoma, including highly durable responses in this multiply relapsed patient population.

Original languageEnglish (US)
Pages (from-to)1059-1066
Number of pages8
JournalClinical Cancer Research
Volume22
Issue number5
DOIs
StatePublished - Mar 1 2016

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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