A Phase I/II Multicenter, Open-Label Study of the Oral Histone Deacetylase Inhibitor Abexinostat in Relapsed/Refractory Lymphoma

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. We conducted a multicenter phase I/II study (N ¼ 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/m 2 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/m 2 twice daily (90 mg/m 2 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 (1.2-22.3þ). 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.

Phase 1 dose-escalation study of oral abexinostat for the treatment of patients with relapsed/refractory higher-risk myelodysplastic syndromes, acute myeloid leukemia, or acute lymphoblastic leukemia

“…[38] ECG changes including QTc prolongation have been reported with other HDAC inhibitors and a potential class effect has been suggested. [39,40] However, in this study and others of abexinostat, [31,32,41] treatment with abexinostat did not result in clinically relevant ECG changes. The MTD was not identified.…”

“…Early studies of single-agent abexinostat in patients with relapsed/refractory lymphomas and chronic lymphocytic leukemia have shown clinical activity and manageable toxicities. [31,32] Abexinostat has been shown to potently inhibit the growth of myeloid and lymphoid malignant cell lines. [29] The primary objective of this study was to evaluate the safety and tolerability of oral abexinostat in patients with relapsed/refractory higher-risk MDS, AML, or ALL.…”

New and emerging HDAC inhibitors for cancer treatment

“…Of these, several have entered the clinic including the class I-specific agents CHR-3966 (60), chidamide (CS055/HBI-8000) (61), class I-and class II-specific AR-42 (62), and hydroxamides quisinostat (JNJ-26481585) (63) and abexinostat (PCI-24781) (64), and some preliminary results are described in Table 2. While still ongoing, early preclinical studies indicate these agents are more potent than the parental compounds, with improved pharmacodynamic and pharmacokinetic values, and are potentially less toxic.…”

Transplantation for mantle cell lymphoma: is it the right thing to do?

“…The oral pan-HDAC inhibitor abexinostat (PCI-24781) has also shown activity in relapsed/refractory MCL and follicular lymphoma in a phase 2 trial. 40 Preclinical data support the use of HDAC inhibitors in combination with proteasome inhibitors and other agents, with early clinical trials in development.…”