Purpose: Additional targeted therapies 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=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 30-60 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 (FL) or mantle cell lymphoma (MCL).

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 FL and MCL patients enrolled in phase II, 25 (14 FL, 11 MCL) were response-evaluable. Tumor size was reduced in 86% of FL patients with an investigator-assessed 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 FL patients, 89% were on study/drug >8 months. In MCL, 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 very well tolerated and had significant clinical activity in FL, including highly durable responses in this multiply relapsed population.

https://clincancerres.aacrjournals.org/content/clincanres/22/5/1059.full.pdf

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

Histone deacetylases play an important role in multiple processes, including gene expression, proliferation, apoptosis, cytoskeletal organization, migration and angiogenesis. Histone deacetylase inhibitors are able to induce cell death and growth arrest as targeted anticancer agents. Whilst only two, vorinostat and romidepsin, are licensed in oncology, several have reached Phase III trials and many more are in Phase I and II. In addition to this, multiple novel drugs, including more targeted agents, are emerging from preclinical studies. This paper examines the outcomes of recent clinical trials in 11 key histone deacetylase inhibitors, both as monotherapy and in combination with other antitumor drugs. An overview of the advantages and disadvantages between the different classes and individual drugs is discussed, as well as a brief outlook on the future developments in the field.

/pdf/histone-deacetylase-inhibitors-recent-outcomes-from-clinical-3hpa9oco07.pdf

Histone deacetylase inhibitors: recent outcomes from clinical trials and the implications for oncology treatment approaches

Abexinostat (S78454/PCI-24781), an Oral Pan-Histone Deacetylas (HDAC) Inhibitor in Patients with Refractory or Relapsed Hodgkin's Lymphoma, Non-Hodgkin Lymphoma and Chronic Lymphocytic Leukemia. Results of a Phase I Dose-Escalation Study in 35 Patients

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Abexinostat (S78454/PCI-24781), an Oral Pan-Histone Deacetylas (HDAC) Inhibitor in Patients with Refractory or Relapsed Hodgkin's Lymphoma, Non-Hodgkin Lymphoma and Chronic Lymphocytic Leukemia. Results of a Phase I Dose-Escalation Study in 35 Patients