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.