Background: Epigenetic manipulation and immunomodulation are therapeutic strategies in hematologic malignancies. Romidepsin (Romi), a histone deacetylase inhibitor, and lenalidomide (Len), an immunomodulatory agent, both have efficacy and lack cumulative toxicity in relapsed/refractory (rel/ref) lymphoma and myeloma. We report the phase I results from an ongoing phase I/II study. Methods: The phase I portion evaluated toxicity (tox), maximum tolerated dose (MTD) and clinical activity of Romi-Len. Romi was given IV on days 1, 8, and 15 and Len was given orally on days 1-21 of a 28-day cycle. A standard 3+3 dose escalation schema was followed and 4 cohorts were planned: 1) Romi 8 mg/m²-Len 15 mg, 2) Romi 8 mg/m²-Len 25 mg, 3) Romi 10 mg/m²-Len 25 mg, 4) Romi 14 mg/m²-Len 25 mg. Dose-limiting tox (DLT) was defined as any of the following in cycle 1: ≥ grade 3 non-heme tox, ≥ grade 4 heme tox or grade 3 heme tox resulting in a significant delay of treatment. Tumor response was based on disease-specific criteria. Patients (pts) could be treated to progression or intolerance. Results: Nineteen pts with rel/ref lymphoma have been enrolled with 15 pts evaluable for DLT (13 pts for response). Three pts progressed prior to study drug and 1 pt progressed in cycle 1; all were replaced for DLT assessment. Two DLTs have occurred to date: cohort 2, 1/7 pts had grade 4 pneumonia; cohort 4, 1/3 pts had grade 3 thrombocytopenia delaying therapy. One grade 3 neutropenic fever has been seen post cycle 1. Of the 13 pts evaluable for response, the overall response rate is 54% (7/13) with complete response in 15% (2/13) and partial response in 39% (5/13). Four responses are ongoing at 4-13 cycles. Responses by subtype include B-cell 50% (2/4), T-cell 67% (4/6), and Hodgkin 33% (1/3). No cumulative tox has been seen. Conclusions: The combination of Romi-Len appears to be well tolerated without unexpected tox up to standard single agent doses of each drug. Responses have been seen across multiple lymphoma subtypes. Disease specific phase II cohorts will include B-cell lymphomas, T-cell lymphomas, and multiple myeloma. Final phase 1 safety and efficacy data will be presented. Clinical trial information: NCT#01755975.