Introduction: Lenalidomide, an immunomodulatory agent, and ibrutinib, a selective and covalent inhibitor of Bruton9s tyrosine kinase, are orally bioavailable agents with single-agent activity in several histologic subtypes of relapsed/refractory B-cell non-Hodgkin lymphoma (NHL). We are conducting a phase I study of the combination of ibrutinib and lenalidomide to determine the maximum tolerated dose, dose limiting toxicities (DLT), and preliminary efficacy in pts with relapsed/refractory NHL and updated results are presented. Methods: Patients (pts) with relapsed/refractory B-cell NHL including diffuse large B-cell (DLBCL), transformed, mantle cell (MCL), marginal zone (MZL), lymphoplasmacytic (LPL), and follicular (FL) lymphoma who have received at least one prior therapy were eligible. Prior autologous but not allogeneic stem cell transplant and prior lenalidomide were permitted. Prior ibrutinib, CNS involvement, and pts requiring anticoagulation were not permitted. ANC > 1000/mm 3 , platelets > 50,000/mm 3 , and creatinine 14 days for toxicity; grade 5 toxicity; tumor lysis syndrome requiring dialysis; tumor flare reaction nonresponsive to corticosteroids; ANC 3 or platelets 3 persisting > 7 days; grade 3 or 4 febrile neutropenia or infection; and any grade 3 or 4 non-hematologic toxicity with the following exceptions: DVT, diarrhea, nausea or vomiting amenable to medical therapy, correctable electrolyte abnormalities; grade 3 fatigue, or grade 3 maculopapular rash that resolved within 7 days. Pts without significant toxicity could continue treatment until disease progression. Response was assessed every 3 months for 12 months and then every 6 months until disease progression. Results: Twenty-five pts have been treated. Median age is 67 years (range 45-85) with 16 males. Histologies include DLBCL/transformed lymphoma (n=9), MCL (n=7), FL (n=4), MZL (n=2), and LPL (n=3). Four pts were treated at dose level (DL) 1 (lenalidomide 15 mg/ibrutinib 420 mg). One pt was replaced for rapid disease progression and 1 pt experienced DLT consisting of a grade 2 ischemic stroke. As a result of this DLT, DL 1 was expanded to 6 evaluable pts. A second DLT was observed, a grade 3 rash that resolved within 7 days but recurred on day 22. A total of 6 pts were then treated at DL-1 (lenalidomide 10 mg/ibrutinib 280 mg), and no DLTs were encountered. The protocol was amended to include additional dose levels. Pts enrolled on dose level -1A with lenalidomide 10 mg and ibrutinib 420 mg. One DLT occurred at this dose level, a grade 3 rash that failed to resolve within 7 days. The dose level was expanded to 6 pts without further DLT. DL-1B includes an intra-pt dose escalation of the lenalidomide from 10 mg in cycle 1 to 15 mg in cycle 2 with ibrutinib 420 mg. Six pts have been enrolled on this dose level. Three pts have been replaced including 2 with cytopenias not meeting DLT criteria but precluding dose escalation and one with progressive disease. Three pts at DL-1B remain on treatment. Related grade 3-4 toxicities occurred in 16/24 currently evaluated pts (67%), including primarily hematologic toxicity, rash, increased LFTs, pneumonia, hypokalemia, and syncope. Pts have received a median of 3 cycles of therapy to date (range 1-19) and 9 remain on therapy. At DL 1, a pt with DLBCL achieved a complete response (CR) and a pt with transformed follicular achieved a partial response (PR). At DL-1, a pt with DLBCL achieved a CR and 1 pt each with MCL and FL achieved PR. At DL -1A, 1 pt each with MCL and MZL achieved a PR. Overall response rate for 18 assessable pts is 39%. Five pts had best response of stable disease. Sixteen pts have discontinued the study including 3 pts with DLTs, 2 for alternative treatment, 2 for toxicity, and 9 pts with progression. Conclusions: Combined therapy with lenalidomide and ibrutinib in pts with relapsed NHL is well-tolerated, although DLTs of recurrent rash and stroke were encountered. Lenalidomide 10 mg and ibrutinib 420 mg was tolerated and pts are currently enrolling in an intra-pt dose escalation cohort. Preliminary efficacy has been observed in pts with relapsed/refractory DLBCL, MCL, FL, MZL, and transformed NHL. Disclosures Christian: Pharmacyclics: Research Funding; Acerta: Research Funding; Immunomedics: Research Funding; Celgene: Consultancy; Novartis: Other: IDSM; Seattle Genetics: Consultancy, Research Funding; Janssen: Research Funding. Off Label Use: The use of ibrutnib and lenalidomide in combination in relapsed/refractory non-Hodgkin9s lymphoma is off-label. Kuruvilla: Karyopharm: Honoraria, Research Funding; Roche Canada: Honoraria; Seattle Genetics: Honoraria, Research Funding. Smith: Celgene: Consultancy; Pharmacyclics: Consultancy. Porcu: Cell Medica: Research Funding; Infinity: Research Funding; Seattle Genetics: Research Funding; Celgene: Research Funding; Shape: Research Funding. Maddocks: Acerta: Research Funding; Pharamcyclics: Research Funding; Novartis: Research Funding. Byrd: Pharmacyclics: Research Funding. Blum: Celgene: Research Funding; cephalon: Research Funding; Pharmacyclics: Research Funding; Janssen: Research Funding.