Background: Bruton’s tyrosine kinase (BTK) and PI3K inhibitors synergize effectively in both in vitro and in vivo models of B-cell non-Hodgkin lymphoma (Griner, et al, PNAS, 2014; Erdmann et al, Blood, 2017). We report on a phase I/II clinical trial of ibrutinib (BTK inhibitor) and buparlisib (pan-PI3K inhibitor) in patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), and mantle cell lymphoma (MCL). Methods: Patients (pts) were eligible if they had relapsed/refractory DLBCL, FL, or MCL, ECOG ≤2, and adequate organ function. Ibrutinib and buparlisib were given daily by mouth on a 28-day cycle with dose reductions permitted after cycle 1 unless a DLT was noted. Tumor response was based on a modified Lugano classification with CRs requiring FDG-PET resolution and ≥ PR by CT. Results: 37 pts were enrolled (DLBCL N = 14, FL N = 5, MCL N = 18) with median prior systemic therapies being 3 for DLBCL (range 1-7), 2 for FL (all had 2 prior regimens), and 1 for MCL (range 1-3). Ibrutinib 560 mg and buparlisib 80 mg was selected for dose expansion cohort based on rash and diarrhea requiring dose reductions. Thirty-six pts were evaluable for toxicity while 1 pt was not evaluable for progression within one week of therapy. Grade 3/4 adverse events related to therapy included rash (22%), hyperglycemia (16%), diarrhea (11%), hypertension (11%), anorexia (8%), mood changes (8%), ALT elevation (5%), lipase elevation (5%), anemia (5%), and hyponatremia (5%). Five pts discontinued buparlisib but continued ibrutinib for neurocognitive toxicities related to buparlisib. Thirty-five pts were evaluable for response with best overall response rate (ORR) as follows: DLBCL 31% (N = 13, 3 CR, 1 PR), FL 20% (N = 5, 1 CR), MCL 88% (N = 17, 11 CR, 4 PR). Conclusions: Combination of BTK and PI3K inhibition such as ibrutinib and buparlisib demonstrate a reasonable safety profile and promising clinical activity, especially in MCL. Long term follow-up and correlative analysis of tumor targeted sequencing and cell free DNA analysis is ongoing. Clinical trial information: NCT02756247