Background: Inhibiting the PI3K or JAK-STAT pathways may be therapeutic in B-cell malignancies due to their contribution to tumor growth and survival and effects on the tumor microenvironment. Blocking both pathways may be synergistic due to JAK-STAT augmentation of BCR activation of the NFκB pathway. Methods: This ongoing dose escalation study with expansion cohorts enrolled adult pts with r/r B-cell malignancies. INCB040093 was given at doses between 100–300 mg QD or BID alone or 150–300 mg QD or BID with INCB039110 at 400–600 mg QD. Safety, efficacy, and pharmacodynamics were evaluated. Results: A total of 83 pts have been enrolled: FL n = 19; cHL n = 17; DLBCL n = 15; CLL/SLL n = 13; others n = 19. Median age was 61 years and 70% were men. The median number of prior regimens was 4 and 24% underwent HSCT. Median exposure was 185 days (range: 5 – 491+ [ongoing]) for INCB040093 alone and 99 days (range: 6 – 337+ [ongoing]) for INCB040093 + INCB039110. The most common AEs were fatigue (28%), headache (19%), pyrexia (19%) and the most common grade ≥ 3 AE was pneumonia (6%). The most common laboratory abnormalities were liver enzyme elevations and cytopenias. One pt had a DLT on INCB040093 100 mg BID (GI bleed secondary to gastric DLBCL regression). Doses of INCB040093 100 mg BID and INCB040093 100 mg BID + INCB039110 400 mg QD were selected for expansion cohorts based on the incidence of liver enzyme elevations with INCB040093 and cytopenias with INCB040093 + INCB039110 at higher doses. At the selected doses, pAKT was decreased by ~90% at trough on INCB040093 and IL6-inducedpSTAT3 was decreased an average of 65% on INCB039110. Of 75 pts thus far evaluated for a response, 28 responses have been reported. Notably, ORR was 60% (3 CRs) for r/r cHL and both pts with the non-GCB subtype of DLBCL had CRs. Conclusions: Treatment with INCB040093 ± INCB039110 was tolerable and produced responses, including CRs, in pts with heavily pretreated r/r B-cell malignancies. Given this activity, the study was expanded to enroll additional cohorts of pts with r/r B-cell malignancies such as DLBCL and cHL, and a phase II study in pts with r/r cHL was initiated. Clinical trial information: NCT01905813