Background: Efficacy of treatment options for pts with r/r cHL is limited. Evidence suggests blocking the PI3K or JAK-STAT pathways may be efficacious in cHL directly and through modulation of the tumor microenvironment. Blocking both pathways may provide synergistic efficacy. Methods: Adult pts with r/r B-cell malignancies were enrolled in this ongoing open-label, dose escalation study. INCB040093 was given at doses of 100–300 mg QD or BID alone or 150–300 mg QD or BID with INCB039110 400–600 mg QD. Safety, efficacy, and pharmacodynamics were evaluated. Data from the r/r cHL pts are reported herein. Results: A total of 17 pts with r/r cHL have been enrolled: median age = 34 yrs, 59% men, median of 5 prior regimens, 82% underwent HSCT, and all had failed brentuximab vedotin. Median exposure was 209 days (range: 22+ [ongoing] – 388). The most common nonhematologic AEs (all grades) in this cHL cohort were fatigue (41%), headache (35%), and decreased appetite (35%). One nonhematologic grade ≥ 3 AE occurred in > 1 pt, pneumonia (12%). All grade neutropenia, thrombocytopenia, and anemia occurred in 47%, 47%, and 41%, respectively. Grade ≥ 3 thrombocytopenia occurred in 18%. Of 6 evaluable pts receiving INCB040093, ORR was 50% (1 CR); of 9 evaluable pts receiving INCB040093 + INCB039110, ORR was 67% (2 CRs). In this limited dataset of proximate dose cohorts, a dose response in efficacy was not evident. In the overall study population, INCB040093 100 mg BID and INCB040093 100 mg BID + INCB039110 400 mg QD were selected for expansion based on pharmacodynamics and the safety profile of higher dose levels. At the selected doses, ORR in the cHL cohort was 50% for INCB040093 and 75% (1 CR) for INCB040093 + INCB039110. Conclusions: INCB040093 ± INCB039110 was tolerable in this heavily pretreated population of pts with r/r cHL. Although the number of evaluable pts is limited, efficacy compares well to approved and promising investigational agents. These results warranted further investigation of INCB040093 alone and in combination with INCB039110 in pts with r/r cHL, leading to the initiation of a phase 2 study. Clinical trial information: NCT01905813