Background: In vitro data suggest that both the PI3K and JAK-STAT pathways contribute to tumor growth and survival in HL. Therapies that block both pathways may prove more beneficial in pts with r/r cHL, where treatment options are limited. INCB040093 is an oral PI3Kδ inhibitor and INCB039110 is an oral JAK1-selective inhibitor. Methods: This ongoing, nonrandomized, open-label trial has a planned enrollment of 122 pts (61 per treatment arm). Eligible pts are ≥ 18 years of age with r/r cHL after autologous stem cell transplant (SCT) and/or after ≥ 2 prior chemotherapy-containing regimens who are not candidates for autologous SCT; have fluorodeoxyglucose-avid disease; ECOG performance status 0 to 2; prior brentuximab vedotin (BV) treatment (or not a candidate for BV). Pts who received prior treatment with an immune checkpoint inhibitor are eligible if disease progression or relapse is confirmed with a second assessment ≥ 28 days later. Pts must have adequate ANC, platelet count, hemoglobin, total bilirubin, AST and ALT levels. Before first dose of study drug, pts must not have investigational agents within 28 days or 5 half-lives (whichever is greater); autologous SCT within 28 days or allogeneic SCT within 3 months; or radiation treatment within 3 weeks. Pts will receive INCB040093 100 mg bid monotherapy or INCB040093 100 mg bid with INCB039110 300 mg qd. Pts receiving benefit may continue on therapy until they meet treatment discontinuation criteria. Pts receiving INCB040093 monotherapy who experience disease progression or relapse on study may be eligible for crossover to combination therapy. The primary endpoint is objective response rate per the Lugano Classification (Cheson et al. J Clin Oncol 2014) determined by an independent review committee. Secondary endpoints include duration of response and progression-free survival. Overall survival is an exploratory endpoint. Final analysis is planned when all pts reach at least the Week 36 disease evaluation. Clinical trial information: EudraCT 2014-005631-13.