Background: Despite impressive activity of PD-1/PD-L1 therapy in HL, proportions of patients do not respond and eventually progress. Growing evidence suggests that high infiltrations of immune-suppressive myeloid cells are responsible for anti-PD-1/PD-L1 therapy resistance. These observations suggest a need for an immunotherapeutic combination to overcome such resistance mechanisms. PI3K δ/γ isoforms are known to play a role in modulating the tumor microenvironment. Tenalisib demonstrated marked reduction of Tumor Associated Macrophages (TAMs) and angiogenesis and showed synergy with checkpoint inhibition in syngeneic mouse models. Tenalisib has demonstrated single agent activity in relapsed refractory heavily pre-treated cHL (ORR 29% CR 7% PR 21%). The proposed study hypothesizes that Tenalisib in combination with Pembrolizumab improve the depth and durability of responses to anti-PD1 therapy. Methods: The primary objective of this phase I/II, open label, 3+3 dose-escalation study is to evaluate the safety, tolerability, and identify the maximum tolerated dose of tenalisib in combination with Pembrolizumab in relapsed/refractory cHL. Patients will be enrolled in two escalating cohorts (Tenalisib 400/ 800 mg BID and Pembrolizumab 200 mg, IV) to determine MTD/ optimal dose. In Expansion part, two groups will be initiated. The first expansion group will enroll 18 patients who are naïve to anti-PD-1 therapy to explore the additive/synergistic effect of the combination by measuring efficacy parameters (ORR, DoR, PFS). The second group will enroll 27 patients who have received treatment with pembrolizumab for at least 6 months and have not demonstrated a complete response. The objective is to understand whether combination therapy will overcome PD-1 resistance by augmenting conversion rates (i.e., improvement from progressive disease to CR or from SD to PR) upon combination. Disease response assessments will be determined per the Lugano classification (Cheson 2014). Eligible subjects will receive Tenalisib BID orally and Pembrolizumab 200 mg, IV every three weeks in a 21-day cycle.