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Introduction: Current therapies for relapsed/refractory (rel/ref) T-cell lymphomas (TCLs) induce responses in only 25-30% of patients (pts). Phosphoinositide-3-kinases (PI3K) play a pivotal role in cell signaling and PI3K isoforms have distinct roles in the development, function and survival of T cells. A phase I study of the oral PI3K-δ/γ inhibitor duvelisib (DUV) in pts with TCLs showed promising activity in rel/ref TCL (Horwitz, Blood 2014). We assessed mechanisms of response and resistance to DUV in T-cell lymphomas in vitro and in vivo. Based on in vitro evidence of synergy, we initiated a phase I study to evaluate the safety and efficacy of DUV combined with romidepsin or bortezomib in pts with rel/ref TCL. Methods: Preclinical: We characterized the PI3K-signaling pathway across 11 cell lines of TCL by immunoblotting and assessed the in vitro activity of isotype specific PI3K inhibitors, including DUV. A targeted phosphoproteomic approach (P100) was utilized to identify mechanisms of resistance and response of DUV across 6 cell lines in vitro. We assessed the effects of DUV on immune response within the TCL microenvironment in vivo using a patient-derived xenograft (PDX). Clinical: We conducted multicenter, parallel phase I trials of DUV in combination with romidepsin (arm A) or bortezomib (arm B) in rel/ref TCL. For each arm, a standard 3+3 phase I design was used to determine maximum tolerated dose (MTD). DUV was dosed at 25mg, 50mg, or 75mg BID on days 1-28. Romidepsin 10mg/m2 was dosed on days 1, 8, and 15 (arm A) or bortezomib 1mg/m2 on days 1, 4, 8, and 11 (arm B), both on 28-day cycles. All pts received prophylaxis against Varicella and Pneumocystis. Results: Preclinical: DUV potently killed 3 of 4 TCL cell lines that showed constitutive phosphorylation of AKT (pAKT) versus 0 of 7 lines lacking pAKT (p=0.024). Killing by DUV exceeded killing by the PI3K-δ-specific inhibitor idelalisib and was similar to pan-PI3K inhibition. The phosphoproteomic analysis identified resistance through either PI3Kα activation, which was overcome by pan-PI3K inhibition, or by epigenetic reprogramming, which was overcome by co-treatment with romidepsin. Administration of DUV to mice engrafted with a TCL PDX resulted in reprogramming of tumor-infiltrating macrophages from the immunosuppressive M2-like phenotype to the pro-phagocytic M1-like phenotype. Clinical: 12 pts (4 in each dose level [DL]) were treated on arm A (romidepsin+DUV); 8 are evaluable for efficacy. There were no dose limiting toxicities (DLTs), therefore DL 3 was accepted as MTD. 2 serious adverse events (SAEs) possibly related to study drug included grade (Gr) 3 fatigue and Gr 2 aspartate aminotransferase (AST) elevation. 1 fatal event (diffuse alveolar hemorrhage following allogeneic transplant) occurred 31 days after last dose of study drug and was assessed as unrelated to study treatment. Gr 3 or 4 adverse events (AEs) occurring in ≥10% of pts included only neutropenia (Gr 3, n=4, Gr 4, n=2). Overall response rate (ORR) and median time to response (TTR) were 4/8 (50%) and 51 (range 49-54) days. Two of 4 responders proceeded to transplant after 90 and 108 days and 1 remains on treatment for 107+ days. 17 pts were treated on arm B (bortezomib+DUV), including 8 in DL 1, 3 in DL 2, and 6 in DL 3; 15 pts are evaluable for efficacy. 1 out of 6 pts evaluable for DLT on DL 1 experienced DLT (pneumonia). There were no other DLTs, however Gr 3 elevations of alanine aminotransferase (ALT) or AST following cycle 2 were observed for 3 pts treated at DL 2 and 2 treated at DL 3 leading to DL 1 being accepted as MTD. There were 5 SAEs possibly related to study drug including Gr 3 pneumonia (n=2), Gr 3 infectious colitis (n=1), Gr 3 colitis (n=1), and Gr 4 AST/ALT elevation (1). Gr 3 or 4 AEs occurring in ≥10% of pts included only neutropenia (Gr 3, n=3). ORR, complete response (CR), and median time to response (TTR), were 8/15 (53%), 3/15 (20%), and 52 (range 47-57) days. Among the 8 responders, 5 remain on treatment for 103-377+ days. Conclusion: DUV shows activity in T-cell lymphomas with pre-clinical evidence of both tumor cell-autonomous and non-autonomous effects. The combinations of DUV plus romidepsin and DUV plus bortezomib are safe and well tolerated, with limited incidence of AST/ALT elevation from romidepsin+DUV. Promising response rates of at least 50% were observed across TCL histologies with both regimens. Expansion cohorts of pts with peripheral and cutaneous TCL are currently enrolling. Disclosures Moskowitz: ADC Therapeutics: Research Funding; Seattle Genetics: Honoraria, Research Funding; Takeda: Honoraria; Incyte: Research Funding; Bristol Myers-Squibb: Consultancy, Research Funding. Mehta-Shah: Celgene: Research Funding; Verastem: Research Funding; Bristol Myers Squibb: Research Funding. Dogan: Roche Pharmaceuticals: Consultancy; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Peer Review Institute: Consultancy; Celgene: Consultancy; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees. Kim: Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Research Funding; Soligenix: Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Portola: Consultancy, Research Funding; Horizon Pharma: Consultancy, Research Funding; Forty Seven Inc: Membership on an entity's Board of Directors or advisory committees, Research Funding; Eisai: Membership on an entity's Board of Directors or advisory committees, Research Funding; Kyowa-Kirin-Pharma: Membership on an entity's Board of Directors or advisory committees, Research Funding; Innate Pharma: Consultancy, Research Funding; Medivir: Membership on an entity's Board of Directors or advisory committees; Merck: Research Funding; miRagen: Research Funding; Neumedicine: Research Funding; Tetralogic: Research Funding; Millennium Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees. Jacobsen: GSK: Membership on an entity's Board of Directors or advisory committees; Spectrum: Membership on an entity's Board of Directors or advisory committees; Kite Pharma: Membership on an entity's Board of Directors or advisory committees. Horwitz: Forty-Seven: Consultancy, Research Funding; Aileron Therapeutics: Research Funding; Kyowa-Hakka-Kirin: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Millenium/Takeda: Consultancy, Research Funding; BMS: Consultancy; Mundipharma: Consultancy; ADCT Therapeutics: Research Funding; Infinity/Verastem: Consultancy, Research Funding; HUYA: Consultancy.