THE COMBINATION OF DUVELISIB AND ROMIDEPSIN (DR) IS HIGHLY ACTIVE AGAINST RELAPSED/REFRACTORY PERIPHERAL T‐CELL LYMPHOMA WITH LOW RATES OF TRANSAMINITIS: FINAL RESULTS

Abstract

Introduction: Standard therapies for most relapsed/refractory (R/R) T-cell lymphomas (TCL) have overall response rates (ORR) of 25%-35%. Phosphoinositide-3-kinase (PI3K) δ and γ isoforms can promote tumor cell autonomous and nonautonomous effects in TCL. Initial studies of the PI3K-δ/γ inhibitor duvelisib (D) in R/R TCL showed an ORR of 50% and CR of 19%, but also a 40% rate of grade (Gr) 3/4 ALT elevation at the MTD of 75 mg BID (Horwitz et al Blood 2018). Based on preclinical data, we initiated a phase I study of D with either romidepsin (R) or bortezomib. Based on efficacy and safety, Arm A (DR) was expanded to further describe safety and subtype-specific efficacy. Methods: 66 patients were treated on Arm A, with 59 at the MTD of D 75mg BID + R 10 mg/m2 on days 1, 8, 15 of a 28 day cycle with prophylaxis against VZV and PJP. Response was assessed q2 cycles x 3 then q3 cycles. 10 patients received 1 cycle (Lead In) of D 75 mg BID alone prior to combination DR. Patients proceeding to transplant were censored. Results: 55 patients with PTCL and 11 with CTCL were treated (Table 1). No DLTs were seen in the phase 1 on Arm A so dose level 3 (D 75 + R 10) was deemed the MTD. At the MTD, 50/59 (85%) had AEs Gr 3-4 (no Gr 5) possibly related to study drug. AEs ≥Gr 3 in ≥10% of pt were: neutropenia (36%), diarrhea (15%), increased ALT/AST (14%), thrombocytopenia (10%), and infection (10%). 5 patients (9%) had ≥Gr 3 rash. 12 had any Gr oropharyngeal/esophageal candidiasis; 2 Gr3. In 10 patients who began on D-only Lead In, 4 (40%) had ≥Gr 3 ALT/AST and 3/10 had ≥Gr 3 diarrhea. By contrast, only 4 /49 (8%) who got R + D in cycle 1 had Gr 3-4 ALT/AST (p = .022) and 6/49 had ≥Gr 3 diarrhea (p = .170). 64/66 patients were evaluable for response. ORR was 55% (35/64) and CR was 34% (22/64). In PTCL, ORR was 58% (31/53) and CR was 42% (22/53). In CTCL, ORR was 36% (4/11), all PR. Response by histology is in Table 1. Of responders, 15/35 (43%) proceeded to allo-SCT with curative intent, after a median of 4 cycles. Median PFS was 6.9 m (PTCL) and 5.5 m (CTCL) and median DOR was 8.1 m. 4 subjects had CR to single agent D on Lead-in and did not proceed to DR; 2/4 went to SCT and 1/4 remains on D at 42m. Conclusion: DR is highly active in R/R PTCL. Adding Romidepsin to Duvelisib 75 mg BID is safe and reduces Gr 3-4 transaminitis compared to Duvelisib at the same dose. The high rates of CR and frequent bridging to allotransplant support the value of DR for patients with R/R PTCL. The research was funded by Verastem/SecuraBio for this clinical trial Keywords: Aggressive T-cell non-Hodgkin lymphoma, Chemotherapy, Combination Therapies Conflicts of interests pertinent to the abstract S. M. Horwitz Consultant or advisory role: Acrotech Biopharma, ADC Therapeutics, Astex, C4 Therapeutics, Celgene, Janssen, Kura Oncology, Kyowa Hakko Kirin, Myeloid Therapeutics, ONO Pharmaceuticals, Seattle Genetics, Shoreline Bio, Takeda, Trillium Therapeutics, Tubulis, Verastem, SecuraBio, and Vividion Therapeutics. Honoraria: Takeda Research funding: ADC Therapeutics, Affimed, Aileron, Celgene, Daiichi Sankyo, Forty Seven, Inc., Kyowa Hakko Kirin, Millennium/Takeda, Seattle Genetics, Trillium Therapeutics, and Verastem/SecuraBio A. J. Moskowitz Consultant or advisory role: Imbrium Therapeutics L.P, Janpix Ltd., Merck, Seattle Genetics, and Takeda Research funding: ADC Therapeutics, Miragen, Seattle Genetics, Merck, Bristol-Myers Squibb, and Incyte N. Mehta-Shah Consultant or advisory role: Kiowa Hakka Kirin, Karyopharm Therapeutics, C4 Therapeutics, Daiichi Sankyo, Ono Pharmaceuticals, SecuraBio Research funding: Bristol Myers Squibb, Celgene, Verastem, Innate Pharmaceuticals, Corvus Pharmaceuticals, Genentech/Roche D. C. Fisher Consultant or advisory role: Verastem A. Kumar Consultant or advisory role: Celgene, Kite Pharmaceuticals Research funding: Abbvie Pharmaceuticals, Adaptive Biotechnologies, Pharmacyclics, Seattle Genetics, Astra Zeneca – Steering Committee for MCL Registry A. Dogan Consultant or advisory role: Corvus Pharmaceuticals, Physicians’ Education Resource, Seattle Genetics, Takeda, Roche, EUSAPharma, PeerView Research funding: Roche and Takeda D. Weinstock Consultant or advisory role: Secura Pharma Research funding: Verastem