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623 Nanatinostat (Nstat) and Valganciclovir (VGCV) in Relapsed/Refractory (R/R) Epstein-Barr Virus-Positive (EBV+) Lymphomas: Final Results from the Phase 1b/2 VT3996-201 Study

Program: Oral and Poster Abstracts
Type: Oral
Session: 624. Hodgkin Lymphomas and T/NK cell Lymphomas: T/NK Cell Lymphoma Relapsed Therapy
Hematology Disease Topics & Pathways:
Clinical Trials, Clinical Research
Monday, December 13, 2021: 11:30 AM

Bradley M. Haverkos, MD, MS, MPH1, Onder Alpdogan, MD2, Robert Baiocchi, MD3, Jonathan E Brammer, MD4, Tatyana A. Feldman, MD5, Marcelo Capra, MD, PhD6, Elizabeth A Brem, MD7, Santosh M Nair, MD8, Phillip Scheinberg, MD9, Juliana Pereira, MD, PhD10, Leyla Shune, MD11, Erel Joffe, MD, MSc12, Afton Katkov, MSc13*, Robert McRae13*, Ivor Royston, MD14, Lisa Rojkjaer, MD15 and Pierluigi Porcu, MD16

1University of Colorado, Aurora, CO
2Division of Hematologic Malignancies and Hematopoietic Stem Cell Transplantation, Department of Medical Oncology, Thomas Jefferson University, Philadelphia, PA
3Division of Hematology, Department of Internal Medicine, College of Medicine, Ohio State University, Columbus, OH
4Division of Hematology, Department of Internal Medicine, The Ohio State University James Comprehensive Cancer Center, Columbus, OH
5Hackensack University Medical Center, NY, NY
6Hospital do Cancer Mae de Deus, Porto Alegre, PB, Brazil
7Division of Hematology/Oncology, Dept. of Medicine, University of California, Irvine, Orange, CA
8Mid Florida Hematology/Oncology, Orange City, FL
9Hospital A Beneficência Portuguesa, Sao Paulo, MT, Brazil
10Department of Hematology- Hospital das Clínicas da Faculdade de Medicina da USP- HCFMUSP, Universidade de São Paulo, SAO PAULO, Brazil
11University of Kansas Cancer Center, Westwood, KS
12Department of Medicine, Lymphoma Service, Memorial Sloan Kettering Cancer Center, New York, NY
13Viracta Therapeutics, Inc, Cardiff, CA
14Viracta, Cardiff, CA
15Viracta Therapeutics, Inc., Cardiff, CA
16Sidney Kimmel Cancer Center, Dept. of Medical Oncology, Thomas Jefferson University, Philadelphia, PA

Introduction: EBV can be associated with several types of lymphomas, with reported frequencies of up to 8-10% in diffuse large B cell lymphoma (DLBCL), 30-100% in peripheral T cell lymphoma (PTCL) subtypes, 80% in post-transplant lymphoproliferative disease (PTLD), and 15-30% in classical Hodgkin lymphoma (HL), with adverse impact on outcomes. Nanatinostat (Nstat) is a Class-I selective oral HDAC inhibitor that induces the expression of the lytic BGLF4 EBV protein kinase in EBV+ tumor cells, activating ganciclovir (GCV) via phosphorylation. This results in GCV-induced inhibition of viral and cellular DNA synthesis and apoptosis. Herein we report the final results from this exploratory study for patients with R/R EBV+ lymphomas (NCT03397706).

Methods: Patients aged ≥18 with histologically confirmed EBV+ lymphomas (defined as any degree of EBER-ISH positivity), R/R to ≥1 prior systemic therapies with an absolute neutrophil count ≥1.0×109/L, platelet count ≥50×109/L, and no curative treatment options per investigator were enrolled into 5 dose escalation cohorts to determine the recommended phase 2 doses (RP2D) of Nstat + VGCV for phase 2 expansion. Phase 2 patients received the RP2D (Nstat 20 mg daily, 4 days per week + VGCV 900 mg orally daily) in 28-day cycles until disease progression or withdrawal. Primary endpoints were safety/RP2D (phase 1b) and overall response rate (ORR) (phase 2); secondary endpoints were pharmacokinetics, duration of response (DoR), time to response, progression free survival and overall survival. Responses were assessed using Lugano 2014 response criteria beginning at week 8.

Results: As of 18 June 2021, 55 patients were enrolled (phase 1b: 25; phase 2: 30). Lymphoma subtypes were DLBCL (n=7), extranodal NK/T-cell (ENKTL) (n=9), PTCL, not otherwise specified (PTCL-NOS) (n=5), angioimmunoblastic T cell lymphoma (n=6), cutaneous T cell (n=1), HL (n=11), other B cell (n=3), and immunodeficiency-associated lymphoproliferative disorders (IA-LPD) (n=13), including PTLD (n=4), HIV-associated (n=5), and other [n=4: systemic lupus erythematosus (SLE) (n=2), common variable/primary immunodeficiency (n=2)]. Median age was 60 years (range 19-84), M/F 35/20, median number of prior therapies was 2 (range 1-11), 76% had ≥2 prior therapies, 78% were refractory to their most recent prior therapy, and 84% had exhausted standard therapies. EBER positivity ranged from <1 to 90% in 42 tumor biopsies with central lab review. The most common treatment-emergent adverse events (TEAEs) of all grades were nausea (38%), neutropenia (34%), thrombocytopenia (34%), and constipation (31%). Grade 3/4 TEAEs in >10% of patients included neutropenia (27%), thrombocytopenia (20%), anemia (20%), and lymphopenia (14%). Dose reductions and interruptions due to treatment-related AEs were reported in 14 (25%) and 16 (29%) patients, respectively. Only 1 patient had to discontinue therapy. There were no cases of CMV reactivation.

For 43 evaluable patients (EBER-ISH+ with ≥ 1 post-treatment response assessment) across all histologies, the investigator-assessed ORR and complete response (CR) rates were 40% (17/43) and 19% (8/43) respectively. Patients with T/NK-NHL (n=15; all refractory to their last therapy) had an ORR of 60% (n=9) with 27% (n=4) CRs. Two patients (ENKTL and PTCL-NOS) in PR and CR respectively were withdrawn at 6.7 and 6.6 months (m) respectively for autologous stem cell transplantation. For DLBCL (n=6), ORR/CR was 67%/33% (both CRs were in patients refractory to first-line R-CHOP). For IA-LPD (n=13), ORR/CR was 30%/20% (PTLD: 1 CR, other: 1 CR, 1 PR). For HL (n=10), there was 1 PR (4 SD). The median DoR for all responders was 10.4 m, with a median follow-up from response of 5.7 m (range 1.9-34.1 m). For the 17 responders, 8 lasted ≥ 6 months.

Conclusions: The combination of Nstat and VGCV was well-tolerated with a manageable toxicity profile and shows promising efficacy in patients with R/R EBV+ lymphomas, particularly in refractory T/NK-NHL, a heterogeneous group of aggressive lymphomas with dismal outcomes, with multiple durable responses. Further evaluation of this novel combination therapy for the treatment of recurrent EBV+ lymphomas is ongoing in the phase 2 VT3996-202 trial.

Disclosures: Haverkos: Viracta Therapeutics, Inc.: Consultancy. Baiocchi: Prelude Therapeutics: Consultancy; viracta: Consultancy, Current holder of stock options in a privately-held company; Codiak Biosciences: Research Funding; Atara Biotherapeutics: Consultancy. Brammer: Celgene: Research Funding; Seattle Genetics: Speakers Bureau; Kymera Therapeutics: Consultancy; Secura Bio: Consultancy, Membership on an entity's Board of Directors or advisory committees; DrenBio: Membership on an entity's Board of Directors or advisory committees; Incyte Pharmaceuticals: Research Funding. Feldman: Alexion, AstraZeneca Rare Disease: Honoraria, Other: Study investigator. Brem: Karyopharm: Membership on an entity's Board of Directors or advisory committees; SeaGen: Speakers Bureau; BeiGene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bayer: Membership on an entity's Board of Directors or advisory committees; KiTE Pharma: Membership on an entity's Board of Directors or advisory committees; TG Therapeutics: Consultancy; ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics/Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Morphosys/Incyte: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Scheinberg: Roche: Consultancy; Abbvie: Consultancy; BioCryst Pharmaceuticals: Consultancy; Alexion pharmaceuticals: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau. Joffe: AstraZeneca: Consultancy; Epizyme: Consultancy. Katkov: Viracta Therapeutics, Inc.: Current Employment. McRae: Viracta Therapeutics, Inc.: Current Employment. Royston: Viracta Therapeutics, Inc.: Current Employment. Rojkjaer: Viracta Therapeutics, Inc.: Current Employment. Porcu: Viracta: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Innate Pharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BeiGene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Research Funding; Daiichi: Honoraria, Research Funding; Kiowa: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Spectrum: Consultancy; DrenBio: Consultancy.

*signifies non-member of ASH