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

Abstract

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 ≥1.0×10 9/L, platelet count ≥50×10 9/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.: Honoraria, Research Funding. Baiocchi: Prelude Therapeutics: Consultancy; viracta: Consultancy, Current holder of stock options in a privately-held company; Codiak Biosciences: Research Funding; Atara Biotherapeutics: Consultancy. Brammer: Seattle Genetics: Speakers Bureau; Celgene: Research Funding; Kymera Therapeutics: Consultancy. 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.

EBV‐positive diffuse large B‐cell lymphoma, not otherwise specified: 2022 update on diagnosis, risk‐stratification, and management

“…Clinical support for combining an HDACi with an antiviral drug was initially provided by a Phase 1/2 proof‐of‐concept study conducted with the pan‐HDACi, arginine butyrate, in combination with ganciclovir in patients with recurrent EBV+ B‐cell lymphomas, which demonstrated significant anti‐tumor activity (4 CR and 6 PR) among 15 patients treated 91 . Final Results from the Phase 1b/2 VT3996‐201 study of the combination of nanatinostat and valganciclovir in relapsed/refractory EBV+ lymphomas were presented at the 2021 ASH annual meeting in Atlanta, GA 92 . As of June 2021, 55 patients were enrolled and 43 patients were evaluable for response.…”

Extranodal Natural Killer/T-Cell Lymphomas: Current Approaches and Future Directions

“…Lytic cycle induction using the histone deacetylase inhibitor nanatinostat in combination with the antiviral agent valganciclovir has also been attempted at targeting relapsed/refractory EBV-positive ENKTL [ 59 ]. Antiviral agents such as ganciclovir require the presence of functional viral thymidine kinase, BGLF4, a lytic phase protein, for activation [ 111 ].…”

“…Antiviral agents such as ganciclovir require the presence of functional viral thymidine kinase, BGLF4, a lytic phase protein, for activation [ 111 ]. Nanatinostat induces the expression of BGLF4 EBV protein kinase in EBV-positive tumor cells, activating ganciclovir (GCV) via phosphorylation [ 59 ]. The Phase 1b/2 VT3996-201 study combined nanatinostat with vanganciclovir for treatment of histologically confirmed EBV-positive lymphomas relapsed/refractory after at least one prior systemic therapy [ 99 ].…”

“…Among the 55 patients enrolled, nine patients had ENKTL; five patients had PTCL, not otherwise specified; six patients had angioimmunoblastic T-cell lymphoma; and one patient had cutaneous T-cell lymphoma. In 15 patients with T/NK non-Hodgkin’s lymphoma with a median follow-up period of 5.7 months (range 1.9–34.1), an ORR of 60% and CR of 27% were achieved, with a median duration of response of 10.4 months [ 59 ]. It is important to note that two patients (ENKTL and PTCL-NOS) in PR and CR, respectively, were withdrawn at 6.7 and 6.6 months, respectively, for consolidation with autologous stem cell transplantation.…”

Recent Advances in the Management of Relapsed and Refractory Peripheral T-Cell Lymphomas

“…BGLF4 can, in turn, activate anti-viral agent Ganciclovir by phosphorylation, making EBV-infected cells susceptible to anti-viral treatment [ 92 ]. A phase 1b/2 VT3996-201 study combined the HDAC inhibitor nanatinostat with valganciclovir for the treatment of histologically confirmed EBV-positive r/r lymphomas [ 68 ]. The study enrolled a total of 15 T/NK non-Hodgkin lymphoma subjects: 5 PTCL-NOS, 1 cutaneous T-cell lymphoma, and 9 extranodal NK-/T-cell lymphoma patients.…”