A GLOBAL PHASE 2 TRIAL OF NANATINOSTAT AND VALGANCICLOVIR IN PATIENTS WITH RELAPSED/REFRACTORY EBV-POSITIVE PERIPHERAL T-CELL LYMPHOMAS (NAVAL-1 STAGE 1-2)

Abstract

Introduction: Patients with Epstein-Barr virus-positive (EBV+) lymphoma are currently faced with challenging outcomes and represent an unmet medical need. Clinical outcomes in this population may be inferior to the EBV– counterpart in different lymphoma subtypes, including Peripheral T-Cell Lymphoma (PTCL). With a novel mechanism of action, nanatinostat (Nstat, a potent Class-I histone deacetylase inhibitor) induces expression of the lytic BGLF4 protein kinase, which activates the nucleoside analog ganciclovir (GCV), derived from valganciclovir (VGCV) via phosphorylation. Incorporation of phospho-GCV into cellular DNA results in termination of DNA synthesis causing apoptosis. Materials and methods: NAVAL-1 (NCR05011058) is an adaptive Phase 2, open-label, single-arm, two-stage, basket trial. Each lymphoma subtype cohort where ≥2 of 10 patients in Stage 1 responded to Nstat (20 mg orally once daily, 4 days/week) and VGCV (900 mg orally once daily, 7 days/week) continued to enroll 11 patients in Stage 2, for a total of 21 patients in each cohort. Efficacy and safety data from the 21-patient relapsed/refractory (R/R) EBV + PTCL cohort are presented herein. Results: As of 28 June, 2024, the investigator-assessed overall response rate (ORR), as assessed by Cheson 2007, in 21 patients treated with Nstat+VGCV was 33% (with a median duration of response that has not yet been reached) with a complete response rate (CRR) of 19% in the intent-to-treat population (ORR 41% and CRR 24% in the efficacy-evaluable population), including 2 patients who were able to proceed to allogeneic hematopoietic stem cell transplant. Patients receiving the combination in the second-line treatment setting had higher ORR (60%), with a CRR of 30% (efficacy-evaluable ORR 67% and CRR 33%). Most TRAEs have been hematological or gastrointestinal in nature and primarily Grade 1-2 in severity, and most Grade ≥3 TRAEs have been generally manageable or reversible except for one Grade 5 TRAE of sepsis in the context of severe cytopenias. Serious TRAEs have included influenza, pneumonia, upper respiratory tract infection, pancytopenia and sepsis (1 each). Conclusion: Nstat+VGCV is emerging as a promising, generally well-tolerated treatment for patients with R/R EBV + PTCL, particularly in the second-line treatment setting. Enrollment in the PTCL expansion is ongoing.