NANATINOSTAT WITH OR WITHOUT VALGANCICLOVIR IN PATIENTS WITH RELAPSED/REFRACTORY EBV-POSITIVE PERIPHERAL T-CELL LYMPHOMA (NAVAL-1 STAGE 1)

Epstein-Barr virus-positive (EBV +) lymphomas are a heterogeneous group of malignancies that harbor latent EBV within the lymphoma cells and are associated with variable clinical features. Outcomes of EBV + Peripheral T-Cell Lymphoma (PTCL) patients are typically inferior to their EBV – counterpart, and thus represent an unmet medical need. Nanatinostat (Nstat) is a potent Class-I histone deacetylase inhibitor. With a novel mechanism of action, Nstat induces expression of the lytic BGLF4 protein kinase, which activates the nucleoside analog ganciclovir (GCV), derived from valganciclovir (VGCV) via phosphorylation. Incorporation of phosho-GCV into cellular DNA results in termination of DNA replication and apoptosis. NAVAL-1 (NCR05011058) is an adaptive Phase 2, open-label, single-arm, two-stage, basket trial. In Stage 1 of the relapsed/refractory (R/R) EBV + PTCL cohort, 20 patients were randomized 1:1 to receive Nstat (20 mg orally once daily, 4 days/week) alone or in combination with VGCV (900 mg orally once daily, 7 days/week) and followed for efficacy and safety. Results: As of 28 June, 2024, the investigator-assessed overall response rate (ORR) by Cheson 2007 in the 10-patient Nstat+VGCV arm was 50% (with a duration of response that is maturing) with a complete response rate (CRR) of 20% in the intent-to-treat (ITT) population (ORR 71% and CRR 29% in the efficacy-evaluable population). One responding patient discontinued Nstat+VGCV to undergo allogeneic stem cell transplantation and remains lymphoma-free over 1 year. In the 10-patient Nstat monotherapy arm, the ORR and CRR were 10% and 0%, respectively, in the ITT population. Five patients without monotherapy response crossed over to combination therapy, including one who had a partial response and another with stable disease for 24+ weeks, both still ongoing. Most TRAEs have been hematological or gastrointestinal in nature and primarily Grade 1-2 in severity. Most Grade ≥3 TRAEs have been generally manageable or reversible except for one patient with Grade 5 TRAE of sepsis in the context of severe cytopenias. Combination Nstat+VGCV is a promising, generally well-tolerated treatment for patients with R/R EBV + PTCL that has shown improved efficacy over Nstat monotherapy in the challenging scenario of R/R PTCL.