354O - A phase Ib/II study of nanatinostat (Nstat) plus valganciclovir (VGCV) in EBV+ solid tumors and with pembrolizumab (PEM) in recurrent/metastatic nasopharyngeal carcinoma (R/M NPC)

Background

Latent EBV is associated with NPC. Nstat is a Class-I selective oral HDAC inhibitor that induces expression of the lytic BGLF4 EBV protein kinase in EBV+ tumor cells, activating ganciclovir (GCV) via phosphorylation. This results in GCV-mediated inhibition of viral + cellular DNA synthesis and apoptosis. Nstat + VGCV (prodrug of GCV) had favorable safety with antitumor activity in a study in patients (pts) with R/R EBV+ lymphoma. For this study, phase 1b (P1b) uses 3+3 dose escalation for Nstat + VGCV dose selection in pts with R/M NPC, then expansion at that dose in other EBV+ solid tumors. In phase 2 (P2), up to 60 R/M NPC pts will be randomized 1:1 to receive Nstat and VGCV +/- PEM. Herein we report safety results from P1b in pts with R/M NPC (NCT05166577).

Methods

Pts ≥18y with measurable R/M EBV+ NPC (1-3 prior Tx) and no curative options receive oral Nstat 20-40 mg/d (4d/wk) with VGCV 900-1800 mg/d in P1b. Primary endpoints are dose-limiting toxicities (DLTs) (P1b) and overall response (P2); secondary endpoints include duration of response, disease control rate, progression-free survival, and overall survival.

Results

As of July 2023, 17 pts (median age 49y [19-66y]) were enrolled across 5 dose level cohorts (DLCs): 3, 4, and 3 pts in DLCs 1, 2, and 3 received Nstat 20, 30, and 40 mg QD 4d/wk + VGCV 900 mg QD; 3 and 4 pts in DLCs 4 and 5 received Nstat 10 mg BID and 20 mg QAM/10 mg QPM 4d/wk + VGCV 900 mg BID x 21d then QD. Median 2 prior systemic Tx, and all pts were refractory to last Tx. Related AEs were mostly G1-2 in severity, most commonly nausea and decreased appetite (n=7 each), increased creatinine (n=5), and fatigue (n=4), with no related SAEs or DLTs reported. Of 15 pts evaluable for response, 1 had PR x 6.9+ mos (at DLC3 with stable plasma EBV DNA [pEBVd]), 2 had SD (at DLC4 + DLC5 with pEBVd reduction), and 12 had PD (with rising pEBVd).

Conclusions

The combination of Nstat and VGCV represents a novel approach for the treatment of R/M EBV+ NPC that is tolerated at doses exceeding the RP2D for lymphoma with early signs of antitumor activity at higher DLCs. Further dose escalation with split daily Nstat + VGCV dosing based on recent murine xenograft results is planned.

Clinical trial identification

NCT05166577.

Editorial acknowledgement

Legal entity responsible for the study

Viract.

Funding

Viract.

Disclosure

A. Elguindy, A. Katkov: Financial Interests, Personal, Other, employee: Viracta. All other authors have declared no conflicts of interest.