Abstract 156P
Background
EBV is associated with NPC, with the virus in a latent state. 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 and cellular DNA synthesis and apoptosis. Nstat plus VGCV (oral prodrug of GCV) showed a favorable safety profile with anti-tumor activity in a phase 1b/2 study in R/R EBV+ lymphoma (recommended phase 2 dose [RP2D]: Nstat 20 mg daily [QD], 4 d/wk + VGCV 900 mg QD). Here, phase 1b uses a 3+3 dose escalation for Nstat + VGCV RP2D selection in RM-NPC, followed by an expansion at the RP2D in other EBV+ solid tumors. In phase 2, up to 60 RM-NPC pts will be randomized 1:1 to receive Nstat + VGCV at the RP2D +/- PEM. Herein we report preliminary safety results from phase 1b in RM-NPC (NCT05166577).
Methods
Pts aged ≥18 with EBV+ RM-NPC (1-3 prior therapies) with measurable disease (RECIST v1.1) and no curative options receive daily Nstat 20-40 mg 4d per wk with VGCV 900-1800 mg daily in phase 1b. Primary endpoints are incidence of dose limiting toxicities (DLTs) (phase 1b) and overall response rate (phase 2); secondary endpoints include duration of response, disease control rate, progression free survival and overall survival. Responses are assessed per RECIST v1.1 from week 8.
Results
As of 15-Sept-22, 7 male pts (median age 51y [19-61y]) were enrolled; 3 in dose level (DL) 1 and 4 in DL2 received Nstat 20 and 30 mg QD, respectively, 4 d/wk, plus VGCV 900 mg QD. Median no. prior systemic therapies was 2; all pts were refractory to last therapy with bone (6/7), liver (5/7), and lung (3/7) metastases. Related AEs were all G1-2, most commonly fatigue, nausea, and increased creatinine (n=3 each); no G3+ AEs/DLTs and 1 SAE (cancer pain) were reported. Of 6 pts evaluable for response, 2 had SD (with decreasing/stable plasma EBV DNA, pEBVd); 4 had PD (with rising pEBVd).
Conclusions
The combination of Nstat and VGCV represents a novel approach for the treatment of EBV+ NPC and is tolerated at doses exceeding the RP2D for lymphoma. Dose escalation continues.
Clinical trial identification
NCT05166577.
Legal entity responsible for the study
Viracta Therapeutics.
Funding
Viracta Therapeutics.
Disclosure
L.L. Siu: Financial Interests, Personal, Advisory Board: Merck, AstraZeneca, Roche, Oncorus, Seattle Genetics, Voronoi, Arvinas, Tessa, Navire, Relay Therapeutics, Janpix, Amgen, Marengo, InterRNA, Medicenna, Hoopika, Coherus; Financial Interests, Personal, Other, Spouse is co-founder: Treadwell Therapeutics; Financial Interests, Personal, Stocks/Shares, Spouse has stock ownership: Agios; Financial Interests, Institutional, Invited Speaker: Novartis, Bristol Myers Squibb, Pfizer, Boerhinger-Ingelheim, GlaxoSmithKline, Roche/Genentech, AstraZeneca, Merck, Astellas, Bayer, Amgen, Symphogen, Intensity Therapeutics, Shattucks, EMD Serono; Non-Financial Interests, Personal, Advisory Role: ICR. D.W. Lim: Financial Interests, Institutional, Advisory Board: Boehringer Ingelheim, MSD, Pfizer, Novartis; Financial Interests, Institutional, Invited Speaker: Roche, Novartis; Financial Interests, Institutional, Invited Speaker, Grant funding for investigator-sponsored study: Bristol Myers Squibb. S.A. Khan: Financial Interests, Personal, Advisory Board, I conduct molecular tumor boards for FMI: Foundation Medicine; Financial Interests, Personal, Advisory Board, Scientific Advisory Board: Eisai; Financial Interests, Personal, Other, give educational lectures to oncologists about molecular testing: Roche Pakistan. P.J. Voon: Financial Interests, Personal, Invited Speaker: AstraZeneca, Merck Sharp & Dohme, Pfizer; Financial Interests, Personal, Advisory Board: Novartis, Ipsen; Financial Interests, Personal and Institutional, Invited Speaker: AstraZeneca, Novartis, Boehringer Ingelheim, Janssen-Cilag, Johnson & Johnson, Viracta Therapeutics Inc, Roche, Merck KGaA, Merck Sharp & Dohme. M. Ahn: Financial Interests, Personal, Advisory Board: AstraZeneca, Lilly, Takeda, MSD, Yuhan, Amgen, Alpha Pharmaceutical, Janssen, BMS, Roche, Daichi Sankyo. A. Elguindy, A. Katkov, L. Rojkjaer, Y. Katz: Financial Interests, Personal, Full or part-time Employment: Viracta Therapeutics. B.B.Y. Ma: Financial Interests, Personal, Invited Speaker, Advisory Board/Consultancy: Novartis, BMS, MSD; Financial Interests, Personal, Advisory Board, Consultancy: Y-biologics, Boehringer Ingelheim, Merck Serono; Financial Interests, Personal, Invited Speaker: Roche; Financial Interests, Personal, Advisory Board and consultancy: Viracta Therapeutics; Financial Interests, Institutional, Research Grant, Preclinical Research Grant: Novartis; Financial Interests, Institutional, Research Grant: Boehringer Ingelheim, Merck Serono; Financial Interests, Institutional, Research Grant, Research Grant Preclinical: Novartis. All other authors have declared no conflicts of interest.