Oral Nanatinostat (Nstat) and Valganciclovir (VGCV) in Patients with Recurrent Epstein-Barr Virus (EBV)-Positive Lymphomas: Initial Phase 2 Results
Authors: Porcu Pierluigi , Haverkos Bradley , Alpdogan Onder , Baiocchi Robert , Brammer Jonathan E , Feldman Tatyana A. , Capra Marcelo , Brem Elizabeth A , Scheinberg Phillip , Pereira Juliana , Shune Leyla , Katkov Afton , McRae Robert , Rojkjaer Lisa , Royston Ivor , Faller Douglas V. 
Published: November 2020

BACKGROUND: EBV-positive (EBV+) lymphomas including Hodgkin, B and T cell lymphomas, are generally associated with poor clinical outcomes, particularly for patients (pts) who have relapsed or are refractory (R/R) to standard therapies. There are currently no approved therapies for EBV+ lymphomas and with the exception of adoptive T-cell therapies, no EBV-targeted anti-lymphoma therapeutics are in development. EBV is detectable in cancer cells by in situ hybridization for EBV-encoded RNAs (EBER-ISH). Nstat (VRx-3996), a Class I-selective oral hydroxamate histone deacetylase (HDAC) inhibitor active against HDAC1-3, induces the expression of EBV protein kinases which activate the anti-viral nucleoside analogue VGCV via mono-phosphorylation. This leads to inhibition of both viral and cellular DNA synthesis in EBV+ tumor cells and potentially in surrounding EBV- tumor cells as well (bystander effect), causing apoptosis. This trial is the first to explore the safety and clinical activity of this targeted approach using oral Nstat in combination with oral VGCV in pts with R/R EBV+ lymphomas. Here we present an update of safety and efficacy for all enrolled patients, plus the preliminary safety of the recommended phase 2 doses (RP2D) of Nstat and VGCV (NCT03397706).
METHODS: Pts with biopsy-proven EBV+ lymphomas (by EBER-ISH; any positive tumor cell) that had failed ≥1 prior systemic therapy and lacked treatment options by investigator's judgment were eligible for enrollment. Phase 1b used a 3x3 design to determine the RP2D of Nstat + VGCV. Phase 2 pts received the RP2D (Nstat 20 mg days (d) 1-4/7 + VGCV 900 mg orally daily in 28 d cycles) until PD or withdrawal. Primary endpoints were safety/RP2D selection (phase 1b) and ORR (phase 2); secondary endpoints were pharmacokinetics, duration of response (DoR), time to response (TTR), progression free survival (PFS) and overall survival (OS). Response assessments began after Cycle 2 using Lugano 2014 response criteria.
RESULTS: As of 5 July 2020, 43 pts have enrolled (phase 1b: 25; phase 2: 18). Lymphoma subtypes were diffuse large B cell (DLBCL) (6), extranodal NK/T-cell (ENKTL) (6), peripheral T cell, NOS (PTCL-NOS) (3), angioimmunoblastic (AITL) (4), cutaneous T cell (CTCL) (1), Hodgkin (HL) (8), other B cell (2), and immunodeficiency-associated lymphoproliferative disorders (IA-LPD) (13), including post-transplant lymphoproliferative disorder (PTLD) (4), HIV-associated (5), and other [4: systemic lupus erythematosus (SLE) (2), common variable immunodeficiency/primary immunodeficiency (2)]. Pts had a median of 2 prior therapies (range 1-11); 77% with ≥2 prior therapies, 86% were refractory to their most recent previous therapy and 77% had exhausted standard therapies in the judgment of the investigator. EBER positivity ranged from &lt;1 to 80% in 18 pre-study tumor biopsies with central lab review. Most treatment-related AEs (TRAEs) were mild or moderate, most commonly thrombocytopenia (33%), nausea (29%), neutropenia (26%) and fatigue (24%). At the RP2D, 23 pts were evaluable for safety. The most frequent G3/4 TRAEs (in ≥5% of pts) were neutropenia (14%), anemia (9%), and nausea (9%). For all evaluable pts (n=34), the ORR was 44% (15/34), with 8 (24%) complete responses (CR). The median TTR was 53 d (range 44-161 d). Responses for the 10 evaluable T/NK-NHL pts (ORR/CR 80%/40%) are shown in Table 1 [ENKTL (n=5; 1 CR 3 PR); T cell (n=5; 3 CR 1 PR)]. Two pts (ENKTL and PTCL-NOS) in PR/CR respectively were withdrawn for autologous stem cell transplantation (ASCT). For DLBCL (n=6), ORR/CR was 66%/33% (both CRs were in pts refractory to first-line R-CHOP). For IA-LPD (predominantly B-cell), ORR/CR was 30%/20% (PTLD: 1 CR, other: 1 CR, 1 PR). The median DoR for all responders is 10.6 months, with a median follow-up from response of 5.0 m (range 0.4-22.9 m).
CONCLUSIONS: Co-administration of oral Nstat with VGCV has a favorable safety profile, may be suitable for combination with additional agents, and shows promising efficacy in pts with a variety of R/R, heavily pre-treated EBV+ lymphomas, the majority of whom were lacking therapeutic options. Preliminary data suggests that this regimen is highly active in EBV+ T/NK-NHL pts who are refractory to standard therapies, including ASCT (Table 1), and promising in EBV+ DLBCL. Thus far, no apparent correlation was noted between degree of EBER positivity in pre-study tumor biopsies and ORR.

Disclosures
Porcu: Viracta Therapeutics: Membership on an entity's Board of Directors or advisory committees; Verastem: Consultancy; Miragen: Research Funding; Kura Oncology: Research Funding; Kiowa Kirin: Research Funding; Innate Pharma: Membership on an entity's Board of Directors or advisory committees, Research Funding; Galderma: Research Funding; Daiichi: Consultancy, Honoraria; Cell Medica: Research Funding; Celgene: Research Funding. Haverkos:Viracta THerapeutics: Consultancy. Alpdogan:Seattle Genetics: Consultancy; Kiowa Kirin: Consultancy. Baiocchi:viracta: Consultancy, Membership on an entity's Board of Directors or advisory committees; Prelude Therapeutics: Consultancy, Research Funding. Brammer:Celgene Corporation: Research Funding; Seattle Genetics, Inc.: Speakers Bureau. Feldman:AstraZeneca: Consultancy; Janssen: Speakers Bureau; Portola: Research Funding; Pfizer: Research Funding; Kyowa Kirin: Consultancy, Research Funding; Eisai: Research Funding; Cell Medica: Research Funding; Amgen: Research Funding; Pharmacyclics: Honoraria, Other, Speakers Bureau; Abbvie: Honoraria; Bayer: Consultancy, Honoraria; Trillium: Research Funding; Viracta: Research Funding; Rhizen: Research Funding; Corvus: Research Funding; BMS: Consultancy, Honoraria, Research Funding; Kite: Honoraria, Other: Travel expenses, Speakers Bureau; Celgene: Honoraria, Research Funding; Takeda: Honoraria, Other: Travel expenses; Seattle Genetics, Inc.: Consultancy, Honoraria, Other: Travel expenses, Research Funding, Speakers Bureau. Brem:KITE: Consultancy; TG Therapeutics: Consultancy; BeiGene: Speakers Bureau; Karyopharm: Consultancy; Morphosys: Consultancy; Celgene: Consultancy; Sanofi: Consultancy; Pharmacyclics: Speakers Bureau. Scheinberg:Novartis Brasil S.A.: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Katkov:Viracta Therapeutics, Inc.: Current Employment. McRae:Viracta Therapeutics, Inc.: Current Employment. Rojkjaer:Viracta Therapeutics, Inc.: Current Employment. Royston:Viracta Therapeutics, Inc.: Current Employment.

OffLabel Disclosure:
Nanatinostat(VRx-3996) is a Class I-selective oral HDAC inhibitor active against HDAC1-3 that induces the expression of EBV protein kinases which activate the anti-viral nucleoside analogue VGCV via mono-phosphorylation. This leads to inhibition of both viral and cellular DNA synthesis in EBV+ tumor cells and potentially in surrounding EBV- tumor cells as well (bystander effect), causing apoptosis.