Combination of Oral Nanatinostat (Nstat), a Novel Histone Deacetylase Inhibitor (HDACi), and the Oral Anti-Viral, Valganciclovir (VGCV), Is Active in Relapsed/Refractory (R/R) Epstein-Barr Virus (EBV)-Positive B-Cell, T-Cell, and Hodgkin Lymphoma: Interim Safety and Efficacy Results from a Phase 1b/2a Study
Authors: Porcu Pierluigi , Haverkos Brad M. , Alpdogan Onder , Capra Marcelo , Feldman Tatyana A. , Brem Elizabeth , Vallurupalli Anusha , Brammer Jonathan E. , Schriefer Ana , Pereira Juliana , Tulpule Anil , Barta Stefan K. , Bryan Locke J. , Trauger Richard , Obrzut Sebastian , Gutheil John , Katkov Afton , McRae Robert , Royston Ivor , Faller Douglas V. 
Published: February 2020

Background: EBV-positive (EBV+) cells are detectable in a variable but significant fraction of lymphomas of all lineages and histologic type by in situ hybridization for EBV-encoded RNA (EBER-ISH). EBV positivity generally confers a worse prognosis in lymphoma but, with the exception of adoptive T-cell therapies, no EBV-targeting mechanism-based anti-lymphoma therapeutics are in development. EBV's DNA genome encodes a viral thymidine kinase (vTK, BXLF1) and a serine/threonine protein kinase (PK, BGLF4), which are expressed only during lytic cycle, and can activate anti-viral nucleoside analogues via mono-phosphorylation, leading to inhibition of EBV DNA synthesis. Nstat is able to induce the expression of PK/BGLF4 and vTK/BXLF1. This effect supports the mechanism-based strategy of leveraging EBV's presence in lymphoma by combining Nstat with VGCV, the oral prodrug for ganciclovir (GCV). EBV's PK phosphorylates GCV, which inhibits both viral and cellular DNA synthesis in EBV+ tumor cells and potentially in surrounding EBV- tumor cells (bystander effect). Based on this targeted approach, a phase 1b/2a trial was launched to determine the safety and activity of this combination in R/R EBV+ lymphomas of various lineages and histology. Here we report the phase 1b results.
Methods: Eligible patients had biopsy-proven R/R EBV+ lymphoma by EBER-ISH (any positive cell) and had failed ≥1 prior systemic therapy. Phase 1b followed a 3+3 design over 5 dose ranging cohorts. The phase 1b primary objectives were safety/tolerability of Nstat/VGCV and recommended phase 2 dose (RP2D). In cohorts 1-4, variable doses of Nstat and VGCV were administered orally continuously on 28-day cycles. In cohort 5 Nstat was administered for the first 4 days of each week with daily VGCV. Toxicity was assessed by CTCAE 5.0. Efficacy was assessed by local and central radiology every 2 cycles by PET/CT (Lugano 2014 Classification). Correlative studies for phase 1b include PK/PD and other exploratory biomarkers.
Results: Phase 1b enrolled 25 patients. The median age was 58 (19-84) with 72% males. Thirteen patients had either EBV+ T/NK-cell lymphoma (N=8; 5 TCL, 3 NKL), or Hodgkin lymphoma (HL) (N=5). Twelve patients had EBV+ B-cell lymphoma (BCL) (Table 1), of which 4 were HIV+ and 3 had a history of PTLD. Median number of prior therapies was 2 (1-9). Two patients with TCL had failed prior HDACi therapy. In cohorts 1-4, the most frequent treatment related hematologic grade 3-4 (G3-4) adverse events (AE) were thrombocytopenia (35%), neutropenia (25%), and lymphopenia (15%), none of which occurred at G3-4 in cohort 5. No non-hematologic G3-G4 AE were observed in &gt;10% of patients in any cohort and no patient discontinued therapy due to AE. The RP2D was declared to be Nstat 20 mg days 1-4 each week and VGCV 900 mg daily on a 28-day cycle. At the RP2D there have been no G3-4AE.
Seventeen patients are evaluable for response (8 BCL 5 T/NK, 4 HL). ORR was 53% (9/17), with 29% CRR (5/17). The Clinical Benefit Rate (CBR; CR/PR/Stable Disease) was 76% (13/17). Responses were seen across histologic subtypes and in heavily pre-treated patients. Durable responses were observed (one &gt;12 months and one &gt;10 months). For the 14 evaluable HIV-negative patients (5 BCL, 5 T/NK, 4 HL) ORR, CRR, and CBR were 64%, 36%, and 93%, respectively, with CRs and PRs in all histologic subtypes. The ORR was 3/5 for BCL (2 CR, 1 PR); 5/5 for T/NK (2 CR, 3 PR); and 1/4 in HL (1 CR). One BCL patient with combined variable immunodeficiency (CVID) achieved a CR. Only 1 of 3 BCL patients with a history of PTLD was evaluable and achieved a CR. All three evaluable HIV+ BCL patients progressed. Of 8 patients with detectable baseline plasma EBV DNA, 7 demonstrated a reduction (-17% to -83%). Other biomarker studies are in progress.
Conclusion: In this phase 1b study, the combination of oral Nstat and VGCV was well tolerated in patients with EBV+ lymphomas, with no unexpected G3-G4 AE, and showed a very encouraging signal of efficacy, especially in HIV-negative patients, with CRs in BCL, TCL, and HL. The combination of Nstat and VGCV is a compelling targeted oral therapy for R/R EBV+ lymphomas of different lineage and histologic type and should be explored in other EBV+ malignancies. The phase 2a portion of this study is actively recruiting (NCT03397706).

Disclosures
Porcu: Viracta: Honoraria, Other: Scientific Board, Research Funding; Innate Pharma: Honoraria, Other: Scientific Board, Research Funding; BeiGene: Other: Scientific Board, Research Funding; Incyte: Research Funding; Daiichi: Research Funding; Kyowa: Honoraria, Other: Scientific Board, Research Funding; ADCT: Research Funding; Spectrum: Consultancy. Feldman:Pharmacyclics: Honoraria, Other: Travel expenses, Speakers Bureau; AbbVie: Honoraria, Other: Travel expenses, Speakers Bureau; Takeda: Honoraria, Speakers Bureau; Celgene: Honoraria, Research Funding, Speakers Bureau; Janssen: Honoraria, Speakers Bureau; Kite Pharma: Honoraria, Other: Travel expenses, Speakers Bureau; Bayer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding; Cell Medica: Research Funding; Roche: Research Funding; Corvus: Research Funding; Eisai: Research Funding; Kyowa Hakko Kirin: Research Funding; Pfizer: Research Funding; Portola Pharma: Research Funding; Roche: Research Funding; Trillium: Research Funding; Viracta: Research Funding; Seattle Genetics: Consultancy, Honoraria, Other: Travel expenses, Speakers Bureau. Brem:Celgene: Honoraria, Speakers Bureau; BMS/Pfizer: Honoraria; Janssen: Honoraria, Speakers Bureau; Bayer: Honoraria; Genetech: Honoraria; Pharmacyclics: Honoraria, Speakers Bureau. Brammer:Celgene: Research Funding; Seatlle Genetics: Honoraria, Speakers Bureau. Barta:Celgene: Research Funding; Merck: Research Funding; Mundipharma: Honoraria; Bayer: Consultancy, Research Funding; Seattle Genetics: Honoraria, Research Funding; Takeda: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Mundipharma: Honoraria; Janssen: Membership on an entity's Board of Directors or advisory committees. Trauger:Viracta: Employment. Gutheil:Viracta Therapeutics: Consultancy. Katkov:Viracta: Employment. McRae:Viracta: Employment. Royston:Viracta: Employment.