EBV+ Lymphoma may be associated with inferior survival outcomes.
Identifying which of your patients have EBV+ tumors may provide a new personalized treatment option.
Learn more about the NAVAL-1 clinical trial evaluating an oral, first-in-class, investigational combination therapy for patients with EBV+ lymphoma.
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Lymphomas are the most common Epstein-Barr virus-positive (EBV+) cancers. There are currently no approved therapies targeting EBV+ lymphomas in the United States.
Incidence of EBV+ Lymphoma
EBV+ malignancies account for ~2% of all new cancer cases globally.
EBV Positivity* by Lymphoma Subtype1,5
EBV Positivity May Have an Adverse Impact on Clinical Survival Outcomes2-6
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DLBCL
(Progression-Free Survival)
![2](https://ebvlymphoma.com/app/uploads/2022/12/2.jpg)
PTCL
(Overall Survival)
About the NAVAL-1 Clinical Trial
The NAVAL-1 clinical trial is a global, pivotal phase 2, multicenter, open-label, single-arm basket study designed to evaluate the safety and efficacy of the all-oral combination of nanatinostat with valganciclovir in patients with relapsed/refractory (R/R) EBV+ lymphoma. The trial will evaluate multiple subtypes of EBV-associated lymphoma (PTCL; DLBCL; PTLD) with an additional cohort that will capture patients with other types of EBV+ lymphoma.
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The Investigational All-Oral Drug Combination: "Kick and Kill” Mechanism of Action
The NAVAL-1 clinical trial represents a novel approach to the treatment of EBV+ lymphoma, using a combination of an oral class-I specific HDAC inhibitor (nanatinostat) with an oral antiviral (valganciclovir, an oral prodrug of ganciclovir).
- EBV exists in a latent form in tumor cells. In that form, it is not susceptible to the cytotoxic activity of ganciclovir.
- Nanatinostat induces EBV lytic activation and expression of the EBV BGLF4 protein kinase (the “Kick”).
- This in turn activates ganciclovir via phosphorylation, resulting in ganciclovir-induced inhibition of viral and cellular DNA synthesis and apoptosis (the “Kill”).
Nana-val “Kick and Kill” Mechanism of Action
![1 (1)-min](https://ebvlymphoma.com/app/uploads/2022/11/1-1-min.png)
LATENCY
EBV latent in cancer cells.
Valganciclovir, antiviral prodrug of ganciclovir (GCV), is inactive without expression of viral protein kinase (PK)
![2 (1)-min](https://ebvlymphoma.com/app/uploads/2022/11/2-1-min.png)
THE KICK
Nanatinostat selectively and potently induces expression of EBV protein kinase (PK), which activates GCV into its cytotoxic form
![3 (1)-min](https://ebvlymphoma.com/app/uploads/2022/11/3-1-min.png)
THE KILL
Cytotoxic GCV inhibits DNA replication leading to apoptosis in EBV+ cancer cells
![31e4b30dc251d9c74bc08407af3c15fef58e50ef-min](https://ebvlymphoma.com/app/uploads/2022/11/31e4b30dc251d9c74bc08407af3c15fef58e50ef-min.png)
Phase 1b/2 Study
In a previous Phase 1b/2 study, the combination of nanatinostat and valganciclovir was evaluated in 55 patients with a variety of relapsed/refractory EBV-associated lymphomas. Eligible patients had received 1 or more prior therapies, had measurable disease, and had exhausted all standard therapies.1
The regimen was generally well tolerated: the most common treatment-emergent adverse events were nausea (38%); thrombocytopenia (36%); neutropenia (34%); anemia and constipation (both 31%); creatinine elevation, diarrhea, and fatigue (all 26%); and decreased appetite (22%).
For the 43 evaluable patients, the ORR was 40% (CR 19%). Complete responses were reported in DLBCL, T- and NK-cell lymphomas, and IA-LPD, with a median duration of response of 10.4 months.
This investigational drug combination received FDA fast track designation for the treatment of R/R EBV+ lymphoid malignancies in 2019. In addition, this drug combination received 4 orphan drug designations from the FDA for plasmablastic lymphoma; PTLD; T-cell lymphoma; and EBV+ DLBCL, NOS.
NAVAL-1 Phase 2 Basket Study in Patients With R/R EBV+ Lymphoma
Key Eligibility Criteria
- Adults ≥ 18 years
- EBV+ relapsed/refractory lymphoma following 2 or more prior systemic therapies
-
For PTCL patients only: Relapsed/refractory disease following 1 or more prior systemic therapies. No available therapies in the opinion of the Investigator
-
- Not eligible for high-dose chemotherapy with allogeneic/autologous stem cell transplantation or CAR-T therapy
- No CNS involvement
-
Adequate hematological and hepatic function
NAVAL-1 Phase 2 Basket Study Design
This global clinical trial is seeking to enroll multiple subtypes of patients with EBV+ relapsed/refractory lymphomas, with a fourth cohort included for patients with other types of EBV+ lymphoma.
Stage 1
Multiple EBV+ lymphoma subtypes
Stage 2
Stage 1
Multiple EBV+ lymphoma subtypes
Stage 2
Participants Who Qualify and Enroll Will Receive:
- The investigational oral drug combination and all study-related medical care at no charge
- Close monitoring by physicians who specialize in virus-related lymphomas
- Reimbursement for study-related expenses such as transportation (as needed)
- The opportunity to advance medical knowledge of EBV+ lymphomas
Take Action
Ask questions about the trial and see if your patients may qualify:
clinicaltrials@viracta.com
For more information about the trial visit:
Clinicaltrials.gov
NAVAL-1 National Trial Reference Number [NCT05011058]
Phase 1b/2 National Trial Reference Number [NCT03397706]
US Trial Locations
References
- Haverkos BM, Alpdogan O, Baiocchi R, Brammer JE, Feldman TA, Capra M, et al. Nanatinostat (Nstat) and valganciclovir (VGCV) in relapsed/refractory (R/R) Epstein-Barr virus-positive (EBV+) lymphomas: final results from the Phase 1b/2 VT3996-201 study. Blood. 2021;138 (suppl 1):623. doi:10.1182/blood-2021-152603
- Lu, T, Liang J, Miao Y, et al. Epstein-Barr virus positive diffuse large B-cell lymphoma predict poor outcome, regardless of the age. Scientific Reports. 2015;5:12168. doi:10.1038/srep12168
- Haverkos B, Huang Y, Gru A. Frequency and clinical correlates of elevate plasma Epstein-Barr virus DNA at diagnosis in peripheral T- cell lymphomas. Int J Cancer. 2017;140(8):1899-1906. doi:10.1002/ijc.30566
- Dupuis J, Emile J, Mounier N, et al. Prognostic significance of Epstein-Barr virus in nodal peripheral T-Cell lymphoma, unspecified. Blood. 2006;108(13)4163-4169. doi:10.1182/blood-2006-04-017632
- Swerdlow SH, Campo E, Harris NL, et al. World Health Organization; 2017
- Mackrides N, Champman J, Larson M, et al. Prevalence, clinical characteristics and prognosis of EBV-positive follicular lymphoma. Am J Hematol. 2019;94(2):E62-E64. doi:10.1002/ajh.25357