Nanatinostat + Valganciclovir for EBV-Positive Lymphoma

(NAVAL-1 Trial)

Recruiting at69 trial locations

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 2

Waitlist Available

Sponsor: Viracta Therapeutics, Inc.

No Placebo Group

Prior Safety Data

Trial Summary

What is the purpose of this trial?

This trial tests a combination of nanatinostat and valganciclovir in patients with relapsed or refractory EBV-positive lymphomas. Nanatinostat helps the virus produce proteins that activate valganciclovir to kill cancer cells. The goal is to improve outcomes for these patients. Nanatinostat has shown promise in making EBV-positive lymphoma cells more responsive to antiviral agents.

Do I have to stop taking my current medications for the trial?

The trial protocol does not specify if you must stop taking your current medications. However, you cannot have had systemic anticancer therapy or CAR-T within 21 days, antibody agents within 28 days, or certain transplants within specified timeframes. Daily corticosteroids above a certain dose are also not allowed within a week before starting the trial.

What data supports the idea that Nanatinostat + Valganciclovir for EBV-Positive Lymphoma is an effective treatment?

The available research shows that the combination of Nanatinostat and Valganciclovir was tested in a study with patients who had EBV-positive lymphomas that did not respond to previous treatments. In this study, 40% of the patients showed a positive response to the treatment, with 19% achieving a complete response, meaning their cancer was no longer detectable. The treatment was particularly effective for a type of lymphoma called angioimmunoblastic T-cell lymphoma, where 60% of patients responded positively. This suggests that Nanatinostat + Valganciclovir can be an effective option for treating EBV-positive lymphomas, especially when other treatments have failed. ^{1 2 3 4 5}

What safety data is available for the treatment of Nanatinostat + Valganciclovir for EBV-positive lymphoma?

The phase 1b/2 study of Nanatinostat combined with Valganciclovir for EBV-positive lymphomas reported that the most common adverse events were nausea (38% any grade) and cytopenia, including grade 3/4 neutropenia (29%), thrombocytopenia (20%), and anemia (20%). This study involved 55 patients and determined the recommended phase 2 dose as Nanatinostat 20 mg daily, 4 days per week, with Valganciclovir 900 mg orally daily. The treatment showed encouraging efficacy and warrants further evaluation. ^{1 2 4 5 6}

Is the drug combination of Nanatinostat and Valganciclovir promising for treating EBV-positive lymphoma?

Yes, the combination of Nanatinostat and Valganciclovir shows promise for treating EBV-positive lymphoma. In a study, this drug combination led to a 40% overall response rate, meaning that 40% of patients saw their cancer shrink or disappear. For a specific type of lymphoma, the response rate was even higher at 60%. This suggests that the drug combination could be effective in helping patients with this type of cancer. ^{1 2 3 4 5}

Research Team

Darrel P Cohen, MD, PhD

Principal Investigator

Viracta Therapeutics

Eligibility Criteria

This trial is for patients with Epstein-Barr Virus-positive lymphomas who have tried at least two prior treatments and aren't eligible for high-dose chemotherapy or stem cell/CAR-T therapies. They should not be candidates for other available therapies, have measurable disease, a decent performance status, and good bone marrow function. Those with CNS lymphoma involvement or recent anticancer therapy are excluded.

Inclusion Criteria

I have had at least one treatment with anti-CD20 and anthracycline for my EBV+ lymphoma.

I am over 12, weigh more than 40kg, and my EBV+ PTLD has not improved after 1 treatment including anti-CD20 therapy.

Measurable disease per Cheson 2007

Exclusion Criteria

My lymphoma has affected or previously affected my brain or spinal cord.

I haven't taken any anticancer antibody drugs in the last 28 days.

I have taken 20 mg or more of corticosteroids daily in the last week.

Treatment Details

Interventions

• Nanatinostat (Histone Deacetylase (HDAC) Inhibitor)
• Valganciclovir (Other)

Trial Overview The study tests the effectiveness of nanatinostat combined with valganciclovir in those whose EBV+ lymphoma has returned after treatment or hasn't responded to previous treatments. It's an open-label Phase 2 trial where all participants receive the same experimental therapy.

Participant Groups

Group I: Nanatinostat with Valganciclovir Experimental Treatment 1 Intervention

Patients will receive nanatinostat 20 mg orally once daily, days 1-4 per week with valganciclovir 900 mg orally once daily. Up to 10 PTCL patients will receive nanatinostat 20 mg orally once daily, days 1-4 per week.

Who Is Running the Clinical Trial?

Viracta Therapeutics, Inc.

Lead Sponsor

Trials

4

Recruited

200+

Findings from Research

In a phase 1b/2 study involving 55 patients with EBV+ lymphomas, the combination of nanatinostat and valganciclovir showed a 40% overall response rate, indicating promising efficacy for patients with relapsed or refractory disease.

The treatment was generally well-tolerated, though common side effects included nausea and cytopenia, with significant cases of neutropenia, thrombocytopenia, and anemia, highlighting the need for monitoring during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Targeted therapy with nanatinostat and valganciclovir in recurrent EBV-positive lymphoid malignancies: a phase 1b/2 study. Haverkos, B., Alpdogan, O., Baiocchi, R., et al.[2023]

In a case study of a 40-year-old woman with angioimmunoblastic T-cell lymphoma (AITL), treatment with valacyclovir led to a significant reduction in Epstein-Barr virus load and complete remission of the lymphoma at an early stage.

Despite the initial success of antiviral therapy, the lymphoma recurred after valacyclovir was discontinued due to side effects, highlighting the challenges in long-term management and the poor prognosis associated with EBV-related lymphomas.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Epstein-Barr virus load correlating with clinical manifestation and treatment response in a patient with angioimmunoblastic T-cell lymphoma. Battegay, M., Berger, C., Rochlitz, C., et al.[2018]

In a case study of a patient with relapsed EBV-positive Diffuse Large B-cell Lymphoma, treatment with the HDAC inhibitor sodium valproate (VPA) and ganciclovir (GCV) led to detectable levels of circulating EBV-DNA, suggesting that this combination can induce lysis of virus-infected lymphoma cells.

While the VPA/GCV treatment did not achieve clinical remission, it supports the idea that stronger HDAC inhibitors, like butyrate or gemcitabine, combined with GCV and possibly chemotherapy, should be explored for treating relapsed EBV-positive lymphomas.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Sodium valproate in combination with ganciclovir induces lysis of EBV-infected lymphoma cells without impairing EBV-specific T-cell immunity. Jones, K., Nourse, J., Corbett, G., et al.[2013]

A combination of histone deacetylase (HDAC) inhibitors and the antiviral drug ganciclovir shows promise in treating EBV-associated lymphomas, with several HDAC inhibitors significantly enhancing the sensitivity of EBV-positive lymphoma cells to ganciclovir in vitro.

Newly identified HDAC inhibitors like LBH589, MS275, and largazole were found to be extremely potent, working at nanomolar concentrations and being 10,000 to 100,000 times more effective than the previously used short-chain fatty acid butyrate.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Histone deacetylase inhibitors are potent inducers of gene expression in latent EBV and sensitize lymphoma cells to nucleoside antiviral agents. Ghosh, SK., Perrine, SP., Williams, RM., et al.[2021]

Valproic acid (VPA), an HDAC inhibitor, demonstrated antitumor effects on both EBV-positive and -negative T and NK lymphoma cells, reducing cell viability by 22% to 56% at a concentration of 1 mM.

The combination of VPA with the proteasome inhibitor bortezomib showed an additive killing effect, particularly enhancing the killing of EBV-infected cells, suggesting a potential synergistic treatment strategy for EBV-associated lymphoproliferative diseases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Antitumor activities of valproic acid on Epstein-Barr virus-associated T and natural killer lymphoma cells. Iwata, S., Saito, T., Ito, Y., et al.[2020]

In a phase I safety study involving children aged 3-15 with EBV-associated Burkitt lymphoma, the combination of valacyclovir and cyclophosphamide was found to be safe, with no dose-limiting toxicities reported.

Patients treated with the combination showed a decrease in serum EBV viral loads, indicating a potential benefit that warrants further investigation in phase II efficacy trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I clinical trial of valacyclovir and standard of care cyclophosphamide in children with endemic Burkitt lymphoma in Malawi. Olson, D., Gulley, ML., Tang, W., et al.[2021]

References

1. United States pubmed.ncbi.nlm.nih.gov

Targeted therapy with nanatinostat and valganciclovir in recurrent EBV-positive lymphoid malignancies: a phase 1b/2 study. [2023]

2. England pubmed.ncbi.nlm.nih.gov

Epstein-Barr virus load correlating with clinical manifestation and treatment response in a patient with angioimmunoblastic T-cell lymphoma. [2018]

3. England pubmed.ncbi.nlm.nih.gov

Sodium valproate in combination with ganciclovir induces lysis of EBV-infected lymphoma cells without impairing EBV-specific T-cell immunity. [2013]

4. United States pubmed.ncbi.nlm.nih.gov

Histone deacetylase inhibitors are potent inducers of gene expression in latent EBV and sensitize lymphoma cells to nucleoside antiviral agents. [2021]

5. England pubmed.ncbi.nlm.nih.gov

Antitumor activities of valproic acid on Epstein-Barr virus-associated T and natural killer lymphoma cells. [2020]

6. United States pubmed.ncbi.nlm.nih.gov

Phase I clinical trial of valacyclovir and standard of care cyclophosphamide in children with endemic Burkitt lymphoma in Malawi. [2021]