Nanatinostat + Valganciclovir for EBV-Positive Lymphoma

(NAVAL-1 Trial)

No longer recruiting at 81 trial locations

Overseen By Strait Hicklin

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Viracta Therapeutics, Inc.

Must be taking: Anti-CD20 immunotherapy

Must not be taking: Corticosteroids, Anticancer agents

Disqualifiers: CNS involvement, Recent transplant, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: Unknown

Duration: Until disease progression or unacceptable toxicity

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores whether a combination of two drugs, nanatinostat (a potential new drug) and valganciclovir, can treat certain types of difficult-to-treat lymphoma, a cancer affecting the lymphatic system. It targets individuals whose lymphoma is linked to the Epstein-Barr Virus (EBV) and who have relapsed or not responded to previous treatments. Suitable candidates have relapsed or hard-to-treat EBV-positive lymphoma and have undergone at least one prior treatment. As a Phase 2 trial, the research focuses on measuring the treatment's effectiveness in an initial, smaller group of participants.

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.

Is there any evidence suggesting that this treatment is likely to be safe for humans?

Previous studies have generally found the combination of nanatinostat and valganciclovir to be safe for patients with EBV-positive lymphomas. Researchers identified no new or unexpected safety issues, which is encouraging. Additionally, the treatment has shown promise as a second option when other treatments have failed. These findings suggest that patients tolerated the combination well, with no major safety concerns reported. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about Nanatinostat plus Valganciclovir for treating EBV-positive lymphoma because it offers a novel approach compared to current therapies. Most treatments for this type of lymphoma, such as chemotherapy and radiation, focus on directly attacking cancer cells. However, Nanatinostat is a histone deacetylase inhibitor, which can reactivate latent viruses like EBV, making the cancer cells more vulnerable to antiviral drugs like Valganciclovir. This combination approach targets the EBV virus within the cancer cells, potentially leading to more effective outcomes with possibly fewer side effects.

What evidence suggests that nanatinostat combined with valganciclovir could be an effective treatment for EBV-positive lymphoma?

Studies have shown that using nanatinostat and valganciclovir together appears promising for treating certain types of lymphomas linked to the Epstein-Barr virus (EBV). In this trial, participants will receive this combination. Patients with these lymphomas often don't respond well to standard treatments. This new combination has shown positive results and is generally easy for patients to tolerate. Both drugs are taken orally, offering convenience. Early research suggests that this treatment might help patients live longer and manage their disease more effectively. ^{1 2 3 6 7}

Who Is on the Research Team?

Darrel P Cohen, MD, PhD

Principal Investigator

Viracta Therapeutics

Are You a Good Fit for This Trial?

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.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive nanatinostat 20 mg orally once daily, days 1-4 per week, with valganciclovir 900 mg orally once daily

Until disease progression or unacceptable toxicity

Follow-up

Participants are monitored for safety and effectiveness after treatment

Approximately 3 years

What Are the Treatments Tested in This Trial?

Interventions

• Nanatinostat
• Valganciclovir

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

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]

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 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 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]

Citations

1. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/37530631/

Targeted therapy with nanatinostat and valganciclovir in ... This phase 1b/2 study investigated the combination of nanatinostat with valganciclovir in patients aged ≥18 years with EBV+ lymphomas relapsed/refractory to ≥1 ...

2. clinicaltrials.gov clinicaltrials.gov/study/NCT05011058

Study Details | NCT05011058 | An Open-Label Phase 2 ... Patients with EBV-associated lymphomas have inferior outcomes with standard-of-care therapies compared to those with EBV-negative disease. Nanatinostat is a ...

3. ashpublications.org ashpublications.org/bloodadvances/article/7/20/6339/497221/Targeted-therapy-with-nanatinostat-and

Targeted therapy with nanatinostat and valganciclovir in ... Lymphomas are not infrequently associated with the Epstein-Barr virus (EBV), and EBV positivity is linked to worse outcomes in several ...

4. viracta.investorroom.com viracta.investorroom.com/2024-04-15-Viracta-Therapeutics-Announces-Positive-Topline-Nana-val-Results-from-Stage-1-of-the-NAVAL-1-Trial-in-Patients-with-Relapsed-or-Refractory-Epstein-Barr-Virus-Positive-EBV-Peripheral-T-Cell-Lymphoma

Viracta Therapeutics Announces Positive Topline Nana-val ... Nana-val is emerging as a promising, generally well-tolerated, convenient all-oral treatment for patients with relapsed or refractory EBV-positive PTCL.

5. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10587711/

Targeted therapy with nanatinostat and valganciclovir in ... This novel oral regimen provided encouraging efficacy across several EBV+ lymphoma subtypes and warrants further evaluation; a confirmatory phase 2 study ( ...

6. sciencedirect.com sciencedirect.com/science/article/pii/S253113792400765X

A GLOBAL PHASE 2 TRIAL OF NANATINOSTAT AND ... Nstat+VGCV is emerging as a promising, generally well-tolerated treatment for patients with R/R EBV + PTCL, particularly in the second-line treatment setting.

7. withpower.com withpower.com/trial/phase-3-lymphoma-7-2021-c70e5

Nanatinostat + Valganciclovir for EBV-Positive Lymphoma Nanatinostat helps the virus produce proteins that activate valganciclovir to kill cancer cells. The goal is to improve outcomes for these patients.