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Tenofovir

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\[Cohort 1\] Patients receive TAF PO QD or TDF PO QD or entecavir PO QD immediately or within 42 days after initial dose of chemotherapy. Treatment continues for up to 6 months after the last dose of chemotherapy or a maximum of 24 months in the absence of disease progression or unacceptable toxicity.

\[Cohort 1\] Patients receive TAF PO QD or TDF PO QD or entecavir PO QD after HBV reactivation during chemotherapy. Treatment continues for up to 6 months after the last dose of chemotherapy or a maximum of 24 months in the absence of disease progression or unacceptable toxicity.

\[Cohort 2\] Patients receive TAF PO QD or TDF PO QD or entecavir PO QD after HBV reactivation during chemotherapy. Treatment continues for up to 6 months after the last dose of chemotherapy or a maximum of 24 months in the absence of disease progression or unacceptable toxicity.

\[Cohort 2\] Patients receive anti-HBV therapy at the discretion of the physician. Any Food and Drug Administration (FDA) approved anti-viral medication for treatment of HBV may be utilized.

Best Practice

Tenofovir Alafenamide

Tenofovir Disoproxil Fumarate

Jessica P Hwang

This phase III trial studies the effect of hepatitis B antiviral (anti-HBV) therapy in preventing liver complications in patients with chronic or past hepatitis B virus (HBV) who are receiving anti-cancer therapy for solid tumors. People with chronic or past HBV who are undergoing therapy for cancer are at an increased risk for changes in the liver which could be minor or severe. Anti-HBV therapy acts against infections caused by HBV and may help reduce the chance that HBV gets worse or comes back in patients receiving anti-cancer therapy for solid tumors.

Co-Primary Objectives

1. To compare the effect of prophylactic anti-HBV therapy versus upon indication anti-HBV therapy on time-to-adverse liver outcomes of liver failure or liver-related death in patients with chronic HBV infection (HBsAg+ and anti-HBc+) receiving anti-cancer therapy for solid tumors.
2. To compare the effect of upon indication anti-HBV therapy versus usual care on time-to-adverse liver outcomes of liver failure or liver-related death in patients with past HBV infection (HBsAg- and anti-HBc+) receiving anti-cancer therapy for solid tumors.

Secondary Objectives

1. Using time-to-event analysis, to compare the effect of anti-HBV therapy versus upon indication anti-HBV therapy on HBV reactivation, on the combined endpoint of adverse liver outcomes (liver failure or liver-related death) and HBV reactivation, and on HBV flare by arm in patients with chronic HBV infection receiving anticancer therapy for solid tumors.
2. Using time-to-event analysis, to compare the effect of upon indication anti-HBV therapy versus usual care on HBV reactivation, on the combined endpoint of adverse liver outcomes (liver failure or liver-related death) and HBV reactivation, and on HBV flare by arm in patients with past HBV infection receiving anti-cancer therapy for solid tumors.

Translational Objectives

1. To compare baseline and changes in overall immune status and HBV-specific immune response in patients with solid tumors and chronic or past HBV infection receiving anti-cancer therapy, and to compare the differences in these immune responses by HBV reactivation status.
2. To identify demographic and clinical predictors and correlative immunologic biomarkers of HBV reactivation after receipt of anti-cancer therapy in patients with solid tumors and chronic or past HBV infection.

OUTLINE: Patients are recruited in two cohorts (Cohort 1: chronic HBV infection, Cohort 2: past HBV infection), with each cohort randomized equally to one of two potential treatment arms.

Chronic HBV Infection (Cohort 1) Arms:

Arm 1: Patients receive tenofovir alafenamide (TAF) orally (PO) once daily (QD) or tenofovir disoproxil fumarate (TDF) PO QD or entecavir PO QD immediately or within 42 days after initial dose of chemotherapy. Treatment continues for up to 6 months after the last dose of chemotherapy or a maximum of 24 months in the absence of disease progression or unacceptable toxicity.

Arm 2: Patients receive TAF PO QD or TDF PO QD or entecavir PO QD after HBV reactivation during chemotherapy. Treatment continues for up to 6 months after the last dose of chemotherapy or a maximum of 24 months in the absence of disease progression or unacceptable toxicity.

Past HBV infection (Cohort 2) Arms:

Arm 3: Patients receive TAF PO QD or TDF PO QD or entecavir PO QD after HBV reactivation during chemotherapy. Treatment continues for up to 6 months after the last dose of chemotherapy or a maximum of 24 months in the absence of disease progression or unacceptable toxicity.

Arm 4: Patients receive anti-HBV therapy at the discretion of the physician. Any Food and Drug Administration (FDA) approved anti-viral medication for HBV may be used.

(Cohort 1: Arm 2 and Cohort 2: Arm 3 follow the same treatment plan, but are considered part of separate parallel studies and are therefore identified as separate arms.)

Patients are followed for 24 months: every 4 weeks from randomization to week 24, then every 8 weeks thereafter up to week 104.

Prophylactic Antiviral Therapy in Patients With Current or Past Hepatitis B Virus Infection Receiving Anti-Cancer Therapy for Solid Tumors

A Phase III Randomized Trial of Prophylactic Antiviral Therapy in Patients With Current or Past Hepatitis B Virus (HBV) Infection Receiving Anti-Cancer Therapy for Solid Tumors

Adverse liver outcome: Defined as liver-related death or liver failure (ascites, hepatic encephalopathy or impaired hepatic synthetic function defined as total bilirubin ≥ 5 mg/dL or INR ≥ 2.0) not due to disease progression in the liver. Assessment of the primary endpoint will be made by sites and subsequently adjudicated by the research oversight team by blinded review.

HBV reactivation is is defined as one of the following:

* ≥ 2 log (100-fold) increase in HBV DNA compared to baseline in patients with detectable HBV DNA at baseline, or
* HBV DNA ≥ 3 log (1,000) IU/mL in a patient with previously undetectable HBV DNA, or
* HBV DNA ≥ 4 log (10,000) IU/mL if baseline HBV DNA not available, or
* HBsAg seroreversion (HBsAg- to HBsAg+) in a patient previously HBsAg-.

Hepatitis flare is defined as ALT \> 3 x baseline and \>100 U/L.

Adverse liver outcome: Defined as liver-related death or liver failure (ascites, hepatic encephalopathy or impaired hepatic synthetic function defined as total bilirubin ≥ 5 mg/dL or INR ≥ 2.0) not due to disease progression in the liver. Assessment of the primary endpoint will be made by sites and subsequently adjudicated by the research oversight team by blinded review.

HBV reactivation is defined as one of the following:

* ≥ 2 log (100-fold) increase in HBV DNA compared to baseline in patients with detectable HBV DNA at baseline, or
* HBV DNA ≥ 3 log (1,000) IU/mL in a patient with previously undetectable HBV DNA, or
* HBV DNA ≥ 4 log (10,000) IU/mL if baseline HBV DNA not available, or
* HBsAg seroreversion (HBsAg- to HBsAg+) in a patient previously HBsAg-.

The combined endpoint of adverse liver outcomes and HBV reactivation is the occurrence of either adverse liver outcome or HBV reactivation as defined above.

National Cancer Institute (NCI)

SWOG Cancer Research Network

No participants received experimental treatment on this study. No participants were registered in the Chronic HBV cohort \[Cohort 1\]. In the Past HBV cohort \[Cohort 2\]:

* no participants assigned to Arm 3 experienced HBV reactivation, which would have prompted treatment with the study-assigned anti-HBV therapy according to protocol
* one participant in Arm 4 (standard of care) began anti-HBV therapy at physician discretion.

\[Cohort 1\] Patients receive TAF PO QD or TDF PO QD or entecavir PO QD immediately or within 42 days after initial dose of chemotherapy. Treatment continues for up to 6 months after the last dose of chemotherapy or a maximum of 24 months in the absence of disease progression or unacceptable toxicity.

Entecavir: Given PO

Tenofovir Alafenamide: Given PO

Tenofovir Disoproxil Fumarate: Given PO

Arm 1 (TAF, TDF, Entecavir: Prophylactic)

\[Cohort 1\] Patients receive TAF PO QD or TDF PO QD or entecavir PO QD after HBV reactivation during chemotherapy. Treatment continues for up to 6 months after the last dose of chemotherapy or a maximum of 24 months in the absence of disease progression or unacceptable toxicity.

Entecavir: Given PO

Tenofovir Alafenamide: Given PO

Tenofovir Disoproxil Fumarate: Given PO

Arm 2 (TAF, TDF, Entecavir: Upon Indication)

\[Cohort 2\] Patients receive TAF PO QD or TDF PO QD or entecavir PO QD after HBV reactivation during chemotherapy. Treatment continues for up to 6 months after the last dose of chemotherapy or a maximum of 24 months in the absence of disease progression or unacceptable toxicity.

Entecavir: Given PO

Tenofovir Alafenamide: Given PO

Tenofovir Disoproxil Fumarate: Given PO

Arm 3 (TAF, TDF, Entecavir: Upon Indication)

\[Cohort 2\] Patients receive anti-HBV therapy at the discretion of the physician. Any Food and Drug Administration (FDA) approved anti-viral medication for HBV may be used.

Arm 4 (Anti-Viral Therapy: Usual Care)

\[Cohort 1\] Patients receive tenofovir alafenamide (TAF) orally (PO) once daily (QD) or tenofovir disoproxil fumarate (TDF) PO QD or entecavir PO QD immediately or within 42 days after initial dose of chemotherapy. Treatment continues for up to 6 months after the last dose of chemotherapy or a maximum of 24 months in the absence of disease progression or unacceptable toxicity.

Total

Age, Continuous

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

There were no participants registered to the Chronic HBV infection cohort \[Cohort 1, Arms 1 and 2\]

On November 15, 2022, the study was discontinued with no further follow-up required after it was determined that the accrual goal could not be met. Four participants had been accrued to Cohort 2 and no participants to Cohort 1. No adverse liver events, hepatitis B flares, or hepatitis B reactivations had occurred at the time the study was discontinued. As a result, planned time-to-event analyses for these outcomes could not be completed.

SWOG Statistician

Number of Participants With Adverse Liver Outcome

\[Cohort 2\] Patients receive anti-HBV therapy at the discretion of the physician. Any Food and Drug Administration (FDA) approved anti-viral medication for treatment of HBV may be utilized.

Best Practice: Receive best practice

Entecavir: Given PO

Tenofovir Alafenamide: Given PO

Tenofovir Disoproxil Fumarate: Given PO

Number of Participants With Hepatitis B Virus (HBV) Reactivation

Number of Participants With Hepatitis B Virus (HBV) Flare

Combined Endpoint of Adverse Liver Outcomes and HBV Reactivation, Number of Participants

Overall Study

Neoplasms

Recurrence

Carcinoma

Carcinoma, Hepatocellular

Hepatitis B, Chronic

Hepatitis, Chronic

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

Adenocarcinoma

Liver Neoplasms

Gastrointestinal Neoplasms

Digestive System Neoplasms

Chronic Graft Versus Host Disease

Hematinics

Liver Extracts

Prompt therapy with Tenofovir disoproxil fumarate (Viread(R)) 300mg p.o

Wait and treat with Tenofovir disoproxil fumarate (Viread(R)) when active liver disease is present \[defined as HBV DNA \>2,000 IU/ml and abnormal ALT (\>40 IU/ml)\]

Tenofovir disoproxil fumarate

Seung Woon Paik, M.D., Ph.D.

Dong Hyun Sinn, M.D., Ph.D.

Antiviral therapy for HBV may play an important role here, as a large observation study from Taiwan reported that the use of nucleos(t)ide analogues (NUC) was associated with 33% reduction in HCC recurrence. In the first randomized controlled trial evaluating the use of NUC after surgical resection for HCC, NUC therapy was associated with better 2-year overall (94% vs. 62%) and recurrence-free (56% vs. 20%) survival. However, patients with active liver disease should be treated regardless of their impact on HCC recurrence (patients with high serum HBV DNA and abnormal ALT). What is less clear is that whether patients with low level HBV DNA, and normal serum ALT levels should be treated to reduce HCC recurrence.

In this trial, we will investigate to determine the efficacy of the treatment with Tenofovir disoproxil fumarate (Viread(R)) as measured by the cumulative incidence rate of hepatocellular carcinoma (HCC) at 3 year after curative treatment with radiofrequency ablation (RFA) or surgical resection (SR) in chronic hepatitis B virus (HBV) infected patients with low viral load.

HCC is a major global health problem, which is the third leading cause of cancer-related deaths, and accounts for 7% of all cancers worldwide. Curative treatment, such as SR, RFA has improved patients prognosis, however, even after successful curative treatment, high rates of disease recurrence limiting overall survival in HCC patients. In this regard, method to reduce HCC recurrence is an essential component of a therapeutic strategy to maximize outcome.

Antiviral therapy for HBV may play an important role here, as a large observation study from Taiwan reported that the use of NUCs was associated with 33% reduction in HCC recurrence. In the first randomized controlled trial evaluating the use of NUC after surgical resection for HCC, NUC therapy was associated with better 2-year overall (94% vs. 62%) and recurrence-free (56% vs. 20%) survival. However, patients with active liver disease should be treated regardless of their impact on HCC recurrence (patients with high serum HBV DNA and abnormal ALT). What is less clear is that whether patients with low level HBV DNA, and normal serum ALT levels should be treated to reduce HCC recurrence.

In the randomized controlled trial by Yin et al, antiviral therapy was also beneficial in Chronic hepatitis B patients with low viral load (HBV DNA \< 104 copies/ml). However, there is a need for further validation of their finding for several reasons. First, the baseline characteristics between two groups were not same (more advanced tumors in the control arm). Second, the recurrence rates in the control arm was too high (about 80%), and the number of patients was small (control = 32, antiviral therapy = 22). Third, HBV DNA levels at 6 months was decreased in the antiviral therapy group (3.36 ± 0.68 log10 copies/ml vs. 4.66 ± 1.38 log10 copies/ml), but was not optimal. The used drugs were lamivudine, adefovir plus lamivudine or entecavir 0.5 mg. With more potent antiviral drug, better outcome is expected.

In this trial, we will investigate to determine the efficacy of the treatment with Tenofovir disoproxil fumarate (Viread(R)) as measured by the cumulative incidence rate of hepatocellular carcinoma (HCC) at 3 year after curative treatment with radiofrequency ablation (RFA) or surgical resection (SR) in chronic hepatitis B virus (HBV) infected patients with low viral load.

Prompt Or Watchful Monitoring for Hepatitis B Virus Related Hepatocellular Carcinoma Without Elevated viRal Load

A Phase 4, Open-Label Study to Investigate the Efficacy and Safety of Tenofovir Disoproxil Fumarate (Viread(R)) in Preventing Hepatocellular Carcinoma Recurrence in Chronic Hepatitis B Virus Infected Patients With Low Viral Load at Baseline Treated With Radiofrequency Ablation or Resection

Increase in DNA 1log IU/mL at least 4 weeks apart

Samsung Medical Center

Blood and Lymph Conditions

Immune System Diseases

Lymphoma

Lymphoproliferative Disorders

Lymphatic Diseases

Immunoproliferative Disorders

Lymphosarcoma

Lamivudine

The medications to be used in this study are Lamivudine (EPIVIR®) and Tenofovir disoproxil fumarate (VIREAD®), medications already used in people with certain other types of viruses \[but not HERV-K(HML2)\] in their body. Treatment will last 16 weeks. This is an experiment combining these two drugs and has been issue an Investigational New Drug (IND) Exemption by the FDA.

Creatinine Clearance (mL/min): ≥50, Recommended Dosage of Epivir: 150 mg twice daily or 300 mg once daily.

Creatinine Clearance (mL/min): 30-49, Recommended Dosage of Epivir: 150 mg once daily.

Subjects will be taking drug for 16 weeks.

Therapy for non-Hodgkin lymphoma (NHL) is in evolution as new molecular pathways and targeted therapies are identified. Although most NHLs respond to currently available therapies, the majority of patients relapse and many never have a complete response to therapy. In the investigators attempts to further understand the pathogenesis of NHLs, the investigators have identified and characterized expression of human endogenous retroviruses (HERVs) at the DNA, RNA and protein levels in association with the presence of NHLs (and other neoplastic diseases). The investigators preclinical evidence suggests a correlation with the level of HERV-K (a particular family of HERVs) expression and NHL disease activity, leading us to hypothesize that HERV-K expression may contribute to the development of the disease and/or to its recurrence. If this hypothesis is correct, then drugs that inhibit HERV-K expression may prevent recurrence of disease and/or may provide a novel therapeutic approach for NHLs.

To test this hypothesis, the investigators eventually intend to study the use of anti-retroviral therapies in patients with NHL. The investigators in vitro studies have demonstrated that HERV-K expression decreases in response to the currently FDA-approved and available, anti-HIV drugs, Lamivudine and tenofovir disoproxil fumarate (tenofovir). These medications are tolerated well in HIV patients, but it is unknown how the combination of Lamivudine and Tenofovir will be tolerated by patients with NHL. To further test the investigators hypotheses, the investigators propose the following Specific Aims of the current study: (1) To evaluate the tolerability, toxicity and safety of administering Lamivudine and Tenofovir in combination to patients with relapsed or refractory NHL; (2) To evaluate the effects of the combination of lamivudine and tenofovir on HERV-K plasma viral RNA load; and (3) To monitor the response rate of the NHL to treatment with the combination of lamivudine and tenofovir.

The investigators study will recruit adult patients with relapsed or refractory NHL whom the investigators have identified as having expression of HERV-K. Volunteer participants will be administered the combination of lamivudine and tenofovir and monitored for tolerability, toxicity, compliance, changes in viral RNA load and disease response.

Safety & Efficacy of Lamivudine & Tenofovir to Lower Plasma Level of Viral RNA in Lymphoma

A Phase I/II Study of Safety and Efficacy of Lamivudine (EPIVIR®) and Tenofovir Disoproxil Fumarate (VIREAD®) Used to Lower the Plasma Level of Viral RNA of HERV-K(HML2) in Patients With Lymphoma

Patients will have HERV-K(HML2) viral load measured at baseline and post-treatment (quantifiable HERV-K(HML2) viral load is an eligibility criterion, and post-treatment loads below the limit of quantitation will be assigned a random value uniformly distributed between 0 and the limit of quantitation).

Linear models will be used to relate tumor regression to change in viral load of RNA levels.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Prophylactic Antiviral Therapy in Patients With Current or Past Hepatitis B Virus Infection Receiving Anti-Cancer Therapy for Solid Tumors	NCT03887702	Hepatitis B Inf... Malignant Solid...	Best Practice Entecavir Tenofovir Alafe... Tenofovir Disop...	18 Years -	SWOG Cancer Research Network
Prompt Or Watchful Monitoring for Hepatitis B Virus Related Hepatocellular Carcinoma Without Elevated viRal Load	NCT02308319	Carcinoma, Hepa...	Tenofovir disop...	18 Years -	Samsung Medical Center
Safety & Efficacy of Lamivudine & Tenofovir to Lower Plasma Level of Viral RNA in Lymphoma	NCT01528865	Lymphoma	Lamivudine Tenofovir disop...	18 Years -	University of Michigan Rogel Cancer Center

Spots Global Cancer Trial Database for tenofovir disoproxil fumarate