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

Study Overview
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Brief Summary
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This phase III trial studies the effect of tenofovir alafenamide in preventing liver complications in patients with current 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. Tenofovir alafenamide is a drug that 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.

Detailed Description
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PRIMARY OBJECTIVES: I. 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 (hepatitis B surface antigen positive [HBsAg+] and antibody to hepatitis B core antigen positive [anti-HBc+]) receiving anti-cancer therapy for solid tumors. II. 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 (hepatitis B surface antigen negative [HBsAg-] and anti-HBc+) receiving anti-cancer therapy for solid tumors. SECONDARY OBJECTIVES: I. 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 anti-cancer therapy for solid tumors. II. 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: I. 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. II. 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 randomized to 1 of 3 groups. GROUP A (Cohorts 1a & 2a): 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. GROUP B (Cohorts 1b & 2b): 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. GROUP C (Cohort 3): Patients receive TAF PO QD or TDF PO QD or entecavir PO QD at the discretion of the physician during usual care. Treatment continues for up to 6 months after discontinuation of usual care or a maximum of 24 months in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up every 4 weeks for up to 24 months.

Official Title
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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

Conditions
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Hepatitis B Infection, Malignant Solid Neoplasm

Intervention / Treatment
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* Other: Best Practice
* Drug: Entecavir
* Drug: Tenofovir Alafenamide
* Drug: Tenofovir Disoproxil Fumarate


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients must be diagnosed with stage I-III solid tumor malignancy; patients with only carcinoma in situ or with stage IV disease are excluded Patients must not have been diagnosed with a malignancy other than the current malignancy within the past five years, with the exception of basal cell or squamous cell skin cancer, or non-invasive (in situ) malignancies of the cervix, breast, or skin Patients must not have lymphoma, leukemia, or myeloma Patients must not have primary liver cancer, known cirrhosis, or evidence of any malignancy that involves the liver Patients must be planning to receive systemic anti-cancer therapy (either single agent or some combination of systemic cytotoxic therapy, systemic immunotherapy or systemic targeted therapy) for this solid tumor Patients must not have been previously treated with the same anti-cancer therapy regimen that is now anticipated; the anti-cancer therapy does not have to be first-line therapy; prior and/or concurrent radiotherapy is allowed Patients must be registered =< 28 days prior to the planned start date of anti-cancer therapy; if the patient has started systemic anti-cancer therapy, patient must be registered =< 42 days after the initiation of first cycle of anti-cancer therapy Patients who have received prior anti-cancer therapy must have discontinued all previous therapies (excluding planned anti-cancer therapy to occur in conjunction with this study) >= 1 day prior to registration to this study Patients must not have had any cancer therapy regimen that includes anti-CD20 Patients must not be receiving antiviral medications active against HBV, including: adefovir, entecavir, lamivudine, telbivudine, tenofovir disoproxil fumarate, tenofovir alafenamide (TAF), or any other Food and Drug Administration (FDA) approved agents for the treatment of hepatitis B; patients who have previously received antiviral medication must not have required any antiviral medication active against HBV >= 90 days prior to registration to this study Patients must not have had hematopoietic stem cell transplantation therapy Patients receiving any of the following medications must discontinue them (under the supervision of their treating physician) prior to registration, and must not be planning to take them during protocol therapy: acyclovir, aminoglycosides, oxcarbazepine, phenobarbital, phenytoin, rifabutin, rifampin, rifapentine, valacyclovir, high-dose nonsteroidal anti-inflammatory drugs (NSAIDs), (high-dose based on package insert), and St. John's wort Patients must have results for the following HBV tests done within 28 days prior to registration: HBsAg AND anti-HBc (total immunoglobulin [Ig] or IgG, but not IgM only) AND hepatitis B surface antibody (anti-HBs); for the anti-HBs test, quantitative or qualitative (including indeterminate) results are allowable Patients must have tested positive for HBsAg or anti-HBc (total Ig, IgG, but not IgM) and must have baseline HBV deoxyribonucleic acid (DNA) completed =< 42 days prior to registration Complete blood count (CBC) must be completed =< 28 days prior to registration; results do not need to be in the institutional limits of normal International normalized ratio (INR) must be completed =< 28 days prior to registration; results must < 1.2 x institutional limits of normal Alanine aminotransferase (ALT) must be obtained =< 28 days prior to registration; ALT must be =< 1.5 x institutional ULN Total bilirubin must be obtained =< 28 days prior to registration; total bilirubin must be =< 1.5 x institutional ULN Creatinine results must be obtained =< 28 days prior to registration; creatinine must be =< 1.5 x institutional ULN Patients must not have known current active hepatitis C infection (HCV); active HCV is defined by a detectable HCV ribonucleic acid (RNA) level; Note: HCV testing is not required for eligibility Patients must not have a history of human immunodeficiency (HIV) infection; patients with unknown HIV status must have HIV testing completed =< 365 days prior to registration Patients must have Zubrod performance status of 0-2 Patients must not be pregnant or nursing, as the safety of the study drug in pregnant and nursing women has not been established; women/men of reproductive potential must have agreed to use an effective contraceptive method; a woman is considered to be of reproductive potential if she has had menses at any time in the preceding 12 consecutive months; in addition to routine contraceptive methods, effective contraception also includes heterosexual celibacy and surgery intended to prevent pregnancy (or with a side-effect of pregnancy prevention) defined as a hysterectomy, bilateral oophorectomy or bilateral tubal ligation; however, if at any point a previously celibate patient chooses to become heterosexually active during the time period for use of contraceptive measures outlined in the protocol, he/she is responsible for beginning contraceptive measures Patients must have specimens collected for submission as outlined Patients must be offered the opportunity to participate in optional translational medicine studies as outlined Patients with impaired decision-making capacity are eligible as long as their neurological or psychological condition does not preclude their safe participation in the study (e.g., tracking pill consumption and reporting adverse events to the investigator) Patients may have concurrent participation in other clinical trials that entail cytotoxic, immunotherapy, targeted therapy; surgical treatment; radiotherapy treatment; or any combination thereof Patients must be informed of the investigational nature of this study and must sign and give written informed consent in accordance with institutional and federal guidelines As a part of the Oncology Patient Enrollment Network (OPEN) registration process the treating institution's identity is provided in order to ensure that the current (within 365 days) date of institutional review board approval for this study has been entered in the system

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group A (TAF, TDF, entecavir)<br>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. | Drug: Entecavir<br>* Given PO<br>* Other names: SQ34676;Drug: Tenofovir Alafenamide<br>* Given PO<br>* Other names: TFV Alafenamide;Drug: Tenofovir Disoproxil Fumarate<br>* Given PO<br>* Other names: Viread;|
| Experimental: Group B (TAF, TDF, entecavir)<br>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. | Drug: Entecavir<br>* Given PO<br>* Other names: SQ34676;Drug: Tenofovir Alafenamide<br>* Given PO<br>* Other names: TFV Alafenamide;Drug: Tenofovir Disoproxil Fumarate<br>* Given PO<br>* Other names: Viread;|
| Experimental: Group C (TAF, TDF, entecavir, usual care)<br>Patients receive TAF PO QD or TDF PO QD or entecavir PO QD at the discretion of the physician during usual care. Treatment continues for up to 6 months after discontinuation of usual care or a maximum of 24 months in the absence of disease progression or unacceptable toxicity. | Other: Best Practice<br>* Receive best practice<br>* Other names: standard therapy;Drug: Entecavir<br>* Given PO<br>* Other names: SQ34676;Drug: Tenofovir Alafenamide<br>* Given PO<br>* Other names: TFV Alafenamide;Drug: Tenofovir Disoproxil Fumarate<br>* Given PO<br>* Other names: Viread;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time until adverse liver outcome, assessed by incidence of adverse liver outcome | Graded according to Common Terminology Criteria for Adverse Events (CTCAE) version (v.) 4.0. 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 international normalized ration [INR] >= 2.0) not due to disease progression in the liver. The study will recruit patients with multiple different cancer types, but predominantly lung, breast, colon, prostate, gynecological, and head and neck cancers. Estimates of adverse liver outcomes at 1 year will be derived using cumulative incidence to account for the competing risk of death. The final analysis will rely on Cox regression, adjusting for the stratification factors. | From the start of study treatment up to 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of hepatitis B Virus (HBV) reactivation among patients with solid malignancies and chronic or past HBV infection during or after completion of anti-cancer therapy | Estimates of HBV reactivation at one year will be derived using cumulative incidence to account for competing risks. Under this scenario, a sample size of n=222 patients for each randomized study will allow the investigators to estimate the confidence interval to within +/- 6% (based on the upper bound of the 95% confidence interval using an exact binomial in patients with complete follow-up), if the assumed incidence is at least 20%. Thus, this sample size will allow the confidence interval to be estimated to within +/- 31.1% of the assumed incidence (the relative accuracy, defined as: (95% confidence interval [CI] upper bound - p)/p], where p is the assumed incidence). | Up to 24 months | 
| HBV reactivation rate | The investigators will compare HBV reactivation rates by arm within each randomized trial. Based on a two-sample survival design accounting for the competing risk of death ( 20% deaths at 1 year [hazard rate of 0.223]), and a one-sided alpha=0.05 test, then n=222 patients (111 per arm) will give 81% power to detect a hazard ratio for HBV reactivation for experimental to standard arms of 0.47, representing a 53% reduction in the hazard risk of HBV reactivation in the first year (from a hazard=0.223 down to hazard = 0.105), or an absolute reduction of 50% (from 20% down to 10%). Multivariable Cox regression will compare the effect of intervention assignment, adjusting for the stratification factors specified in the main clinical study. | Up to 24 months | 
| Hepatitis flare | Defined as alanine aminotransferase (ALT) > 3 x baseline and > 100 U/L. | Up to 24 months | 
| Initiation of upon indication tenofovir alafenamide (TAF) therapy |  | Up to 24 months | 
| Cancer therapy interruption | Defined as dose reduction, treatment delay, or termination of anti-cancer therapy due to hepatic-related reasons other than disease progression in the liver. | Up to 24 months | 
| Death due to any cause |  | From date of randomization up to 24 months |