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

Phase 3

Terminated

Conditions: Hepatitis B Infection
Malignant Solid Neoplasm

Interventions: Drug: Entecavir
Other: Best Practice
Drug: Tenofovir Alafenamide
Drug: Tenofovir Disoproxil Fumarate

Registration Number: NCT03887702

Lead Sponsor: SWOG Cancer Research Network

Brief Summary: 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.

Detailed Description: 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.

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 4

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 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 must not be taking or planning to take warfarin
Patients who will be treated with TAF must not be taking or planning to take oxcarbazepine, phenobarbital, phenytoin, rifabutin, rifampin, rifapentine, or St. John's Wort
Patients who will be treated with TAF and are concomitantly taking or plan to take carbamazepine must be given an increased dose of TAF or alternatively be given ETV or TDF
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
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

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Arm 1 (TAF, TDF, entecavir: prophylactic)	Entecavir	\[Cohort 1\] 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.
Arm 1 (TAF, TDF, entecavir: prophylactic)	Tenofovir Disoproxil Fumarate	\[Cohort 1\] 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.
Arm 2 (TAF, TDF, entecavir: upon indication)	Tenofovir Alafenamide	\[Cohort 1\] 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.
Arm 4 (Anti-Viral therapy: usual care)	Best Practice	\[Cohort 2\] 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.
Arm 1 (TAF, TDF, entecavir: prophylactic)	Tenofovir Alafenamide	\[Cohort 1\] 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.
Arm 2 (TAF, TDF, entecavir: upon indication)	Entecavir	\[Cohort 1\] 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.
Arm 2 (TAF, TDF, entecavir: upon indication)	Tenofovir Disoproxil Fumarate	\[Cohort 1\] 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.
Arm 3 (TAF, TDF, entecavir: upon indication)	Entecavir	\[Cohort 2\] 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.
Arm 3 (TAF, TDF, entecavir: upon indication)	Tenofovir Alafenamide	\[Cohort 2\] 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.
Arm 4 (Anti-Viral therapy: usual care)	Entecavir	\[Cohort 2\] 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.
Arm 3 (TAF, TDF, entecavir: upon indication)	Tenofovir Disoproxil Fumarate	\[Cohort 2\] 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.
Arm 4 (Anti-Viral therapy: usual care)	Tenofovir Alafenamide	\[Cohort 2\] 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.
Arm 4 (Anti-Viral therapy: usual care)	Tenofovir Disoproxil Fumarate	\[Cohort 2\] 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.

Primary Outcome Measures

Name	Time	Method
Number of Participants With Adverse Liver Outcome	From randomization to 24 months	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.

Secondary Outcome Measures

Name	Time	Method
Number of Participants With Hepatitis B Virus (HBV) Flare	From randomization to 24 months	Hepatitis flare is defined as ALT \> 3 x baseline and \>100 U/L.
Combined Endpoint of Adverse Liver Outcomes and HBV Reactivation, Number of Participants	From randomization to 24 months	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.
Number of Participants With Hepatitis B Virus (HBV) Reactivation	From randomization up to 24 months	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-.

Trial Locations

Locations (193): Mercy Hospital Fort Smith
🇺🇸
Fort Smith, Arkansas, United States
Kaiser Permanente-Anaheim
🇺🇸
Anaheim, California, United States
Kaiser Permanente-Deer Valley Medical Center
🇺🇸
Antioch, California, United States
Kaiser Permanente-Baldwin Park
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Baldwin Park, California, United States
Kaiser Permanente-Bellflower
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Bellflower, California, United States
Epic Care-Dublin
🇺🇸
Dublin, California, United States
Kaiser Permanente Dublin
🇺🇸
Dublin, California, United States
Bay Area Breast Surgeons Inc
🇺🇸
Emeryville, California, United States
Epic Care Partners in Cancer Care
🇺🇸
Emeryville, California, United States
Kaiser Permanente-Fontana
🇺🇸
Fontana, California, United States
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Mercy Hospital Fort Smith
🇺🇸Fort Smith, Arkansas, United States