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Anti-Infective Agents

All Drugs and Chemicals

Tenofovir

Antiviral Agents

Entecavir

Reverse Transcriptase Inhibitors

Enzyme Inhibitors

Anti-HIV Agents

Anti-Retroviral Agents

\[Cohort 1\] 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

Carcinoma

Carcinoma, Hepatocellular

Recurrence

Hepatitis C

Liver Cirrhosis

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

Adenocarcinoma

Liver Neoplasms

Gastrointestinal Neoplasms

Digestive System Neoplasms

Flaviviridae Infections

Antineoplastic Agents

Sorafenib

Navitoclax

Protein Kinase Inhibitors

Patients receive navitoclax PO QD on days 1-21 (days 1-28 cycle of 1 only) and sorafenib tosylate PO BID on days 1-21. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.

Laboratory Biomarker Analysis

Pharmacological Study

Sorafenib Tosylate

Brian A Costello

This phase I trial studies the side effects and the best dose of navitoclax when given together with sorafenib tosylate in treating patients with solid tumors that have returned (relapsed) or do not respond to treatment (refractory). Navitoclax and sorafenib tosylate may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

PRIMARY OBJECTIVES:

I. To determine the maximum tolerated dose (MTD) of the combination of navitoclax and sorafenib tosylate (sorafenib) in patients with advanced solid tumors. (Dose escalation cohort) II. To better characterize the toxicity profile of the combination of navitoclax and sorafenib. (Dose expansion cohort)

SECONDARY OBJECTIVES:

I. To identify any activity of this treatment combination in patients with metastatic cancer. (Dose escalation cohort) II. To seek preliminary evidence of activity of this treatment combination in patients with hepatoma. (Dose expansion cohort)

CORRELATIVE OBJECTIVES:

I. To determine whether the combination of navitoclax and sorafenib induces apoptosis that can be detected by peripheral blood biomarker analysis. (Dose escalation cohort) II. To assess peripheral blood biomarkers and pharmacokinetics in a more homogenous population. (Dose expansion cohort) III. To determine whether treatment is associated with Mcl-1 down regulation in hepatocellular carcinoma (HCC) at the maximum tolerated dose (MTD). (Dose expansion cohort) IV. To assess in a preliminary fashion whether pretreatment tumor cell levels of Mcl-1 predict response to this regimen through serial biopsies. (Dose expansion cohort)

OUTLINE: This is a dose-escalation study of navitoclax.

Patients receive navitoclax orally (PO) once daily (QD) on days 1-21 (days 1-28 cycle of 1 only) and sorafenib tosylate PO twice daily (BID) on days 1-21. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months.

Navitoclax and Sorafenib Tosylate in Treating Patients With Relapsed or Refractory Solid Tumors

A Phase I Trial of ABT-263 (Navitoclax), a Bcl-2 Inhibitor, and Sorafenib (Nexavar) in Patients With Relapsed or Refractory Solid Organ Tumors

To assess changes in each antigen, dot plots will be constructed with H-score on the Y axis and pre-or post-treatment status on the X axis, looking for patterns of change that emerge. To assess whether changes occur predominantly in one direction, a sign test will be applied.

Will be assessed by immunohistochemistry. The relationship between pretreatment Mcl-1 expression and clinical response will be examined in a post hoc and exploratory fashion. To assess the relationship between Mcl-1 and response the H score (0-300) vs. response will be graphed. Chi-squared tests will be used to assess significance of relationships between these dichotomous variables and response. In addition, associations between molecular markers and time-to-event variables (progression-free-survival \[PFS\]) will be illustrated graphically using Kaplan-Meier curves and log-rank tests in an exploratory fashion.

Will be assessed by enzyme-linked immunosorbent assay (ELISA). Will be summarized descriptively and plotted along time by dose levels and as a whole. The changes of the serum levels of cleaved and total CK18 at each time point against pre-treatment baseline will be correlated with toxicity and clinical endpoints. The relationships between cleaved and total CK18, caspase 3 and cytochrome c at various time points and dose levels will be explored in longitudinal data analysis. Tissue expression of Mcl-1 will be correlated with serum levels of cleaved and total CK18 at different time points and clinical toxicity and tumor response.

Will be defined as the dose level below the lowest dose that induces dose-limiting toxicity in at least one-third of patients (at least 2 of a maximum of 6 new patients) per National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version (v.) 4.0.

Will be graded per NCI CTCAE v. 4.0. The number and severity of all adverse events (overall, by dose-level, and by tumor group) will be tabulated and summarized in this patient population. The grade 3+ adverse events will also be described and summarized in a similar fashion.

Will be assessed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline version 1.1. Response will be summarized by simple descriptive summary statistics delineating complete and partial responses as well as stable and progressive disease. The waterfall plot may be used to display best tumor response. Exploratory analysis of the relationship between response and other clinical endpoints may be performed.

The data on time-related variables will be summarized descriptively.

Chronic Graft Versus Host Disease

Patients with unknown HBV infection status undergo 3 HBV screening tests (HBsAg, anti-HBc, and anti-HBs) before chemotherapy. Patients with known HBV infection status undergo either HBsAg or anti-HBc screening tests if there is no evidence of HBV testing in the last 3 months. All patients complete HBV risk assessment survey.

Undergo 3 HBV screening tests (HbsAg, anti-HBc, and anti-HBs)

Hepatitis B Screening

Survey Administration

This trial studies hepatitis B screening strategies of new cancer patients scheduled to undergo chemotherapy. Patients with cancer and hepatitis B virus infection are at risk of reactivation of infection after chemotherapy. Hepatitis B virus infection reactivation can be prevented by starting antivirals before chemotherapy in patients who are hepatitis B virus infection positive. Hepatitis B screening may help doctors prevent the reactivation of hepatitis B virus infection after chemotherapy.

PRIMARY OBJECTIVES:

I. To derive a selective screening strategy that optimizes the identification of positive hepatitis B virus (HBV) infection cases in comparison to widespread screening of new cancer patients undergoing chemotherapy.

SECONDARY OBJECTIVES:

I. To determine the prevalence of risk factors among patients with unknown HBV infection status as well as among patients known to have HBV infection, determine the incidence of reactivation of hepatitis B virus (HBV) infection, rates of disruptions in cancer therapy, co-infection with hepatitis C virus (HCV) or human immunodeficiency virus (HIV), and mortality rates.

OUTLINE:

Patients with unknown HBV infection status undergo 3 HBV screening tests (hepatitis B surface antigen \[HBsAg\], hepatitis B core antibody \[anti-HBc\], and hepatitis B surface antibody \[anti-HBs\]) before chemotherapy. Patients with known HBV infection status undergo either HBsAg or anti-HBc screening tests if there is no evidence of HBV testing in the last 3 months. All patients complete HBV risk assessment survey.

After completion of study, patients with HBV infection are followed up every 3 months for at least 12 months after completion of chemotherapy or end of study period.

Widespread vs. Selective Screening for Hepatitis B Infection Prior to Chemotherapy

Number of screened participants (new cancer patients undergoing chemotherapy) with positive hepatitis B virus (HBV) infection compared to total screened. Prospective, universal screening of eligible MD Anderson cancer patients not known to have HBV infection using three HBV screening tests (HBsAg, anti-HBc, and anti-HBs) prior to chemotherapy.

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
Navitoclax and Sorafenib Tosylate in Treating Patients With Relapsed or Refractory Solid Tumors	NCT02143401	Cirrhosis Hepatitis B Inf... Hepatitis C Inf... Metastatic Mali... Recurrent Hepat... Recurrent Malig... Refractory Mali... Stage IV Hepato... Unresectable So...	Laboratory Biom... Navitoclax Pharmacological... Sorafenib Sorafenib Tosyl...	18 Years -	National Cancer Institute (NCI)
Navitoclax and Sorafenib Tosylate in Treating Patients With Relapsed or Refractory Solid Tumors	NCT02143401	Cirrhosis Hepatitis B Inf... Hepatitis C Inf... Metastatic Mali... Recurrent Hepat... Recurrent Malig... Refractory Mali... Stage IV Hepato... Unresectable So...	Laboratory Biom... Navitoclax Pharmacological... Sorafenib Sorafenib Tosyl...	18 Years -	National Cancer Institute (NCI)
Widespread vs. Selective Screening for Hepatitis B Infection Prior to Chemotherapy	NCT01970254	Cancer Hepatitis B HBV Hepatitis B Inf... Malignant Neopl...	Hepatitis B Scr... Survey Administ...	18 Years -	M.D. Anderson Cancer Center

Spots Global Cancer Trial Database for hepatitis b infection