Conditions: Hepatitis B Infection Malignant Solid Neoplasm
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 4
Healthy volunteers: no

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.

Arms:
arm 1: \[Cohort 1\] 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: \[Cohort 1\] 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: \[Cohort 2\] 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: \[Cohort 2\] 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.

Interventions: intervention 1: Best Practice intervention 2: Entecavir intervention 3: Tenofovir Alafenamide intervention 4: Tenofovir Disoproxil Fumarate
Intervention descriptions: intervention 1: Receive best practice intervention 2: Given PO intervention 3: Given PO intervention 4: Given PO

Protocol document:
Prot_SAP_000.pdf: 
 
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PRIVILEGED COMMUNICATION 
FOR INVESTIGATIONAL USE ONLY 
 
SWOG CANCER RESEARCH NETWORK 
TITLE 
 
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 
 
NCT# 03887702 
 
STUDY CHAIRS: 
AGENTS: 
 
Jessica Hwang, M.D., M.P.H.  
Commercially Available Agents  
(Study Chair, Internal Medicine) 
Tenofovir alafenamide (TAF)  
MD Anderson Cancer Center 
Tenofovir disoproxil fumarate (TDF) 
1400 Pressler St., Unit 1465  
Entecavir (ETV) 
Houston, TX  77030 
 
Phone: 713/745-4516 
 
FAX: 713/563-4491 
E-mail: jphwang@mdanderson.org  
BIOSTATISTICIANS: 
 
Anna S. Lok, M.D. (Study Co-Chair, Hepatology) 
Joseph M. Unger, Ph.D. 
University of Michigan 
Edward Mayerson, M.S. 
1500 E Medical Center Drive 
SWOG Statistics and Data Management Center 
3912 Taubman Center, SPC 5362 
Fred Hutchinson Cancer Research Center 
Ann Arbor, MI 48109-5362 
1100 Fairview Avenue N., M3-C102 
Phone: 734/936-7511 
P.O. Box 19024 
E-mail: aslok@med.umich.edu  
Seattle, WA 98109 
 
Phone: 206/667-4623 
Adam Gehring, Ph.D. (TM Co-Chair) 
FAX: 206/667-4408 
Toronto Centre for Liver Disease 
E-mail: junger@fredhutch.org   
Toronto General Hospital Research Institute 
E-mail: emayerso@fredhutch.org  
101 College St, Rm 10-356 
 
 
Toronto, ON M5G 1L7 
 
 
Phone: 416/634-7095 
 
 
E-mail: Adam.Gehring@uhnresearch.ca  
 
 
 
 
Jordan Feld M.D., M.P.H. (TM Co-Chair) 
NCTN-Group CHAMPION: 
Toronto Centre for Liver Disease 
 
Toronto General Hospital, University Health Network 
Edith Mitchell, M.D., ECOG-ACRIN 
Sandra Rotman Centre for Global Health 
 
200 Elizabeth Street, 9EB-240 
 
Toronto, ON M5G 2C4 
 
Phone Clinical: 416/340-4584 
 
Phone Lab: 416/581-8595 
 
Fax: 416/340-4533  
 
E-mail: Jordan.Feld@uhn.ca  
 
PARTICIPANTS 
 
ALLIANCE/Alliance for Clinical Trials in Oncology 
ECOG-ACRIN/ECOG-ACRIN Cancer Research Group 
NRG/NRG Oncology 
SWOG/SWOG Cancer Research Network 
 


 
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TABLE OF CONTENTS 
 
TITLE ………………………………………………………………………………………………………………..1 
PARTICIPANTS ............................................................................................................................................ 1 
TABLE OF CONTENTS ............................................................................................................................... 2 
CANCER TRIALS SUPPORT UNIT (CTSU) ADDRESS AND CONTACT INFORMATION ....................... 4 
SCHEMA ....................................................................................................................................................... 5 
1.0 
OBJECTIVES .................................................................................................................................. 6 
1.1 
Co-Primary Objectives ..................................................................................................................... 6 
1.2 
Secondary Objectives ...................................................................................................................... 6 
1.3 
Translational Objectives ................................................................................................................... 6 
2.0 
BACKGROUND ............................................................................................................................... 6 
2.1 
General............................................................................................................................................. 6 
2.2 
Inclusion of Women and Minorities .................................................................................................. 9 
3.0 
DRUG INFORMATION .................................................................................................................. 10 
3.1 
Entecavir (ETV) .............................................................................................................................. 10 
3.2 
Tenofovir alafenamide (TAF) ......................................................................................................... 11 
3.3 
Tenofovir disoproxil fumarate (TDF) .............................................................................................. 13 
4.0 
STAGING CRITERIA ..................................................................................................................... 15 
5.0 
ELIGIBILITY CRITERIA ................................................................................................................ 15 
5.1 
Disease Related Criteria ................................................................................................................ 15 
5.2 
Prior/Concurrent Therapy Criteria .................................................................................................. 15 
5.3 
Clinical/Laboratory Criteria ............................................................................................................. 16 
5.4 
Specimen Submission Criteria ....................................................................................................... 17 
5.5 
Regulatory Criteria ......................................................................................................................... 17 
6.0 
STRATIFICATION FACTORS ....................................................................................................... 17 
6.1 
Cohort 1: Chronic HBV cohort ....................................................................................................... 17 
6.2 
Cohort 2: Past HBV cohort ............................................................................................................. 18 
7.0 
TREATMENT PLAN ...................................................................................................................... 18 
7.1 
General Treatment Information ...................................................................................................... 18 
7.2 
Cohort 1 - Chronic HBV Anti-Viral Treatment ................................................................................ 19 
7.3 
Cohort 2: Past HBV Anti-Viral Treatment....................................................................................... 21 
7.4 
HBV Monitoring and Adverse Liver Outcomes .............................................................................. 22 
7.5 
Drug Compliance Documentation .................................................................................................. 23 
7.6 
Criteria for Removal from Protocol Treatment ............................................................................... 23 
7.7 
Discontinuation of Treatment ......................................................................................................... 23 
7.8 
Follow-Up Period ............................................................................................................................ 23 
8.0 
TOXICITIES TO BE MONITORED AND DOSE MODIFICATIONS .............................................. 24 
8.1 
NCI Common Terminology Criteria for Adverse Events ................................................................ 24 
8.2 
Modifications .................................................................................... Error! Bookmark not defined. 
8.3 
Adverse Event Reporting ............................................................................................................... 25 
9.0 
STUDY CALENDAR ...................................................................................................................... 26 
9.1 
ARM 1: Prophylactic anti-HBV therapy Arm (HBsAg+ Patients) ................................................... 26 
9.2 
ARM 2 & ARM 3: Upon Indication Arms (HBsAg+ or HBsAg- Patients)........................................ 28 
9.3 
ARM 4: Usual Care Arm (HBsAg- Patients)................................................................................... 30 
10.0 
CRITERIA FOR EVALUATION AND ENDPOINT ANALYSIS ..................................................... 32 
10.1 
Primary Endpoint ............................................................................................................................ 32 
10.2 
Other Endpoints ............................................................................................................................. 32 
11.0 
STATISTICAL CONSIDERATIONS .............................................................................................. 32 
11.1 
Primary Endpoint ............................................................................................................................ 32 
11.2 
Secondary Endpoints ..................................................................................................................... 33 
11.3 
Data and Safety Monitoring Committee ......................................................................................... 34 
12.0 
DISCIPLINE REVIEW .................................................................................................................... 35 
13.0 
REGISTRATION GUIDELINES ..................................................................................................... 35 
13.1 
Registration Timing ........................................................................................................................ 35 
13.2 
Investigator/Site Registration ......................................................................................................... 35 
13.3 
CTEP Registration Procedures ...................................................................................................... 35 


 
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13.4 
CTSU Registration Procedures ...................................................................................................... 36 
13.5 
Oncology Participant Enrollment Network (OPEN) Registration Requirements ............................ 38 
13.6 
Exceptions to SWOG registration policies will not be permitted. ................................................... 40 
14.0 
DATA SUBMISSION SCHEDULE ................................................................................................ 40 
14.1 
Data Submission Requirement ...................................................................................................... 40 
14.2 
Master Forms ................................................................................................................................. 40 
14.3 
Data Submission Procedures ........................................................................................................ 40 
14.4 
Data Submission Overview and Timepoints .................................................................................. 42 
15.0 
SPECIAL INSTRUCTIONS............................................................................................................ 43 
15.1 
Blood Serum Specimens (REQUIRED) ......................................................................................... 43 
15.2 
Whole Blood Specimens (OPTIONAL for Patient) ....................................................................... 44 
15.3 
SHIPPING SAMPLES .................................................................................................................... 44 
16.0 
ETHICAL AND REGULATORY CONSIDERATIONS ................................................................... 46 
16.1  
Expedited reporting for commercial agents ................................................................................... 46 
17.0 
BIBLIOGRAPHY ............................................................................................................................ 48 
18.0 
APPENDIX ..................................................................................................................................... 52 
18.1 
Translational Medicine ................................................................................................................... 53 
18.2 
Instructions for the SWOG Biospecimen Bank .............................................................................. 57 
18.3 
Viral Status Information .................................................................................................................. 58 
18.4 
Intake Calendar .............................................................................................................................. 60 
18.5 
Blinded Central Review of Primary Endpoint ................................................................................. 62 
18.6 
Approved Antiviral Therapies in Adults .......................................................................................... 63 
 
 
 
 


 
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CANCER TRIALS SUPPORT UNIT (CTSU) ADDRESS AND CONTACT INFORMATION 
CONTACT INFORMATION 
For regulatory requirements: 
For patient enrollments: 
For study data submission: 
Regulatory documentation must 
be submitted to the Cancer 
Trials Support Unit (CTSU) via 
the Regulatory Submission 
Portal: 
 
 (Sign in at 
https://www.ctsu.org, and select 
Regulatory > Regulatory 
Submission.)  
 
Institutions with patients waiting 
that are unable to use the Portal 
should alert the CTSU 
Regulatory Office immediately 
by phone or email: 1-866-651-
CTSU (2878) to receive further 
instruction and support.   
 
Contact the CTSU Regulatory 
Help Desk at 1-866-651-CTSU 
(2878)  for regulatory 
assistance. 
 
Refer to the patient enrollment 
section of the protocol for 
instructions on using the 
Oncology Patient Enrollment 
Network (OPEN). OPEN can be 
accessed at 
https://www.ctsu.org/OPEN_SYS
TEM/ or https://OPEN.ctsu.org . 
 
Contact the CTSU Help Desk with 
any OPEN-related questions at 
ctsucontact@westat.com. 
 
 
Data collection for this study will 
be done exclusively through 
Medidata Rave.  Refer to the 
data submission section of the 
protocol for further instructions.  
 
 
The most current version of the study protocol and all supporting documents must be downloaded 
from the protocol-specific Web page of the CTSU members’ website (https://www.ctsu.org).  Access to 
the CTSU members’ website is managed through the Cancer Therapy and Evaluation Program - Identity 
and Access Management (CTEP-IAM) registration system and requires user log in with CTEP-IAM 
username and password.  
For patient eligibility or data submission questions contact the SWOG Statistics and Data 
Management Center (SDMC) by phone or email: 
206/652-2267 
cancercontrolquestion@crab.org  
 
For treatment or toxicity related questions contact the Study Chair by phone or email: Jessica 
Hwang, M.D., M.P.H., Phone: 713/745-4516, e-mail: jphwang@mdanderson.org or Anna S. Lok, M.D., 
Phone: 734/936-7511, e-mail: aslok@med.umich.edu. 
For non-clinical questions (i.e. unrelated to patient eligibility, treatment, or clinical data 
submission) contact the CTSU Help Desk by phone or e-mail:  
CTSU General Information Line – 1-888-823-5923, or ctsucontact@westat.com.  All calls and 
correspondence will be triaged to the appropriate CTSU representative.  
 
 
 


 
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SCHEMA 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
* See Section 10.2c. 
COHORT 1: 
CHRONIC HBV 
(HBsAg positive and  
anti-HBc positive) 
COHORT 2:  
PAST HBV 
(HBsAg negative 
and 
anti-HBc positive) 
Randomization 
Arm 1 
PROPHYLACTIC 
Tenofovir alafenamide 
(TAF), Tenofovir disoproxil  
fumarate (TDF), OR 
Entecavir  
(ETV) 
Arm 2 
UPON 
INDICATION*  
Tenofovir 
alafenamide 
(TAF), 
Tenofovir 
disoproxil  
fumarate 
(TDF), OR 
Entecavir  
(ETV) 
Arm 3 
UPON INDICATION* 
Tenofovir alafenamide 
(TAF), Tenofovir disoproxil  
fumarate (TDF), OR 
Entecavir  
(ETV) 
Arm 4 
USUAL 
CARE 
(physician 
discretion) 
Solid tumor patients with chronic or 
past HBV+ infection 
planning to receive anti-cancer 
therapy (cytotoxic, targeted, and/or 
immunotherapy) 
Randomization 


 
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1.0 
OBJECTIVES 
 
1.1 
Co-Primary Objectives 
 
a. 
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. 
 
b. 
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. 
 
1.2 
Secondary Objectives 
 
a. 
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. 
 
b. 
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. 
 
1.3 
Translational Objectives 
 
a. 
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. 
 
b. 
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.  
 
 
2.0 
BACKGROUND 
 
2.1 
General 
 
Hepatitis B virus (HBV) reactivation is a potentially severe adverse sequela of anti-cancer 
therapy in patients with chronic HBV infection [hepatitis B surface antigen (HBsAg)+ and 
hepatitis B core antibody (anti-HBc) + or past HBV infection (HBsAg- and anti-HBc+). HBV 
reactivation can lead to hepatitis flare, liver failure, and death. Previous studies conducted 
in Asian countries, where HBV infection is endemic, showed that reactivation of HBV 
replication during chemotherapy occurred in approximately 40-50% of patients with chronic 
infection and 10-20% of patients with past infection. (1,2,3,4,5) Most of the studies on HBV 
reactivation were conducted in patients receiving chemotherapy for hematologic 
malignancies or hematopoietic stem cell transplantation. (6,7,8,9,10,11) These studies 
provide strong evidence in support of administering anti-HBV prophylaxis before certain 
therapies for hematologic malignancies or hematopoietic stem cell transplantation.  (12,13) 
However, patients with hematologic malignancies represent a small proportion of patients 
with cancer. Small studies on HBV reactivation have been conducted in patients with solid 
tumors. (14,15,16,17) 


 
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Not all HBV patients receiving anti-cancer therapies experience HBV reactivation or 
hepatitis flare. Some clinical factors, such as HBV viral load and exposure to certain 
targeted therapies, are well-established risk factors for HBV reactivation, but most data 
were derived from studies in patients with hematologic malignancies. Due to the 
inefficiency of HBV risk-based screening, ASCO recommends that all patients with cancer 
be tested for HBV prior to the initiation of systemic anticancer therapy. (18) 
 
HBV-associated immune responses in patients with cancer and HBV infection have not 
been well studied, but a growing body of evidence indicates that immune responses may 
have clinical relevance in mitigating the risk of reactivation and liver failure. Understanding 
the clinical predictors and immune mechanisms of HBV reactivation will be important in 
developing personalized strategies to mitigate the risk of adverse liver outcomes in HBV 
patients with solid tumors receiving anti-cancer therapy.  
 
In the United States, the prevalence of chronic HBV infection is reported to be 0.3%, and 
the prevalence of past HBV infection is 4.6%, but these rates may underestimate the true 
prevalence since the National Health and Nutrition Examination Survey cohort on which 
they are based underrepresents populations with high HBV prevalence. (19,20) 
 
In patients with HBV infection, the balance between liver injury and viral control is 
influenced by the host immune system, and immunosuppressive therapies that disrupt this 
immune balance can lead to reactivation of HBV replication and resultant adverse liver 
outcomes. (21,22) Reactivation can lead to elevated alanine aminotransferase (ALT) levels 
and in severe cases hepatitis flare, liver failure, and death. (23) Reactivation is manifested 
by elevation in serum HBV DNA levels, appearance of HBV DNA in patients with 
undetectable HBV DNA at baseline, or a positive HBsAg test in patients who were HBsAg-
negative but anti-HBc-positive at baseline. (24) To date, the incidence and associated risk 
factors of HBV reactivation among patients with solid tumors with chronic or past HBV 
infection have not been defined. Many previous studies of HBV reactivation in patients with 
solid tumors were conducted in single institutions and are limited by referral and selection 
biases, and the total number of patients with solid tumors and HBV infection in these 
studies was inadequate to permit comprehensive analysis of the effect of cancer type, 
chemotherapy agents, and patient and viral characteristics on the risk of reactivation. 
(25,26) 
 
Oral anti-HBV medication administered once daily can prevent reactivation, especially if 
administered before or at the onset of cytotoxic cancer therapy. (27,28,29,30,) Previous 
studies of anti-HBV therapy focused primarily on patients with hematologic malignancies; 
minimal data exist to guide anti-HBV therapy use during treatment for solid malignancies. 
Anti-HBV prophylaxis can be given concomitantly with cancer therapy. Currently, there are 
six approved anti-HBV medications: adefovir, entecavir, lamivudine, telbivudine, tenofovir 
disoproxil fumarate, and tenofovir alafenamide. The interventional arms of this trial will 
focus on antiviral therapy for HBV using the physicians choice of one of three commercially 
available agents that have high potency and low risk of drug resistance:  tenofovir 
alafenamide (TAF), tenofovir disoproxil fumarate (TDF) or entecavir (ETV).  
 
Hepatitis flare, or elevated ALT level, is common and can lead to interruptions in anti-cancer 
therapy in patients with solid tumors. (31,32) In a systematic review, the median incidence 
of hepatitis flare among patients with solid tumors and chronic HBV infection was reported 
to be 23%, but the incidences in individual studies ranged from 2% to 60%, likely because 
of the variability in definitions and reporting. (33) The risk of hepatitis flare among patients 
with solid tumors and past HBV infection has not been well studied. Further complicating 
analysis of hepatitis flare in HBV patients with solid tumors, such patients may experience 
hepatitis flare that is not related to HBV reactivation; hepatitis flare in such patients can 
also be caused by anti-cancer therapy–associated hepatotoxicity or withdrawal of anti-HBV 
therapy or even occur spontaneously. (34,35,36,37)  
 


 
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HBV-associated immune responses in patients with cancer and HBV infection have not 
been well studied but may have clinical relevance in mitigating the risk of reactivation and  
liver failure.  
 
Chronic HBV infection impairs HBV-specific T cells, leading to T cell exhaustion and loss 
of T cell functions such as production of interleukin-2 (IL-2), tumor necrosis factor-alpha 
(TNFa), and interferon-gamma (IFNg). (38,39) B cell–depleting agents directly affect 
antibody production and also indirectly affect cellular immunity mediated through low levels 
of IL-10. (40,41) Subsequent dysregulation of the usual T cell exhaustive response to 
chronic viral antigen stimulation then occurs; therefore, HBV patients receiving anti-CD20 
monoclonal antibody therapy such as rituximab have demonstrated high rates of HBV 
reactivation. (42,43,44) IFNg-induced chemokines increase during hepatitis flare and may 
lead to defects in NK cell functions, which may contribute to the HBV-associated immune 
response. (45)  
 
In this protocol, the investigators will determine the optimal anti-HBV treatment strategy in 
a heterogeneous population of 444 patients with solid tumors and chronic or past HBV 
infection receiving anti-cancer therapy in the NCI’s National Clinical Trials Network 
(NCTN), including NCI Community Oncology Research Program (NCORP) sites. The 
investigators will explore the mechanisms of HBV-specific immune responses by 
comparing cases with HBV reactivation (estimated number 44) with an equal number of 
matched controls without reactivation (Translational Aim 1), and identify the demographic 
and clinical predictors along with immune correlates of cancer therapy-induced severe 
adverse sequelae, including HBV reactivation and hepatitis flare, among all 444 patients in 
the study (Translational Aim 2).   
 
This protocol is significant because it will permit the development of personalized 
approaches to prevent HBV reactivation, a potentially serious adverse sequela, in patients 
with solid tumors with chronic or past HBV infection treated with anti-cancer therapy. The 
data from this protocol will also permit development of evidence-based guidelines for 
monitoring of patients with HBV infection during anti-cancer therapy and use of anti-HBV 
therapy before and during anti-cancer therapy. The expected research contribution will also 
facilitate design of new anti-cancer strategies or anti-HBV management approaches that 
may decrease the risk of anti-cancer therapy-induced HBV reactivation. This study will 
create an important biorepository of plasma and peripheral blood mononuclear cell 
specimens from 444 patients with solid tumors and chronic or past HBV infection receiving 
anti-cancer therapy. These specimens will be available for future studies that will employ 
new technologies to investigate the contributions of HBV virologic markers and HBV-
specific immune responses identified in this study to determine the mechanisms of HBV 
reactivation.  
 
Figure 1. Conceptual model of immune mechanisms of reactivation 


 
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This protocol is novel because it will be the first to produce evidence-based data through 
a randomized clinical trial in HBV patients with solid tumors in a cooperative cancer network 
in the United States. The key collaborators have the requisite expertise in oncology, 
hepatology, immunology, and outcomes research. There is guidance available from the 
updated ASCO provisional clinical opinion (PCO) on HBV screening and management prior 
to cancer therapy (46).  This PCO was intended to provide oncology teams with practical 
guidance for immediate use, but the recommendations were written with soft language 
regarding treatment details for chronic (as well as past) HBV patients with a solid 
tumor.  This is because for both chronic and past HBV, the evidence about the treatment 
details is weak and thus recommendations could only be based on informal consensus.  As 
noted in the Future Directions part of the PCO, large, randomized trials are needed to better 
understand the issue of HBV reactivation, especially for patients with a solid tumor.  A key 
step forward is to conduct this trial and ultimately reveal the evidence-based best practice 
for these patients at risk for HBV reactivation. 
  
This project will harness synergistic multidisciplinary collaborations to benefit patients with 
solid tumors and HBV infection. The results of this project can be used even beyond HBV 
to open new horizons of research on personalized prevention of severe sequelae from anti-
cancer therapy for patients with cancer and other oncogenic viruses. 
 
A priority of the NCORP is to “increase the knowledge base through the conduct of 
research as part of cancer control clinical trials focusing on identifying effective treatments 
for toxicities, side effects, and symptoms arising from cancer and its treatments and to 
discover mechanisms of action whereby interventions are effectively treating symptoms, 
toxicities, and side effects.” (47) Although this protocol does not fit in one of the 9 priority 
areas identified by the NCI Symptom Control and Quality of Life (SXQOL) committee, this 
therapeutic trial is focused on preventing adverse liver outcomes as a toxicity of systemic 
cancer treatment, and it is important for patients across the United States and worldwide 
who are facing cancer in the context of chronic or past HBV infection. This trial is poised to 
define the evidence-based standard of cancer control care for patients with solid tumors 
and HBV infection receiving anti-cancer therapy, and it will also provide key mechanistic 
information through the conduct of complementary translational studies. 
 
This trial is expected to determine whether patients with solid tumors and HBV infection 
should start prophylactic anti-HBV medication before anti-cancer therapy or be monitored 
and have anti-HBV therapy started only if necessary. The trial will also identify immune 
mechanisms of HBV reactivation and provide strong evidence regarding predictors of HBV 
reactivation. This will allow the development of personalized approaches to prevent HBV 
reactivation due to anti-cancer therapy. 
 
2.2 
Inclusion of Women and Minorities 
 
This study was designed to include women and minorities, but was not designed to 
measure differences of intervention effects.  The anticipated accrual in the ethnicity/race 
and sex categories is shown in the table below.  
 
DOMESTIC PLANNED ENROLLMENT REPORT 
Racial Categories 
Ethnic Categories 
Total 
Not Hispanic or 
Latino 
Hispanic or Latino 
Female 
Male 
Female 
Male 
American Indian/ Alaska Native 
1 
1 
1 
1 
4 
Asian 
8 
5 
3 
2 
18 
Native Hawaiian or Other 
Pacific Islander 
1 
1 
1 
1 
4 
Black or African American 
40 
23 
13 
8 
84 
White 
154 
89 
50 
28 
321 
More Than One Race 
6 
4 
2 
1 
13 


 
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Total 
210 
123 
70 
41 
444 
 
 
3.0 
DRUG INFORMATION 
 
Investigator Brochures 
 
For information regarding Investigator Brochures, please refer to SWOG Policy 15. 
 
For this study, Tenofovir alafenamide (TAF), Tenofovir disoproxil Fumarate (TDF), and Entecavir 
(ETV), are commercially available; therefore, Investigator Brochures are not applicable to this drug.  
Information about commercial drugs is publicly available in the prescribing information and other 
resources. 
 
Black Box Warnings: TAF, TDF, and ETV share a warning indicting severe acute exacerbations of 
HBV have been reported in HBV-infected patients who have discontinued anti-hepatitis B therapy. 
Hepatic function should be monitored closely in HBV-infected patients who discontinue therapy. 
Resumption of anti-hepatitis B therapy may be warranted, as clinically appropriate. 
 
3.1 
Entecavir (ETV)  
 
a. 
PHARMACOLOGY 
 
Mechanism of Action:  
 
Entecavir is a guanosine nucleoside analogue. The phosphorylated active form 
inhibits the activity of hepatitis B virus (HBV) polymerase in base priming, reverse 
transcription of the negative strand pregenomic messenger RNA, and synthesis of 
the positive strand of HBV DNA.  
 
b. 
PHARMACOKINETICS 
 
1. 
Absorption:  
 
The peak plasma concentration (Cmax) of entecavir is achieved in 0.5 to 
1.5 hours at doses ranging between 0.1 and 1 mg, and the steady state is 
achieved in 6 to 10 days. Both Cmax and area under the concentration-
time curve (AUC) at steady state increases proportionally to increasing 
doses of entecavir. The oral tablet and the oral solution have a 
bioavailability ratio of 1:1 and may be used interchangeably. 
 
Co-administration of entecavir with food has been shown to delay 
absorption, decrease Cmax by 44 to 46%, and decrease AUC by 18 to 
20%. Entecavir should be administered at least 2 hours before or after a 
meal. 
 
2. 
Distribution:  
 
Pharmacokinetic studies have shown that entecavir distributes extensively 
into tissues and have an approximate protein binding of 13%. 
 
3. 
Metabolism:  
 
Entecavir is not metabolized by the cytochrome P450 enzymes, and it 
does not inhibit or induce the P450 enzymes. 
 


 
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4. 
Elimination:  
 
Entecavir is mainly eliminated by the kidneys as 62 to 73% unchanged 
drug through glomerular filtration and net tubular secretion. The half-life of 
entecavir is approximately 128 to 149 hours, and the renal clearance 
ranges between 360 to 471 mL/min. 
 
c. 
ADVERSE EFFECTS  
 
1. 
Possible Side Effects of Entecavir: 
 
Refer to the current FDA-approved package insert for the most 
comprehensive and up to date information on adverse reactions. 
 
Adverse effects reported in > 10% of subjects treated with entecavir 
include elevated alanine aminotransferases.  
Adverse effects reported in 1% to 10% of subjects include: headache, 
fatigue, skin rash, hematuria, glycosuria, hyperglycemia, abdominal pain, 
nausea, vomiting, diarrhea, unpleasant taste, elevated serum lipase, 
bilirubin, and creatinine. 
Serious adverse effects reported in < 1% of subjects include: 
anaphylactoid shock, hepatomegaly with steatosis, lactic acidosis, 
macular edema, and thrombocytopenia. 
 
2. 
Pregnancy and Lactation: 
 
There is insufficient data from human studies to adequately assess the 
risk of using entecavir during pregnancy (including the risks of birth 
defects, miscarriage or adverse maternal or fetal outcomes). Animal 
studies in rats and rabbits have shown evidence of embryofetal toxicity 
and maternal toxicity at doses above the maximum recommended human 
dose. The use of entecavir should be avoided in pregnant women, as there 
are other agents available. For those who are pregnant and have been 
exposed to entecavir, a pregnancy registration is available to monitor fetal 
outcomes.  
 
Entecavir has been found in the milk of rats, but its presence is unknown 
in human milk. Breast-feeding mothers should avoid taking entecavir. 
 
3. 
Drug Interactions:  
 
Coadministration of ETV with drugs that reduce renal function or compete 
for active tubular secretion may alter the pharmacokinetic or 
pharmacodynamics properties of ETV. See Section 7.1 for details. 
 
d. 
DOSING & ADMINISTRATION 
 
See Section 7.0 Treatment Plan 
 
e. 
HOW SUPPLIED 
 
Entecavir is commercially available and will not be supplied. Refer to the current 
FDA-approved package insert for the most comprehensive and up to date 
information. 
 
3.2 
Tenofovir alafenamide (TAF) 
 


 
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a. 
PHARMACOLOGY 
 
Mechanism of Action: Tenofovir alafenamide (TAF) is an antiviral drug against the 
hepatitis B virus. It is a phosphonamidite prodrug that is converted intracellularly 
by hydrolysis to tenofovir, and then phosphorylated into active tenofovir 
diphosphate. The active moiety inhibits replication of hepatitis B virus (HBV) by 
incorporating into the viral DNA by HBV reverse transcriptase, thus resulting in 
DNA chain termination. 
 
b. 
PHARMACOKINETICS 
 
1. 
Absorption: There is an increased systemic exposure when taking with 
food.  After administration of tenofovir alafenamide with a high-fat meal 
(800 kcal, 50% fat), mean AUC increased by 65% (range 51 to 81%).  
 
2. 
Distribution: TAF is 80% bound to plasma proteins. 
 
3. 
Metabolism: TAF is extensively metabolized in the liver, primarily by 
carboxyesterase 1 and minimally by CYP3A. TAF is metabolized by 
cathepsin A in peripheral blood mononuclear cells.  Over 80% of TAF is 
metabolized to tenofovir, the active major metabolite. 
 
4. 
Elimination: Kidney (Less than 1%); Feces (31.7%); Elimination Half-life 
(0.51 hours). 
 
c. 
ADVERSE EFFECTS  
 
1. 
Possible Side Effects of tenofovir alafenamide (TAF): 
 
Refer to the current FDA-approved package insert for the most 
comprehensive and up to date information on adverse reactions. 
 
Adverse effects reported in 1% to 10% of subjects treated with TAF include 
the following: 
CNS: headache (9%), fatigue (6%) 
Endocrine & metabolic: increased LDL cholesterol (4%), glycosuria, 
increased amylase 
Gastrointestinal: abdominal pain (7%), nausea (5%) 
Hepatic: increased serum ALT, increase serum AST 
Neuromuscular & skeletal: decrease bone mineral density (3% to 6%), 
back pain (5%), increased serum creatine phosphokinase 
Respiratory: cough (6%) 
 
 
2. 
Pregnancy and Lactation: There are no human data on the use of tenofovir 
alafenamide (TAF) in pregnant women to inform drug-associated risks of 
adverse fetal developmental outcome. The background risk of major birth 
defects and miscarriage for the indicated population is unknown.   
 
It is not known whether TAF and its metabolites are present in human 
breast milk, affect human milk production, or have effects on the breastfed 
infant.  
 
The developmental and health benefits of breastfeeding should be 
considered along with the mother’s clinical need for TAF and any potential 
adverse effects on the breastfed infant from TAF or from the underlying 
maternal condition. 


 
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Drug Interactions:  
Concomitant administration of TAF with carbamazepine, oxcarbazepine, 
phenobarbital, phenytoin, rifabutin, rifampin, rifapentine, St. John’s Wort, 
and inducers or inhibitors of P-gp may alter the pharmacokinetic or 
pharmacodynamics properties of TAF. Coadministration of TAF with drugs 
that reduce renal function or compete for active tubular secretion may also  
alter the pharmacokinetic or pharmacodynamics properties of TAF See 
Section 7.1 for details. 
 
d. 
DOSING & ADMINISTRATION 
 
See Section 7.0 Treatment Plan 
 
TAF has oral route of administration, intended to be taken as a whole tablet.  
 
e. 
HOW SUPPLIED 
 
TAF is commercially available and will not be supplied. Refer to the current FDA-
approved package insert for the most comprehensive and up to date information.  
 
3.3 
Tenofovir disoproxil fumarate (TDF) 
 
a. 
PHARMACOLOGY 
 
Mechanism of Action: tenofovir disoproxil fumarate (TDF) is a reverse 
transcriptase inhibitor and an analog of adenosine 5'-monophosphate. TDF first 
undergoes hydrolytic conversion to tenofovir and then subsequent phosphorylation 
to its active form, tenofovir diphosphate (TFV-DP). TFV-DP inhibits the activity of 
hepatitis B virus reverse transcriptase (HBV RT) by competing with the natural 
substrate deoxyadenosine 5'-triphosphate and acting as an obligate DNA chain 
terminator. HBV viral replication is thereby inhibited. TFV-DP also inhibits human 
immunodeficiency virus type 1 (HIV-1) reverse transcriptase.   
 
b. 
PHARMACOKINETICS 
 
1. 
Absorption: In the fasted state, the bioavailability of TDF is approximately 
25% and Cmax occurs approximately 1 hour after administration. Addition 
of a high-fat meal increases AUC by approximately 40%, and food delays 
Cmax by approximately 1 hour. However, these effects have not been 
deemed to be clinically significant and doses may be given with or without 
food.  
 
2. 
Distribution: Tenofovir binds to less than 7.2% of serum proteins. Volume 
of distribution is 1.2 to 1.3 L/kg.  
 
3. 
Metabolism: TDF is converted intracellularly by hydrolysis to tenofovir, 
which is then phosphorylated to active tenofovir diphosphate. Neither TDF 
nor tenofovir are substrates of CYP enzymes. 
 
4. 
Elimination: TDF is eliminated by a combination of glomerular filtration and 
active tubular secretion, with 32% excreted as unchanged drug after oral 
administration. The terminal elimination half-life of tenofovir is 
approximately 17 hours. 
 
c. 
ADVERSE EFFECTS  
 


 
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1. 
Possible side effects of tenofovir disoproxil fumarate: 
 
Refer to the current FDA-approved package insert for the most 
comprehensive and up to date information on adverse reactions. 
 
Adverse effects reported in > 20% of subjects treated with TDF include: 
hypercholesterolemia, abdominal pain, nausea, decreased bone mineral 
density 
 
Adverse effects reported in 4% to 20% of subjects include: insomnia, 
headache, pain, back pain, arthralgia, myalgia, dizziness, depression, 
anxiety, skin rash, pruritus, diarrhea, flatulence, vomiting, increased 
creatine phosphokinase, increased serum ALT/AST, increased serum 
amylase, increased serum creatinine, renal failure, fever, fatigue, 
peripheral neuropathy, sinusitis, upper respiratory tract infections 
 
Serious adverse effects reported in ≤ 3% of subjects include: bone loss 
and mineralization defects, lactic acidosis, immune reconstitution 
syndrome, new onset or worsening renal impairment, and severe 
hepatomegaly with steatosis 
 
2. 
Pregnancy and Lactation:  
 
Tenofovir has a high level of transfer across the human placenta. 
However, data from the Antiretroviral Pregnancy Registry (APR) have not 
shown an increase in the incidence of birth defects in pregnancies 
exposed to TDF (across all trimesters) compared with the incidence in the 
general U.S. population; the APR does not report the rate of miscarriage. 
Published studies have not demonstrated an increased risk of adverse 
pregnancy related outcomes.  
 
Tenofovir has been shown to be present in human breast milk. In a study 
of 50 breastfeeding women taking tenofovir post-partum, tenofovir was 
undetectable in the plasma of most infants after 7 days of treatment in 
mothers. No serious adverse events were observed in mothers or infants.  
 
Use in these populations is not contradicted, but clinical risk versus benefit 
for mother and infant should be considered.  
 
3. 
Drug Interactions:  
 
Coadministration of TDF with P-gp inhibitors or inducers may alter the 
pharmacokinetic 
or 
pharmacodynamics 
properties 
of 
TDF. 
Coadministration of TDF with drugs that reduce renal function or compete 
for active tubular secretion may also alter the pharmacokinetic or 
pharmacodynamics properties of TDF. See Section 7.1 for details. 
 
d. 
DOSING & ADMINISTRATION 
 
See Section 7.0 Treatment Plan 
 
e. 
HOW SUPPLIED 
 


 
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Tenofovir disoproxil fumarate is commercially available and will not be supplied. 
Refer to the current FDA-approved package insert for the most comprehensive 
and up to date information. 
 
 
4.0 
STAGING CRITERIA 
 
Patients must have Stage I-III disease (AJCC 8TH EDITION, 2017). 
 
 
5.0 
ELIGIBILITY CRITERIA 
 
Each of the criteria in the following section must be met in order for a participant to be considered 
eligible for registration in OPEN.  Section 5 may be printed and used to by the site, but is not to be 
uploaded in RAVE (unless specially stated). For each criterion requiring test results and dates, 
please record this information on the Onstudy Form and submit via Medidata Rave® (see Section 
14.0).  Any potential eligibility issues should be addressed to the SWOG SDMC in Seattle at 
206/652-2267 or cancercontrolquestion@crab.org prior to registration. NCI policy does not allow 
for 
waiver 
of 
any 
eligibility 
criterion 
(http://ctep.cancer.gov/protocolDevelopment/policies_deviations.htm). 
 
In calculating days of tests and measurements, the day a test or measurement is done is 
considered Day 0.  Therefore, if a test is done on a Monday, the Monday 4 weeks later would be 
considered Day 28.  This allows for efficient participant scheduling without exceeding the 
guidelines.  If Day 28 falls on a weekend or holiday, the limit may be extended to the next 
working day.  
 
5.1 
Disease Related Criteria 
 
a. 
Patients must be diagnosed with Stage I-III solid tumor malignancy. Patients with 
only carcinoma in situ or with Stage IV disease are excluded.  
 
b. 
Patients must not have lymphoma, leukemia, or myeloma.  
 
c. 
Patients must not have primary liver cancer, known cirrhosis, or evidence of any 
malignancy that involves the liver.   
 
5.2 
Prior/Concurrent Therapy Criteria 
 
a. 
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. 
 
b. 
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. 
 
c. 
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. 
 
d. 
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. 
 
e. 
Patients must not have had any cancer therapy regimen that includes anti-CD20. 
 


 
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f. 
Patients must not be receiving antiviral medications active against HBV, including: 
adefovir, entecavir, lamivudine, telbivudine, tenofovir disoproxil fumarate, tenofovir 
alafenamide (TAF), or any other 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. 
 
g. 
Patients must not have had hematopoietic stem cell transplantation therapy. 
 
h. 
Patients must not be taking or planning to take warfarin.  
 
i. 
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.   
 
NOTE: Patients taking or planning to take the above listed concomitant 
medications may be treated with ETV or TDF (instead of TAF).  
 
j. 
Patients who will be treated with TAF and are concomitantly taking or plan to take  
carbamazepine must be given an increased dose of TAF (see Section 7.1) or 
alternatively be given ETV or TDF.  
 
5.3 
Clinical/Laboratory Criteria 
 
a. 
Patients must have results for the following HBV tests done within 28 days prior to 
registration: HBsAg AND anti-HBc (total Ig or IgG, but not IgM only) AND anti-HBs. 
For the anti-HBs test, quantitative or qualitative (including “indeterminate”) results 
are allowable. Refer to Appendix 18.2 for viral status information. 
 
b. 
Patients must have tested positive for HBsAg or anti-HBc (total Ig, IgG, but not 
IgM) and must have baseline HBV DNA completed ≤ 42 days prior to registration. 
See Appendix 18.2 for viral status information. 
 
c. 
Complete blood count (CBC) must be completed ≤ 28 days prior to registration. 
Results do not need to be in the institutional limits of normal. 
 
d. 
International Normalized Ratio (INR) must be completed ≤ 28 days prior to 
registration. Results must <1.2x institutional limits of normal. 
 
e. 
ALT and total bilirubin results must be obtained ≤ 28 days prior to registration. ALT 
and total bilirubin must be < 1.5x institutional ULN.  
 
f. 
Patients must have a baseline calculated creatinine clearance within 28 days prior 
to registration.  
 
NOTE: Patients with reduced creatinine clearance may need a reduced dose of an 
antiviral drug (see details in Dose Modifications, Section 8.2).  
 
g. 
Patients must not have known current active hepatitis C infection (HCV). Active 
HCV is defined by a detectable HCV RNA level. Note: HCV testing is not required 
for eligibility. 
 
h. 
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.  
 
i. 
Patients must have Zubrod performance status of 0-2. 


 
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j. 
Patients must be at least 18 years old. 
 
k. 
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. 
 
5.4 
Specimen Submission Criteria 
 
a. 
Patients must have specimens collected for submission as outlined in Section 
15.1. 
 
b. 
Patients must be offered the opportunity to participate in optional translational 
medicine studies as outlined in Section 15.2. 
 
5.5 
Regulatory Criteria 
 
a. 
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). 
 
b. 
Patients may have concurrent participation in other clinical trials that entail 
cytotoxic, immunotherapy, targeted therapy; surgical treatment; radiotherapy 
treatment; or any combination thereof. 
 
c. 
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. 
 
d. 
As a part of the OPEN registration process (see Section 13.3 for OPEN access 
instructions) 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. 
 
 
6.0 
STRATIFICATION FACTORS 
 
6.1 
Cohort 1: Chronic HBV cohort  
 
Patients with chronic HBV will be randomized between Arm 1 (prophylactic anti-HBV 
therapy) or Arm 2 (upon indication anti-HBV therapy) using a dynamic allocation 
scheme.  Patient randomization to the two treatment arms will be balanced on:  
 
• 
Planned cancer therapy type: cytotoxic (with or without immunotherapy or targeted 
therapy) vs. immunotherapy alone vs. targeted therapy alone vs. immunotherapy 
and targeted therapy. 
 


 
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6.2 
Cohort 2: Past HBV cohort  
 
Patients with past HBV will be randomized between or Arm 3 (upon indication anti-HBV 
therapy) or Arm 4 (usual care) using a dynamic allocation scheme.  Patient randomization 
to the two treatment arms will be balanced on: 
 
• 
Planned cancer therapy type: cytotoxic (with or without immunotherapy or targeted 
therapy) vs. immunotherapy alone vs. targeted therapy alone vs. immunotherapy 
and targeted therapy. 
• 
Anti-HBV status: positive vs. negative. 
 
 
7.0 
TREATMENT PLAN 
 
For treatment or dose modification questions, please contact Jessica Hwang, M.D., M.P.H., Phone: 
713/745-4516, E-mail: jphwang@mdanderson.org or Anna Lok, M.D., Phone: 734-936-7511 or E-
mail:  aslok@med.umich.edu. For dosing principles or questions, please consult the SWOG Policy 
#38 "Dosing Principles for Patients on Clinical Trials" at http://swog.org (then click on "Policies & 
Procedures " under the "About" menu and choose Policy 38). 
 
7.1 
General Treatment Information 
a. 
Concomitant Medications 
 
Concomitant medications must be assessed prior to initiation of antiviral therapy 
in Arm 1 (prophylaxis) or if initiated if HBV reactivation occurs (upon indication) in 
Arms 2 and 3.  
 
Refer to the current FDA-approved package insert for the most comprehensive 
and up to date information on concomitant medications. 
 
TAF: 
Concomitant administration of oxcarbazepine, phenobarbital, phenytoin, 
rifabutin, rifampin, rifapentine, or St. John’s Wort is not recommended. If 
co-administered with carbamazepine, TAF dose should be increased to 
two tablets once daily. Alternatively, if the above medications cannot be 
stopped, then study patients may take TDF or ETV.  
 
TDF:  
none  
 
ETV:  
none 
 
If possible, avoid use of warfarin. If medically necessary, warfarin may be used 
during protocol participation after enrollment. For patients who need to take 
warfarin, monitor INR per Section 9. If the patient has an INR increase, the treating 
investigator should review to determine if the cause is due to warfarin, study 
treatment, or acute liver injury. If INR increase is due to acute liver injury, and the 
increased INR is accompanied by AST, ALT, and bilirubin increase, evaluate the 
cause per Section 9. Document this determination in the patient’s chart.   
 
b. 
Guidance for Offsite and Virtual Options during the Conduct of the Trial 
1. 
Laboratory assessments and specimen collections: All laboratory 
assessments and specimen collections must be completed at protocol-
specified timepoints (see Section 9.0).  
 
2. 
Conducting labs at an offsite facility: In order to provide participating 
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allow for laboratory assessments to be drawn and resulted by local 
healthcare providers (with appropriate oversight by the Responsible 
Investigator [local treating investigator]), where administration of the 
assessment at an off-site facility is in the best interest of the patient and 
provides for continuity of patient care. Utilization of offsite / local healthcare 
resources for conduct of patient’s laboratory assessments must be 
documented including procedures for oversight (by the Responsible 
Investigator) of assessments performed offsite. 
3. 
Assessments via virtual methods: The following assessments may be 
performed by a research RN, CRA, Advanced Practice Provider (APP), or 
physician. The assessments may be conducted virtually via phone or 
videoconferencing: 
• 
HBV Assessment 
o 
Obtain the HBV assessment in person, over the phone, 
or videoconference with the patient and document on the 
HBV Assessment Form (Section 14.4) 
• 
Toxicity Notation (AE Assessment) 
o 
Obtain the AE assessment in person, over the phone, or 
videoconference with the patient and document on the 
Anti-Viral Adverse Event Form (Section 14.4) 
• 
Review of Intake Calendar  
o 
Patient may be instructed to submit Intake Calendar 
electronically per site institutional standards.  
 
7.2 
Cohort 1 - Chronic HBV Anti-Viral Treatment 
 
a. 
Arm 1: Prophylactic Anti-Viral Therapy 
 
The treating investigator and patient will choose the appropriate anti-viral therapy 
from one of the three anti-viral therapies below.  Patients may initiate anti-viral 
therapy with a reduced dose based on creatinine clearance (see Dose 
Modifications, Section 8.2) 
 
Start anti-HBV treatment before anti-cancer therapy or up to 42 days after initial 
anti-cancer therapy. Continue anti-HBV treatment for 6 months after last dose of 
anti-cancer therapy or for up to 24 months after registration, whichever occurs first.  
 
Agent 
Dose 
Route 
Start Day 
Schedule 
 
Tenofovir alafenamide 
25 mgA 
POB 
As soon as 
Daily for up to 
(TAF) 
 
 
possible after  
6 months after 
 
 
 
registration;  
the last dose 
 
 
 
before or up 
of anti-cancer 
 
 
 
to 42 days after 
therapy or  
 
 
 
initial dose of  
maximum of 
 
 
 
anti-cancer  
24 monthsC 
 
 
 
therapy 
 
Tenofovir disoproxil  
300mg PO  
As soon as  
Daily for up to 
fumarate  (TDF) 
 
 
possible after  
6 months after 
 
 
  
registration; before the last dose 
 
 
  
or up to 42 days  
of anti-cancer 
                                       
 
   
after initial dose 
therapy or 
of anti-cancer  
Maximum of 
 
 
 
therapy   
 24 months 
 


 
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Entecavir  
0.5mg 
 
As soon as  
Daily for up to  
(ETV) 
 
 
possible after 
6 months after 
 
 
    
registration; before  the last dose  
 
 
   
or up to 42 days 
 of anti-cancer 
                                       
 
    
after initial dose of therapy or 
           
  
   
anti-cancer 
Maximum of 24 
 
 
 
therapy. 
months.  
 
A In patients taking carbamazepine the TAF dose will be increased to 50 mg daily. 
B  See dosage administration details in Section 3.1d.  
C  Note: Chronic HBV patients should not abruptly stop antiviral therapy after 24 
months.  Please see Section 8.2 for details on cessation of anti-HBV therapy in 
chronic HBV patients.  
 
b. 
Arm 2: Upon Indication Anti-Viral Therapy  
 
The treating investigator and patient will choose the appropriate anti-viral therapy 
from one of the three anti-viral therapies below. Patients may initiate anti-viral 
therapy with a reduced dose based on creatinine clearance (see Dose 
Modifications, Section 8.2). 
 
Monitor ALT at least every 4 weeks (+/- 2 weeks) as part of trial monitoring for the 
first 24 weeks, then every 8 weeks thereafter. If hepatitis flare occurs (see 
definition for hepatitis flare in Section 10.2b), then obtain an HBV DNA test per 
usual care. Start anti-HBV therapy if HBV reactivation occurs.  
 
 
Agent 
Dose 
Route 
Start Day 
Schedule 
 
Tenofovir alafenamide 
25 mg A 
PO B 
As soon as 
Daily for up to 
(TAF) 
 
 
possible after  
6 months after 
 
 
 
HBV reactivation 
the last dose 
 
 
 
occurs (see  
of anti-cancer 
 
 
 
criteria for HBV 
therapy or a 
 
 
 
reactivation 
maximum of  
 
 
 
Section 10.2a). 
24 months C. 
 
Tenofovir disoproxil  
fumarate  
300mg  
 PO        As soon as  
Daily for up to 
(TDF) 
 
             possible after  
6 months after 
 
 
             HBV reactivation 
the last dose 
 
 
             occurs ( see   
of anti-cancer 
                                       
 
             criteria for HBV 
therapy or 
           
  
             reactivation  . 
Maximum of 
 
 
             Section 10.2a 
24 months 
 
Entecavir     
0.5mg  
PO                    
 
            
 
 
           As soon as  
Daily for up to  
(ETV) 
 
           possible after 
6 months after 
 
 
            HBV reactivation 
 the last dose  
 
 
            occurs (see 
 of anti-cancer 
                                       
 
            criteria for HBV 
therapy or 
           
  
            reactivation . 
Maximum of 24 
 
 
           Section 10.2a 
months.  
   
 
A In patients taking carbamazepine the TAF dose will be increased to 50 mg daily. 


 
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B  See dosage administration details in Section 3.1d.  
C  Note: Chronic HBV patients should not abruptly stop antiviral therapy after 24 
months.  Please see Section 8.2 for details on cessation of anti-HBV therapy in 
chronic HBV patients.  
 
Anti-HBV therapy is initiated only when HBV reactivation. Once started, anti-HBV 
therapy continues for a minimum of 6 months after discontinuation of all anti-
cancer therapy or for up to 24 months after registration, whichever comes first. 
 
7.3 
Cohort 2: Past HBV Anti-Viral Treatment  
 
a. 
Arm 3: Upon Indication Anti-Viral Therapy 
 
The treating investigator and patient will choose the appropriate anti-viral therapy 
from one of the three anti-viral therapies below. Patients may initiate anti-viral 
therapy with a reduced dose based on creatinine clearance (see Dose 
Modifications, Section 8.2). 
 
Monitor ALT at least every 4 weeks (+/- 2 weeks) as part of trial monitoring for the 
first 24 weeks, then every 8 weeks thereafter. If hepatitis flare occurs (see 
definition for hepatitis flare in Section 10.2b), then obtain HBV DNA test per usual 
care. Start anti-HBV therapy if HBV reactivation occurs.  
 
 


 
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Agent 
Dose 
Route Start Day 
Schedule 
 
 
Tenofovir alafenamide 
25 mg A 
PO B 
As soon as 
Daily for up to 
(TAF) 
 
 
possible after  
6 months after 
 
 
 
HBV reactivation 
the last dose 
 
 
 
occurs (see  
of anti-cancer 
 
 
 
criteria for HBV 
therapy or a 
 
 
 
reactivation 
maximum of  
 
 
 
Section 10.2a). 
24 months C. 
 
Tenofovir disoproxil  
fumarate  
300mg  
 PO   
As soon as  
Daily for up to 
(TDF) 
 
    
possible after  
6 months after 
 
 
         
HBV reactivation 
the last dose 
 
 
          
occurs (see  
of anti-cancer 
                                       
 
          
criteria for HBV 
therapy or 
           
  
       
reactivation. 
Maximum of 
 
 
             Section 10.2a 
24 months 
 
 
 
Entecavir     
0.5mg  
PO  
As soon as  
Daily for up to  
(ETV) 
 
 
possible after 
6 months after 
 
 
 
HBV reactivation 
 the last dose  
 
 
  
occurs (see 
 of anti-cancer 
                                       
 
    
criteria for HBV 
therapy or 
           
  
 
reactivation. 
Maximum of 24 
 
 
   
Section 10.2a 
months.  
 
 
A In patients taking carbamazepine the TAF dose will be increased to 50 mg daily. 
B See dosage administration details in Section 3.1d.  
 
Anti-HBV therapy is initiated only when HBV reactivation. Once started, anti-HBV 
therapy continues for a minimum of 6 months after discontinuation of all anti-
cancer therapy or for up to 24 months after registration, whichever comes first. 
 
b. 
Arm 4: Usual Care Anti-Viral Therapy 
 
Initiate anti-HBV therapy at the discretion of the physician. Any FDA approved anti-
viral medication for treatment of HBV may be utilized. See Section 18.5. 
 
7.4 
HBV Monitoring and Adverse Liver Outcomes 
 
During anti-cancer therapy and for 24 months from initial registration, all patients will 
undergo monitoring for HBV reactivation and adverse liver outcomes (see Section 10.0). 
Patients will have ALT and total bilirubin assessed every 4 weeks (± 2 weeks) for the first 
24 weeks, then every 8 weeks thereafter. Per usual care, if total bilirubin > 3 mg/dL or if 
ALT > 5x IULN or > 200 U/L then INR will be assessed. 
 
As part of adverse liver outcome assessment, if a hepatitis flare occurs (defined as ALT > 
3 x baseline and > 100 U/L) the following labs should be ordered on the same day as the 
flare or within 7 days of the flare:  
• 
direct bilirubin,  
• 
HBV DNA,  
• 
IgM anti-HAV, and  
• 
either anti-HCV or HCV RNA.  


 
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• 
Patients on Arms 1, and 2 must have HBeAg tested. HBV test results must be 
reported on the S1614 Laboratory Values Form. 
• 
If Patients on Arms 3 and 4 become HBsAg positive and have a hepatitis flare, HBeAg 
testing is required. HBV test results must be reported on the S1614 Laboratory Values 
Form. 
 
Additionally, for all HBsAg+ patients, it is recommended that the treating investigator 
contact Dr. Jessica Hwang, M.D., Dr. Anna Lok, M.D., or Dr. Jordan Feld at 
cancercontrolquestion@crab.org for evaluation during the study treatment and after 
discontinuation of study treatment to ensure continued monitoring and to determine 
whether antiviral therapy should be maintained after discontinuation of study treatment. 
 
7.5 
Drug Compliance Documentation 
 
Drug compliance will be recorded by patients in the Intake Calendar (see Appendix 18.3). 
Institutional CRAs will review and ascertain patient adherence with protocol therapy at the 
end of treatment.  Calendar should be kept in the patient's research chart. Sites utilizing 
the CIRB must use the Intake Calendar provided.  Sites not utilizing the CIRB may utilize 
institutional pill diaries or other source documentation in place of the Intake Calendar at 
the discretion of the treating physician. 
 
7.6 
Criteria for Removal from Protocol Treatment 
 
a. 
Completion of 24 months on study. 
 
b. 
If receiving anti-viral treatment, completion of anti-viral treatment 6 months after 
discontinuing all anti-cancer therapy or for up to 24 months after registration, 
whichever comes first. 
 
c. 
Cumulative delay of anti-viral treatment > 30 days for any reason. 
 
d. 
Unacceptable toxicity to anti-viral treatment. (See Section 8.2) 
 
e. 
The patient may withdraw from the study at any time for any reason. If the patient 
allows for indirect follow-up or is refusing to complete any further patient forms but 
will allow the site to follow them indirectly, continue to submit the site-completed 
forms through Week 104. 
 
7.7 
Discontinuation of Treatment 
 
All reasons for discontinuation of treatment must be documented in the Off Anti-Viral 
Protocol Treatment Notice. 
 
7.8 
Follow-Up Period 
 
All patients will be followed until death or 24 months after registration, whichever occurs 
first. No further follow-up will be required once the patient completes 104 weeks (2 years) 
of protocol participation. Patients should continue to have their protocol-scheduled 
assessments until one of the outlined criteria for removal listed in Section 7.6 has been 
met. 
 
 
 


 
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8.0 
TOXICITIES TO BE MONITORED AND DOSE MODIFICATIONS 
 
8.1 
NCI Common Terminology Criteria for Adverse Events 
 
This study will utilize the CTCAE (NCI Common Terminology Criteria for Adverse Events) 
Version 5.0 for toxicity and Serious Adverse Event reporting.  A copy of the CTCAE Version 
5.0 can be downloaded from the CTEP home page (http://ctep.cancer.gov).  All appropriate 
treatment areas should have access to a copy of the CTCAE Version 5.0. 
 
8.2 
Dose Modifications 
General Considerations: 
For a more comprehensive list of managing toxicities or management see package insert. 
Treatment and dose modifications are at the discretion of the treating investigator. 
Unacceptable (Grade 3 or greater) and related toxicity necessitating removal from protocol 
treatment is expected to be rare. Cause of all ≥ Grade 3 toxicity should be investigated and 
changes to protocol treatment made only if toxicity deemed to be related (definite, probable 
or possible). Antiviral should not be stopped as withdrawal of antiviral may precipitate flare 
of hepatitis. Instead, patient should be switched to another antiviral that is not associated 
with that toxicity. 
 
Acute kidney injury has only been reported for TDF. If deemed to be related to TDF, then 
stop TDF and switch to TAF or ETV.  
 
Lactic acidosis is considered a class effect although data associating it with TDF or TAF 
are lacking. If deemed to be related, then stop the drug, monitor closely, and when 
resolved, switch to an alternate antiviral. (48)   
 
Exacerbation of hepatitis associated with discontinuation of antiviral is not related to the 
antiviral drug itself. This is not applicable to this oncology population where antiviral therapy 
discontinuation is not expected during anticancer therapy. 
TAF-treated patients: 
No dosage adjustment of tenofovir alafenamide (TAF) is required in patients with renal 
impairment with a creatinine clearance >15 ml/min. Patients with a creatinine clearance 
<15 ml/min who are receiving hemodialysis may take the usual dose of TAF (25 mg) on 
days of dialysis after completion of hemodialysis treatment. TAF is not recommended for 
patients with creatinine clearance <15 ml/min who are not receiving hemodialysis.  
 
If a study patient develops creatinine clearance below 15 mL/minute during study 
participation and is not receiving hemodialysis, then TAF will be discontinued with 
substitution with an appropriate alternative antiviral as described below at the discretion of 
the investigator. 
 
TDF-treated patients: 
 
The following guidelines should be used for dose modification of TDF based on creatinine 
clearance. 
 
Creatinine clearance (mL/min) 
Dose 
>50 
300 mg daily 
30-49 
300 mg every 48 hours 
10-29 
300 mg every 72 to 96 hours 
Hemodialysis 
300 mg every 7 days 
 


 
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ETV-treated patients: 
 
The following guidelines should be used for dose modification of ETV based on creatinine 
clearance. 
 
Creatinine clearance(mL/min) 
Dose 
>50 
0.5 mg daily 
30-50 
0.25 mg daily or 0.5 mg every 48 hours 
10-30 
0.15 mg daily or 0.5 mg every 72 hours 
<10 or hemodialysis or peritoneal dialysis 
0.05 mg daily or 0.5 mg every 7 days 
 
Dose Modification Contacts 
 
For treatment or dose modification questions, please contact Jessica Hwang, M.D., M.P.H., 
Phone: 713/745-4516, E-mail: jphwang@mdanderson.org or Anna Lok, M.D., Phone: 
734/936-7511 or E-mail: aslok@med.umich.edu. 
 
8.3 
Adverse Event Reporting 
 
Toxicities (including suspected reactions) that meet the expedited reporting criteria as 
outlined in Section 16.0 of the protocol must be reported to the Operations Office, Study 
Chair and NCI via CTEP-AERS, and to the IRB per local IRB requirements. 
 


 
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9.0 
STUDY CALENDAR 
 
9.1 
ARM 1: Prophylactic anti-HBV therapy Arm (HBsAg+ Patients) 
REQUIRED STUDIES 
Week 0 
(Registration) 
 
Weeks from Registration  
(± 2 weeks unless otherwise specified) 
Follow-Up 
after 
Off HBV 
Treatment 
(Every 8 
Weeks 
Through 
Week 104) 
at HBV 
Reactivation  
4 
8 
12 
16 
20 
24 
Every  
8 Weeks 
from Week 32 
through Week 
104  
(24 months)  
 
 
PHYSICAL 
History and Physical 
Exam 
X 
 
 
 
HBV Assessment (F) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Toxicity Notation (F) 
X 
X 
X 
X 
X 
X 
X 
 
Review Intake Calendar (F) 
X 
X 
X 
X 
X 
X 
X 
 
LABORATORY 
Serum 
creatinine/Creatinine 
Clearance 
X 
X 
X 
X 
X 
X 
X 
X 
 
Total Bilirubin  
X 
X 
X 
X 
X 
X 
X 
X 
X 
Direct Bilirubin (A) (E) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
ALT 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
International 
Normalized Ratio (INR) 
(A) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Complete Blood Count 
(CBC) 
X 
 
 
 
 
 
 
 
 
 
HBV DNA (B) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
IgM anti-HAV (B) (E) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
anti-HCV (B) (E) or HCV 
RNA (B) (E) 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
HBeAg (B)   
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Calendar 9.1 continued on next page.    Click here for Footnotes 


 
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NOTE: Forms are found on the protocol abstract page on the SWOG website (www.swog.org).  Forms submission guidelines are found in Section 
14.0.  Click here for Footnotes. 
NOTE: Unless indicated otherwise in the protocol, scheduled procedures and assessments (treatment administration, toxicity assessment for 
continuous treatment, disease assessment, specimen collection and follow-up activities) must follow the established SWOG guidelines as outlined 
in SWOG Best Practices, https://www.swog.org/clinical-trials/protocol-workbench. 
FOOTNOTES: 
 
 
 
(A) If total bilirubin > 3 mg/dL, or if ALT > 5 x IULN or > 200 U/L, per usual care (see Section 7.4). 
 
(B)  If hepatitis flare (defined as ALT > 3 x baseline and > 100 U/L). 
 
 
 
 
 
 
 
(C)  See Sections 15.0 and Appendix 18.1. 
 
 
 
 
 
 
 
(D)  See Section 7.2a. 
 
(E) To be ordered the same day (or within 7 days) if hepatitis flare occurs. 
(F) See Section 7.1b.  
 
 
 
 
 
 
 
Allowable Windows 
All visits and procedures must occur within ± 2 weeks of target date (based on date of registration), unless otherwise specified. 
 
 
REQUIRED STUDIES 
Week 0 
(Registration) 
 
Weeks from Registration 
(± 2 weeks unless otherwise specified) 
Follow-Up 
after 
Off HBV 
Treatment 
(Every 8 
Weeks 
Through 
Week 104) 
at HBV 
Reactivation  
4 
8 
12 
16 
20 
24 
Every  
8 Weeks 
from Week 32 
through Week 
104  
(24 months) 
 
 
SPECIMEN SUBMISSION (C) 
Serum (10 ml blood in 
red top tube)  
X 
 
X 
 
X 
X 
X  
 
X 
Whole blood (50 ml in 
EDTA tubes) 
X 
X 
 
 
X 
 
X 
TREATMENT 
Arm 1- Prophylactic 
Anti-HBV Therapy(D) 
X 
X 
X 
X 
X 
X 
X 
X 
 


 
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9.2 
ARM 2 & ARM 3: Upon Indication Arms (HBsAg+ or HBsAg- Patients) 
 
REQUIRED STUDIES 
Week 0 
(Registration) 
 
Weeks from Registration 
(± 2 weeks unless otherwise specified) 
Follow-Up 
after 
Off HBV 
Treatment 
(Every 8 
Weeks 
Through 
Week 104) 
at HBV 
Reactivation  
4 
8 
12 
16 
20 
24 
Every 
8 Weeks 
from Week 32 
through Week 
104 
(24 months) 
PHYSICAL 
History and Physical 
Exam 
X 
 
 
 
HBV Assessment (H) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Toxicity Notation (G) (H) 
X 
X 
X 
X 
X 
X 
X 
 
Review Intake Calendar (G) 
(H) 
X 
X 
X 
X 
X 
X 
X 
 
LABORATORY 
Serum 
creatinine/Creatinine 
Clearance 
X 
X 
X 
X 
X 
X 
X 
X 
 
Total Bilirubin  
X 
X 
X 
X 
X 
X 
X 
X 
X 
Direct Bilirubin (A) (F) 
 
 
 
 
 
 
 
 
 
 
ALT 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
International 
Normalized Ratio(INR)(A) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Complete Blood Count  
X 
 
 
 
 
 
 
 
 
 
HBV DNA (B) (C) (F) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
HBsAg (C) 
Not Indicated in Arm 
2* 
 
 
 
 
 
 
 
 
 
IgM anti-HAV (B) (C) (F) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
anti-HCV (B) (C) (F) or 
HCV RNA (B) (C) (F) 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
Anti-HBs (Arm 3) (B) (C)(F) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
HBeAg (if become 
HBsAg+) (B) (C) (F) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 


 
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REQUIRED STUDIES 
Week 0 
(Registration) 
Weeks from Registration 
(± 2 weeks unless otherwise specified) 
Follow-Up 
after 
Off HBV 
Treatment 
(Every 8 
Weeks 
Through 
Week 104) 
at HBV 
Reactivation  
4 
8 
12 
16 
20 
24 
Every 
8 Weeks 
from Week 32 
through Week 
104 
(24 months)  
 
 
SPECIMEN SUBMISSION (D) 
Serum (10 ml blood in 
red top tube)  
X 
X 
 
X 
X 
X 
 
X 
Whole blood (50 ml in 
EDTA tubes) 
X 
X 
 
 
X 
 
X 
TREATMENT 
Upon-Indication anti-
HBV therapy (E) 
X 
X 
X 
X 
X 
X 
X 
X 
 
NOTE: Forms are found on the protocol abstract page on the SWOG website (www.swog.org).  Forms submission guidelines are found in Section 
14.0. 
 
NOTE: Unless indicated otherwise in the protocol, scheduled procedures and assessments (treatment administration, toxicity assessment for 
continuous treatment, disease assessment, specimen collection and follow-up activities) must follow the established SWOG guidelines as outlined 
in SWOG Best Practices, https://www.swog.org/clinical-trials/protocol-workbench. 
FOOTNOTES for Calendar 9.2: 
 
(A)  If total bilirubin > 3 mg/dL, or if ALT > 5x IULN or > 200 U/L, per usual care (see Section 7.4). 
 
 
 
 
 
 
 
(B)  If hepatitis flare (defined as ALT > 3 x baseline and > 100 U/L) if patient is HBsAg-positive. 
 
 
 
 
 
 
 
(C) If hepatitis flare (defined as ALT > 3 x baseline and > 100 U/L) in patient with baseline HBsAg-negative. 
 
(D)  See Sections 15.0 and Appendix 18.1. 
 
 
 
 
 
 
 
(E)  See Section 7.0 
 
(F) To be ordered the same day (or within 7 days) if hepatitis flare occurs. 
 
(G) If patient initiated anti-viral treatment per protocol. 
(H) See Section 7.1b. 
 
Allowable Windows 
All visits and procedures must occur within ± 2 weeks of target date (based on date of registration), unless otherwise specified. 


 
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9.3 
ARM 4: Usual Care Arm (HBsAg- Patients) 
REQUIRED 
STUDIES 
Week 0 
(Registration) 
 
Weeks from Registration 
(± 2 weeks unless otherwise specified) 
Follow-Up 
after 
Off HBV 
Treatment 
(Every 8 
Weeks 
Through 
Week 104) 
at HBV 
Reactivation  
4 
8 
12 
16 
20 
24 
Every 
8 Weeks 
from Week 32 
through Week 
104 
(24 months)  
 
PHYSICAL 
History and Physical 
Exam 
X 
 
 
 
HBV Assessment (H) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Toxicity Notation (G) 
(H) 
X 
X 
X 
X 
X 
X 
X 
 
Review Intake 
Calendar (G) (H) 
X 
X 
X 
X 
X 
X 
X 
 
LABORATORY 
Serum 
creatinine/Creatinine 
Clearance 
X 
X 
X 
X 
X 
X 
X 
X 
 
Total Bilirubin   
X 
X 
X 
X 
X 
X 
X 
X 
X 
Direct Bilirubin (A) (F) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
ALT 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
International 
Normalized Ratio 
(INR) (A) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Complete Blood 
Count (CBC) 
X 
 
 
 
 
 
 
 
 
 
HBV DNA (B) (C) (F) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
HBsAg (B) (C) (F) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
IgM anti-HAV (B) (C) (F) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
anti-HCV (B) (C) (F) or 
HCV RNA (B) (C) (F) 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
Anti-HBs (B) (C) (F) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
HBeAg (if 
becomeHBsAg+) (B) 
(C) (F) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 


 
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SPECIMEN SUBMISSION (D) 
Serum (10 ml blood 
in red top tube)  
X 
X 
 
X 
X 
X 
 
X 
Whole blood (50 ml 
in EDTA tubes) 
X 
X 
 
 
X 
 
X 
TREATMENT 
Usual HBV Care (E) 
X 
X 
X 
X 
X 
X 
X 
X 
 
NOTE: Forms are found on the protocol abstract page on the SWOG website (www.swog.org).  Forms submission guidelines are found in Section 
14.0. Click here for Footnotes. 
 
NOTE: Unless indicated otherwise in the protocol, scheduled procedures and assessments (treatment administration, toxicity assessment for 
continuous treatment, disease assessment, specimen collection and follow-up activities) must follow the established SWOG guidelines as outlined 
in SWOG Best Practices, https://www.swog.org/clinical-trials/protocol-workbench. 
 
 
FOOTNOTES for Calendar 9.3: 
 
(A)  If total bilirubin > 3 mg/dL, or if ALT > 5x IULN or > 200 U/L, per usual 
care (see Section 7.4). 
 
 
 
 
 
 
(B)  If hepatitis flare (defined as ALT > 3 x baseline and > 100 U/L) if patient is HBsAg-positive. 
 
 
 
 
(C) If hepatitis flare (defined as ALT > 3 x baseline and > 100 U/L) in patient with baseline HBsAg-negative 
(D) See Sections 15.0 and Appendix 18.1 
(E) Treat at discretion of physician. See Section 7.2ba. 
 
(F) To be ordered the same day (or within 7 days) if hepatitis flare occurs 
(G) If patient initiated anti-viral treatment per protocol. 
(H) See Section 7.3b. 
 
Allowable Windows 
 
All visits & procedures must occur within ± 2 weeks of target date (based on date of registration), unless otherwise specified. 
 
 
 
 
 
 


 
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10.0 
CRITERIA FOR EVALUATION AND ENDPOINT ANALYSIS 
 
10.1 
Primary Endpoint 
 
a. 
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 (see Appendix 18.4). 
 
10.2 
Other Endpoints 
 
a. 
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-. 
 
b. 
Hepatitis flare: Hepatitis flare is defined as ALT > 3 x baseline and >100 U/L.  
 
c. 
Upon indication:  On Arms 2 and 3, anti-HBV therapy is initiated only when HBV 
reactivation occurs (see Section 10.2a). Once started, anti-HBV therapy continues 
for a minimum of 6 months after discontinuation of all anti-cancer therapy or for up 
to 24 months after registration, whichever comes first (see Section 7.6). 
 
d. 
Cancer therapy interruption is defined as dose reduction, treatment delay, or 
termination of anti-cancer therapy due to hepatic-related reasons other than 
disease progression in the liver. 
 
e. 
Death due to any cause measured from date of randomization to date of death. 
 
 
11.0 
STATISTICAL CONSIDERATIONS 
 
11.1 
Primary Endpoint 
 
The following design pertains to each of the different study cohorts (chronic HBV [Cohort 
1] and past HBV [Cohort 2]). 
 
The primary endpoint for the clinical study is the time until adverse liver outcome. Patients 
will be assessed every 4 weeks (+/- 2 weeks) for the first 24 weeks, then every 8 weeks 
until 24 months. The study will recruit patients with multiple different cancer types, but 
predominantly lung, breast, colon, prostate, gynecological, and head and neck cancers. 
Since patient prognosis is sufficiently poor to be receiving anti-cancer therapy, dropout due 
to non-liver related death will be a significant factor in the design. One-year overall survival 
is anticipated to be 80% for the combined cohort. Therefore, non-liver related death 
represents a competing risk in the detection of adverse liver outcomes, which is accounted 
for in the study design. Both time to first evidence of adverse liver event and non-liver 
related death are assumed to exhibit exponential decline.  
 
The rate of adverse liver outcomes in this population is not well characterized, as most 
studies in the literature only report on rates of HBV reactivation or hepatitis flares. For 
design purposes, the best estimate of the researchers is that 10% of both chronic (Cohort 
1) and past (Cohort 2) HBV patients will experience an adverse liver outcome within one 


 
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year after registration with standard care. 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=200 participants will give 80% power to detect a 
hazard ratio for adverse liver outcomes for experimental to standard arms of 0.30, 
representing a 70% reduction in the hazard risk of adverse liver events in the first year 
(from 10% down to 3.1%). Dropout for reasons other than death (e.g., transferring care to 
another institution, withdrawal of consent) following enrollment in the study is estimated to 
be around 10%. Non-death related dropouts will be censored. To account for non-death 
related dropouts, the sample size will need to be increased by a factor of N/(1-0.1) = 11%, 
giving a total required sample size of n=222 eligible patients (111 per arm) for each 
randomized experiment, or 444 total registered patients to the protocol.  A single formal 
interim analysis for efficacy for each randomized trial will be conducted at the alpha=0.005 
level when one half of patients have reached one year of follow-up. Therefore, the final 
analyses will be conducted at the alpha=0.045 level. 
 
Under the condition of constant effect size, if the 1-year event rate on the standard arm is 
20% (15%), then a hazard ratio of 0.3 can be detected with 97% (92%) power, identifying 
a change from 20% (15%) down to 6.5% (4.9%). Alternatively, under the condition of 
constant power, if the 1-year event rate on the standard arm is 20% (15%), then 222 total 
patients allow detection from 20% (15%) down to 10.0% (6.5%) with 80% power and a 
hazard ratio of 0.48 (0.41). 
 
Power will also vary as a function of the baseline event rate and the one-year overall 
survival, representing a competing risk, as shown in Table 2 below. 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. 
 
Table 2. Main clinical study power calculations 
 
1-year death rate 
Hazard ratio 
70% 
75% 
80% 
85% 
90% 
0.20 
84% 
86% 
89% 
91% 
92% 
0.25 
80% 
82% 
85% 
87% 
89% 
0.30 
75% 
77% 
80% 
83% 
85% 
0.35 
68% 
71% 
74% 
77% 
79% 
0.40 
62% 
65% 
67% 
70% 
73% 
 
The primary analysis for each randomized experiment will be based on central, blinded 
review of adverse liver events among all randomized, eligible patients. A secondary 
examination in all randomized patients irrespective of their eligibility status will also be 
conducted under a fully intent-to-treat approach. To account for the potential for liver events 
to vary by cancer stage over and above what is reflected by the stratification variable 
(planned treatment type), in a secondary analysis, the investigators will adjust for cancer 
stage (adjuvant vs. advanced disease) as a covariate in the multivariable Cox regression 
model.  
 
11.2 
Secondary Endpoints 
 
The main secondary objective for each randomized cohort is to determine the incidence of 
HBV reactivation among patients with solid malignancies and chronic or past HBV infection 
during or after completion of anti-cancer therapy. Based on preliminary data, it is 
anticipated that 20% of patients will experience HBV reactivation on the standard arm of 
each of the randomized trials. 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 


 
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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% CI upper bound – p)/p], where p is the assumed incidence). This estimate is 
conservative as it is based on the assumption of no information from the 10% of patients 
estimated to drop out. 
 
The investigators will also 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.  
 
The investigators will also determine the cumulative incidence of the combined endpoint of 
adverse liver events plus HBV reactivation, as well as the cumulative incidence of hepatitis 
flare, by arm within each randomized trial and compare it between the arms in similar 
fashion. 
 
The accrual for this study is expected to come primarily from NCORP community sites. The 
estimated rate of past HBV infection in the cancer population is 4.6% based on studies by 
Ioannou and Roberts. (49,50) A slightly higher rate of 5% is assumed based on the 
expected enrollment distribution by race for this study using data from S1204.  To enroll 
222 eligible patients to the past HBV cohort, 222/0.05 = 4440 patients would need to be 
screened. Although it is typically estimated that one in 20 patients agree to enroll to a 
clinical trial, within SWOG sites this rate was found to be higher (14%) in a prospective 
SWOG barriers study. (51) Therefore, it is estimated that 1 in 7 patients identified as having 
past HBV infection will enroll to this trial, so 4440*7 = 31,080 patients in total will need to 
be screened. If 60 sites participate equally, each site would need to screen 18 
patients/month to complete the study in 2.5 years.  
 
The estimated rate of chronic HBV infection in the cancer population is 0.3% based on 
studies by Ioannou and Roberts. (52,53) Again, a higher rate, of 0.5% is assumed, based 
on the expected enrollment distribution by race for this study using data from S1204. To 
enroll 222 eligible patients to the chronic HBV cohort, using the same approach as above, 
it is estimated that 310,800 patients will need to be screened. Each participating site would 
need to screen 110 patients/month to complete this portion of the study in 4.0 years. 
 
11.3 
Data and Safety Monitoring Committee 
 
A Data and Safety Monitoring Committee will oversee the conduct of the study.  The 
Committee consists of four members from outside of SWOG, 3 SWOG members, 3 non-
voting representatives from the National Cancer Institute (NCI), and the Group Statistician 
(non-voting).  The members of this Committee will receive confidential reports every 6 
months from the SWOG Statistics and Data Management Center and will meet at the 
Group's bi-annual meetings as necessary.   
 
The event rate on the standard arm will be monitored. If lower than anticipated, 
consideration will be given to extending accrual in order to achieve sufficient power to 
detect the design-specified effect size. Also, the treatment rate on Arm 4 (usual care) will 
be monitored.  If deemed to be high enough to lead to meaningful loss of power, 
consideration will be given to extending accrual to Cohort 2. Additionally, the DSMC will 
monitor Grade 3-4 adverse events as part of routine monitoring. 
 


 
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Accrual will be monitored monthly. Accrual to the past and chronic HBV patient cohorts will 
be monitored on an ongoing basis to assess feasibility. NCI guidelines for accrual 
monitoring will be followed, including assessment of accrual at quarters 4 and 8 after 
activation, where activation is indexed according to the first patient enrolled. If quarter 4 
accrual is <15% of total accrual or if quarter 8 accrual is <20% of total accrual for either the 
past or chronic HBV studies, changes to the study design – including eligibility 
modifications, recruitment procedures – will be considered. If study modifications fail to 
meaningfully impact accrual such that the studies can be conducted within a reasonable 
timeframe, closure of the study cohort (past or chronic) will be considered. The DSMC will 
be responsible for decisions regarding possible termination and/or early reporting of the 
study and they will have access to any available data needed to inform their decisions. 
 
 
12.0 
DISCIPLINE REVIEW 
 
This study does not require a discipline review. 
                  
 
13.0 
REGISTRATION GUIDELINES 
 
13.1 
Registration Timing 
 
Patients must be registered ≤ 28 days prior to initial anti-cancer therapy. If the patient has 
already started systemic anti-cancer therapy, patient must be registered ≤ 42 days after 
the initiation of first cycle of anti-cancer therapy. 
 
13.2 
Investigator/Site Registration 
 
Prior to the recruitment of a patient for this study, investigators must be registered members 
of a Cooperative Group.  Each investigator must have an NCI investigator number and 
must maintain an “active” investigator registration status through the annual submission of 
a complete investigator registration packet to CTEP. 
 
13.3 
CTEP Registration Procedures 
 
Food and Drug Administration (FDA) regulations and National Cancer Institute (NCI) policy 
require all individuals contributing to NCI-sponsored trials to register and to renew their 
registration annually.  To register, all individuals must obtain a Cancer Therapy Evaluation 
Program 
(CTEP) 
Identity 
and 
Access 
Management 
(IAM) 
account 
(https://ctepcore.nci.nih.gov/iam).  In addition, persons with a registration type of 
Investigator (IVR), Non-Physician Investigator (NPIVR), or Associate Plus (AP) must 
complete their annual registration using CTEP’s web-based Registration and Credential 
Repository (RCR) at https://ctepcore.nci.nih.gov/rcr.   
 
RCR utilizes five-person registration types. 
• 
IVR — MD, DO, or international equivalent; 
• 
NPIVR — advanced practice providers (e.g., NP or PA) or graduate level 
researchers (e.g., PhD); 
• 
AP — clinical site staff (e.g., RN or CRA) with data entry access to CTSU 
applications such as Roster Update Management System (RUMS), OPEN, Rave, 
acting as a primary site contact, or with consenting privileges; 
• 
Associate (A) — other clinical site staff involved in the conduct of NCI-sponsored 
trials; and 
• 
Associate Basic (AB) — individuals (e.g., pharmaceutical company employees) 
with limited access to NCI-supported systems. 
 
RCR requires the following registration documents: 


 
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Documentation Required 
IVR 
NPIVR 
AP 
A 
AB 
FDA Form 1572 
 
 
Financial Disclosure Form 
 
 
 
NCI Biosketch (education, training, 
employment, license, and certification) 
 
 
 
GCP training 
 
 
 
Agent Shipment Form (if applicable) 
 
CV (optional) 
 
 
 
 
An active CTEP-IAM user account and appropriate RCR registration is required to access 
all CTEP and Cancer Trials Support Unit (CTSU) websites and applications.  In addition, 
IVRs and NPIVRs must list all clinical practice sites and Institutional Review Boards (IRBs) 
covering their practice sites on the FDA Form 1572 in RCR to allow the following: 
 
• 
Addition to a site roster; 
• 
Assign the treating, credit, consenting, or drug shipment (IVR only) tasks in OPEN; 
• 
Act as the site-protocol Principal Investigator (PI) on the IRB approval; and 
• 
Assign the Clinical Investigator (CI) role on the Delegation of Tasks Log (DTL).     
 
In addition, all investigators act as the Site-Protocol PI (investigator listed on the IRB 
approval), consenting/treating/drug shipment investigator in OPEN, or as the CI on the DTL 
must be rostered at the enrolling site with a participating organization. 
 
Additional information is located on the CTEP website at  
https://ctep.cancer.gov/investigatorResources/default.htm.  For questions, please contact 
the RCR Help Desk by email at RCRHelpDesk@nih.gov.   
 
13.4 
CTSU Registration Procedures 
 
This study is supported by the NCI Cancer Trials Support Unit (CTSU). 
 
a. 
IRB Approval:   
 
For CTEP and Division of Cancer Prevention (DCP) studies open to the National 
Clinical Trials Network (NCTN) and NCI Community Oncology Research Program 
(NCORP) Research Bases after March 1, 2019, all U.S.-based sites must be 
members of the NCI Central Institutional Review Board (NCI CIRB). In addition, 
U.S.-based sites must accept the NCI CIRB review to activate new studies at the 
site after March 1, 2019. Local IRB review will continue to be accepted for studies 
that are not reviewed by the CIRB, or if the study was previously open at the site 
under the local IRB. International sites should continue to submit Research Ethics 
Board (REB) approval to the CTSU Regulatory Office following country-specific 
regulations.  
 
Sites participating with the NCI CIRB must submit the Study Specific Worksheet 
(SSW) for Local Context to the CIRB using IRBManager to indicate their intent to 
open the study locally. In order for the SSW approval to be processed, the Signatory 
Institution must inform the CTSU which CIRB-approved institutions aligned with the 
Signatory Institution are participating in the study. The NCI CIRB’s approval of the 
SSW is automatically communicated to the CTSU Regulatory Office, but sites are 
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to establish site preferences for applying NCI CIRB approvals across their 
Signatory Network. Site preferences can be set at the network or protocol level. 
Questions about establishing site preferences can be addressed to the CTSU 
Regulatory Office by emailing the email address above or calling 1-888-651-CTSU 
(2878). 
 
In addition, the Site-Protocol Principal Investigator (PI) (i.e., the investigator on the 
IRB/REB approval) must meet the following criteria in order for the processing of 
the IRB/REB approval record to be completed: 
• 
Holds an Active CTEP status; 
• 
Active status at the site(s) on the IRB/REB approval (applies to US and 
Canadian sites only) on at least one participating organization’s roster; 
• 
If using NCI CIRB, active on the NCI CIRB roster under the applicable CIRB 
Signatory Institution(s) record; 
• 
Includes the IRB number of the IRB providing approval in the Form FDA 
1572 in the RCR profile;  
• 
Lists all sites on the IRB/REB approval as Practice Sites in the Form FDA 
1572 in the RCR profile; and 
• 
Holds the appropriate CTEP registration type for the protocol.  
 
Additional Requirements 
Additional site requirements to obtain an approved site registration status include: 
• 
An active Federal Wide Assurance (FWA) number; 
• 
An active roster affiliation with the Lead Protocol Organization (LPO) or a 
Participating Organization (PO);  
• 
An active roster affiliation with the NCI CIRB roster under at least one 
CIRB Signatory Institution (US sites only); and 
• 
Compliance with all protocol specific requirements (PSRs). 
 
b. 
Downloading Site Registration Documents:   
 
Download the site registration forms from the protocol specific page located on the 
CTSU members’ website. Permission to view and download this protocol and its 
supporting documents is restricted to institutions and its associated investigators 
and staff on a participating roster. To view/download site registration forms: 
 
• 
Log in to the CTSU members’ website (https://www.ctsu.org) using your 
CTEP-IAM username and password; 
• 
Click on Protocols in the upper left of the screen: 
o 
Enter the protocol number in the search field at the top of the protocol 
tree; or 
o 
Click on the By Lead Organization folder to expand, then select 
SWOG, and protocol number S1614 
• 
Click on Documents, Protocol Related Documents, and use the Document 
Type filter and select Site Registration to download and complete the 
forms provided. (Note: For sites under the CIRB initiative, IRB data will 
load automatically to the CTSU.)  
 
c. 
Submitting Regulatory Documents:  
 
Submit required forms and documents to the CTSU Regulatory Office via the 
Regulatory Submission Portal, on CTSU members’ website.  
 
To access the Regulatory Submission Portal log in to the CTSU members’ website, 
go to the Regulatory section and select Regulatory Submission. 


 
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Institutions with participants waiting that are unable to use the Regulatory 
Submission Portal should alert the CTSU Regulatory Office immediately by phone 
or email: 1-866-651-CTSU (2878), or CTSURegHelp@coccg.org in order to 
receive further instruction and support. 
 
d. 
Checking Your Site’s Registration Status: 
 
Site registration status may be verified on the CTSU members’ website.  
• 
Click on Regulatory at the top of the screen; 
• 
Click on Site Registration; and 
• 
Enter the site 5-character CTEP Institution Code and click on Go: 
o 
Additional filters are available to sort by Protocol, Registration 
Status, Protocol Status, and/or IRB Type. 
Note: The status shown only reflects institutional compliance with site registration 
requirements as outlined within the protocol. It does not reflect compliance with 
protocol requirements for individuals participating on the protocol or the enrolling 
investigator’s status with the NCI or their affiliated networks. 
 
13.5 
Oncology Participant Enrollment Network (OPEN) Registration Requirements 
 
The Oncology Participant Enrollment Network (OPEN) is a web-based registration system 
available on a 24/7 basis. OPEN is integrated with CTSU regulatory and roster data and 
with the LPOs registration/randomization systems or the Theradex Interactive Web 
Response System (IWRS) for retrieval of patient registration/randomization assignment. 
OPEN will populate the patient enrollment data in NCI’s clinical data management system, 
Medidata Rave. 
 
Requirements for OPEN access:   
• 
A valid CTEP-IAM account; 
• 
To perform enrollments or request slot reservations:  Must be on an LPO roster, 
ETCTN Corresponding roster, or participating organization roster with the role of 
Registrar. Registrars must hold a minimum of an AP registration type; 
• 
If a Delegation of Tasks Log (DTL) is required for the study, the registrar(s) must 
hold the OPEN Registrar task on the DTL for the site; and 
• 
Have an approved site registration for a protocol prior to patient enrollment. 
 
To assign an Investigator (IVR) or Non-Physician Investigator (NPIVR) as the treating, 
crediting, consenting, drug shipment (IVR only), or receiving investigator for a participant 
transfer in OPEN, the IVR or NPIVR must list the IRB number used on the site’s IRB 
approval on their Form FDA 1572 in RCR. If a DTL is required for the study, the IVR or 
NPIVR must be assigned the appropriate OPEN-related tasks on the DTL. 
 
Prior to accessing OPEN, site staff should verify the following: 
• 
Participant has met all eligibility criteria within the protocol stated timeframes and 
the affirmation of eligibility on the Registration Worksheet has been signed by the 
registering investigator or another investigator designate. Site staff should refer to 
Section 5.0 to verify eligibility. 
• 
All participants have signed an appropriate consent form and Health Insurance 
Portability and Accountability Act (HIPAA) authorization form (if applicable). 
 
Note:  The OPEN system will provide the site with a printable confirmation of registration 
and treatment information. Please print this confirmation for your records. 
 


 
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Access OPEN at https://open.ctsu.org or from the OPEN link on the CTSU members’ 
website. Further instructional information is in the OPEN section of the CTSU website at 
https://www.ctsu.org or https://open.ctsu.org. For any additional questions, contact the 
CTSU Help Desk at 1-888-823-5923 or ctsucontact@westat.com. 
 
OPEN will also ask additional questions that are not present on the SWOG Registration 
Worksheet.  The individual registering the patient must be prepared to provide answers to 
the following questions: 
 
a. 
Institution CTEP ID 
 
b. 
Protocol Number 
 
c. 
Registration Step 
 
d. 
Treating Investigator 
 
e. 
Credit Investigator 
 
f. 
Patient Initials 
 
g. 
Patient’s Date of Birth 
 
h. 
Patient SSN (SSN is desired, but optional.  Do not enter invalid numbers.) 
 
i. 
Country of Residence 
 
j. 
ZIP Code 
 
k. 
Gender (select one): 
• 
Female Gender 
• 
Male Gender 
 
l. 
Ethnicity (select one): 
• 
Hispanic or Latino 
• 
Not Hispanic or Latino 
• 
Unknown 
 
m. 
Method of Payment (select one): 
• 
Private Insurance 
• 
Medicare 
• 
Medicare and Private Insurance 
• 
Medicaid 
• 
Medicaid and Medicare 
• 
Military or Veterans Sponsored NOS 
• 
Military Sponsored (Including Champus & Tricare) 
• 
Veterans Sponsored 
• 
Self Pay (No Insurance) 
• 
No Means of Payment (No Insurance) 
• 
Other 
• 
Unknown 
 
n. 
Race (select all that apply): 
• 
American Indian or Alaska Native 
• 
Asian 
• 
Black or African American 
• 
Native Hawaiian or other Pacific Islander 


 
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• 
White 
• 
Unknown 
 
The OPEN system will provide a printable confirmation of the non-patient registration and 
additional instructions as needed. You may print this confirmation for your records. 
 
13.6 
Exceptions to SWOG registration policies will not be permitted. 
 
a. 
Patients must meet all eligibility requirements. 
 
b. 
Institutions must be identified as approved for registration. 
 
c. 
Registrations may not be cancelled. 
 
d. 
Late registrations (after initiation of treatment) will not be accepted. 
 
 
14.0 
DATA SUBMISSION SCHEDULE 
 
14.1 
Data Submission Requirement 
 
Data must be submitted according to the protocol requirements for ALL patients 
registered, whether or not assigned treatment is administered, including patients 
deemed to be ineligible.  Patients for whom documentation is inadequate to 
determine eligibility will generally be deemed ineligible 
 
14.2 
Master Forms 
 
Master forms can be found on the protocol page on the CTSU website (www.ctsu.org). 
 
14.3 
Data Submission Procedures 
 
a. 
Medidata Rave is a clinical data management system being used for data 
collection for this trial/study. Access to the trial in Rave is controlled 
through the CTEP-IAM system and role assignments.   
 
Requirements to access Rave via iMedidata:  
• 
A valid CTEP-IAM account; and   
• 
Assigned a Rave role on the LPO or PO roster at the enrolling site of: Rave 
CRA, Rave Read Only, Rave CRA (LabAdmin), Rave SLA, or Rave 
Investigator.   
  
Rave role requirements:  
• 
Rave CRA or Rave CRA (Lab Admin) role must have a minimum of an 
Associate Plus (AP) registration type;  
• 
Rave Investigator role must be registered as an Non-Physician 
Investigator (NPIVR) or Investigator (IVR); and  
• 
Rave Read Only role must have at a minimum an Associates (A) 
registration type.  
 
Refer to https://ctep.cancer.gov/investigatorResources/default.htm for registration 
types and documentation required.  
   
Upon initial site registration approval for the study in Regulatory Support System 
(RSS), all persons with Rave roles assigned on the appropriate roster will be sent 


 
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a study invitation email from iMedidata. To accept the invitation, site staff must 
either click on the link in the email or log in to iMedidate via the CTSU membrs’ 
website under Data Management > Rave Home and click to accept the invitation 
in the Tasks pane located in the upper right corner of the iMedidata screen. Site 
staff will not be able to access the study in Rave until all required Medidata and 
study specific trainings are completed. Trainings will be in the form of electronic 
learnings (eLearnings) and can be accessed by clicking on the eLearning link in 
the Tasks pane located in the upper right corner of the iMedidata screen. If an 
eLearning is required for a study and has not yet been taken, the link to the 
eLearning will appear under the study name in the Studies pane located in the 
center of the iMedidata screen; once the successful completion of the eLearning 
has been recorded, access to the study in Rave will be granted, and a Rave 
EDC link will replace the eLearning link under the study name.   
  
Site staff that have not previously activated their iMedidata/Rave account at the 
time of initial site registration approval for the study in RSS will receive a separate 
invitation from iMedidata to activate their account. Account activation instructions 
are located on the CTSU website in the Data Management section under the Rave 
resource materials (Medidata Account Activation and Study Invitation 
Acceptance). Additional information on iMedidata/Rave is available on the CTSU 
members’ 
website 
in 
the 
Data 
Management 
> Rave 
section 
at www.ctsu.org/RAVE/ or by contacting the CTSU Help Desk at 1-888-823-5923 
or by email at ctsucontact@westat.com.    
 
b. 
You may also access Rave® via the SWOG CRA Workbench via the SWOG 
website (www.swog.org).  
 
For 
difficulties 
with 
the 
CRA 
Workbench, 
please 
email 
technicalquestion@crab.org.  
 
c. 
Institutions participating through the Cancer Trials Support Unit (CTSU), please 
refer to the CTSU Participation Table. 
 
d. 
Data Quality Portal 
 
The Data Quality Portal (DQP) provides a central location for site staff to manage 
unanswered queries and form delinquencies, monitor data quality and timeliness, 
generate reports, and review metrics.   
  
The DQP is located on the CTSU members’ website under Data Management. The 
Rave Home section displays a table providing summary counts of Total 
Delinquencies and Total Queries. DQP Queries, DQP Delinquent Forms, DQP 
Form Status and the DQP Reports modules are available to access details and 
reports of unanswered queries, delinquent forms, forms with current status and 
timeliness reports. Review the DQP modules on a regular basis to manage 
specified queries and delinquent forms.  
  
The DQP is accessible by site staff that are rostered to a site and have access to 
the CTSU website. Staff that have Rave study access can access the Rave study 
data using a direct link on the DQP.  
  
To learn more about DQP use and access, click on the Help icon displayed on the 
Rave Home, DQP Queries, DQP Delinquent Forms, DQP Form Status, and DQP 
Reports modules.  
  


 
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14.4 
Data Submission Overview and Timepoints  
 
a. 
WITHIN 15 DAYS OF REGISTRATION:   
 
Submit the following: 
 
S1614 Onstudy Form 
 
*Source documentation for cancer diagnosis (Pathology Report preferred) 
 
*Source documentation for pre-registration HIV, HBsAg, anti-HBc, anti-HBs, and 
HBV DNA test results  
 
Specimens as outlined Section 15.0 
 
*NOTE: Upload reports via the Source Documentation: Baseline form in Rave® 
 
b. 
WITHIN 15 DAYS AFTER EVERY HBV MONITORING VISIT (per Section 7.4): 
 
Submit the following: 
 
S1614 HBV Assessment Form 
 
S1614 Laboratory Values Form (if laboratory tests performed) 
 
S1614 Anti-Cancer Treatment Form 
 
S1614 Anti-Viral Treatment Form (if anti-viral treatment initiated per protocol) 
 
S1614 Anti-Viral Adverse Event Form (if anti-viral treatment initiated per protocol) 
Specimens as outlined Section 15.0 
 
*Source documentation for HBV DNA test documenting HBV reactivation.  NOTE: 
Upload report via the Source Documentation: Follow-up Form in Rave®. Select 
HBV DNA/HBsAg/Anti-HBs/Anti-HBC Test” as the “Type of scan.” 
 
c. 
WITHIN 15 DAYS OF HBV REACTIVATION: 
 
Submit the following: 
 
S1614 HBV Assessment Form 
 
S1614 Laboratory Values Form (if laboratory tests performed) 
 
S1614 Anti-Cancer Treatment Form 
 
S1614 Anti-Viral Treatment Form (if anti-viral treatment initiated per protocol) 
 
S1614 Anti-Viral Adverse Event Form (if anti-viral treatment initiated per protocol) 
 
Specimens as outlined in Section 15.0 
 
d. 
WITHIN 15 DAYS OF DISCONTINUATION OF HBV ANTI-VIRAL PROTOCOL 
TREATMENT: 
 
Submit the following: 


 
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S1614 HBV Assessment Form 
 
S1614 Off Anti-Viral Treatment Notice 
 
S1614 Anti-Viral Treatment Form (if anti-viral treatment initiated per protocol) 
 
S1614 Anti-Viral Adverse Event Form (if anti-viral treatment initiated per protocol) 
 
e. 
WITHIN 15 DAYS OF DISCONTINUATION OF ANTI-CANCER TREATMENT: 
 
S1614 HBV Assessment Form 
 
S1614 Laboratory Values Form  
 
S1614 Anti-Cancer Treatment Form 
 
S1614 Anti-Viral Treatment Form (if anti-viral treatment initiated per protocol) 
 
S1614 Anti-Viral Adverse Event Form (if anti-viral treatment initiated per protocol) 
 
f. 
WITHIN 15 DAYS OF ADVERSE LIVER OUTCOME: 
 
*Submit source documentation supporting diagnosis of adverse liver outcome per 
Section 10.1. 
 
*NOTE: Upload reports via the Source Documentation: Follow-up form in 
Rave®.  Select “Adverse Liver Outcome” as the “Type of scan” and add a comment 
in the “Comments” field to specify the type of adverse liver outcome documentation 
as appropriate. 
 
S1614 HBV Assessment Form 
 
S1614 Laboratory Values Form (if laboratory tests performed) 
 
S1614 Anti-Cancer Treatment Form 
 
S1614 Anti-Viral Treatment Form (if anti-viral treatment initiated per protocol) 
 
S1614 Anti-Viral Adverse Event Form (if anti-viral treatment initiated per protocol) 
 
g. 
WITHIN 30 DAYS OF KNOWLEDGE OF DEATH: 
 
Submit the following: 
 
Notice of Death Form 
 
S1614 Anti-Cancer Treatment Form 
 
S1614 Anti-Viral Treatment Form (if anti-viral treatment initiated per protocol) 
 
S1614 Anti-Viral Adverse Event Form (if anti-viral treatment initiated per protocol) 
 
 
15.0 
SPECIAL INSTRUCTIONS 
 
15.1 
Blood Serum Specimens (REQUIRED) 


 
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Specimens for translational medicine and banking (submitted to the Biospecimen Bank – 
Solid Tissue, Myeloma and Lymphoma Division, Lab #201) required for patient: 
 
a. 
Blood serum for HBV DNA, HBsAg, ultrasensitive HBsAg, anti-HBs, HBV RNA, 
HBV core-related antigen (HBcrAg) testing and serum cytokine analysis must be 
submitted at the following time points (see Section 9.0): 
 
1. 
At the time of registration (+/- 4 weeks) 
 
2. 
Every 8 weeks (+/- 2 weeks) from date of registration 
 
3. 
At time of HBV re-activation 
 
b. 
At each time point, 10 mL of blood will be drawn into red top tube(s) using 
institutional supplies, spun down at 1500 G for 10 minutes at room temperature, 
and serum aliquoted into 1 mL aliquots.  Serum should be stored in a -70 to -80ºC 
freezer (preferred, if available). Samples stored in a -70 to -80ºC freezer may be 
batch shipped. If batch shipped, samples must be shipped within 3 months of 
collection.    
 
If -70 to -80°C freezer is not available, then ship immediately on dry ice (ship 
overnight Monday – Thursday), or store in a -20°C to -80°C freezer and ship within 
2 weeks, noting the storage temperature in the Specimen Tracking System.  
 
Samples must be shipped (Monday – Thursday) on dry ice by overnight shipping 
for receipt Tuesday - Friday.  Samples should not be shipped prior to a holiday. 
The SWOG Biospecimen bank is not able to receive frozen samples on Saturdays, 
Sundays, or holidays.  See Section 15.3 for specimen shipment instructions. 
 
15.2 
Whole Blood Specimens (OPTIONAL for Patient)  
 
a. 
With patient’s consent whole blood specimens for intracellular cytokine staining 
(ICC), ELISA, IFN-gamma elispot testing (submitted to the SWOG Biospecimen 
Bank – Solid Tissue, Myeloma, and Lymphoma Division, Lab #201) must be 
submitted at the following time points (see Section 9.0). 
 
1. 
At time of registration (+/- 4 weeks) 
 
2. 
8-12 weeks from registration 
 
3. 
24 weeks (+/- 4 weeks) from date of registration  
 
4. 
At time of HBV-re-activation 
 
b. 
At each time point, a total 50 mL of blood will be drawn into five to eight purple top 
(EDTA) tubes using institutional supplies. Blood should be shipped the day of 
collection, overnight at ambient temperature. Blood may be shipped on Monday 
through Friday for Tuesday through Saturday delivery.  If shipping for Saturday 
delivery, please mark Saturday delivery and notify the Bank.   See Section 15.3 for 
specimen shipment instructions. 
 
15.3 
SHIPPING SAMPLES 
 
All specimens for this protocol should be shipped as Category B Infectious Substances. 
 
a. 
Specimen Labeling  


 
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Liquid specimens must be labeled with the following: 
• 
SWOG patient number 
• 
Patient initials 
• 
Collection date (date the specimen was collected from the patient) 
• 
Specimen type (e.g., blood, serum, etc.) 
 
b. 
For additional information about labeling and shipping instructions (including 
address) 
refer 
to 
the 
SWOG 
Specimen 
Submission 
webpage 
(https://www.swog.org/clinical-trials/biospecimen-resources/biospecimen-
processing-and-submission-procedures).  
 
c. 
SWOG Specimen Tracking System (STS) 
 
All specimen submissions for this study must be entered and tracked using the 
SWOG online Specimen Tracking system. SWOG members may log on the online 
system via the CRA Workbench. To access the CRA Workbench, go to the SWOG 
Web site (http://swog.org). Non- SWOG users may log into SpecTrack using their 
CTSU UserID and password on the SpecTrack login page located at 
https://spectrack.crab.org (select the option “SWOG – SWOG – CTSU”.  
SpecTrack start-up instructions (both written and demo) are available after signing 
in to SpecTrack.  
 
A copy of the Shipment Packing List produced by the online Specimen Tracking 
system should be printed and placed in the pocket of the specimen bag if it has 
one, or in a separate resealable bag.  
 
ALL SPECIMENS MUST BE LOGGED VIA THIS SYSTEM; THERE ARE NO 
EXCEPTIONS. 
 
(NOTE: If a specimen had an incomplete submission, this must be documented in 
the Specimen Tracking System under “Special Instructions” at time of specimen 
submission.  If no specimen was available, this must be documented in the 
Specimen Tracking System by choosing “Notify that Specimen Cannot be 
Submitted”). 
 
To report technical problems with Specimen Tracking, such as database errors or 
connectivity issues, please send an email to technicalquestion@crab.org.  For 
procedural help with logging and shipping specimens, there is an introduction to 
the system on the Specimen Tracking main page  
(https://spectrack.crab.org/Instructions); or contact the SWOG Statistics and Data 
Management Center at 206/652-2267 to be routed to the Data Coordinator for 
further assistance. 
 
In the online specimen tracking system, the appropriate SWOG laboratory for 
submission of tissue and blood samples for SWOG Biospecimen Bank Submission 
is identified as follows: 
 
Lab #201:  
SWOG Biospecimen Bank 
Solid Tissue, Myeloma, and Lymphoma Division 
Phone: 614-722-2865 
FAX: 614-722-2897 
E-mail: bpcbank@nationwidechildrens.org  
 
 


 
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16.0 
ETHICAL AND REGULATORY CONSIDERATIONS 
 
The following must be observed to comply with Food and Drug Administration regulations for the 
conduct and monitoring of clinical investigations; they also represent sound research practice: 
 
Informed Consent 
 
The principles of informed consent are described by Federal Regulatory Guidelines (Federal 
Register Vol. 82, No. 12, January 19, 2017) and the Office for Protection from Research Risks 
Reports:  Protection of Human Subjects (Code of Federal Regulations 45 CFR 46).  They must be 
followed to comply with FDA regulations for the conduct and monitoring of clinical investigations. 
 
Institutional Review 
 
This study must be approved by an appropriate institutional review committee as defined by Federal 
Regulatory Guidelines (Ref. Federal Register Vol. 82, No. 12, January 19, 2017) and the Office for 
Protection from Research Risks Reports:  Protection of Human Subjects (Code of Federal 
Regulations 45 CFR 46). 
 
Drug Accountability 
 
An investigator is required to maintain adequate records of the disposition of investigational drugs 
according to procedures and requirements governing the use of investigational new drugs as 
described in the Code of Federal Regulations 21 CFR 312.  
 
Monitoring 
 
This study will be monitored by the Clinical Data Update System (CDUS) Version 3.0.  Cumulative 
CDUS data will be submitted quarterly to CTEP by electronic means.  Reports are due January 31, 
April 30, July 31 and October 31. 
 
Confidentiality 
 
Please note that the information contained in this protocol is considered confidential and should 
not be used or shared beyond the purposes of completing protocol requirements until or unless 
additional permission is obtained. 
 
16.1  
Expedited reporting for commercial agents 
 
Commercial reporting requirements are provided in Table 16.1. If there is any question 
about the reportability of an adverse event or if on-line CTEP-AERS cannot be used, 
please telephone or email the SAE Program at the Operations Office, 210/614-8808 or 
adr@swog.org, before preparing the report. 
 
 


 
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Table 16.1. Expedited reporting requirements for adverse events experienced by patients on all 
study arms within 30 days of the last administration of the commercial agent.  
 
Attribution 
 
Grade 3 
 
Grade 4 
 
Grade 5a 
Unexpected 
Expected 
Unexpected 
Expected 
Unexpected 
Expected 
Unrelated or 
Unlikely 
 
CTEP-
AERS 
 
CTEP-
AERS 
 
CTEP-
AERS 
 
CTEP-AERS 
 
CTEP-
AERS 
 
CTEP-
AERS 
Possible, 
Probable, 
Definite 
 
CTEP-
AERS 
 
CTEP-
AERS 
 
CTEP-
AERS 
 
CTEP-AERS 
 
CTEP-
AERS 
 
CTEP-
AERS 
CTEP-AERS: Indicates an expedited report is to be submitted via CTEP-AERS within 15 calendar 
days of learning of the eventb. 
 
a This includes all deaths within 30 days of the last dose of treatment with a commercial agent(s), 
regardless of attribution. Any death that occurs more than 30 days after the last dose of treatment 
with a commercial agent(s) and is attributed (possibly, probably, or definitely) to the agent(s) and 
is not due to cancer recurrence must be reported according to the instructions above. 
 
b Submission of the on-line CTEP-AERS report plus any necessary amendments generally 
completes the reporting requirements. You may, however, be asked to submit supporting clinical 
data to the Operations Office in order to complete the evaluation of the event. If requested, the 
specified data should be sent within 5 calendar days by fax to 210/614-0006. 
 
 
 
 


 
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17.0 
BIBLIOGRAPHY 
 
1  
Lok AS, Liang RH, Chiu EK, Wong KL, Chan TK, Todd D. Reactivation of hepatitis B virus 
replication in patients receiving cytotoxic therapy. Report of a prospective study. Gastroenterology. 
1991;100(1):182-188 
 
2  
Lau GK, Yiu HH, Fong DY, et al. Early is superior to deferred preemptive lamivudine therapy for 
hepatitis B patients undergoing chemotherapy. Gastroenterology. 2003;125(6):1742-1749. 
 
3  
Jang JW, Choi JY, Bae SH, et al. A randomized controlled study of preemptive lamivudine in 
patients receiving transarterial chemo-lipiodolization. Hepatology. 2006;43(2):233-240. 
 
4  
Borentain P, Colson P, Coso D, et al. Clinical and virological factors associated with hepatitis B 
virus reactivation in HBsAg-negative and anti-HBc antibodies-positive patients undergoing 
chemotherapy and/or autologous stem cell transplantation for cancer. J. Viral Hepat. 
2010;17(11):807-815. 
 
5  
Huang YH, Hsiao LT, Hong YC, et al. Randomized controlled trial of entecavir prophylaxis for 
rituximab-associated hepatitis B virus reactivation in patients with lymphoma and resolved hepatitis 
B. J. Clin. Oncol. 2013;31(22):2765-2772. 
 
6  
Lau GK, Yiu HH, Fong DY, et al. Early is superior to deferred preemptive lamivudine therapy for 
hepatitis B patients undergoing chemotherapy. Gastroenterology. 2003;125(6):1742-1749. 
 
7  
Keam B, Lee JH, Im SA, Yoon JH. Why, when, and how to prevent hepatitis B virus reactivation in 
cancer patients undergoing chemotherapy. J. Natl. Compr. Canc. Netw. 2011;9(5):465-477. 
 
8  
Loomba R, Rowley A, Wesley R, et al. Systematic review: The effect of preventive lamivudine on 
hepatitis B reactivation during chemotherapy. Ann. Intern. Med. 2008;148(7):519-528. 
 
9  
Hwang JP, Lok AS. Management of patients with hepatitis B who require immunosuppressive 
therapy. Nat. Rev. Gastroenterol. Hepatol. 2014;11(4):209-219. 
 
10  
Huang H, Li X, Zhu J, et al. Entecavir vs lamivudine for prevention of hepatitis B virus reactivation 
among patients with untreated diffuse large B-cell lymphoma receiving R-CHOP chemotherapy: A 
randomized clinical trial. JAMA. 2014;312(23):2521-2530. 
 
11  
Hsu C, Hsiung CA, Su IJ, et al. A revisit of prophylactic lamivudine for chemotherapy-associated 
hepatitis B reactivation in non-Hodgkin's lymphoma: A randomized trial. Hepatology. 
2008;47(3):844-853. 
 
12  
Hwang JP, Somerfield MR, Alston-Johnson DE, et al. Hepatitis B virus screening for patients with 
cancer before therapy: American Society of Clinical Oncology provisional clinical opinion update. 
J. Clin. Oncol. 2015;33(19):2212-2220. 
 
13  
Baden LR, Bensinger W, Angarone M, et al. Prevention and treatment of cancer-related infections. 
J. Natl. Compr. Canc. Netw. 2012;10(11):1412-1445. 
 
14  
Ling WH, Soe PP, Pang AS, Lee SC. Hepatitis B virus reactivation risk varies with different 
chemotherapy regimens commonly used in solid tumours. Br. J. Cancer. 2013. 
 
 


 
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15  
Yeo W, Chan PK, Zhong S, et al. Frequency of hepatitis B virus reactivation in cancer patients 
undergoing cytotoxic chemotherapy: a prospective study of 626 patients with identification of risk 
factors. J. Med. Virol. 2000;62(3):299-307. 
 
16  
Yeo W, Chan PK, Hui P, et al. Hepatitis B virus reactivation in breast cancer patients receiving 
cytotoxic chemotherapy: a prospective study. J. Med. Virol. 2003;70(4):553-561. 
 
17  
Saitta C, Musolino C, Marabello G, et al. Risk of occult hepatitis B virus infection reactivation in 
patients with solid tumours undergoing chemotherapy. Dig. Liver Dis. 2013;45(8):683-686. 
 
18  
JP Hwang, JJ Feld, SP Hammond, et al. Hepatitis B Virus Screening and Management for Patients 
With Cancer Prior to Therapy: ASCO Provisional Clinical Opinion Update J Clin Oncol. 2020 Nov 
1;38(31):3698-3715. doi: 10.1200/JCO.20.01757. Epub 2020 Jul 27. PMID: 32716741 
 
19  
Ioannou GN. Hepatitis B virus in the United States: infection, exposure, and immunity rates in a 
nationally representative survey. Ann. Intern. Med. 2011;154(5):319-328. 
 
20  
Ioannou GN. Hepatitis B virus in the United States: infection, exposure, and immunity rates in a 
nationally representative survey. Ann. Intern. Med. 2011;154(5):319-328. 
 
21  
Park JJ, Wong DK, Wahed AS, et al. Hepatitis B Virus--Specific and Global T-Cell Dysfunction in 
Chronic Hepatitis B. Gastroenterology. 2016;150(3):684-695.e685. 
 
22  
Hwang JP, Lok AS. Management of patients with hepatitis B who require immunosuppressive 
therapy. Nature reviews. Gastroenterology & hepatology. 2014;11(4):209-219. 
 
23  
Keam B, Lee JH, Im SA, Yoon JH. Why, when, and how to prevent hepatitis B virus reactivation in 
cancer patients undergoing chemotherapy. J. Natl. Compr. Canc. Netw. 2011;9(5):465-477. 
 
24  
Hwang JP, Lok AS. Management of patients with hepatitis B who require immunosuppressive 
therapy. Nature reviews. Gastroenterology & hepatology. 2014;11(4):209-219. 
 
25  
Voican CS, Mir O, Loulergue P, et al. Hepatitis B virus reactivation in patients with solid tumors 
receiving systemic anticancer treatment. Ann. Oncol. 2016. 
 
26  
Paul S, Saxena A, Terrin N, Viveiros K, Balk EM, Wong JB. Hepatitis B Virus Reactivation and 
Prophylaxis During Solid Tumor Chemotherapy: A Systematic Review and Meta-analysis. Ann. 
Intern. Med. 2016;164(1):30-40. 
 
27  
Loomba R, Rowley A, Wesley R, et al. Systematic review: The effect of preventive lamivudine on 
hepatitis B reactivation during chemotherapy. Ann. Intern. Med. 2008;148(7):519-528. 
 
28  
Lau GK, Yiu HH, Fong DY, et al. Early is superior to deferred preemptive lamivudine therapy for 
hepatitis B patients undergoing chemotherapy. Gastroenterology. 2003;125(6):1742-1749. 
 
29  
Huang YH, Hsiao LT, Hong YC, et al. Randomized controlled trial of entecavir prophylaxis for 
rituximab-associated hepatitis B virus reactivation in patients with lymphoma and resolved hepatitis 
B. J. Clin. Oncol. 2013;31(22):2765-2772. 
 
30  
Hsu C, Hsiung CA, Su IJ, et al. A revisit of prophylactic lamivudine for chemotherapy-associated 
hepatitis B reactivation in non-Hodgkin's lymphoma: A randomized trial. Hepatology. 
2008;47(3):844-853. 
 
 


 
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31  
Yeo W, Chan PK, Hui P, et al. Hepatitis B virus reactivation in breast cancer patients receiving 
cytotoxic chemotherapy: a prospective study. J. Med. Virol. 2003;70(4):553-561 
 
32  
Paul S, Saxena A, Terrin N, Viveiros K, Balk EM, Wong JB. Hepatitis B Virus Reactivation and 
Prophylaxis During Solid Tumor Chemotherapy: A Systematic Review and Meta-analysis. Ann. 
Intern. Med. 2016;164(1):30-40. 
 
33  
Paul S, Saxena A, Terrin N, Viveiros K, Balk EM, Wong JB. Hepatitis B Virus Reactivation and 
Prophylaxis During Solid Tumor Chemotherapy: A Systematic Review and Meta-analysis. Ann. 
Intern. Med. 2016;164(1):30-40. 
 
34  
Bahirwani R, Reddy KR. Drug-induced liver injury due to cancer chemotherapeutic agents. Semin. 
Liver Dis. 2014;34(2):162-171. 
 
35  
Lee KW, Chan SL. Hepatotoxicity of targeted therapy for cancer. Expert Opin. Drug Metab. Toxicol. 
2016;12(7):789-802. 
 
36  
Rodriguez-Frias EA, Lee WM. Cancer chemotherapy I: hepatocellular injury. Clin. Liver Dis. 
2007;11(3):641-662, viii. 
 
37  
Chang M-L, Liaw Y-F. Hepatitis B flares in chronic hepatitis B: pathogenesis, natural course, and 
management. J. Hepatol. 2014;61(6):1407-1417. 
 
38  
Schmidt J, Blum HE, Thimme R. T-cell responses in hepatitis B and C virus infection: similarities 
and differences. Emerging microbes & infections. 2013;2(3):e15. 
 
39  
Bertoletti A, Ferrari C. Adaptive immunity in HBV infection. J. Hepatol. 2016;64(1 Suppl):S71-83. 
 
40  
Bertoletti A, Ferrari C. Adaptive immunity in HBV infection. J. Hepatol. 2016;64(1 Suppl):S71-83. 
 
41  
Das A, Ellis G, Pallant C, et al. IL-10-producing regulatory B cells in the pathogenesis of chronic 
hepatitis B virus infection. J. Immunol. 2012;189(8):3925-3935. 
 
42  
Bertoletti A, Ferrari C. Adaptive immunity in HBV infection. J. Hepatol. 2016;64(1 Suppl):S71-83. 
 
43  
van der Kolk LE, Baars JW, Prins MH, van Oers MH. Rituximab treatment results in impaired 
secondary humoral immune responsiveness. Blood. 2002;100(6):2257-2259. 
 
44  
Cooper N, Arnold DM. The effect of rituximab on humoral and cell mediated immunity and infection 
in the treatment of autoimmune diseases. Br. J. Haematol. 2010;149(1):3-13. 
 
45  
Tan AT, Koh S, Goh W, et al. A longitudinal analysis of innate and adaptive immune profile during 
hepatic flares in chronic hepatitis B. J. Hepatol. 2010;52(3):330-339. 
 
46  
JP Hwang, JJ Feld, SP Hammond, et al. Hepatitis B Virus Screening and Management for Patients 
With Cancer Prior to Therapy: ASCO Provisional Clinical Opinion Update J Clin Oncol. 2020 Nov 
1;38(31):3698-3715. doi: 10.1200/JCO.20.01757. Epub 2020 Jul 27. PMID: 32716741 
 
47  
Symptom Managment & Quality of Life Steering Committee. 2015 Strategic Priorities.  
https://www.cancer.gov/about-nci/organization/ccct/steering-committees/2015-SxQoLSC-
StrategicPriorities. Accessed January 20, 2017. 
 
 


 
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48  
Lange CM, Bojunga J, Hofmann WP, Wunder K, Mihm U, Zeuzem S, Sarrazin C. Severe lactic 
acidosis during treatment of chronic hepatitis B with entecavir in patients with impaired liver 
function. Hepatology. 2009 Dec;50(6):2001-6. doi: 10.1002/hep.23346. PMID: 19937695.. 
 
49  
Ioannou GN. Hepatitis B virus in the United States: infection, exposure, and immunity rates in a 
nationally representative survey. Ann. Intern. Med. 2011;154(5):319-328. 
 
50  
Roberts H, Kruszon-Moran D, Ly KN, et al. Prevalence of chronic hepatitis B virus (HBV) infection 
in U.S. households: National Health and Nutrition Examination Survey (NHANES), 1988-2012. 
Hepatology. 2016;63(2):388-397. 
 
51  
Javid SH, Unger JM, Gralow JR, et al. A prospective analysis of the influence of older age on 
physician and patient decision-making when considering enrollment in breast cancer clinical trials 
(SWOG S0316). Oncologist. 2012;17(9):1180-1190. 
 
52  
Ioannou GN. Hepatitis B virus in the United States: infection, exposure, and immunity rates in a 
nationally representative survey. Ann. Intern. Med. 2011;154(5):319-328. 
 
53  
Roberts H, Kruszon-Moran D, Ly KN, et al. Prevalence of chronic hepatitis B virus (HBV) infection 
in U.S. households: National Health and Nutrition Examination Survey (NHANES), 1988-2012. 
Hepatology. 2016;63(2):388-397. 
 
 
 


 
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18.0 
APPENDIX 
 
18.1 
Translational Medicine 
 
18.2 
Instructions for the SWOG Biospecimen Bank 
 
18.3 
Viral Status Information  
 
18.4 
Intake Calendar 
 
18.5 
Blinded Central Review of Primary Endpoint 
 
18.6 
Approved Antiviral Therapies in Adults 
 
 
 
 
 


 
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18.1 
Translational Medicine  
 
HBV DNA, HBsAg, ultrasensitive HBsAg, anti-HBs, HBV RNA, HBV core-related antigen 
(HBcrAg) 
 
Blood specimens for 444 study participants enrolled in the main clinical study will be 
collected at baseline and at regular intervals after registration as outlined above in Section 
9.0 Study Calendar and Section 15.0. Sixty sites will enroll 222 chronic HBV and 222 past 
HBV patients, collect blood specimens at study time points, and send specimens to the 
SWOG Biospecimen Bank. The SWOG Biospecimen Bank will prepare and batch-ship 
specimens to Toronto Centre for Liver Disease Laboratories during the main clinical study 
for research tests (HBV DNA, HBsAg, ultrasensitive HBsAg, HBV RNA, HBcAg, anti-HBs, 
and HBeAg tests) to retrospectively identify patients with HBV reactivation. The results 
from labs at Toronto Centre for Liver Disease will be used to determine cases of HBV 
reactivation and matched controls.  
 
a. 
Specimen Collection and Processing: 
 
Specimens for the TM studies will be collected in red top tubes at 5 time points (+/- 
4 weeks) and processed at the site as detailed in Section 15.0. 
See Section 18.1d for SWOG Biospecimen Banking Instructions 
 
At the end of the study, the bank will ship specimens to The Toronto Centre for 
Liver Disease labs where the following HBV tests will be performed: HBV DNA, 
HBsAg, ultrasensitive HBsAg, HBV RNA, HBcAg, anti-HBs, and HBeAg tests. ALT, 
total bilirubin, and INR will be performed as part of routine monitoring in the main 
clinical study SWOG S1614.  
 
b. 
Translational Aim 1. To determine baseline and changes in overall immune 
status and HBV-specific immune response in solid tumor patients with 
chronic or past HBV infection receiving anti-cancer therapy, and to compare 
the differences in these immune responses by HBV reactivation status. 
 
HBV-specific T cell and B cell responses are weak in patients with chronic HBV 
infection. However, evidence from patients receiving immunosuppressive therapy 
confirms that there is ongoing immune control in chronic HBV infection. Multiple 
agents with different immunosuppressive and/or immunomodulatory properties 
have been associated with HBV-reactivation. Reactivation occurs with non-specific 
therapy like corticosteroids, as well as with targeted treatments like B cell-depleting 
agents and anti-TNF therapies. Therefore, perturbation of immune composition 
and/or specific antiviral pathways can result in reactivation. However, HBV 
reactivation does not occur in all patients who receive immunomodulatory 
therapies. We hypothesize that the composition, phenotype and function of 
immune cells at baseline will predict HBV reactivation after starting anti-cancer 
chemotherapy. 
 
Aim 2 will conduct a case-control study comparing immune status in patients who 
develop HBV reactivation during chemotherapy with a 1:1 matched set of controls 
who were not on anti-HBV therapy and did not develop HBV reactivation. 
Specimens will be collected at the time points detailed in Section 9.0 Study 
Calendar and Section 15.0. Participants who are clinically diagnosed to have HBV 
reactivation will have an additional blood draw for future immune studies. All blood 
specimens will be collected from 444 study participants then shipped overnight to 
SWOG Biospecimen Bank for processing and storage in a -80°C freezer. 
Specimens will be sent from SWOG Biospecimen Bank to Drs. Jordan Feld and 
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studies detailed below. Dr. Hwang and her immunology collaborators will have 
priority access to the specimens at SWOG Biospecimen Bank at all times.  
 
The samples are the key novel aspect of the study. Using data from 
Translational Aim 1, we will identify patients with reactivation defined by increasing 
HBV viral load with an equal number of patients not experiencing HBV reactivation 
after treatment. The primary analysis will be performed on longitudinal samples 
comparing change from baseline upon starting chemotherapy in HBV reactivation 
patients and those without reactivation. Patients will be matched by age (5-year 
strata), sex, type of anti-cancer therapy (cytotoxic, immune or targeted) and 
chronic vs. past HBV.  
 
Chemotherapeutic disruption of the immunological profile maintaining HBV control 
(500,000 cells). To identify population-based changes in patients experiencing 
HBV reactivation after chemotherapy, we will use an extensive (30+) parameter 
CyTOF analysis to quantify CD4, CD8, γδ, MAIT, Treg, NK CD56br, NK CD56dim, 
memory B cells, plasma blasts, CD14, CD14/16, CD16 monocytes, CD1c, CD141, 
and plasmacytoid dendritic cells. Comparison between patients that do and do not 
experience reactivation will identify key biomarkers to stratify patient risk of 
reactivation and antiviral prophylaxis decisions. 
 
Chemotherapeutic disruption of immunological functions responsible for HBV 
control (1 – 2 mil cells). To measure how chemotherapeutic agents alter the 
functional profile of leukocytes we will stimulate lymphocytes and myeloid cells 
with non-specific agonists such as anti-CD3, IL-12 + IL-18, and TLR agonists. To 
evaluate the cytokine profile we will use conventional 13 color flow cytometry 
panels to measure the frequency of single/multiple cytokine positive cells. We will 
compare samples longitudinally within patients and between patients with and 
without HBV reactivation. These data have the potential to identify a functional 
biomarker associated with HBV reactivation and an immunological pathway 
responsible for HBV control. 
 
Longitudinal analysis of HBV-specific T & B cell immunity (3 – 5 mil cells). To 
determine whether reactivation is the result of suppression of HBV-specific 
immunity vs. frequency/functional alterations we will perform HBV-specific T and 
B cell ELISpot. We will use a pool of overlapping peptides covering the entire HBV 
genome.37 Because of the low frequency of HBV-specific T cells, even in patients 
with previous HBV infection (anti-HBc+), we will use in vitro expansion to increase 
the rate of HBV-specific T cell detection. To investigate the HBV-specific B cell 
frequency, we will isolate B cells by magnetic selection and perform HBsAg-
specific B cell ELISpot. B cell frequency will be compared longitudinally in patients 
with and without reactivation and correlated with detection of anti-HBs antibodies 
in the serum of patients with both chronic and resolved HBV infection. This will 
allow us to evaluate how the decay of anti-HBs antibodies in the serum correlates 
with HBV reactivation and quantify the extent to which anti-HBV antibodies are 
maintaining control of HBV replication in both chronic and resolved HBV infection. 
 
Serum analysis to identify serum biomarkers predicting HBV reactivation. We will 
use clinical assays to quantify HBV-specific antibodies in the serum and a 
comprehensive 
CBA 
or 
luminex 
assay 
to 
analyze 
immunological 
cytokines/chemokines in longitudinal serum samples. Arginase will be measured 
by ELISA. HBV RNA, HBcrAg and ultrasensitive HBsAg will be measured in the 
serum by qPCR (RNA) and ELISA (HBcrAg and ultrasensitive HBsAg) in patients 
who do and do not experience HBV reactivation to determine if the levels of these 
markers that indicated active transcription of HBV DNA in the liver increase prior 
to clinical reactivation and could be used as biomarkers of impending reactivation. 


 
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Understanding the serum profile of key molecules associated with HBV 
reactivation may provide a baseline predictor of HBV control during chemotherapy. 
 
c. 
Translational Aim 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. 
 
The determinants of HBV reactivation in patients with solid tumors are not known. 
In this aim, we will identify the demographic and clinical predictors as well as 
immune correlates of HBV reactivation and hepatitis flare among all 444 study 
patients. For Aim 2, all immune studies will be performed on stored plasma and 
PBMCs that would have already been prospectively collected at predetermined 
time points as noted in Section 9.0 Study Calendar and Section 15.0 above. 
Immune tests will include ELISA, ICC assay, IFN-gamma elispot. If any immune 
test listed for Aim 2 has already been performed as part of the case control study 
in Aim 1, it will not be repeated in this aim. In the main clinical study, SWOG sites 
will collect clinical information for use in Aim 2. The following tests will be 
considered usual care monitoring for HBV patients receiving anti-cancer therapy 
and will be recorded at the study follow up time points listed in Section 9.0 Study 
Calendar: ALT, total bilirubin, and INR. The primary outcome for Aim 2 is time to 
first evidence of HBV reactivation.  
 
Statistical Analyses plan 
 
Only the patients randomized to the standard arm of each randomized study 
(chronic vs. past HBV infection) will be the potential participants for this aim. A 
case-control analysis, using a ratio of cases to controls of 1:1, will be conducted to 
explore baseline and changes of overall immune status and HBV-specific immune 
response factors that differ between patients with vs. without HBV reactivation. 
Based on expected rates of HBV reactivation for patients with chronic and past 
HBV infection (20%), we estimate that 22 patients with chronic and 22 patients 
with past HBV infection (n=44 total cases) will develop HBV reactivation. Under 
this scenario, we will also examine a matched set of 44 control patients. Matching 
will occur based on age and randomized study type (chronic vs. past HBV 
infection). Power is low in this setting and therefore this aim is considered 
exploratory, with any positive findings requiring validation in future studies. For a 
given binary predictor (i.e. immune status, group 1 = high vs. group 2 = low), 88 
total patients (44 cases and 44 controls) is sufficient to detect an absolute 
difference of 26% in HBV reactivation rates (i.e. 7% for group 1 and 33% for group 
2), assuming the overall rate of HBV reactivation is 20%, using a 2-arm binomial 
alpha=.05 test with 80% power. In addition, changes in overall immune status and 
HBV-specific immune responses after onset of cytotoxic chemotherapy or 
immunotherapy will be described for the cases and controls using descriptive 
statistics (means, standard deviations). To avoid incorrect inference induced by 
the potentially endogenous relationship between HBV reactivation and immune 
response, landmark analyses will be used, conditioning on patients surviving to a 
given assessment time without developing HBV reactivation.  
 
The study will also assess the association of potential risk factors (including 
demographic, clinical, and immunologic markers) for HBV reactivation. For any 
potential demographic, clinical, or immunologic factor, time-to-HBV reactivation 
will be examined using Cox regression, adjusting for the stratification factors 
specified in the main clinical study. Analyses will be conducted for each 
randomized study (chronic vs. past HBV), each with a total sample size of n=222 
patients. For instance, to identify a hazard ratio of 2.5 between patients with or 
without a given condition (say, status for a specified candidate marker or 


 
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composite, yes vs. no), 222 patients will give 87% power using alpha=.05 two sided 
tests with 80% survival at 1 year of follow-up data. Power will vary as a function of 
the proportion in subgroups (i.e. 40% have risk factor vs. 60% do not) and the 
hazard ratio as indicated in Table 18.1 below, and it will generally be adequate to 
identify hazard ratios of ≥ 2.5. 
 
Table 18.1. Power to detect a specified difference in risk of HBV reactivation 
or hepatitis flare  
 
 
 
 
 
 
 
 
 
TM Endpoints 
 
Hepatitis B-associated hepatitis defined as ALT>3xULN and 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 B reactivation 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-. 
 
 
Power 
 % of Patients with vs. without a Risk Factor 
Hazard 
Ratio  
50 vs. 50  
40 vs. 60 
30 vs. 70 
20 vs. 80 
2.0 
77% 
73% 
66% 
54% 
2.5 
90% 
87% 
81% 
68% 
3.0 
95% 
93% 
88% 
76% 
3.5 
97% 
96% 
91% 
81% 


 
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18.2 
Instructions for the SWOG Biospecimen Bank  
 
NOTE: The SWOG Biospecimen Bank will prepare specimens for immune studies by 
separating the plasma, isolating the peripheral blood mononuclear cells (PBMCs), and then 
cryopreserving 
 
1. 
Frozen serum 
Processed, frozen serum aliquots will be received at up to 7 time 
points.  Upon receipt, the Bank will accession and barcode before banking 
in a -80°C freezer until distribution for testing.  
 
At the end of the study, the Bank will receive notification from the SWOG 
Statistics and Data Management Center with the cases to distribute for 
HBV DNA, HBsAg, anti-HBs, HBV RNA, HBV core-related antigen testing, 
and serum cytokine analysis.  
 
2. 
Blood in EDTA tubes 
Fresh whole blood collected in EDTA tubes will arrive at ambient 
temperature from up to 7 time points per patient. At each time point, the 
Bank will accession and process all specimens for white blood cells (WBC) 
using a red blood cell lysing technique. WBCs will be aliquoted with 
freezing media in vials with 1 x 107 cells per vial. WBCs will be stored in a 
liquid nitrogen vapor phase freezer until distribution for future testing.  
 
At the end of the study, the Bank will receive notification from the SWOG 
Statistics and Data Management Center with the cases to distribute for 
ICC, ELISA, IFNg, and ELIspot testing.  
 
 


 
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18.3 
Viral Status Information  
 
HBV STATUS BASED ON HBV TEST RESULTS 
 
Results of Standard Tests 
HBV 
HBsAg 
anti-HBc 
anti-HBs 
Status 
Positive 
Positive 
Negative 
Positive (chronic infection)* 
Positive  
Negative  
Negative 
Positive (chronic infection) 
Negative 
Positive 
Positive 
Positive (past HBV exposure, now 
immune)** 
Negative 
Positive 
Negative 
Positive (chronic infection or past 
HBV exposure)** 
Negative 
Negative 
Positive 
Negative (prior vaccination, now 
immune) 
Negative 
Negative 
Negative 
Negative 
* At high risk for HBV reactivation due to chemotherapy. Consider ordering confirmatory 
HBV DNA.  
** At risk for reactivation due to chemotherapy, although risk is lower than those who are 
HBsAg-positive. Consider ordering confirmatory HBV DNA. 
 
Three HBV screening tests should be done to determine HBV status: HBsAg: hepatitis B 
surface antigen; anti-HBc: antibody to hepatitis B core antigen (total Ig or IgG, but not IgM 
only); anti-HBs: antibody to hepatitis B surface antibody.  
  
 
Refer to protocol Section 10.2a for the definition for HBV reactivation. 
 
HCV STATUS BASED ON HCV TEST RESULTS 
 
Results of Standard Tests 
 
anti-HCV Screening 
Test 
anti-HCV 
Confirmatory Test 
HCV 
(CIA or EIA) 
(HCV RNA) 
Status 
Positive 
Detectable 
Positive (active infection) 
Positive 
Not detectable 
Negative (prior infection) 
Negative 
Not needed 
Negative 
 
CIA: chemiluminescence immunoassay; EIA: enzyme immunoassay. 
 
HIV STATUS BASED ON HIV TEST RESULTS 
 
Results of Standard Tests 
 
Antibody OR combination Antigen 
and Antibody Test 
(Rapid HIV Antibody, EIA or ELISA) 
Western Blot  
Confirmatory 
Test 
HIV 
Status 
Positive 
Positive 
Positive 
Positive 
Negative 
Negative* 
Negative 
Not needed 
Negative* 
 


 
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Rapid HIV antibody test:  dot blot or immunoblot; EIA: enzyme immunoassay; ELISA: 
enzyme-linked immunosorbent assay; PCR: Polymerase Chain Reaction. 
 
* If the patient is suspected to have acute retroviral infection, viral load (by PCR) should 
be obtained to confirm HIV status.  
 
CONFIRMATORY TESTING  
 
Tests for viral load (viral DNA or RNA) are typically done as confirmation of a positive 
screening test or to monitor patients who are known to have positive viral test results. Viral 
load tests should not be ordered as primary screening tests. Upload source documentation 
for both the initial and the confirmatory testing results in Rave. 
 
FEDERAL GUIDANCE: GUIDELINES AND RECOMMENDATIONS 
 
Please refer to the following links for more information on federal guidelines and 
recommendations for testing.  
 
HBV: http://www.cdc.gov/hepatitis/HBV/TestingChronic.htm  
HCV: http://www.cdc.gov/hepatitis/hcv/guidelinesc.htm  
HIV: http://www.cdc.gov/hiv/guidelines/testing.html  
 
 
 


 
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18.4 
Intake Calendar 
 
Site Staff Instructions: There is the option for site staff to instruct patients to submit the 
Intake Calendar electronically (See Section 7.1b).  
 
(Intake Calendar Page 1) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SWOG Patient ID________  Patient Initials (L, F, M) ________ SWOG Study #__________
 
 
 
Institution/Affiliate _______________________  Physician _____________________________ 
Instructions for the participant: 
This is a monthly calendar on which you are to record the number of tablets/pills/capsules you 
take each day.  Be sure you have enough calendars to last until your next appointment.  If you 
develop any side effects from the tablets/pills/capsules, mark this on the calendar on the day 
you note the effect.  Bring your calendars with you each time you have an appointment. 
 
If you have questions contact: ____________________ Telephone: _____________________ 
 
Your study drug is: _____________________________ 
 
Your next appointment is: _______________________ 
Special instructions: Please note the following instructions when taking your an antiviral study 
drug: 
• 
Take all of your doses as scheduled; do not miss a dose.  If you forget a dose, take it as 
soon as possible, as long as it is at least 12 hours before your next dose is due.  If your 
next dose is due within the next 12 hours, skip the missed dose. 
• 
The antiviral drug is an oral administration, to be taken as a whole tablet. However, the 
tablet can be crushed, split or administered via feeding tube with guidance from the 
treating physician is permitted. 
• 
Take the antiviral drug with food. 
• 
The antiviral drug has interactions with other drugs.  Tell your doctor you are taking an 
antiviral drug before starting any new medications. 
• 
The antiviral drug can cause damage to your liver (called hepatotoxicity).  This can 
cause stomach pain, nausea, unusual tiredness, dark-colored urine, light-colored stools, 
yellowing of the skin and eyes, loss of appetite, and fever.  If you experience these 
symptoms, contact your doctor immediately. 
• 
The antiviral drug can cause a build-up of lactic acid in your body.  This can cause 
stomach pain, loss of appetite, diarrhea, fast and shallow breathing, general feeling of 
discomfort, muscle pain or cramping, unusual sleepiness, or tiredness.  If you 
experience these symptoms, contact your doctor immediately. 
• 
Talk to your doctor before you stop taking the antiviral drug. 


 
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(Intake Calendar Page 2) 
 
 
Patient Signature: 
 
 
 
Sunday 
Monday 
Tuesday 
Wednesday 
Thursday 
Friday 
Saturday 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SWOG Study # ________________ 
Your Study Drug is: __________________________ 
Month: _______________________ 
Year: ___________________ 


 
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18.5 
Blinded Central Review of Primary Endpoint 
 
The blinded review will be conducted by the Study Chairs, and representatives from the 
SWOG Statistics and Data Management Center, Oncology Nursing Professionals 
Committee, and Committee Leadership. The blinded review will be facilitated by provision 
to the review team of all patient chart information pertaining to the primary endpoint. 
Identifying information about patient identifiers and treatment assignment will be 
abstracted, the information will be compiled into a single PDF for each patient, and 
transmitted to the reviewers in encrypted, password protected electronic files. The blinded 
review will occur at the completion of study follow-up. 
 
 
 


 
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18.6 
Approved Antiviral Therapies in Adults 
 
Dose in 
Use in 
Pregnancy 
Potential 
Drug 
Adults* 
Children* 
Category† 
Side Effects† 
Monitoring on Treatment‡ 
Preferred 
Peg-IFN-a-2a 
(adult) 
IFN-a-2b 
(children) 
180 mcg 
weekly 
;::1 year dose: 
6 million IU/m2 
three times 
weekly§ 
C 
Flu-like symptoms, fatigue, 
mood disturbances, 
cytopenia, autoimmune 
disorders in adults, 
anorexia and weight 
loss in children 
Complete blood count (monthly to every 
3 months) 
TSH (every 3 months) 
Clinical monitoring for autoimmune, 
ischemic, neuropsychiatric, and 
infectious complications 
Entecavir 
0.5 mg 
dailyk 
;::2 years dose: 
weight-based 
to 10-30 kg; 
above 30 kg: 
0.5 mg dailyk 
C 
Lactic acidosis 
(decompensated 
cirrhosis only) 
Lactic acid levels if there is clinical 
concern 
Test for HIV before treatment initiation 
Tenofovir 
dipovoxil 
fumarate 
300 mg 
daily 
;::12 years 
B 
Nephropathy, Fanconi 
syndrome, osteomalacia, 
lactic acidosis 
Creatinine clearance at baseline 
If at risk for renal impairment, creatinine 
clearance, serum phosphate, urine 
glucose, and protein at least annually 
Consider bone density study at baseline 
and during treatment in patients with 
history of fracture or risks for 
osteopenia 
Lactic acid levels if there is clinical 
concern 
Test for HIV before treatment initiation 
Tenofovir 
alafenamide 
Nonpreferred 
25 mg 
daily 
— 
There are insufficient 
human data on 
use during 
pregnancy to 
inform a 
drug-associated 
risk of birth defects 
and miscarriage. 
Lactic acidosis 
Lactic acid levels if clinical concern 
Assess serum creatinine, serum 
phosphorus, creatinine clearance, 
urine glucose, and urine protein before 
initiating and during therapy in all 
patients as clinically appropriate 
Test for HIV before treatment initiation 
Lamivudine 
100 mg 
daily 
;::2 years 
dose: 3 mg/kg 
daily to max 
100 mg 
C 
Pancreatitis 
Lactic acidosis 
Amylase if symptoms are present 
Lactic acid levels if there is clinical 
concern 
Test for HIV before treatment initiation 
Adefovir 
10 mg 
daily 
Telbivudine 
600 mg 
daily 
;::12 years 
C 
Acute renal failure 
Fanconi syndrome 
Lactic acidosis 
 
 
 
 
 
 
 
— 
B 
Creatine kinase elevation 
and myopathy 
Peripheral  neuropathy 
Lactic acidosis 
Creatinine clearance at baseline 
If at risk for renal impairment, creatinine 
clearance, serum phosphate, urine 
glucose, and urine protein at least 
annually 
Consider bone density study at baseline 
and during treatment in patients with 
history of fracture or risks for 
osteopenia 
Lactic acid levels if clinical concern 
Creatine kinase if symptoms are present 
Clinical evaluation if symptoms are 
present 
Lactic acid levels if there is clinical 
concern 


 
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* Dose adjustments are needed in patients with renal dysfunction. 
†In 2015, the U.S. Food and Drug Administration replaced the pregnancy risk designation by letters A, B, 
C, D, and X with more speciﬁc language on pregnancy and lactation. This new labeling is being phased in 
gradually, and to date only TAF includes these additional data. 
‡Per package insert. 
§Peg-IFN-a-2a is not approved for children with chronic hepatitis B, but is approved for treatment of chronic 
hepatitis C. Providers may consider using this drug for children with chronic HBV. The duration of treatment 
indicated in adults is 48 weeks. 
kEntecavir dose is 1 mg daily if the patient is lamivudine experienced or if they have decompensated 
cirrhosis. 
Abbreviation: TSH, thyroid stimulating hormone. 
https://aasldpubs.onlinelibrary.wiley.com/doi/pdfdirect/10.1002/hep.29800