Clinical trial NCT02717949
Conditions: Liver Disease
Keywords: hepatitis C low-grade lymphoma
Sponsor: University of Texas Southwestern Medical Center
Start date: 2016-02-25; Completion date: 2017-07-18
Enrollment: 1 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
There still remains the question if hepatitis C eradication with all oral therapy will lead to a regression or cure of the low grade lymphoma. Thus, the hypothesis of this study is that oral HCV therapy will lead to a high rate of hepatitis C eradication which will correlate with a reduction of the size and extent of low-grade lymphoma. The hypothesis of this study is that subjects with hepatitis C,regardless of genotype, who have low grade lymphoma, when treated for hepatitis C without pegylated interferon will have a regression of low grade non-Hodgkin's lymphoma. In this pilot study we will evaluate the effect of Sofosbuvir/ledipasvir or sofosbuvir/ribavirin based antiviral therapy on the course of a subset of HCV-related low grade B cell non-Hodgkin's lymphoma

Primary Objective This study will assess the safety, as measured by adverse events, in subjects receiving hepatitis C treatment.

Secondary Objective The secondary objective of this study is to assess the rate of overall response of B cell non-Hodgkin's lymphoma defined as either as partial response or complete response according to revised international working group criteria for non-Hodgkin lymphoma.

Primary Endpoint Safety and tolerability of sofosbuvir/ledipasvir or sofosbuvir/ribavirin in subjects with B-cell non-Hodgkin's lymphoma will be assessed by number of adverse events and serious adverse events. In addition, the study will assess the number of subjects who had to stop treatment due to adverse events or serious adverse events. The study will also examine the number of subjects in which treatment for lymphoma had to be given due to clinical progression.

Secondary Endpoints The secondary endpoint(s) of this study is to (1) Assess the rate of overall response of B-cell Non-Hodgkin's lymphoma defined as either as partial response or complete response according to revised international working group criteria for non-Hodgkin lymphoma. (2) Determine the rate of sustained viral response in subjects with low-grade lymphoma.

Detailed description:
Methods and Study Design

The study will plans to enroll approximately 21 subjects over the next 6-12 months for this study.

Subjects with low grade lymphoma with confirmed diagnosis of hepatitis C with a viral load \> 1000 will be included in this study. Subjects may be treatment naïve or experienced to hepatitis C therapy, however subjects must be treatment naïve to non-Hodgkin's lymphoma treatment to be included in this study. All subjects will undergo staging studies at the time of study screening which will include a whole body scans and a bone marrow biopsy. In those with a prior bone marrow biopsy, those who had bone marrow involvement and biopsy was \<3 months from screening, then an additional biopsy is not needed. If bone marrow biopsy did not show bone marrow involvement, a repeat bone marrow biopsy is needed at screening. If complete data is not available from a prior biopsy, a repeat bone marrow biopsy will need to be done. In addition, patients will have staging of liver disease by serologic markers of liver inflammation, such as aspartate aminotransferase (AST) to platelet ratio (APRI) and FibroTest® or (Fibro Sure®) or FibroScan®. If these methods are inconclusive, then a liver biopsy may be obtained to determine if the patient has cirrhosis. Patients will be treated regardless of stage of fibrosis. The rationale for examining cirrhosis is that these patients may not respond as well and will require further surveillance for hepatocellular cancer every 6 months. Additionally, hepatitis C viral load and genotype will be determined prior to initiation of hepatitis C treatment.

Setting:

This will be a multi- center study conducted at University of Texas Southwestern Medical Center, Cornell Medical Center, and Memorial Sloan Kettering Cancer Center. Each site would be expected to enroll 7 subjects in 6-12 months.

Treatment

Genotype 1:

Treatment Naïve, with or without cirrhosis: sofosbuvir/ledipasvir one pill once a day for 12 weeks.

Treatment experienced, with cirrhosis: sofosbuvir/ledipasvir one pill once a day with weight-based ribavirin for 12 weeks. Weight-based ribavirin refers to use 1200 mg of ribavirin in divided doses for those ≥75 kg and 1000 mg in divided dose for those \<75kg.

Treatment experienced with cirrhosis : sofosbuvir/ledipasvir one pill once a day for 24 weeks. This option is for subjects who are unable to take ribavirin.

Genotype 2:

Treatment naïve or experienced without cirrhosis: sofosbuvir 400mg once daily and ribavirin 1000/1200 mg weight-based dosing in divided dose twice a day for 12 weeks.Treatment naïve or experienced with cirrhosis: sofosbuvir 400 mg and weight-based ribavirin for 16 weeks

Genotype 3:

Treatment naïve, non-cirrhotic: sofosbuvir/ledipasvir fixed dose combination combined with weight-based ribavirin for 12 weeks or treatment naïve with cirrhosis: sofosbuvir 400 mg daily with weight-based ribavirin for 24 weeks.

Treatment experienced with cirrhosis will be excluded as the best treatment for this population would require pegylated interferon.

Genotype 4:

Treatment naïve with or without cirrhosis or treatment experienced without cirrhosis: sofosbuvir/Ledipasvir fixed dose combination for 12 weeks.

Treatment experienced with cirrhosis: sofosbuvir/ledipasvir for 24 weeks.

Arms: arm 1: sofosbuvir and ledipasvir fixed dose combination given orally once a day for genotype 1 and 4. arm 2: Sofosbuvir 400 mg given orally once a day with weight-base ribavirin of 1200 mg for those \>75 kg and 1000 mg for those \<75kg given in divided dose twice a day. This intervention is for genotype 2 and 3
Interventions: intervention 1: sofosbuvir/ledipasvir intervention 2: sofosbuvir intervention 3: Ribavirin
Intervention descriptions: intervention 1: sofosbuvir ledipasvir fixed dose combination given once a day by mouth intervention 2: sofosbuvir 400 mg given one a daily orally and weight-based ribavirin given twice a day orally intervention 3: ribavirin 1200 mg given orally in divided dose for those \>75kg and 1000 mg in divided dose for those \<75 kg.

Protocol documents:
Prot_SAP_000.pdf: 
 
CONFIDENTIAL 
This material is the property of the UTSW Simmons Cancer Center. Do not disclose or use except as authorized in writing by the 
study sponsor. 
 
Template Updated: 12/2012; 9/2013; 8/2014; 4/2015; 10/2015 
 
 
Oral HePatitis C Treatment for Indolent Lymphoma (OPTImaL) Study  
 
Principal Investigator:  
Mamta K. Jain, MD, MPH 
 
 
 
 
Infectious Diseases 
 
 
 
 
UT Southwestern Medical Center 
 
 
 
 
5323 Harry Hines Blvd. 
 
 
 
 
Dallas, Texas 75390-9113 
 
 
 
 
214-648-6703 
 
 
 
 
214-590-2689 
 
 
 
 
Mamta.jain@utsouthwestern.edu 
 
Sub-Site PI/ Investigators:  
 Sonal Kumar, MD 
 
 
 
 
GI/Liver Disease 
 
 
 
 
 Weil Cornell Medical Center 
 
 
 
 
1305 York Ave 
 
 
 
 
New York, New York 10021 
 
 
 
 
 
Jia Ruan, MD 
 
 
 
 
Hematology/Oncology 
 
 
 
 
 Weil Cornell Medical Center 
 
 
 
 
1305 York Ave 
 
 
 
 
New York, New York 10021 
 
 
 
 
 
 
Maya Gambarin-Gewlan, MD 
 
 
 
 
GI/Liver Disease 
 
 
 
 
Memorial Sloan Kettering 
 
 
 
 
1275 York Avenue 
 
 
 
 
New York, New York 10065 
 
 
 
 
 
Lia Palomba, MD 
 
 
 
 
Hematology/Oncology 
 
 
 
 
Memorial Sloan Kettering 
 
 
 
 
1275 York Avenue 
 
 
 
 
New York, New York 10065 
 
 
 
 
 
Harris  Nania, MD 
 
 
 
 
Hematology/Oncology  
 
 
 
 
Plaza Medical Center of Forth Worth 
 
 
 
 
900 Eight Avenue 
 
 
 
 
Fort Worth, TX 76104 
 
 
 
 
Sub-Investigators (at UT)  
Robert Collins, MD 
 
 
 
 
Hematology/Oncology 
 
 
 
 
UT Southwestern Medical Center 
 
 
 
 
5323 Harry Hines Blvd. 
 
 
 
 
Dallas, Texas 75390  
 
 
 
 
 
 
 
 
 
Madhuri Vusirikala, MD 
 
 
 
 
Hematology/oncology 


 
CONFIDENTIAL 
This material is the property of the UTSW Simmons Cancer Center. Do not disclose or use except as authorized in writing by the 
study sponsor. 
 
Template Updated: 12/2012; 9/2013; 8/2014; 4/2015; 10/2015 
 
 
 
 
 
 UT Southwestern Medical Center 
 
 
 
 
5323 Harry Hines  
 
 
 
 
Dallas, Texas 75390 
 
 
 
 
 
 
Prapti Patel, MD 
 
 
 
 
Hematology Oncology 
 
 
 
 
UT Southwestern Medical Center 
 
 
 
 
5323 Harry Hines Blvd. 
 
 
 
 
Dallas, Texas 75390  
 
 
 
 
 
Siayareh Rambally, MD 
 
 
 
 
Hematology Oncology 
 
 
 
 
UT Southwestern Medical Center 
 
 
 
 
5323 Harry Hines Blvd. 
 
 
 
 
Dallas, Texas 75390  
 
 
 
 
 
 
Jenny Li, MD 
 
 
 
 
Hematology Oncology 
 
 
 
 
UT Southwestern Medical Center 
 
 
 
 
5323 Harry Hines Blvd. 
 
 
 
 
Dallas, Texas 75390  
 
 
 
 
 
Biostatistician: 
 
Beverley Huet 
 
 
 
 
UT Southwestern Medical Center 
 
 
 
 
5323 Harry Hines Blvd 
 
 
 
 
Dallas, Texas 75390 
 
 
 
 
 214-648-2788 
 
 
 
 
Beverley.Huet@utsouthwestern.edu 
 
Study Drug: 
 
 
Ribavirin, Sofobuvir, Sofosbuvir/Ledipasvir (Harvoni) 
 
 
 
 
Sofosbuvir/Velpatasvir 
 
Funding Source:  
Gilead Sciences, Inc. – IN-US-337-1811 
 
Initial version: 
Version 4   
 
Amended: 
 
6/12/16 
 
 
UT Southwestern Medical Center (UTSW) 
HIV/ID Research Unit  
1936 Amelia Court 
2nd floor Research Unit 
Dallas, Texas 75235 
 


 
CONFIDENTIAL 
This material is the property of the UTSW Simmons Cancer Center. Do not disclose or use except as authorized in writing by the 
study sponsor. 
 
Template Updated: 12/2012; 9/2013; 8/2014; 4/2015; 10/2015 
 
 
Signature Page 
 
 
The signature below constitutes the approval of this protocol and the attachments, and provides the 
necessary assurances that this trial will be conducted according to all stipulations of the protocol, including 
all statements regarding confidentiality, and according to local legal and regulatory requirements and 
applicable U.S. federal regulations and ICH guidelines. 
 
 
 
Principal Investigator (PI) Name:_____________________________ 
 
 
 
PI Signature: _____________________________ 
 
 
 
Date:____________________ 
 


Gilead IN-US-337-1811 
Version 3. 19/MAR/2016 
Protocol Number (SCCC-01416)  
______________________________________________________________________________ 
i 
TABLE OF CONTENTS 
LIST OF ABBREVIATIONS ............................................................................................. 7 
STUDY SCHEMA............................................................................................................... 9 
STUDY SUMMARY ......................................................................................................... 10 
1.0 
BACKGROUND AND RATIONALE ................................................................. 11 
1.1 
Background ............................................................................................................ 11 
1.2 
Treatment ..................................................................................................................... 12 
1.2.1 
Rationale for Sofosbuvir and Lediapasvir fixed dose combination ....................... 12 
1.2.2 Sofosbuvir and Ledipasvir (SOF/LDV) Common Adverse Events ................... 13 
1.2.3 Rationale for Sofosbuvir and ribavirin ................................................................ 14 
1.2.4 Sofosbuvir Common Adverse Events ................................................................... 16 
1.2.5 Ribavirin Common Adverse Events ..................................................................... 17 
1.3 
Other Agents........................................................................................................... 17 
1.4 
Rationale ................................................................................................................. 18 
1.5 
Correlative Studies................................................................................................. 19 
2.0 
STUDY OBJECTIVES .......................................................................................... 19 
2.1 
Primary Objectives ................................................................................................ 19 
2.2 
Secondary Objectives............................................................................................. 19 
2.3 
Endpoints ................................................................................................................ 19 
3.0 
Subject ELIGIBILITY .......................................................................................... 19 


Gilead IN-US-337-1811 
Version 3. 19/MAR/2016 
Protocol Number (SCCC-01416)  
______________________________________________________________________________ 
ii 
3.1 
Inclusion Criteria ................................................................................................... 19 
3.2 
Exclusion Criteria .................................................................................................. 21 
4.0 
TREATMENT PLAN ............................................................................................ 21 
4.1 
Treatment Dosage and Administration ............................................................... 21 
4.1.1 
Genotype 1: .................................................................................................................. 21 
4.1.2 
Genotype 2: .................................................................................................................. 22 
4.1.3 
Genotype 3: .................................................................................................................. 22 
4.1.4 Genotype 4: ............................................................................................................. 22 
4.2 
Toxicities and Dosing Delays/Dose Modifications ............................................... 23 
4.2.1 Dose reduction or discontinuation of RBV .......................................................... 23 
4.3 
Concomitant Medications ..................................................................................... 23 
4.4 
Other Modalities or Procedures ........................................................................... 25 
4.5 
Duration of Treatment .......................................................................................... 25 
4.6 
Duration of Follow Up ........................................................................................... 25 
4.7 
Removal patients from Protocol Therapy ........................................................... 25 
4.8 
Subject  Replacement ................................................ Error! Bookmark not defined. 
5.0 
STUDY PROCEDURES ....................................................................................... 26 
5.1 
Screening and Baseline .............................................................................................. 26 
5.1.2.1 
Informed Consent ........................................................................................... 27 
5.1.2.2 
Medical History............................................................................................... 27 
5.1.2.3 
Review Subject inclusion /exclusion criteria ................................................ 27 


Gilead IN-US-337-1811 
Version 3. 19/MAR/2016 
Protocol Number (SCCC-01416)  
______________________________________________________________________________ 
iii 
5.1.2.4 
Concomitant Medications .............................................................................. 27 
5.1.2.5 
Vital Signs ........................................................................................................ 28 
5.1.2.6 
Labs .................................................................................................................. 28 
5.1.2.7 
Pregnancy Testing .......................................................................................... 28 
5.1.2.8 
Blood and Tissue for storage for future studies and back-up .................... 28 
5.1.2.9 
Karnofsky Score ............................................................................................. 29 
5.1.2.10 Creatinine Clearance ...................................................................................... 29 
5.1.2.11 Body Mass Index (BMI) ................................................................................. 29 
5.1.2.1 
Whole Body PET/CT SCAN .......................................................................... 29 
5.1.1.1 
Complete Physical Examination .................................................................... 29 
5.1.1.2 
Drug dispensation ........................................................................................... 29 
5.2 
Procedures During Treatment .............................................................................. 30 
5.2.1.1 
Adverse Event Log.......................................................................................... 30 
5.2.1.2 
Targeted PE..................................................................................................... 30 
5.3 
Procedures Post-Treatment .................................................................................. 32 
5.3.4.1 
Bone Marrow biopsy ...................................................................................... 33 
5.4 
Time and Events Table .......................................................................................... 35 
5.5 
Removal of Subjects from Study .......................................................................... 36 
5.5.1 Subject voluntarily withdraws from treatment (follow-up permitted); ........... 36 
5.5.2 Subject withdraws consent (termination of treatment and follow-up); ............ 36 


Gilead IN-US-337-1811 
Version 3. 19/MAR/2016 
Protocol Number (SCCC-01416)  
______________________________________________________________________________ 
iv 
5.5.3 Subject is unable to comply with protocol requirements; .................................. 36 
5.5.4 Subject demonstrates disease progression ........................................................... 36 
5.5.5 Subject experiences toxicity that makes continuation in the protocol unsafe;. 36 
5.5.6 Treating physician judges continuation on the study would not be in the subject’s 
best interest ........................................................................................................................ 36 
5.5.7 Subject  becomes pregnant .................................................................................... 36 
5.5.8 Development of second malignancy ..................................................................... 36 
6.0 
MEASUREMENT EFFECT ................................................................................. 36 
6.1 
HCV Treatment Response: ................................................................................... 36 
6.2 
Lymphoma Treatment Response.......................................................................... 37 
6.3 
Safety and Tolerability .......................................................................................... 40 
7.0 
ADVERSE EVENTS AND SERIOUS EVENTS ................................................ 40 
7.1 
Experimental Therapy........................................................................................... 40 
7.2 
Adverse Events Monitoring .................................................................................. 40 
7.2.1 Definition ................................................................................................................ 40 
7.2.2 Unanticipated Problems: ....................................................................................... 42 
7.2.3 Reporting ................................................................................................................ 42 
7.3 
Steps to Determine If an Adverse Event Requires Expedited Reporting ......... 43 
7.4 
Unblinding Procedures .......................................................................................... 44 
7.5 
Stopping Rules ........................................................................................................ 44 
8.0 
DRUG INFORMATION ....................................................................................... 44 


Gilead IN-US-337-1811 
Version 3. 19/MAR/2016 
Protocol Number (SCCC-01416)  
______________________________________________________________________________ 
v 
8.1 
Sofosbuvir ............................................................................................................... 44 
8.2 
Sofosbuvir/ledipasvir ............................................................................................. 45 
8.3 
Ribavirin ................................................................................................................. 46 
8.3.1 Return and Retention of Study Drug ................................................................... 46 
9.0 
CORRELATIVES/SPECIAL STUDIES ............................................................. 47 
10.0 STATISTICAL CONSIDERATIONS ................................................................. 48 
10.1 Study Design/Study Endpoints ............................................................................. 48 
10.2 Sample Size and Accrual ....................................................................................... 49 
10.3 Data Analyses Plans ............................................................................................... 49 
11.0 Other Risks Related to Study Participation ........................................................ 49 
11.1 Viral Resistance ...................................................................................................... 49 
11.2 Loss of Confidentiality ........................................................................................... 49 
11.3 Risks to Sperm, Embryo, Fetus or Breast-fed Infant ......................................... 49 
11.3.1 
Women Only ................................................................................................... 50 
11.3.2 
Men Only ......................................................................................................... 50 
11.4 Risks of Radiation – Diagnostic Test .................................................................... 51 
11.5 Risks of Blood Drawing ......................................................................................... 51 
12.0 STUDY MANAGEMENT ..................................................................................... 51 
12.1 Conflict of Interest ................................................................................................. 51 
12.2 Institutional Review Board (IRB) Approval and Consent ................................. 51 


Gilead IN-US-337-1811 
Version 3. 19/MAR/2016 
Protocol Number (SCCC-01416)  
______________________________________________________________________________ 
vi 
12.3 
Required Documentation (for multi-site studies) ..................................................... 52 
12.3.1 
Registration/Randomization Procedures ..................................................... 52 
12.3.2 
Data Management and Monitoring/Auditing .............................................. 53 
12.3.3 
Method and Frequency of Analysis: ............................................................. 54 
12.3.4 
Reporting Unanticipated Problems .............................................................. 54 
12.3.5 
Adherence to the Protocol .............................................................................. 55 
12.3.6 
Amendments to the Protocol ......................................................................... 56 
12.3.7 
Record Retention ............................................................................................ 56 
12.3.8 
Obligations of Investigators ........................................................................... 57 
13.0 REFERENCES ....................................................................................................... 57 
14.0 APPENDICES ........................................................................................................ 58 
14.1 Appendix 1: Karnofsky Performance Status Scale............................................. 58 
14.2 
Appendix 2.  Follicular Lymphoma International Prognostic Index 2 (FLIPI2) ………….59 
Prognostic score for untreated follicular lymphoma ..................................................... 59 
Applies at the time of first treatment. ............................................................................. 59 


Gilead IN-US-337-1811 
Version 3. 19/MAR/2016 
Protocol Number (SCCC-01416)  
______________________________________________________________________________ 
7 
LIST OF ABBREVIATIONS 
AASLD 
American Association for the Study of Liver Disease 
ACD 
Anticoagulant 
AE 
Adverse Event 
ALT 
Alanine Aminotransferase 
APRI 
AST to Platelet Ratio Index 
AST 
Aspartate Aminotransferase 
BCRP 
Breast Cancer Resistance Protein 
BID 
Twice a day 
BMI 
Body Mass Index 
BUN 
Blood Urea Nitrogen 
BW 
Body weight 
CAP 
College of American Pathologists 
CBC 
Complete Blood Count 
CLIA 
Clinical Laboratory Improvement Amendments  
CMP 
Comprehensive Metabolic Panel 
CT 
Computed Tomography 
CV 
Curriculum Vitae 
DAIDS 
Division of AIDS 
dL 
Deciliter 
DNA 
Deoxyribonucleic acid 
EDTA 
Ethylenediaminetetraacetic acid 
FDA 
Food and Drug Administration 
FDC 
Fixed-dose Combination 
FDG 
Fluorodeoxyglucose 
FLIPI 
Follicular Lymphoma International Prognostic Index 
g 
Gram 
GCP 
Good Clinical Practice 
HCC 
Hepatocellular Carcinoma 
HCV 
Hepatitis C 
Hg 
Hemoglobin 
HIV 
Human immunodeficiency virus 
IDSA 
Infectious Disease Society of America 
IFN 
Interferon 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
LD 
Longest diameter 
Kg 
Kilogram 
kPA 
Kilopascal 
LDH 
Lactate Dehydrogenase 
LDV 
Ledipasvir 
LFTS 
Liver Function Tests 


Gilead IN-US-337-1811 
Version 3. 19/MAR/2016 
Protocol Number (SCCC-01416)  
______________________________________________________________________________ 
8 
LLOQ 
Lower limit of quantification 
MC 
Mixed cryoglobulinemia 
Mcg 
Microgram 
NCI 
National Cancer Institute 
NHL 
Non-Hodgkins Lymphoma 
NS5A 
Non-structural 5A 
PCR 
Polymerase chain reaction 
PD 
Progressive Disease 
PE 
Physical Exam 
PEG 
Pegylated interferon 
PET 
Positron Emission Tomography 
PFS 
Progression Free Survival 
P-gp 
P-glycoprotein 
PK 
pharmacokinetics 
PR 
Partial Response 
PT 
Prothrombin time 
PTT 
Partial thromboplastin time 
RBV 
Ribavirin 
REDCap 
Research Electronic Data Capture 
RNA 
Ribonucleic Acid 
SAE 
Serious Adverse Event 
SCCC 
Simmons Comprehensive Cancer Center 
Scr 
Serum creatinine 
SD 
Stable disease 
sMZL 
Splenic Marginal Zone Lymphoma 
SPD 
Sum of productions of the diameters 
SOC 
Standard of care 
SOF 
Sofosbuvir 
SVR 
Sustained Viral response 
d. bili 
Direct bilirubin 
T. bili 
Total bilirubin 
UTSW 
University of Texas Southwestern Medical Center 
VL 
Viral load 
 
 
 
 
 
 


Gilead IN-US-337-1811 
Version 3. 19/MAR/2016 
Protocol Number (SCCC-01416)  
______________________________________________________________________________ 
9 
 
STUDY SCHEMA 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 Lymphoma Assessment  
Post-treatment week 12 and 36 by PET/CT scan 
   
Viral Relapse (Positive HCV RNA 
12 weeks after treatment 
 
Sustained Viral Response (no 
HCV RNA detected 12 weeks 
post treatment) 
Patient registration/enrollment 
Lymphoma Evaluation by PET/CT Scan and 
Bone Marrow Biopsy 
Liver Disease Evaluation by blood testing/fibroscan  
(genotype, fibrosis stage) 
HCV treatment with either  
Sofosbuvir/ledipasvir or  
Sofosbuvir/ribavirin or 
Sofosbuvir/velpatasvir for 12-24 weeks 
 
Complete Response/Partial 
Response 
And further assessed by bone 
marrow biopsy 
 
 
Disease Progression 
Adverse Events Assessment 


Gilead IN-US-337-1811 
Version 3. 19/MAR/2016 
Protocol Number (SCCC-01416)  
______________________________________________________________________________ 
10 
STUDY SUMMARY 
Title 
Oral HePatitis C Treatment for Indolent Lymphoma Study 
Short Title 
OPTImal 
Protocol Number 
STU 042015-086 
Phase 
IV 
Methodology 
This is a prospective, open-label, non-randomized interventional trial 
Study Duration 
 2 years  
Study Center(s) 
Multi-center: UT Southwestern, Weil-Cornell Medical Center,  Memorial 
Sloan Kettering 
Objectives 
This study will assess the safety, as measured by adverse events, in 
patients receiving Hepatitis C (HCV) treatment; lymphoma response; and 
sustained HCV viral response 
Number of Subjects 
21 
Diagnosis and Main 
Inclusion Criteria 
Patients must have hepatitis C and have low grade lymphoma that is 
stable and does not require chemotherapy.  
Study Product(s), Dose, 
Route, Regimen 
Ribavirin, Sofosbuvir (Sovaldi),  Sofosbuvir/Ledipasvir (Harvoni), 
Sofosbuvir/velpatasvir 
Duration of administration 
12 weeks to 24 weeks depending on HCV genotype and stage of fibrosis 
and treatment regimen selected 
Reference therapy 
There is no reference therapy; this is an exploratory study 
Statistical Methodology 
The statistical analysis will be primarily descriptive. Descriptive statistics 
(e.g., mean, median, ranges, and frequencies) will be used to summarize 
AEs, SAEs, HCV treatment discontinuation and lymphoma treatment 
initiation.   In addition these descriptive statistics will be used to for 
partial and complete response and SVR.   95% confidence intervals will 
be used to summarize the response for lymphoma and HCV. Any 
hypothesis testing will be considered exploratory and interpreted 
cautiously. 
 
 
 


Gilead IN-US-337-1811 
Version 3. 19/MAR/2016 
Protocol Number (SCCC-01416)  
______________________________________________________________________________ 
11 
 
1.0 
BACKGROUND AND RATIONALE 
1.1 
Background 
Over 180 million people worldwide are chronically infected with the hepatitis C virus (HCV), a 
hepatotropic and potentially lymphotropic virus. HCV infection frequently leads to chronic 
hepatitis and is a major cause of liver cirrhosis and its sequelae such as hepatocellular carcinoma 
(HCC). While hepatocytes are the main reservoir and replication space for the virus, HCV is also 
potentially lymphotropic. A large body of clinical data supports the association of HCV infection 
and B-Non-Hodgkin’s lymphoma (NHL). Epidemiologic studies, therapeutic approaches, and 
experimental data gathered in the last two decades established not only the mere association of 
viral infection and tumor development, but also suggests a causal relationship; e.g., sequencing 
of the Ig M heavy chain of patients with mixed cryoglobulinemia (MC) with and without B-NHL 
showed clonal B-cell expansion in 100% of HCV infected individuals in the peripheral blood. In 
a recent study of transgenic mice HCV genome was expressed in B cells which led to the 
development of NHL, thus further supporting the role of HCV in the pathogenesis of NHL.  The 
most compelling argument for a causal relationship between HCV and B-NHL is made by 
interventional studies demonstrating that a sustained virologic response (SVR) to antiviral 
treatment containing alfa interferon and ribavirin treatment induced a regression of HCV-
associated lymphomas and a viral relapse of HCV after initial virologic response led to 
lymphoma recurrence. 
 
Hermine et al. evaluated the effect of HCV infection and antiviral therapy on the course of 
splenic marginal zone lymphoma (sMZL) with villous lymphocytes. Nine patients with HCV 
associated sMZL and 6 patients without HCV received recombinant interferon alfa-2b 
subcutaneously three times a week for six months. All nine patients had a negative HCV RT-
PCR assay after antiviral therapy. Of the nine patients with HCV infection who received alfa 
interferon, seven had complete remission after the loss of detectable HCV RNA. The other two 
patients had a partial and complete remission after the addition of ribavirin and the loss of 
detectable HCV RNA. In contrast, none of the six HCV-negative patients had a response to 
interferon therapy. 
 
A small multicenter prospective study conducted by Valliesa et al in which patients were treated 
with pegylated interferon alfa-2b 1.5 mcg/kg subcutaneously once a week and ribavirin 1,000 mg 
orally daily for 6 months, showed that of thirteen assessable patients with low grade lymphomas 
(one follicular lymphoma, four lymphoplasmacytic lymphomas, and eight marginal zone 
lymphomas), seven (58%) achieved complete response and two (16%) partial hematologic 
response at 14.1 -9.7 months (range, 2 to 24 months, median follow-up, 14 months), while two 
had stable disease with only one patient experiencing progression of disease.  Hematologic 
responses (complete and partial, 75%) were highly significantly associated with clearance or 
decrease in serum HCV viral load following treatment (P= .005). Virologic response was more 
likely to be seen in HCV genotype 2 (P= 0.035), while hematologic response did not correlate 
with the viral genotype. Treatment-related toxicity did not cause discontinuation of therapy in all 
but two patients, one of whom, however, achieved complete response1 . A recent 
epidemiological study from Italy showed 59% of HCV infection is due to genotype 2 and 


Gilead IN-US-337-1811 
Version 3. 19/MAR/2016 
Protocol Number (SCCC-01416)  
______________________________________________________________________________ 
12 
remaining genotype 1.   However, in the US, the predominant genotype is 1a/b followed by 
genotypes 2 and 3.  These data suggest that treatment of HCV can treat low-grade B cell 
lymphoma. What remains unclear is if improvement of B-NHL is due, in part, to the indirect 
effect of interferon and cytokine modulation or if clearance of HCV itself leads to the response.   
  
A recent retrospective analysis of 704 HIV-negative, HCV-positive, and patients with indolent 
NHL found the 5 year-survival was 78% and 5-year progression free survival was 48%. In a 
multivariate analysis, treatment for hepatitis C improved 5-year survival.  Forty-four percent of 
those treated for HCV had a complete response and 33% had a partial response.  The treatments 
occurred between 1993 and 2009 when interferon-based treatment was the only treatment option.  
Pegylated interferon and ribavirin combination therapy has efficacy of 40-50% in genotype 1 and 
60-70% in genotype 2 and 3.  However, new treatments for HCV is currently interferon free, all 
oral regimen(s), with high efficacy. 
 
1.2 
Treatment 
 
1.2.1 
Rationale for Sofosbuvir and Ledipasvir fixed dose combination 
 The combination of SOF 400 mg and LDV 90 mg has been administered in   Phase 2 and Phase 
3 studies to over 1600 subjects. After oral administration of SOF/LDV, SOF is rapidly absorbed 
and subject to extensive first-pass hepatic extraction. In clinical pharmacology studies, both 
Sofosbuvir and its inactive metabolite GS-331007 were monitored for purposes of 
pharmacokinetic analyses. Ledipasvir is an inhibitor of the drug transporters P-gp and breast 
cancer resistance protein (BCRP) and may increase intestinal absorption of co-administered 
substrates for these transporters. Ledipasvir and Sofosbuvir are substrates of drug transporters P-
gp and BCRP while GS-331007 is not. P-gp inducers (e.g., rifampin or St. John’s wort) may 
decrease ledipasvir and Sofosbuvir plasma concentrations, leading to reduced therapeutic effect 
of SOF/LDV, and the use with P-gp inducers is not recommended with SOF/LDV.  
 
 The efficacy and safety of Sofosbuvir/ledipasvir were evaluated in four trials in genotype 1 
HCV mono-infected subjects including one trial exclusively in treatment-experienced subjects 
with compensated cirrhosis (Child-Pugh A), one trial in genotype 1 or 4 HCV/HIV-1 co-infected 
subjects, and two trials in genotype 4, 5 or 6 HCV mono-infected subjects.  Sofosbuvir/ledipasvir 
was administered once daily by mouth in these trials. For subjects who received ribavirin (RBV), 
the RBV dosage was 1000 mg per day for subjects weighing less than 75 kg or 1200 mg per day 
for subjects weighing at least 75 kg. RBV dose adjustments were performed according to the 
RBV labeling. Sustained virologic response (SVR12) was the primary endpoint and was defined 
as HCV RNA less than LLOQ at 12 weeks after the cessation of treatment. Relapse was a 
secondary endpoint, which was defined as HCV RNA greater than or equal to LLOQ with 2 
consecutive values or last available post-treatment measurement during the post-treatment period 
after achieving HCV RNA less than LLOQ at end of treatment. 
 
 ION-3 was a randomized, open-label trial in treatment-naïve non-cirrhotic subjects with 
genotype 1HCV. Subjects were randomized in a 1:1:1 ratio to one of the following three 
treatment groups and stratified by HCV genotype (1a vs 1b): Sofosbuvir/ledipasvir for 8 weeks, 
HARVONI for 12 weeks, or HARVONI + ribavirin for 8 weeks. Demographics and baseline 
characteristics of the 647 subjects were balanced across the treatment groups. SVR was 93% in 8 


Gilead IN-US-337-1811 
Version 3. 19/MAR/2016 
Protocol Number (SCCC-01416)  
______________________________________________________________________________ 
13 
week arm and 96% in 12 week arm for genotype 1a. For genotype 1b it was 98% in 8 week and 
12 week arm.  
 
ION-1 was a randomized, open-label trial that evaluated 12 and 24 weeks of treatment with 
Sofosbuvir/ledipasvir with or without ribavirin in 865 treatment-naïve subjects with genotype 1 
HCV including those with cirrhosis. Subjects were randomized in a 1:1:1:1 ratio to receive 
Sofosbuvir/ledipasvir for 12 weeks, Sofosbuvir/ledipasvir + ribavirin for 12 weeks, 
Sofosbuvir/ledipasvir for 24 weeks, or Sofosbuvir/ledipasvir + ribavirin for 24 weeks. 
Randomization was stratified by the presence or absence of cirrhosis and HCV genotype (1a vs 
1b). Demographics and baseline characteristics were balanced across the groups. Ribavirin + 
Sofosbuvir/ledipasvir was not found to impact SVR. SVR was 99% in treatment naïve patients   
without cirrhosis. Those with cirrhosis had SVR of 94%. 
 
ION-2 was a randomized, open-label trial that evaluated 12 and 24 weeks of treatment with 
Sofosbuvir/ledipasvir with or without ribavirin in genotype 1 HCV-infected subjects with or 
without cirrhosis who failed prior therapy with an interferon-based regimen, including regimens 
containing an HCV protease inhibitor. Subjects were randomized in a 1:1:1:1 ratio to receive 
Sofosbuvir/ledipasvir for 12 weeks, Sofosbuvir/ledipasvir + ribavirin for 12 weeks, 
Sofosbuvir/ledipasvir for 24 weeks, or Sofosbuvir/ledipasvir + ribavirin for 24 weeks. 
Randomization was stratified by the presence or absence of cirrhosis, HCV genotype (1a vs 1b) 
and response to prior HCV therapy (relapse/breakthrough vs nonresponse). Demographics and 
baseline characteristics were balanced across the treatment groups. SVR was 94% in 12 week 
and 99% in 24 week group. Those with cirrhosis had SVR in 12 week group of 86% and 100% in 
24 week group.  
 
In two open-label studies (Study 1119 and ION-4), Sofosbuvir/ledipasvir was administered for 
12 weeks to treatment-naïve and previously-treated subjects with genotype 4 HCV infection. 
Study 1119 enrolled 44 treatment-naïve or previously-treated subjects with genotype 4 HCV, 
with or without cirrhosis. ION-4 enrolled 4 treatment-naïve and 4 previously-treated subjects 
with genotype 4 HCV infection who were coinfected with HIV-1, none of whom had cirrhosis.  
In Study 1119, the overall SVR12 rate was 93% (41/44). SVR12 was similar based upon prior 
HCV treatment history and cirrhosis status. In ION-4, all 8 subjects achieved SVR12. 
 
Clinical studies have demonstrate >90% sustained viral response with Sofosbuvir/ledipasvir in 
genotype 1 and 4 patients.  The combination of SOF 400 mg and LDV 90 mg as a fixed dose 
combination was approved by the FDA in October 2014 and will be the key treatment for HCV 
for this study.  
 
Although limited, there is data for the use of Sofosbuvir/ledipasvir with ribavirin in patients with 
HCV genotype 3.  In a phase 2 study, Sofosbuvir/ledipasvir plus ribavirin cured 73% (16/22) 
HCV genotype 3 patients with cirrhosis and 89% (25/28) non-cirrhotic treatment experienced 
patients.  
1.2.2 
Sofosbuvir and Ledipasvir (SOF/LDV) Common Adverse Events 
Sofosbuvir with LDV have been given as two separate tablets and as one FDC tablet to over 
2000 subjects. In the first part of one study, 200 patients who were being treated with the FDC 


Gilead IN-US-337-1811 
Version 3. 19/MAR/2016 
Protocol Number (SCCC-01416)  
______________________________________________________________________________ 
14 
were evaluated 12 weeks after starting therapy. In this group, the most common adverse events 
that occurred in more than 15% of subjects were headache (29%), fatigue (22%), and nausea 
(19%). 
 
Rare, but serious: 
 
One healthy volunteer developed significantly elevated liver tests (ALT) consistent with 
liver damage while taking SOF/LDV with abacavir/lamivudine (medications used to treat HIV). 
The patient’s liver tests were normal after taking 10 days of SOF/LDV and then were elevated 
after taking another 5 days of SOF/LDV with abacavir/lamivudine. All study drugs were stopped 
and his liver tests improved a little but stayed elevated.  Two weeks later, the patient had 
abdominal (belly) pain. An ultrasound showed he had gallstones and mild inflammation of the 
gallbladder.  His gallbladder was removed.  His liver tests completely returned to normal only 
after his gallbladder was removed. We do not know why he had elevated liver tests. The 
investigator thought that the elevated liver tests were related to SOF/LDV and 
abacavir/lamivudine. However, the volunteer’s gallbladder disease may have played a role. 
 
 
One HCV-infected person developed superior mesenteric vein thrombosis (a clot in the 
blood vessel that drains blood from the small intestine) during treatment with SOF and LDV.  
The patient was a 52 year-old man with cirrhosis of the liver.  About two weeks after starting 
treatment, he developed abdominal pain and then nausea and vomiting.  The CT scan at the 
hospital showed a clot partially blocking a vessel draining blood from the small intestine.  He 
was treated with pain medication and blood thinners. The event was considered to be related to 
the study drugs. 
 
 
A serious slowing of the heart rate (symptomatic bradycardia) can occur when this drug 
is used with antiarrhythmic drug amiodarone. This was a warning issued by the Federal Drug 
Administration as a Warnings and Precautions, Drug Interactions, and Postmarketing 
Experience. 
 
1.2.3 
Rationale for Sofosbuvir and ribavirin 
Sofosbuvir 400 mg is pangenotypic inhibitor of NS5B RNA-dependent RNA polymerase, which 
is essential for viral replication. Sofosbuvir is a nucleotide prodrug that undergoes intracellular 
metabolism to form uridine analog triphosphate that leads to chain termination. Sofosbuvir is 
extensively metabolized in the liver to form the pharmacologically active nucleoside analog 
triphosphate GS-461203.  Following a single 400 mg oral dose of [14C]-Sofosbuvir, mean total 
recovery of the dose was greater than 92%, consisting of approximately 80%, 14%, and 2.5% 
recovered in urine, feces, and expired air, respectively. The majority of the Sofosbuvir dose 
recovered in urine was GS-331007 (78%) while 3.5% was recovered as Sofosbuvir. These data 
indicate that renal clearance is the major elimination pathway for GS-331007. The median 
terminal half-lives of Sofosbuvir and GS-331007 were 0.4 and 27 hours, respectively. Sofosbuvir 
is a substrate of drug transporter P-gp and breast cancer resistance protein (BCRP) while GS-
331007 is not. Drugs that are P-gp inducers in the intestine (e.g., rifampin or St. John’s wort) 
may decrease Sofosbuvir plasma concentration, leading to reduced therapeutic effect of 
Sofosbuvir, and thus concomitant use with Sofosbuvir is not recommended. Coadministration of 
Sofosbuvir with drugs that inhibit P-gp and/or BCRP may increase Sofosbuvir plasma 


Gilead IN-US-337-1811 
Version 3. 19/MAR/2016 
Protocol Number (SCCC-01416)  
______________________________________________________________________________ 
15 
concentration without increasing GS-331007 plasma concentration; accordingly, sofosbuvir may 
be coadministered with P-gp and/or BCRP inhibitors. Sofosbuvir and GS-331007 are not 
inhibitors of P-gp and BCRP and thus are not expected to increase exposures of drugs that are 
substrates of these transporters. 
 
RBV is a guanosine analogue that inhibits the in vitro replication of a wide range of RNA and 
DNA viruses. RBV monotherapy has little or no effect on the replication of HCV in vivo but can 
result in normalization of serum ALT activity and improvement in liver histology. When 
combined with IFN or PEG-IFN therapy, RBV decreases substantially the relapse rate seen after 
cessation of IFN therapy. 
Ribavirin is a known teratogen [Food and Drug Administration (FDA) category X]. 
Furthermore, RBV is known to accumulate intracellularly where it is cleared slowly, and is also 
excreted in semen. Therefore, extreme care must be taken to avoid pregnancy during RBV 
therapy and for up to 6 months following completion of treatment (7 months for males). 
 
 
The safety and efficacy of Sofosbuvir was evaluated in five Phase 3 trials in a total of 1724 HCV 
mono-infected subjects with genotypes 1 to 6 chronic hepatitis C virus and one Phase 3 trial in 
223 HCV/HIV-1 co-infected subjects with genotype 1, 2 or 3 HCV. 
 
FISSION was a randomized, open-label, active-controlled trial that evaluated 12 weeks of 
treatment with Sofosbuvir and ribavirin compared to 24 weeks of treatment with peg interferon 
alfa 2a and ribavirin in treatment-naïve subjects with genotype 2 and 3 HCV. The ribavirin 
dosage used in the Sofosbuvir + ribavirin and peg interferon alfa 2a + ribavirin arms were 
weight-based 1000-1200 mg per day and 800 mg per day regardless of weight, respectively. 
Subjects were randomized in a 1:1 ratio and stratified by cirrhosis (presence vs. absence), HCV 
genotype (2 vs. 3) and baseline HCV RNA level (less than 6 log10 IU/mL vs. at least 6 log10 
IU/mL). Subjects with genotype 2 or 3 HCV were enrolled in an approximately 1:3 ratio. SVR in 
genotype 2 without cirrhosis was 97% and 83% in those with cirrhosis compared to 81% without 
cirrhosis and 62% with cirrhosis in those receiving pegylated interferon and ribavirin for 24 
weeks. 
 
POSITRON was a randomized, double-blinded, placebo-controlled trial that evaluated 12 weeks 
of treatment with Sofosbuvir and ribavirin (N=207) compared to placebo (N=71) in subjects who 
are interferon intolerant, ineligible or unwilling. Subjects were randomized in 3:1 ratio and 
stratified by cirrhosis (presence vs. absence). SVR was 93%; with 92% in those without cirrhosis 
and 94% in those with cirrhosis.  
 
FUSION was a randomized, double-blinded trial that evaluated 12 or 16 weeks of treatment with 
Sofosbuvir and ribavirin in subjects who did not achieve SVR with prior interferon-based 
treatment (relapsers and nonresponders). Subjects were randomized in a 1:1 ratio and stratified 
by cirrhosis (presence vs. absence) and HCV genotype (2 vs. 3). SVR was 82%; 90% in those 
without cirrhosis and 60% in those with cirrhosis.  
 
The VALENCE trial evaluated Sofosbuvir in combination with weight-based ribavirin for the 
treatment of genotype 2 or 3 HCV infection in treatment-naïve subjects or subjects who did not 


Gilead IN-US-337-1811 
Version 3. 19/MAR/2016 
Protocol Number (SCCC-01416)  
______________________________________________________________________________ 
16 
achieve SVR with prior interferon-based treatment, including subjects with compensated 
cirrhosis. The original trial design was a 4 to 1 randomization to Sofosbuvir + ribavirin for 12 
weeks or placebo. Based on emerging data, this trial was unblinded and all genotype 2 HCV-
infected subjects continued the original planned treatment and received Sofosbuvir + ribavirin 
for 12 weeks, and duration of treatment with Sofosbuvir + ribavirin in genotype 3 HCV-infected 
subjects was extended to 24 weeks. Eleven genotype 3 subjects had already completed 
Sofosbuvir + ribavirin for 12 weeks at the time of the amendment. SVR was 93% for genotype 2 
and 84 % in genotype 3.  Genotype 2, treatment naïve with or without cirrhosis had SVR of 97% 
but those who were treatment experienced had SVR of 91 without cirrhosis and 88% in those 
with cirrhosis. Genotype 3, treatment naïve patients without cirrhosis had SVR of 93% and with 
cirrhosis 92% (24 week treatment); however, treatment experienced patients without cirrhosis 
had SVR of 85% and those with cirrhosis was 60%.   
 
Studies for HCV genotype 2 and 3 patients show that SOF 400mg in combination with weight-
based RBV is effective with sustained viral response of >90% in genotype 2 and >80% in 
genotype 3. The combination of SOF and RBV weight-based, i.e. 1200 mg if≥75 kg or 1000 mg 
if <75 kg has been recommended by the AASLD/IDSA guidance as acceptable oral treatment for 
patients with genotype 2 and 3.   Genotype 3, treatment experienced patients with cirrhosis 
would receive better response rates if treated with pegylated interferon, weight based RBV, and 
SOF. Thus, this group of patients will be excluded from the current protocol.  SOF is and FDA 
approved agent.   
 
1.2.4 
Sofosbuvir Common Adverse Events 
The safety profile of SOF in patients is based on the combined safety data from 4 studies where 
it was given for 12-16 weeks. In these studies, SOF was given at 400 mg once a day in 
combination with ribavirin (RBV) to 664 patients and in combination with RBV and pegylated 
interferon alfa 2a (PEG) to 327 patients. In patients taking SOF with RBV for 12-16 weeks, the 
most commonly reported side effects of these drugs were  (≥10%) were fatigue (41%), trouble 
sleeping (18%), and irritability (10%).In patients taking SOF with RBV and PEG for 12 weeks, 
the most commonly reported adverse drug reactions (≥10%) were:   
 
fatigue (59%) 
 
headache (36%)  
 
nausea (34%)  
 
trouble sleeping (25%)  
 
low red blood cell count (21%)  
 
decreased appetite (18%)  
 
fever (18%)  
 
rash (18%)  
 
chills (17%)  
 
decreases in the blood cells that 
fight infection (17%) 
 
 
itchiness (17%)  
 
flu-like illness (16%)  
 
joint pain (14%)  
 
muscle pain (14%)  
 
dizziness (13%)  
 
irritability (13%)  
 
diarrhea (12%)  
 
shortness of breath (12%)  
 
vomiting (12%)  
 
cough (10%)  
 
pain (10%) 
Most of these side effects were considered to be mild. These side effects overall were similar to 
those seen in subjects who took PEG and RBV without SOF. About one in forty subjects taking 


Gilead IN-US-337-1811 
Version 3. 19/MAR/2016 
Protocol Number (SCCC-01416)  
______________________________________________________________________________ 
17 
SOF, RBV, and PEG had to stop their study medications early because of side effects. About one 
in sixty-five subjects taking SOF and RBV had to stop their study medications early because of 
side effects. Most of these side effects were believed to have been caused by PEG or RBV. 
1.2.5 
 Ribavirin Common Adverse Events 
RBV is usually taken with pegylated interferon (a once per week shot).  The most common side 
effects when taking RBV combined with pegylated interferon are flu-like symptoms consisting 
of: 
 body aches and pains 
 fever 
 chills 
 headache 
 overall feeling of sickness 
 rash 
 
Other common side effects are: anxiety, mood changes, depression, and irritability. 
The most serious side effect seen with RBV is anemia (a decrease in the number of red blood 
cells in your body that carry oxygen).  This may cause tiredness and lack of energy.  RBV can 
cause severe damage and even death of an unborn child or fetus.  Extreme care should be taken 
to prevent pregnancy while you are taking ribavirin and afterwards. 
It is not expected that there will be all of these side effects.  Other side effects may occur which 
are not listed here or were not seen before.  Study subjects should speak to their study doctor for 
more information.  Side effects are usually temporary and can often be treated.  However, it is 
very important that you report all side effects as it is possible that these side effects could be 
serious or fatal. 
 
 
 
1.2.6  Rationale for Sofosbuvir/Velpatasvir 
Sofosbuvir/velpatasvir is a new combination of nucleotide polymerase inhibitor 
sofosbuvir with NS5A inhibitor velpatasvir.  
 
Astral-2/ Astral-3 
 In a randomized phase 3 trial, open-label, study of previously treated genotype 2 or 3 and 
treatment naïve patients ,including patients with compensated cirrhosis. In genotype 2, 
subjects were randomized to sofosbuvir 400 mg/weight-based ribavirin (n=132)  versus 
sofosbuvir/velpatasvir  (n=134) for 12 weeks. Subjects on sofosbuvir 400 mg/velpatasvir 
100mg achieved SVR 12 of 99% (95% CI, 96-100) vs. 94% (95% CI, 88-97) in the 
sofosbuvir/ribavirin arm, p=0.02) In genotype 3, subjects were assigned to 
sofosbuvir/velpatasvir (n=277) for 12 weeks versus sofosbuvir/weight-based ribavirin 
(n=275) for 24 weeks. SVR 12 was achieved in 95% (95% CI, 92-98) in the 
sofosbvuvir/velpatasvir compared to 80% (95% CI, 75-85) in the sofosbuvir/weight-
based ribavirin group, p<0.001).  Because of the superior efficacy of 


Gilead IN-US-337-1811 
Version 3. 19/MAR/2016 
Protocol Number (SCCC-01416)  
______________________________________________________________________________ 
18 
sofosbuvir/velpatasvir, this fixed-dose combination will be considered the preferred 
threatment for genotype 2 and 3 2.  
 
Astral-1 
  In this study subjects with genotype 1, 2, 4, 5, 6 were enrolled. Subjects included those 
with compensated cirrhosis and prior treatment failure to interferon.  Subjects were 
randomized 5:1 fashion to sofosbuvir/velpatasvir (400mg/100mg) versus placebo for 12 
weeks. The overall SVR 12 was 99% (95% CI, 98 to >99) which was superior to 
prespecified performance goal of 85% (P,0.001). By genotype SVR 12 was 98% (95% 
CI, 95 to>99) for genotype 1a, 99% (95% CI, 95-100) with genotype 1b, 100% (95% CI, 
97-100) with genotype 2, 100% (95% CI, 97 to100) with genotype 4, 97% (95% CI, 85to 
>99) with genotype 5, and 100% (95% CI, 91to 100) with genotype 6 3. Because of the 
high efficacy, subjects with genotype 1 or 4 will also be allowed to take 
sofosbuvir/velpatasvir if deemed appropriate by the study investigator.  
 
1.2.7 
Sofosbuvir/velpatasvir common adverse events 
 
Of the 624 patients on fixed-dose combination of sofosbuvir/velpatasvir, 1 discontinued 
treatment prematurely because of an adverse event.  There were 15 subjects (2%) had 19 
serious adverse events. There was one death in the sofosbuvir/velpatasvir group. There 
were no significant differences in adverse events between sofosbvuir/velpatasvir 
compared to placebo (78% vs . 77%, respectively).  Most common adverse events were 
headache, fatigue, nasopharyngitis, and nausea. Hematologic abnormalities were 
infrequent in sofosbuvir/velpatasvir group (1%).  No patients in either study group had 
grade 3 or 4 elevation of creatinine or total bilirubin.  
The most frequent AEs were headache (29%), fatigue (20%), nasopharyngitis (13%), 
nausea (12%), insomnia (8%), diarrhea (8%), asthenia (7%), arthralgia (6%), cough (6%), 
back pain (5%), myalgia (4%). Hematolgic events hemoglobin <10 g/dl (<1%), 
lymphocyte count 350<500 per mm3 (<1%), Neutrophil count 500 to <750 per mm3 
(1%), platelet count 25,000 to <50,000 (<1% )3. 
 
1.3 
Other Agents  
      No investigational agents will be used in this study.  
1.4 
Rationale 
There still remains the question if HCV eradication with all oral therapy will lead to a regression 
or cure of the low grade lymphoma.  Thus, our hypothesis is that oral HCV therapy will lead to a 
high rate of HCV eradication which will correlate with a reduction of the size and extent of low-
grade lymphoma. We hypothesize that patients with HCV, regardless of genotype and who have 
low grade lymphoma when treated for HCV without pegylated interferon will have a regression 
of low grade NHL. In this pilot study we will evaluate the effect of Sofosbuvir/ledipasvir or 
Sofosbuvir/ribavirin based antiviral therapy on the course of a subset of HCV-related low grade 
B-NHL. 
 


Gilead IN-US-337-1811 
Version 3. 19/MAR/2016 
Protocol Number (SCCC-01416)  
______________________________________________________________________________ 
19 
1.5 
 Correlative Studies 
Blood will be stored for future genetic testing /mutational analysis if funding is available. Blood 
will be collected at three time points during the study and stored. In the future if funding is 
available, mutational analysis from the blood will be compare to mutational analysis from bone 
marrow biopsy. We hypothesize that clonal changes will be detected in the blood that will 
correlate with changes found in bone marrow. In addition, these changes will be detected at an 
earlier time point than the bone marrow biopsy.  This study will be exploratory and hypothesis 
generating.  Blood will be collected at baseline, post-treatment week 12 and post-treatment week 
36.  The blood will stored at each local site and shipped together (batched) at the end of the 
study.  
2.0 
STUDY OBJECTIVES 
2.1 
Primary Objectives 
This study will assess the safety, as measured by adverse events, in patients receiving HCV 
treatment. 
2.2 
Secondary Objectives 
The secondary objective(s) of this study is to assess the (1) rate of overall response of B-NHL 
defined as either as partial response or complete response according to revised international 
working group criteria for non-Hodgkin lymphoma and (2) rate of sustained viral response to 
hepatitis C treatment. 
2.3 
Endpoints 
 
Primary Endpoints 
 
Safety and tolerability of Sofosbuvir/ledipasvir or Sofosbuvir/ribavirin in patients with B-NHL 
will be assessed by number of AEs and SAEs. In addition, we will assess the number of patients 
who had to stop treatment due to AEs or SAEs.  And we will also examine the number of 
patients in which treatment for lymphoma had to be given due to clinical progression. 
 
Secondary Endpoints 
 
The secondary endpoint(s) of this study is to (1) Assess the rate of overall response of B-NHL 
defined as either as partial response or complete response according to revised international 
working group criteria for non-Hodgkin lymphoma. (2) Determine the rate of SVR in patients 
with low-grade lymphoma. 
3.0 
Subject ELIGIBILITY 
Eligibility waivers are not permitted. Subjects must meet all of the inclusion and exclusion 
criteria to be registered to the study. Study treatment may not begin until a subject is registered. 
3.1 
Inclusion Criteria 
3.1.1 Willing and able to provide written informed consent.  


Gilead IN-US-337-1811 
Version 3. 19/MAR/2016 
Protocol Number (SCCC-01416)  
______________________________________________________________________________ 
20 
3.1.2 Male or female >18 years of age 
3.1.3 Serum HCV RNA levels of >1,000 IU per milliliter or higher 
3.1.4 HCV treatment experienced or naïve. 
i.HCV treatment naïve: No prior exposure to any IFN, RBV, or other approved or 
experimental HCV-specific DAA. 
ii.HCV Treatment-Experienced: Virologic failure after treatment with PEG- 
IFN + RBV, 
NS3 protease inhibitor plus PEG-IFN + RBV, or regimen of SOF±RBV±PEG-IFN regimen. 
3.1.5 Chronic Hepatitis C based on the judgment of the investigator  
3.1.6 HCV genotype 1, 2, 3, 4  
3.1.7 If the patient is determined to be cirrhotic (based on criteria outlined earlier), the  patient 
must have an ultrasound done within 6 months prior to enrollment with no evidence of 
hepatocellular carcinoma.  
3.1.8 Indolent Non-Hodgkin’s lymphoma , which may include the following : 
a. Nodal Marginal zone lymphoma  
b. Extranodal marginal zone lymphoma MALT 
c. Splenic marginal zone lymphoma  
d. Follicular lymphoma Grade 1-3a with low tumor burden*, FLIPI 2 risk category of   
either low (i.e. no risk factors) or intermediate (1-2 risk factors), and with no B symptoms. B 
symptoms are defined as: 
i.Fever (i.e., temperature >38°C [>100.4°F]) for 3 consecutive days 
ii.Weight loss exceeding 10% of body weight in 6 months 
iii.Drenching night sweats 
e. Lymphoplasmacytic lymphoma 
3.1.9 No prior chemotherapy 
*Low tumor burden is defined as normal lactate dehydrogenase, largest nodal or extranodal mass 
less than 7 cm, up to three nodal sites containing nodes with a diameter greater than 3 cm, no 
clinically significant serous effusions detectable by physical examination or  PET/CT scan, and 
spleen enlargement up to 16 cm by CT without any evidence of portal hypertension. 
 
3.1.10 Karnofsky performance status > 70% 
3.1.11 Creatinine clearance  ≥60 mL/min, as calculated by  Cockcroft-Gault equation 
3.1.12 If patient will need ribavirin in their regimen then the following inclusion: 


Gilead IN-US-337-1811 
Version 3. 19/MAR/2016 
Protocol Number (SCCC-01416)  
______________________________________________________________________________ 
21 
a. Hg >12 g/dL for male 
b. Hg >11 g/dL for female 
3.1.13 All women of child-bearing potential who take ribavirin will need to have a 
 
negative pregnancy test 
 
3.2 
Exclusion Criteria 
 
3.2.1 Life expectancy < 6 months based on judgement of investigator  
3.2.2 Any subject who currently needs HCV treatment which uses pegylated interferon 
3.2.3 Co-infection with hepatitis B 
3.2.4 Prior chemotherapy for lymphoma 
3.2.5 Lymphomas of other histologies other than the ones listed in section 3.1.8 above 
3.2.6 Follicular lymphoma with large cell transformation 
3.2.7 Decompensated liver disease in which pegylated interferon is contraindicated.  
3.2.8  Female who is pregnant or breast feeding and HCV treatment requires use of ribavirin.  
3.2.9 Solid organ transplant 
3.2.10  Any IFN- containing agent  within 8 weeks  prior to screening  or any prior exposure to 
HCV-specific antivirals agent(s), other than NS3/4A protease inhibitor and  Sofosbuvir 
3.2.11 Known hypersensitivity to ledipasvir, Sofosbuvir, or formulation excipients.  
3.2.12 On a prohibited medication which cannot be stopped during the duration of HCV 
treatment. 
3.2.13  Female subject who is pregnant or breastfeeding 
3.2.14 HIV-infection 
 
4.0 
TREATMENT PLAN 
4.1 
Treatment Dosage and Administration 
All treatment for this study will be administered orally and in the outpatient setting.  
 
4.1.1 
Genotype 1:   
Treatment Naïve, with or without cirrhosis: Sofosbuvir/ledipasvir one pill once a day for 12 
weeks. 
Or 


Gilead IN-US-337-1811 
Version 3. 19/MAR/2016 
Protocol Number (SCCC-01416)  
______________________________________________________________________________ 
22 
Sofosbuvir/velpatasvir one pill once a day for 12 weeks.  
 
Treatment experienced, with or without cirrhosis:  
Sofosbuvir/velpatasvir one pill once a day for 12 weeks  
Or  
Alternative: Sofosbuvir/ledipasvir one pill once a day with weight-based ribavirin for 12 weeks. 
Weight-based ribavirin refers to use 1200 mg of ribavirin in divided doses for those ≥75 kg and 
1000 mg in divided dose for those <75kg. 
Or 
 
Alternative: Treatment experienced with cirrhosis unable to take ribavirin: Sofosbuvir/ledipasvir 
one pill once a day for 24 weeks.   
 
 
4.1.2 
Genotype 2:  
Treatment naïve or experienced  with or without cirrhosis: Sofosbuvir/velpatasvir one pill once a 
day for 12 weeks.  
 
Alternative: Sofosbuvir 400mg  once daily and ribavirin 1000/1200 mg weight-based dosing in 
divided dose BID for 12 weeks. 
 
 Alternative: Treatment naïve or experienced with cirrhosis: Sofosbuvir 400mg and weight-based 
ribavirin for 16 weeks. 
 
4.1.3 
Genotype 3: 
 Treatment naïve, non-cirrhotic or with cirrhosis: 
Sofosbuvir/velpatasvir one pill once a day for 12 weeks.  
 
or 
Alternative:  Sofosbuvir/ledipasvir fixed dose combination combined with weight-based 
ribavirin for 12 weeks  
or  
 
Alternative: Treatment naïve with cirrhosis:  Sofosbuvir 400 mg daily with weight-based 
ribavirin for 24 weeks 
or 
Alternative:Treatment experienced, non-cirrhotic: Sofosbuvir 400mg daily with weight-based 
ribavirin for 24 weeks.  
 
  
 
4.1.4 
Genotype 4:     
  
Treatment naïve or experienced with or without cirrhosis: 
Sofosbuvir/velpatasvir one pill once a day for 12 weeks.  
Or  


Gilead IN-US-337-1811 
Version 3. 19/MAR/2016 
Protocol Number (SCCC-01416)  
______________________________________________________________________________ 
23 
Alternative:  Sofosbuvir/ledipasvir fixed dose combination for 12 weeks.  
 
 or 
 
Alternative: Treatment experienced with cirrhosis: Sofosbuvir/ledipasvir for 24 weeks. 
  
 
** Please note all regimens given must be orally administered and not include interferon. 
Thus, if FDA label and/or AASLD/IDSA guidance gives multiple options for treatment, the 
choice selected should be oral and include Sofosbuvir. 
 
4.2 
Toxicities and Dosing Delays/Dose Modifications 
Any subject who receives treatment on this protocol will be evaluable for toxicity. Each patient 
will be assessed for the development of toxicity during each study visit as outlined in the 
schedule of events Table 5.1. Toxicity will be assessed according to the Division of AIDS 
(DAIDS) Toxicity Management guidelines: http://rsc.tech-
res.com/Document/safetyandpharmacovigilance/DAIDS_AE_Grading_Table_v2_NOV2014.pdf
.  
  
 
4.2.1 
Dose reduction or discontinuation of RBV  
Dose reduction or discontinuation of ribavirin due to hemoglobin toxicity or related 
symptoms is allowed at the discretion of the Investigator. 
 
Laboratory Values 
Reduce RBV Dose to 600 
mg/day if: 
Discontinue RBV if: 
Hemoglobin in subjects with 
no cardiac disease 
< 10 g/dL 
< 8.5 g/dL 
Hemoglobin in subjects with 
history of stable cardiac 
disease 
.> 2 g/dL decrease in 
hemoglobin during 
any 4 week period 
< 12 g/dL despite 4 weeks at 
reduced dose 
 
4.3 
Concomitant Medications 
Concomitant medications taken within 30 days prior to Screening, up to and including post-
treatment visit 48 weeks or Early Termination.   
 
The following medications are prohibited during the screening period and for a minimum of 28 
days prior to the Baseline/Day 1 Visit through the end of study: 
 


Gilead IN-US-337-1811 
Version 3. 19/MAR/2016 
Protocol Number (SCCC-01416)  
______________________________________________________________________________ 
24 
Investigational agents or devices for any indication, concomitant use of certain medications or 
herbal/natural supplements (inhibitors or inducers of drug transporters i.e., P-gp) with study 
drug(s) may result in PK interactions resulting in increases or decreases in exposure of study 
drug(s) are prohibited from 21 days prior to Baseline/Day 1 Visit through the end of study. 
P-gp inducers such as St. John’s wort and rifampin should not be used.  
 
 Examples of representative medications which are listed below: 
 
Disallowed and Concomitant Medications to be used with Caution  
  
 
 
Drug  Class 
Agents Disallowed 
Use with Caution 
Acid Reducing 
Proton Pump Inhibitors > 20 
mg of omeprazole or 
equivalent   
H2 blockers  
Antacids separated by 4 
hours 
Antiarrhythmics 
Amiodarone 
Quinidine 
Anticonvulsants 
Phenobarbital, Phenytoin, 
Carbamazepine, 
Oxcarbazepine 
 
Antimycobacterials 
Rifabutin, Rifapentine, 
Rifampin 
 
Cardiac Medications 
 
Valsartan, Olmesartan, 
Telmisartan, 
Ranolazine, Bosentan, 
Digoxin 
Herbal/Natural 
Supplements 
 
St. John’s Wort, Echinacea, 
Milk thistle 
(i.e., silymarin), Chinese herb 
 


Gilead IN-US-337-1811 
Version 3. 19/MAR/2016 
Protocol Number (SCCC-01416)  
______________________________________________________________________________ 
25 
sho-saikoto 
(or Xiao-Shai-Hu-Tang) 
HMG-CoA Reductase 
Inhibitors 
Rosuvastatin 
Atorvastatin (<10 mg per 
day), Simvastatin,   
Pitavastatin, 
Fluvastatin, Lovastatin 
 
 
 
4.4 
Other Modalities or Procedures  
There are no other treatment modalities that will be used in this protocol. 
4.5 
Duration of Treatment 
The duration of HCV treatment will be determined by the principal investigator based on 
genotype, treatment experience, and presence of cirrhosis. Duration of treatment may vary.  
Please refer to section 4.0 
4.6 
Duration of Follow Up 
Participations will be followed for 36 weeks post-treatment. Subject will have HCV RNA 
checked post-treatment week 12 to determine SVR. Subjects will have CT/PET scan post-
treatment week 12 and 36 to measure any changes in lymphoma size.  
4.7 
Removal patients from Protocol Therapy 
A subject may be discontinued from treatment for the following reasons:  
1. 
Unacceptable toxicity,  or toxicity that, in the judgment of the Investigator, compromises 
the ability to continue study-specific procedures or is considered to not be in the subject’s best 
interest 
2. 
Pregnancy of female subject 
3. 
HCV efficacy failure defined as HCV RNA >LLOQ on two separate measurements at 
least 1 week apart.  Patient may remain in follow-up on study but off drug.  
 
If a subject discontinues study drug dosing (for example, as a result of an AE), every attempt 
should be made to keep the subject in the study and to continue to perform the required study-
related follow-up tests and procedures. If this is not possible or acceptable to the subject or 
Investigator, the subject may be withdrawn from the study. 
4.8 
Subject Replacement 
There will be no subject replacement.  


Gilead IN-US-337-1811 
Version 3. 19/MAR/2016 
Protocol Number (SCCC-01416)  
______________________________________________________________________________ 
26 
 
5.0 
STUDY PROCEDURES 
Patients will have HCV RNA quantification done at baseline, week4, end of treatment, 4-weeks 
post-treatment and then 12-weeks post-treatment (SVR 12) and 24-weeks post-treatment (SVR 
24). If patients are on extended treatment, HCV RNA will be collected at each visit during 
treatment except for week 8.  We do not anticipate late relapses after 24 weeks post therapy. 
Patients will undergo a detailed clinical examination to assess the size of lymph nodes, liver and 
spleen. Patients will get a complete blood count, complete metabolic panel, β2 microglobulin, 
and LDH at baseline, 4 week, 8 week, and 12 weeks, then every 3 months to assess 
hematological response. LDH will also be collected at extended treatment visits.  At screening a 
bone marrow biopsy will be done with flow cytometry. In those patients with bone marrow 
involvement who have evidence of complete remission by PET/CT scan, a repeat bone marrow 
biopsy with flow cytometry will be conducted to determine if patient achieved a complete 
remission.  In addition to the clinical examination, patients will have a full body CT –PET scan 
at the time of enrollment, at 12 weeks post-HCV treatment and at 36 weeks post-HCV treatment. 
5.1 
Screening and Baseline 
 
Assessments performed exclusively to determine eligibility for this study will be done only after 
obtaining informed consent. Assessments performed for clinical indications (not exclusively to 
determine study eligibility) may be used for baseline values even if the studies were done before 
informed consent was obtained. 
 
All screening procedures must be performed within 45 days prior to enrollment unless otherwise 
stated. The screening procedures include: 
 
5.1.1 
Pre-screen >1 month before enrollment. 
 
Hepatitis C:  
Patient will have evidence of hepatitis C based or standard of care serology. HCV RNA and 
HCV genotype will also be obtained as part of standard of care.  The patient will be considered 
to have cirrhosis by one of the following methods:  
 
 
Liver biopsy showing cirrhosis 
 
FibroScan® showing cirrhosis or results >12.5 kPa  
 
A FibroTest®  (or FibroSure®) score of >0.75 and an aspartate aminotransferase 
(AST):platelet ratio index (APRI) of >2 during Screening  
 
If the patient has cirrhosis by the above criteria, then an ultrasound must be obtained to rule out 
hepatocellular carcinoma within 6 months of enrollment. This will be obtained as part of 
standard of care.  
 
Lymphoma: 
  


Gilead IN-US-337-1811 
Version 3. 19/MAR/2016 
Protocol Number (SCCC-01416)  
______________________________________________________________________________ 
27 
Patients must have a bone marrow biopsy with flow cytometry to assess for presence of low 
grade lymphoma performed at screening if there is no prior bone marrow biopsy or if prior 
biopsy showed no bone marrow involvement. A prior biopsy which shows bone marrow 
involvement may be used if obtained <3 months prior to screening.       
 
5.1.2 
Screen 
Screen may take place 45 days to 1 day prior to enrollment.   
Patients will have the following obtained during the screening period; 
 
5.1.2.1 Informed Consent 
The subject will read the informed consent. Study coordinator or site investigator will review key 
aspects of the study with the study participant. Subjects will be encouraged to ask questions. The 
subject will sign and date the consent after study treatment and procedures are explained and all 
questions answered.  
 
Subjects will also sign a release of information (if needed) to obtain data outlined in the pre-
screen section.   
5.1.2.2 Medical History 
Medical history including details regarding illnesses and allergies, date(s) of onset, and whether 
condition(s) is currently ongoing or stopped (date of resolution), and medication history will be 
collected on all subjects during screening. HCV treatment history will be used to categorize the 
subject as either a treatment intolerant, non-responder or relapse/breakthrough   defined as: 
 
 
Treatment Intolerant: Subject discontinued prior HCV treatment regimen due to 
development or significant worsening of a treatment related AE. 
 
Non-Responder: Subject did not achieve undetectable HCV RNA levels (HCV RNA 
≥ LLOQ) while on treatment. Subject must not have discontinued prior therapy due to an AE. 
 
~For PEG-IFN/RBV non-responders, subjects should be further defined as Null or Partial 
Responders: 
o 
Null Responders: HCV RNA < 2 Log10 reduction during the first 12 weeks of treatment. 
o 
Partial Responders: HCV RNA ≥ 2 Log10 reduction during the first 12 weeks of 
treatment. 
o 
Relapse/Breakthrough: Subject achieved undetectable HCV RNA levels (HCV RNA < 
LLOQ) during treatment but did not achieve a SVR. Subject must not have discontinued prior 
therapy due to an AE 
5.1.2.3 Review Subject inclusion /exclusion criteria 
From the medical history and medical records, the coordinator will assess to determine if subject 
meets entry requirements. All inclusion/exclusion criteria must be verified by the site 
investigator.  
5.1.2.4 Concomitant Medications 


Gilead IN-US-337-1811 
Version 3. 19/MAR/2016 
Protocol Number (SCCC-01416)  
______________________________________________________________________________ 
28 
All medications which a subject is currently taking will be recorded. Start dates will be recorded 
and the reason for taking the medication. Medications will be check against prohibited and 
cautionary medications to make sure subject qualifies for study. If subject stops medications 
previously recorded, then a stop date will be recorded and reason for stopping the medication. 
Study medications will not be included in concomitant medications.  
5.1.2.5 Vital Signs 
Assessment of vital signs will include measurement of resting blood pressure, pulse, respiratory 
rate, and temperature, weight, height. The vital signs performed at Study Day 1 will serve as the 
baseline for clinical assessments. Height will only be measured at Screening; the subject will not 
wear shoes.  
 Blood pressure will be measured using the following standardized process: 
1. 
Subject should sit for > 5 minutes with feet flat on the floor and measurement arm 
supported so that the midpoint of the manometer cuff is at heart level;  
2. 
Use a mercury sphygmomanometer or automatic blood pressure device with an 
appropriately sized cuff with the bladder centered over the brachial artery; 
3. 
Measure and record the blood pressure to the nearest 2 mmHg mark on the manometer or 
to the nearest whole number on an automatic device. 
 
5.1.2.6 Labs 
The following labs will be obtained during the screening visit.  
CBC with diff 
Liver function tests (ALT, AST, T. Bili, D. Bili, alkaline phosphatase, total protein and albumin) 
PT/PTT 
Electrolytes (Sodium, potassium, carbon dioxide, chloride, glucose, calcium) 
BUN 
Creatinine 
LDH  
B2 microglobulin 
Hepatitis B surface antigen 
HIV antibody 1& 2 
5.1.2.7 Pregnancy Testing 
All females of childbearing potential will have a urine pregnancy dipstick test at screen. All 
women of child bearing potential who will be on ribavirin as part of their HCV regimen will 
have a  urine pregnancy dipstick test at baseline and then  every 4 weeks during the dosing 
period ( until week 12) and then at week 12, 16, 24, and 36 of study . Positive urine pregnancy 
result, subjects will be instructed to stop study drugs immediately (if applicable) and return to the 
clinic as soon as possible for a serum pregnancy test. 
 
5.1.2.8  Blood and Tissue for storage for future studies and back-up 
Patient will be required to sign a separate consent for acquisition of extra blood samples for 
research purposes. Blood will be collected and stored for future genetic analysis and compared to 
B cell mutations found from bone marrow biopsy.  10 ml of whole blood will be collected in 


Gilead IN-US-337-1811 
Version 3. 19/MAR/2016 
Protocol Number (SCCC-01416)  
______________________________________________________________________________ 
29 
ACD or EDTA vacutainer tubes and must be completely filled. The samples collected will be 
batched and sent to UT Southwestern for storage.  The de-identified samples will be sent for 
analysis once funding is available for the project.   Blood will be stored locally as a back-up if a 
mishap occurs in the lab and if stored sample could be used for a replacement.     
 
5.1.2.9 Karnofsky Score 
The Karnofsky score will be determined based on the appendix (14.0) 
 
5.1.2.10 
Creatinine Clearance 
Creatinine clearance is calculated by the Cockcroft-Gault equation using actual body weight 
(BW). 
Male: CLcr (mL/min) =  
 
[140 - age (years)] X BW (kg) 
 
 
 
 
 
 
 
72 X Scr 
Female: CLcr (mL/min) = 
[140 - age (years)] X BW (kg) X0.85 
 
 
 
 
 
 
 
72 X Scr 
Scr = serum creatinine (mg/dL)  
 
 
5.1.2.11 
Body Mass Index (BMI) 
Height and weight will be measured without shoes. Height will be measured at Screening only; 
BMI will be calculated at Screening for inclusion criteria using the following formula: 
BMI = weight (pounds) X 703                            or weight in kilograms           
           (height in inches) 2                                   (height in meters) 2 
5.1.2.1 Whole Body PET/CT SCAN  
A whole body PET or CT scan will be obtained. The decision of PET vs. CT will be made by the 
treating oncologist or oncology investigator and will be based on the type of lymphoma the 
subject has.  
  
 
5.1.1 
Baseline   
5.1.1.1 
Complete Physical Examination 
A complete physical examination must include source documentation of general appearance, and 
the following body systems: Head, neck and thyroid; eyes, ears, nose, throat, mouth and tongue; 
chest (excluding breasts); respiratory; cardiovascular; lymph nodes, abdomen; skin, hair, nails; 
musculoskeletal; neurological. 
 
5.1.1.2 
Drug dispensation 
Drug will be dispensed as prescribed by the study investigator in accordance to the protocol. The 
number of bottles with number of pills will be recorded.   
 


Gilead IN-US-337-1811 
Version 3. 19/MAR/2016 
Protocol Number (SCCC-01416)  
______________________________________________________________________________ 
30 
 
Concomitant medications (as described above) 
 
Vital signs including BMI 
 
Karnofsky Score 
 
Labs: 
HCV RNA 
CBC with diff 
LFTS 
BUN 
Creatinine 
Electrolytes 
LDH 
B2 microglobulin 
Urine pregnancy test by dipstick in women of child bearing potential 
 
Blood for storage 
 
Blood for genetic analysis 
 
5.2 
Procedures During Treatment 
 
5.2.1 
Week 2 visit (+/- 2 days) 
5.2.1.1 
Adverse Event Log 
A record of symptoms experienced by the subject will be recorded. Start and stop dates will be 
recorded. Symptoms will be rated by NCI grading toxicity as defined in 7.2.1. Any action taken 
due to the adverse event will be recorded.  Any laboratory abnormalities will be recorded and 
graded by grade 1-5.  
 
5.2.1.2 
Targeted PE 
 The subject will have target physical exam if there are any symptoms. If no symptoms, the exam 
will consist of examination of heart, lung, abdomen, skin and lymph nodes.  
 
 
Concomitant medication   
 
Vital signs 
 
Labs: 
CBC with diff 
 Blood for storage 
 
5.2.2 
Week 4 visit (+/- 2 days) 
 
Concomitant medication and Adverse Event Log 
 
Vital signs 
 
Drug Dispensation 
 
Targeted PE 
 
Labs: 
CBC with diff 


Gilead IN-US-337-1811 
Version 3. 19/MAR/2016 
Protocol Number (SCCC-01416)  
______________________________________________________________________________ 
31 
Electrolytes 
BUN 
Creatinine 
HCV RNA 
LFTS 
LDH 
B2 microglobulin 
Blood for storage  
 
5.2.3 
Week 8 (+/- 2 days)    
 
Concomitant medication and Adverse Event Log 
 
Vital signs 
 
Drug Dispensation  
 
Labs: 
CBC with diff 
Electrolytes 
BUN 
Creatinine 
LFTs 
LDH 
B2 microglobulin 
Blood for storage 
 
5.2.4 
Week 12, 16, 20 (+/- 2 days) for patients on extended therapy  
 
Concomitant medication and Adverse Event Log 
 
Vital signs 
 
Drug Dispensation  
 
Labs: 
CBC with diff 
Electrolytes 
BUN 
Creatinine 
LFTs 
LDH 
HCV RNA 
B2 microglobulin 
Blood for storage 
 
5.2.5 
End of Treatment (+/- 2 days) 
 
Concomitant medication and adverse event log 
 
Vital signs 
 
Complete Physical Exam 
 
Labs: 
CBC with diff 
Electrolytes 


Gilead IN-US-337-1811 
Version 3. 19/MAR/2016 
Protocol Number (SCCC-01416)  
______________________________________________________________________________ 
32 
BUN 
Creatinine 
LFTs 
LDH 
B2 microglobulin 
HCV RNA   
Blood for storage 
 
5.3 
Procedures Post-Treatment 
 
5.3.1 
Post Treatment Week 4 (+/-5 days)   
 
Concomitant medication and Adverse Event Log 
 
Vital signs 
 
Physical Exam 
 
Labs: 
CBC with diff 
Electrolytes 
BUN 
Creatinine 
LFTs 
HCV RNA  
LDH  
B2 microglobulin 
Blood for storage 
 
5.3.2 
Post Treatment Week 12 (+/-7 days)   
 
Concomitant medication and Adverse Event Log 
 
Vital signs 
 
Physical Exam 
 
Whole body PET/CT Scan 
 
Labs: 
CBC with diff 
Electrolytes 
BUN 
Creatinine 
LFTs 
LDH 
B2 microglobulin 
HCV RNA   
Labs for genetic analysis (batched) 
Blood for storage 
 
5.3.3 
Post Treatment Week 24 (+/-7 days)   
 
Concomitant medication and Adverse Event Log 


Gilead IN-US-337-1811 
Version 3. 19/MAR/2016 
Protocol Number (SCCC-01416)  
______________________________________________________________________________ 
33 
 
Vital signs 
 
Physical Exam 
 
Labs: 
CBC with diff 
Electrolytes 
BUN 
Creatinine 
LFTs 
LDH 
B2 microglobulin 
HCV RNA   
Blood for storage 
 
5.3.4 
Post Treatment Week 36 (+/-7 days) 
5.3.4.1 Bone Marrow biopsy 
A bone marrow biopsy with flow cytometry in those who have evidence of complete remission 
on PET/CT Scan 
 
 
Concomitant medication and Adverse Event Log 
 
Vital signs 
 
Physical Exam 
 
Whole Body PET/CT Scan 
 
Labs: 
CBC with diff 
Electrolytes 
BUN 
Creatinine 
LFTs 
LDH 
Beta 2 microglobulin 
HCV RNA   
Labs for genetic analysis (batched) 
Blood for storage  
 
5.3.5 
Early Termination Visit 
 
Concomitant Medications and Adverse Events Log 
 
Complete Physical Exam 
 
Vital Signs 
 
Labs: 
CBC with diff 
Complete Metabolic Panel 
HCV RNA 
Electrolytes 
BUN 


Gilead IN-US-337-1811 
Version 3. 19/MAR/2016 
Protocol Number (SCCC-01416)  
______________________________________________________________________________ 
34 
Creatinine 
LDH 
B2 microglobulin 
Blood for storage 
 
5.3.6 
Unscheduled visit  
A subject should attend an unscheduled visit if requested by the Sponsor or the Investigator. The 
assessments are at the Investigator’s discretion, and will at a minimum collect adverse events 
(AE’s) and concomitant medication information. At all unscheduled visits initiated for the 
purpose of confirming HCV failure a sample for viral RNA sequencing/phenotyping or 
genotyping/phenotyping, respectively, may be collected.  Blood may be stored for HCV   
genotyping.  
 
 


Gilead IN-US-337-1811 
Version 3. 19/MAR/2016 
Protocol Number (SCCC-01416)  
______________________________________________________________________________ 
35 
5.4 
Time and Events Table 
  
 
 
a. 
For those on extended therapy of 16 or 24 weeks 
b. 
Karnofsky Score: See Appendix 1. 
c. 
If needed for liver biopsy or bone marrow biopsy 
d. 
Urine Pregnancy Test: To be done at screening for WOCBP 
e. 
Urine Dipstick: To be done at all visits from baseline forward for WOCBP. 
f. 
If needed for those who have complete response by Pet Scan 
g. 
 CMP includes electrolytes (Na, K, Chloride, Bicarb), BUN, Cr, LFT (ALT, AST, Alk phos, T. Bili, D. Bili, albumin, total protein), Calcium, glucose 
h. 
Optional: Separate consent would need to be signed. 
 
Screen 
Screening 
period 
Baseline 
Week 
2 
Week 
4 
Week 
8 
 
Week 
12, 16, 
20 a 
EOT 
PT 
Week 
4 
PT 
Week 
12 
PT 
Week 
24 
PT 
Week 36 
Early 
Terminati
on Visit 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Review Inclusion/Exclusion 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Exam (initial) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signs, Weight, Height 
X 
 
 
X 
X 
X 
X 
X 
X 
 
 
 
X 
Medication review /Accountability 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Brief visit /Vitals 
 
 
X 
 
 
 
 
X 
 
X 
X 
X 
 
Karnofsky Scoreb 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
PET scan 
 
X (SOC) 
 
 
 
 
 
 
 
X 
 
X 
 
HIV Antibody 1& 2 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Hepatitis B surface antigen 
X 
 
 
 
 
 
 
 
 
 
 
 
 
HCV RNA 
 
 
X 
- 
X 
 
X 
X 
X 
X 
X 
 
X 
HCV genotype 
X (SOC) 
 
 
 
 
 
 
 
 
 
 
 
 
CBC 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
B2 microglobulin 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CMPg/LDH 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
PT/PTT 
 
Xc 
 
 
 
 
 
 
 
 
 
X 
 
Urine pregnancy testc   or urine dipstickd 
Xd 
 
Xe 
 
Xe 
Xe 
Xe 
Xe 
Xe 
Xe 
X 
 
 
Lymphoma, type stage 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Bone marrow biopsy  and flow 
 
X (SOC) 
 
 
 
 
 
 
 
 
 
Xf 
 
Fibrosis staging 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Blood draw 
X 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
Ribavirin insurance/pap 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Drug dispensation 
 
 
X 
 
X 
X 
 
 
 
 
 
 
 
Drug accountability 
 
 
 
 
X 
X 
X 
X 
 
 
 
 
 
Adverse Events 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Special mutation analysish 
 
 
X 
 
 
 
 
 
 
X 
 
X 
 
Blood for storage 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 


Gilead IN-US-337-1811 
Version 3. 19/MAR/2016 
Protocol Number (SCCC-01416)  
______________________________________________________________________________ 
36 
 
5.5 
Removal of Subjects from Study 
Subjects can be taken off the study treatment and/or study at any time at their own request, or 
they may be withdrawn at the discretion of the investigator for safety, behavioral or 
administrative reasons. The reason(s) for discontinuation will be documented and may include: 
5.5.1 Subject voluntarily withdraws from treatment (follow-up permitted); 
5.5.2 Subject withdraws consent (termination of treatment and follow-up); 
5.5.3 Subject is unable to comply with protocol requirements; 
5.5.4 Subject demonstrates disease progression   
5.5.5 Subject experiences toxicity that makes continuation in the protocol unsafe; 
5.5.6 Treating physician judges continuation on the study would not be in the subject’s best 
interest 
5.5.7 Subject becomes pregnant 
Pregnancy to be reported along same timelines as a serious adverse event 
5.5.8 Development of second malignancy 
 Except for basal cell carcinoma or squamous cell carcinoma of the skin) that requires treatment, 
which would interfere with this study; 
  
6.0 
MEASUREMENT EFFECT 
6.1 
HCV Treatment Response:  
SVR: A patient will be considered to have achieved sustained viral response (SVR) if 
HCV RNA is undetectable 12 weeks after completion of HCV treatment.  
Relapse:  A patient will be considered to be a relapse if HCV RNA became undetectable during 
HCV treatment but became detectable post week 4 or 12.  
Breakthrough: A patient will be considered to have breakthrough if HCV RNA becomes 
undetectable and then subsequently is confirmed detectable during HCV treatment.  
Treatment Failure: The following on-treatment HCV virologic response-based treatment 
stopping criteria will be utilized: 
· Confirmed HCV RNA ≥ LLOQ after 2 consecutive HCV RNA < LLOQ 
· Confirmed > 1 log10 increase from nadir 
· HCV RNA ≥ LLOQ through 8 weeks of treatment 
Confirmation should be performed as soon as possible and must occur no later than 2 weeks after 
an initial observation indicating virologic failure. All subjects who terminate treatment early will 
complete the Early Termination (ET) Visit, Week 4, Week 12, and Week 24 Post-Treatment 
Visits.  
 


Gilead IN-US-337-1811 
Version 3. 19/MAR/2016 
Protocol Number (SCCC-01416)  
______________________________________________________________________________ 
37 
6.2 
 Lymphoma Treatment Response 
The 2014  Lugano classification criteria will be used for initial staging and treatment 
response assessment.  
Evaluable for objective response.  Only those subjects who have measurable disease present at 
baseline, have received at least one dose of HCV treatment, and have had their disease re-
evaluated will be considered evaluable for response. These subjects will have their response 
classified according to the definitions stated below.   
Response Definitions for Clinical Trials 
Response 
Definition 
Nodal Masses 
Spleen, Liver 
Bone Marrow 
CR 
Disappearance of all 
evidence of disease 
(a) FDG-avid or PET 
positive prior to therapy; 
mass of any size 
permitted if PET 
negative (b) Variably 
FDG-avid or PET 
negative; regression to 
normal size on CT 
Not palpable, 
nodules disappeared 
Infiltrate cleared on repeat 
biopsy; if indeterminate by 
morphology, 
immunohistochemistry 
should be negative 
PR 
Regression of measurable 
disease and no new sites 
≥ 50% decrease in SPD 
of up to 6 largest 
dominant masses; no 
increase in size of other 
nodes (a) FDG-avid or 
PET positive prior to 
therapy; one or more 
PET positive at 
previously involved site 
(b) Variably FDG-avid 
or PET negative; 
regression on CT 
≥ 50% decrease in 
SPD of nodules (for 
single nodule in 
greatest transverse 
diameter); no 
increase in size of 
liver or spleen 
Irrelevant if positive prior 
to therapy; cell type should 
be specified 
SD 
Failure to attain CR/PR or 
PD 
(a) FDG-avid or PET 
positive prior to therapy; 
PET positive at prior 
 
 


Gilead IN-US-337-1811 
Version 3. 19/MAR/2016 
Protocol Number (SCCC-01416)  
______________________________________________________________________________ 
38 
Response 
Definition 
Nodal Masses 
Spleen, Liver 
Bone Marrow 
sites of disease and no 
new sites on CT or PET 
(b) Variably FDG-avid 
or PET negative; no 
change in size of 
previous lesions on CT 
Relapsed 
disease or 
PD 
Any new lesion or 
increase by ≥ 50% of 
previously involved sites 
from nadir 
Appearance of a new 
lesion(s) > 1.5 cm in any 
axis, ≥ 50% increase in 
SPD of more than one 
node, or ≥ 50% increase 
in longest diameter of a 
previously identified 
node > 1 cm in short axis 
> 50% increase from 
nadir in the SPD of 
any previous lesions 
New or recurrent 
involvement 
 
 
Lesions PET positive if 
FDG-avid lymphoma or 
PET positive prior to 
therapy 
 
 
 
Abbreviations: CR, complete remission; FDG, [18F]fluorodeoxyglucose; PET, 
positron emission tomography; CT, computed tomography; PR, partial remission; SPD, sum 
of the product of the diameters; SD, stable disease; PD, progressive disease. 
Disease Parameters 
Measurable disease. Measurable lesions are defined as those that can be accurately measured in 
at least one dimension (longest diameter to be recorded) as >20 mm with conventional 
techniques (CT, MRI, x-ray) or as >10 mm with spiral CT scan. All tumor measurements must 
be recorded in millimeters (or decimal fractions of centimeters). 
 
Note: Previously irradiated lesions are non-measurable except in cases of documented 
progression of the lesion since the completion of radiation therapy. 
 
Non-measurable disease. All other lesions (or sites of disease), including small lesions (longest 
diameter <20 mm with conventional techniques or <10 mm using spiral CT scan), are considered 


Gilead IN-US-337-1811 
Version 3. 19/MAR/2016 
Protocol Number (SCCC-01416)  
______________________________________________________________________________ 
39 
non-measurable disease. Bone lesions, leptomeningeal disease, ascites, pleural/pericardial 
effusions, lymphangitis cutis/pulmonis, inflammatory breast disease, abdominal masses (not 
followed by CT or MRI), and cystic lesions are all non-measurable. 
 
Target lesions. All measurable lesions up to a maximum of 3 lesions per organ and 6 lesions in 
total, representative of all involved organs, should be identified as target lesions and recorded 
and measured at baseline. Target lesions should be selected on the basis of their size (lesions 
with the longest diameter) and their suitability for accurate repeated measurements (either by 
imaging techniques or clinically). A sum of the longest diameter (LD) for all target lesions will 
be calculated and reported as the baseline sum LD. The baseline sum LD will be used as 
reference by which to characterize the objective tumor response. 
 
Non-target lesions. All other lesions (or sites of disease) including any measurable lesions over 
and above the 6 target lesions should be identified as non-target lesions and should also be 
recorded at baseline. Measurements of these lesions are not required, but the presence or absence 
of each should be noted throughout follow-up.  
Methods for Evaluation of Measurable Disease 
All measurements should be taken and recorded in metric notation using a ruler or calipers. All 
baseline evaluations should be performed as closely as possible to the beginning of treatment and 
never more than 28 days before the beginning of the treatment. 
 
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. Imaging-based evaluation is 
preferred to evaluation by clinical examination when both methods have been used to assess the 
antitumor effect of a treatment 
  
Duration of Response 
Duration of overall response: The duration of overall response is measured from the time 
measurement criteria are met for CR or PR (whichever is first recorded) until the first date that 
recurrent or progressive disease is objectively documented (taking as reference for progressive 
disease the smallest measurements recorded since the treatment started). 
 
The duration of overall CR is measured from the time measurement criteria are first met for CR 
until the first date that recurrent disease is objectively documented.  
 
Duration of stable disease: Stable disease is measured from the start of the treatment until the 
criteria for progression are met, taking as reference the smallest measurements recorded since the 
treatment started.  
Progression-Free Survival 
Progression-free survival (PFS) is defined as the duration of time from start of treatment to time 
of progression. 
 


Gilead IN-US-337-1811 
Version 3. 19/MAR/2016 
Protocol Number (SCCC-01416)  
______________________________________________________________________________ 
40 
6.3 
Safety and Tolerability 
At each study visits, adverse side effects to study treatment will be assessed in order to determine 
safety and tolerability of this treatment in this population.  
7.0 
ADVERSE EVENTS AND SERIOUS EVENTS 
 
7.1 
Experimental Therapy 
There is no experimental therapy given.  
 
7.2 
Adverse Events Monitoring 
Adverse events are reported in a routine manner at scheduled times during a trial. Additionally, 
certain adverse events must be reported in an expedited manner to allow for optimal monitoring 
of subject safety and care.  
 
All subjects experiencing an adverse event, regardless of its relationship to study drug, will be 
monitored until:  
 
the adverse event resolves or the symptoms or signs that constitute the adverse event 
return to baseline;  
 
any abnormal laboratory values have returned to baseline;  
 
there is a satisfactory explanation other than the study drug for the changes observed; or 
 
Death. 
 
7.2.1 
Definition 
Adverse Events will be reported as indicated by the appropriate following table (see below).    
An adverse event is defined as any untoward or unfavorable medical occurrence in a human 
research study participant, including any abnormal sign (for example, abnormal physical exam or 
laboratory finding), symptom, clinical event, or disease, temporarily associated with the subject’s 
participation in the research, whether or not it is considered related to the subject’s participation 
in the research. 
Adverse events encompass clinical, physical and psychological harms. Adverse events occur 
most commonly in the context of biomedical research, although on occasion, they can occur in 
the context of social and behavioral research. Adverse events may be expected or unexpected. 
Laboratory abnormalities (e.g., clinical chemistry, hematology, and urinalysis) that require 
medical or surgical intervention or lead to study drug interruption, modification, or 
discontinuation must be recorded as an AE, as well as an SAE, if applicable. In addition, 
laboratory or other abnormal assessments (e.g., electrocardiogram, x-rays, vital signs) that are 
associated with signs and/or symptoms must be recorded as an AE or SAE if they meet the 
definition of an AE or SAE. If the laboratory abnormality is part of a syndrome, record the 
syndrome or diagnosis (e.g., anemia), not the laboratory result (i.e., decreased hemoglobin). 


Gilead IN-US-337-1811 
Version 3. 19/MAR/2016 
Protocol Number (SCCC-01416)  
______________________________________________________________________________ 
41 
 
Severity  
Adverse events will be graded by a numerical score according to the defined by the Division of 
AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events. http://rsc.tech-
res.com/Document/safetyandpharmacovigilance/DAIDS_AE_Grading_Table_v2_NOV2014.pdf 
 
 
The Investigator or qualified Sub-Investigator is responsible for assessing the relationship 
to study drug treatment using clinical judgment and the following considerations: 
 
 
 
No: Evidence exists that the adverse event has an etiology other than the study drug. For 
SAEs, an alternative causality must be provided (e.g., pre-existing condition, underlying disease, 
intercurrent illness, or concomitant medication). 
 
 
 
Yes: There is reasonable possibility that the event may have been caused by the 
investigational medicinal product. It should be emphasized that ineffective treatment should not 
be considered as causally related in the context of adverse event reporting. The relationship to 
study procedures (e.g., invasive procedures such as venipuncture or biopsy) should be assessed 
using the following considerations: 
 
 
 
No: Evidence exists that the adverse event has an etiology other than the study procedure. 
 
 
 
Yes: The adverse event occurred as a result of protocol procedures, (e.g., venipuncture) 
 
 
 
The severity grading of AEs will be assessed as Grade 1, 2, 3, 4  per the Division of 
AIDS grading document (http://rsc.tech-
res.com/Document/safetyandpharmacovigilance/DAIDS_AE_Grading_Table_v2_NOV2014.pdf
) 
 
Serious Adverse Events  
ICH Guideline E2A and the UTSW IRB define serious adverse events as those events, occurring 
at any dose, which meets any of the following criteria:  
 
Results in death   
 
Immediately life-threatening  
 
Results in inpatient hospitalization or prolongation of existing hospitalization  
 
Results in persistent or significant disability/incapacity  
 
Results in a congenital anomaly/birth defect  
 
Based upon appropriate medical judgment, may jeopardize the subject’s health and may 
require medical or surgical intervention to prevent one of the other outcomes listed in this 
definition. 
Note: A “Serious adverse event” is by definition an event that meets any of the above criteria. 
Serious adverse events may or may not be related to the research project. A serious adverse event 
determination does not require the event to be related to the research. That is, both events 
completely unrelated to the condition under study and events that are expected in the context of 


Gilead IN-US-337-1811 
Version 3. 19/MAR/2016 
Protocol Number (SCCC-01416)  
______________________________________________________________________________ 
42 
the condition under study may be serious adverse events, independent of relatedness to the study 
itself. As examples, a car accident requiring overnight hospitalization would be a serious adverse 
event for any research participant; likewise, in a study investigating end-stage cancer care, any 
hospitalization or death which occurs during the protocol-specified period of monitoring for 
adverse and serious adverse events would be a serious adverse event, even if the event observed 
is a primary clinical endpoint of the study. 
7.2.2 
Unanticipated Problems: 
The term “unanticipated problem” is found, but not defined in the regulations for the Protection 
of Human Subjects at 45 CFR 46, and the FDA regulations at 21 CFR 56. Guidance from the 
regulatory agencies considers unanticipated problems to include any incident, experience, or 
outcome that meets each of the following criteria: 
• 
Unexpected (in terms of nature, severity or frequency) AND 
• 
Definitely, probably, or possibly related to participation in the research AND  
• 
Serious or a possible unexpected problem in that the research places subjects or others at 
greater risk of harm than was previously known or recognized. Note: Any serious adverse event 
would always suggest a greater risk of harm. 
 
Follow-up  
All adverse events will be followed up according to good medical practices.  
  
7.2.3 
Reporting 
The UTSW IRB requires reporting of all unanticipated problems according to the guidance 
below. For participating centers other than UTSW, local IRB guidance should be followed for 
local reporting of serious adverse events. All SAEs occurring during the protocol-specified 
monitoring period should be submitted to the UTSW study team within 2 business days of the 
center learning of the event. 
Unanticipated problems occurring on the study require expedited reporting, and are submitted to 
the UTSW IRB through the UTSW eIRB by the UTSW study team and to the SCC DSMC 
Coordinator.  Hardcopies or electronic versions of the eIRB report; FDA Form #3500A forms, or 
other sponsor forms, if applicable; and/or any other supporting documentation available should be 
submitted to the UTSW study team and will be forwarded to the DSMC Coordinator.  The DSMC 
Coordinator forwards the information onto the DSMC Chairman who determines if immediate 
action is required.  Follow-up eIRB reports and all subsequent SAE documentation that is available 
are also submitted to the DSMC Chair who determines if further action is required. (See Appendix 
IV of the SCC DSMC Plan for a template Serious Adverse Event Form which may be utilized when 
a sponsor form is unavailable and SAE submission to the eIRB in not required). 
  
All serious adverse events which occur on research subjects on protocols for which the SCC is 
the DSMC of record require reporting to the DSMC regardless of whether IRB reporting is 
required. Hardcopies or electronic versions of the FDA Form #3500A forms, or other sponsor 
forms, if applicable; and/or any other supporting documentation available should be forwarded to 
the DSMC Coordinator.   


Gilead IN-US-337-1811 
Version 3. 19/MAR/2016 
Protocol Number (SCCC-01416)  
______________________________________________________________________________ 
43 
 
 
If the event occurs on a multi-institutional clinical trial coordinated by the UTSW Simmons 
Cancer Center, the DOT Manager or lead coordinator ensures that all participating sites are 
notified of the event and resulting action, according to FDA guidance for expedited reporting. 
DSMC Chairperson reviews all serious adverse events upon receipt from the DSMC 
Coordinator.  The DSMC Chairperson determines whether action is required and either takes 
action immediately, convenes a special DSMC session (physical or electronic), or defers the 
action until a regularly scheduled DSMC meeting.  
  
Telephone reports to: 
Optimal Study: 
Tianna Petersen 
214-590-0611   
 
 
Written reports to:  
Optimal Study/ Tianna Petersen 
214-590-2689 
1936 Amelia Court, 2nd floor Research Unit 
Dallas, Texas 75235 
  
 
UTSW SCC Data Safety Monitoring Committee Coordinator 
Email: SCCDSMC@utsouthwestern.edu 
Fax: 214-648-5949 or deliver to BLB.306 
 
UTSW Institutional Review Board (IRB) 
Submit via eIRB with a copy of the final sponsor report as attached supporting 
documentation 
 
1. 
SAEs 
Serious adverse events (SAEs) for studies where SCC DSMC is the DSMC of record require 
reporting to the DSMC coordinator within 2 working days of PI awareness, or as described in the 
protocol.   
2. 
Unanticipated Problems  
Unanticipated problems require reporting to the UTSW IRB within 2 working days of PI 
awareness of the event.   
Unanticipated problems, including those that occur as non-local events, require reporting to the 
UTSW IRB within 10 working days of PI awareness of the event. 
For further guidance for Investigators regarding safety reporting requirements for INDs and 
BA/BE studies, refer to FDA Draft Guidance document: 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/U
CM227351.pdf 
  
 
7.3 
Steps to Determine If an Adverse Event Requires Expedited Reporting 
 


Gilead IN-US-337-1811 
Version 3. 19/MAR/2016 
Protocol Number (SCCC-01416)  
______________________________________________________________________________ 
44 
Step 1: Identify the type of adverse event using the DAIDS Adverse Event Table 
http://rsc.techres.com/Document/safetyandpharmacovigilance/DAIDS_AE_Grading_Table_v2_
NOV2014.pdf) 
 
Step 2: Grade the adverse event using the DAIDS Adverse Event Table 
 
Step 3: Determine whether the adverse event is related to the protocol therapy  
Attribution categories are as follows: 
- Definite – The AE is clearly related to the study treatment. 
- Probable – The AE is likely related to the study treatment. 
- Possible – The AE may be related to the study treatment. 
- Unrelated – The AE is clearly NOT related to the study treatment. 
Note: This includes all events that occur within 30 days of the last dose of protocol treatment. 
Any event that occurs more than 30 days after the last dose of treatment and is attributed 
(possibly, probably, or definitely) to the agent(s) must also be reported accordingly. 
 
Step 4: Determine the prior experience of the adverse event.  
The reporting purposes only, when either the type of event or the severity of the event is not 
listed in: 
 the current known adverse events listed in the Agent Information Section of this protocol; 
 the drug package insert; 
 the current Investigator’s Brochure 
7.4 
Unblinding Procedures 
This study is not blinded. There are no unblinding procedures.  
7.5 
Stopping Rules 
 The Principal Investigator may terminate the study prematurely, either in its entirety or at any 
study site, for reasonable cause provided that written notice is submitted in advance of the 
intended termination. The investigator may also terminate the study at his/her site for reasonable 
cause, after providing written notice to the Principal Investigator in advance of the intended 
termination. Advance notice is not required by either party if the study is stopped due to safety 
concerns. If the Principal Investigator terminates the study for safety reasons, the Principal 
Investigator will immediately notify the investigator(s) by phone and subsequently provide 
written instructions for study termination. The drugs used in this study are FDA approved and 
very well tolerated. It is not expected that drug toxicity would lead to a need to stop the study.  
 
 
8.0 
DRUG INFORMATION 
8.1 
Sofosbuvir   
 Other names for the drug(s): Sovaldi 
 
 Classification - type of agent: HCV nucleotide analog NS5B polymerase inhibitor 
 
 Mode of action: Sofosbuvir is a direct-acting antiviral agent against the hepatitis C virus.  


Gilead IN-US-337-1811 
Version 3. 19/MAR/2016 
Protocol Number (SCCC-01416)  
______________________________________________________________________________ 
45 
 
 Storage and stability: Store at room temperature 30° C (86° F). Dispense only in original 
container. Do not use if seal over bottle is opening is broken or missing.  
 
 Protocol dose: 400 mg 
 
 Preparation: Sovaldi tablets are yellow, capsule-shaped, film-coated tablets containing 
400 mg of Sofosbuvir debossed with “GSI” on one side and “7977” on the other side.  
Each bottle contains 28 tablets, a silica gel desiccant and polyester coil with a child-
resistant closure.   
 
 Route of administration for this study: oral 
 
 Incompatibilities: amiodarone 
 
 Availability: medication will be provided by the study 
 
 Side effects:  Most common adverse events include: fatigue, headache, nausea, insomnia, 
pruritus. Please see Sofosbuvir package insert for comprehensive information on adverse 
events.  
 
8.2 
Sofosbuvir/ledipasvir 
 Other names for the drug(s): Harvoni 
 
 Classification - type of agent: HCV NS5A inhibitor (ledipasvir); HCV N5B5 polymerase 
inhibitor (Sofosbuvir) 
 
 Mode of action:   direct-acting antiviral agent against the hepatitis C virus.  
 
 Storage and stability: Store at room temperature 30° C (86° F). Dispense only in original 
container. Do not use if seal over bottle is opening is broken or missing.  
 
 Protocol dose: Ledipasvir 90 mg;/Sofosbuvir 400 mg (fixed dose combination): one pill 
 
 Preparation:  tablets are orange, diamond-shaped, film-coated, debossed with “GSI” on 
one side and “7985”on the other side.   
 
 Route of administration for this study: oral 
 
 Incompatibilities: amiodarone 
 
 Availability: medication will be provided by the study 
 


Gilead IN-US-337-1811 
Version 3. 19/MAR/2016 
Protocol Number (SCCC-01416)  
______________________________________________________________________________ 
46 
 Side effects:  Most common adverse events include: fatigue, headache, nausea, diarrhea, 
and insomnia. Please see Sofosbuvir/ledipasvir package insert for comprehensive 
information on adverse events.  
 
8.3 
Ribavirin 
 Other names for the drug(s): copegus 
 
 Classification - type of agent: HCV NS5A inhibitor (ledipasvir); HCV N5B5 polymerase 
inhibitor (Sofosbuvir) 
 
 Mode of action:   direct-acting antiviral agent against the hepatitis C virus.  
 
 Storage and stability: Store at room temperature 25° C (77° F). Excursions are permitted 
between 15°C and 30°C (59° F and 86° F)  
 
 Protocol dose:  200mg tablets. Subjects will take 1000 mg in divided dose twice a day if 
≤75kg and 1200 mg in divided dose twice a day if >75 kg.  
 
 Preparation:  tablets are light pink to pink colored, flat, oval-shaped, film-coated, and 
engraved with RIB 200 on one side and ROCHE on the other. They are packaged as 
bottle of 168.    
 
 Route of administration for this study: oral 
 
 Incompatibilities:  women who are pregnant should not take this drug; men whose female 
partner is pregnant should not take this drug; Do not use with Didanosine.  
 
 Availability: medication will be provided by the study 
 Side effects:  Most common adverse events include: anemia, rash, irritability, and 
insomnia.  Please see ribavirin package insert for comprehensive information on adverse 
events 
 
8.4 
Sofosbuvir/velpatasvir 
 Other name for the drug:  
 Classification- type of drug: sofosbuvir is a nucleotide analogue inhibitor of the 
HCV NS5B polymerase.  Velpatasvir is a pangenotypic HCV NS5A inhibitor 
with antiviral activity against HCV replicons in genotypes 1 through 6.  
 Mode of action: direct-acting antiviral agent against the hepatitis C virus.  


Gilead IN-US-337-1811 
Version 3. 19/MAR/2016 
Protocol Number (SCCC-01416)  
______________________________________________________________________________ 
47 
 Storage and stability: Store at room temperature 30° C (86° F). Dispense only in 
original container. Do not use if seal over bottle is opening is broken or missing.  
 Protocol dose: sofosbuvir 400 mg and velpatasvir 100 mg fixed dose 
combination: one pill  
 Preparation:  
 Route of administration of study drug: oral 
 Incompatibilities: amiodorone 
 Availability:  medication will be provided by the study 
 Side effects: headache, fatigue, nasopharyngitis, nausea, insomnia, diarrhea, 
asthenia, arthralgia, cough, back pain, myalgia.  
 
8.4.1 
Return and Retention of Study Drug 
Drug will be returned to study coordinator. Pharmacy will destroy all returned drug per UT 
Southwestern Institutional guidelines.  
 
8.4.2 
Compliance with study drug will be measured by the study coordinator through pill 
count.   
 
9.0 
CORRELATIVES/SPECIAL STUDIES 
 
Patient will be required to sign a separate consent for acquisition of extra blood samples for 
research purposes. Blood will be collected and stored for future genetic analysis and compared to 
B cell mutations found from bone marrow biopsy.  10 ml of whole blood will be collected in 
ACD or EDTA vacutainer tubes and must be completely filled. The samples collected will be 
batched and sent to UT Southwestern for storage.  The de-identified samples will be sent for 
analysis once funding is available for the project.   Blood will be stored locally as a back-up if a 
mishap occurs in the lab and if stored sample could be used for a replacement.  Samples will be 
collected at baseline, post-treatment week 12, and post-treatment week 36.      
 
   Subject samples collected for this study will be retained at UT Southwestern at the end of the 
study. Specimens will be stored indefinitely or until they are used up. If future use is denied or 
withdrawn by the subject, best efforts will be made to stop any additional studies and to destroy 
the specimens. 
 


Gilead IN-US-337-1811 
Version 3. 19/MAR/2016 
Protocol Number (SCCC-01416)  
______________________________________________________________________________ 
48 
Mamta K. Jain will be responsible for reviewing and approving requests for clinical specimen 
from potential research collaborators outside of UT Southwestern. Collaborators will be required 
to complete an agreement (a Material Transfer Agreement or recharge agreement) that states 
specimens will only be released for use in disclosed research. Any data obtained from the use of 
clinical specimen will be the property of UT Southwestern for publication and any licensing 
agreement will be strictly adhered to.  
 
The specimens, DNA, and their derivatives may have significant therapeutic or commercial 
value. The Informed Consent form contains this information and informs the subject that there is 
the potential for financial gain by UT Southwestern, the investigator or a collaborating researcher 
or entity.  
 
The following information obtained from the subject's medical record may be provided to 
research collaborators when specimens are made available: 
 
Diagnosis  
 
Collection time in relation to study treatment 
 
Clinical outcome – if available 
 
Demographic data 
10.0 
STATISTICAL CONSIDERATIONS 
 
 
10.1 
Study Design/Study Endpoints 
This is a prospective, non-randomized, interventional, exploratory study. The statistical analysis 
will be primarily descriptive. Descriptive statistics (e.g., mean, median, ranges, and frequencies) 
will be used to summarize AEs, SAEs, HCV treatment discontinuation and lymphoma treatment 
initiation.  Adverse events at each visit and for the entire study duration will be summarized as 
frequency counts and percentages. For the safety analysis, data will be collected at each visit on 
side effects that the patient may be experiencing while on medication. These symptoms will be 
graded and recorded in REDCaps.  The grading will be from 1-4. The labs will be entered and 
abnormal labs will be graded by the DAIDS laboratory manual. This too will be recorded in 
REDCaps.  REDCap provides data validation at time of entry with variable fields that have 
custom ranges and rules or coded drop down lists. In addition, monitoring visits will occur in 
which source documentation is compared to REDCaps data entry. 
 
Symptoms will be categorized in binary fashion (yes/no) such as fatigue, headache, 
nausea/vomiting, etc.  It will be graded 1-4 based on DAIDS AE grading scale (see link).  Lab 
values will be reported in categorical fashion depending on grade of abnormality. Grade of 
abnormality will be determined by Division of AIDS AE grading table 
(http://rsc.techres.com/Document/safetyandpharmacovigilance/DAIDS_AE_Grading_Table_v2_
NOV2014.pdf ) 
 
For the secondary endpoint, we will examine change in the size of the lymph node after HCV 
treatment. Patients will be classified as partial responders or complete responders or non-
responders by post-treatment week 36 according to the international lymphoma grading scale. 


Gilead IN-US-337-1811 
Version 3. 19/MAR/2016 
Protocol Number (SCCC-01416)  
______________________________________________________________________________ 
49 
The site investigator in oncology at each site will be responsible for making this assessment 
based on the PET/CT scans. The oncologist will have to write their assessment in a document.  
The assessment will be recorded in RedCaps by the study coordinator.   The study team 
composed of the liver and hematology experts will review cases collectively if there are 
questions about classification of response to adjudicate discrepancies and to maintain 
consistency.  
 
SVR data will be determine by HCV RNA results and will be based on having a negative HCV 
RNA >12 weeks post-treatment.  The hepatology investigator for each site will be responsible 
for making this assessment and will document in source note.  This data will be entered into 
REDCaps. It can also be verified by the monitor based on laboratory data and date of laboratory 
compared to treatment completion date.  
 
 In addition these descriptive statistics will be used to for partial and complete response and 
SVR.   95% confidence intervals will be used to summarize the response for lymphoma and 
HCV. Any hypothesis testing will be considered exploratory and interpreted cautiously 
  
10.2 
Sample Size and Accrual 
The number of patients selected for this study was based on the feasibility of being able to recruit 
patients with the inclusion/exclusion criteria outlined within 6-12 months at each center. 
  
10.3 
Data Analyses Plans 
The primary and secondary objectives will be analyzed in a descriptive fashion as this study is an 
exploratory study.    
11.0 
Other Risks Related to Study Participation 
11.1 
Viral Resistance 
 
Treatment with drugs that directly inhibit the Hepatitis C virus has been shown to lead to 
development of Hepatitis C virus that is resistant to that drug and other drugs with the same type 
of action.  These resistance mutations have been observed in the body as late as 4 to 5 years after 
treatment has ended. It is unknown whether having these resistance mutations might reduce the 
chance of treatment success with future drugs with the same type of action or with different types 
of action (such as protease inhibitors). 
11.2 
Loss of Confidentiality 
 
Any time information is collected; there is a potential risk for loss of confidentiality.  Every 
effort will be made to keep the subject’s information confidential; however, this cannot be 
guaranteed. 
11.3 
Risks to Sperm, Embryo, Fetus or Breast-fed Infant 
 


Gilead IN-US-337-1811 
Version 3. 19/MAR/2016 
Protocol Number (SCCC-01416)  
______________________________________________________________________________ 
50 
Because the effects of SOF and LDV on an unborn baby (fetus) or a nursing infant are not 
known, any female who is pregnant or breast feeding an infant will not be enrolled in this study. 
 
For subjects taking SOF/LDV FDC, extreme care must be taken to avoid pregnancy in female 
subjects or in female partners of male subjects during this study and following completion of study 
treatment (30 days after completion for women, 90 days after completion for men).   
 
Because of the evidence of risks of RBV on an unborn baby (fetus) or a nursing infant, extreme 
care should be taken to prevent pregnancy (in female subjects, female partners of male subjects, 
and must not donate sperm) during this study and for 6 months after completion of RBV. 
 
Ribavirin is a category X drug. Women of child-bearing potential will need to use two forms of 
birth control during the course of treatment and for 6 months after completion of treatment. 
11.3.1 Women Only 
Women who can get pregnant should not take study drug(s) unless they and their partner do not 
have intercourse ever or are using 2 methods of birth control for the duration of the study 
(starting 3 weeks prior to the Baseline/Day 1 visit) and for a minimum of 30 days after last dose 
of study drug or longer as directed by the Study Doctor.  If on ribavirin, the subject should not 
get pregnant for a minimum of 6 months after last dose of study drug or longer as directed by the 
Study Doctor.  
 
At least one method of birth control must be a condom used correctly by your male partner.  The 
Study Doctor will discuss with you other methods of birth control that can be used in 
combination with a condom.   
 
Women who can get pregnant must have a negative pregnancy test at screening and at the 
Baseline/Day 1 visit, prior to taking the first dose of study medication.  Pregnancy tests will be 
repeated every 4 weeks during the study treatment through the Post-Treatment week 4 follow up 
visit or longer depending on the use of ribavirin.   
 
In the event of a positive urine pregnancy result, the subject will be instructed to stop study drugs 
immediately and return to the study clinic as soon as possible for a serum (blood) pregnancy test.  
The pregnancy will be followed to its completion and the outcome, including any premature 
termination, must be reported to the Sponsor. 
11.3.2 Men Only 
 
If the female partner becomes pregnant, the subject and his partner must use two forms of birth 
control for the entire study and for a minimum of 90 days after the last dose of study drug or 
longer if on ribavirin as directed by the Study Doctor.  The subject must use a condom while his 
female partner uses 1 other method of birth control.     
 
If the female sex partner becomes pregnant while the subject is in the study or within 90 days 
after the last dose of study drug (or within 6 months after last dose of ribavirin), the study drug 
may harm an unborn baby.  If the subject has a female partner who becomes pregnant or suspects 


Gilead IN-US-337-1811 
Version 3. 19/MAR/2016 
Protocol Number (SCCC-01416)  
______________________________________________________________________________ 
51 
that she has become pregnant while the subject is in the study or within 90 days after your last 
dose of study drug (or within 6 months of last dose of ribavirin), the subject will be required to 
notify the Study Doctor immediately.  As the risk to the female partner and unborn baby are not 
known, it is recommended for the female partner to receive appropriate prenatal care.  If the 
subject agrees, the female partner will be asked to sign a consent form to allow disclosure of 
medical information related to the pregnancy.  The Study Doctor may need to disclose to his 
female partner details the study.  The Study Sponsor and the Study Doctor will not be 
responsible for the costs related to the pregnancy, delivery, or care of your child.   
 
Male subjects must also agree not to donate sperm from the time you take your first dose of 
study medication until 90 days after the last dose of study drug. If ribavirin was used than they 
must agree not donate sperm for 6 months after last dose was taken.  
 
Please note: Hormonal birth control may be more effective when taken for at least 3 months.  
Even if the subject and his female partner use a medically proven birth control method, could 
still cause his partner to become pregnant. 
11.4 
Risks of Radiation – Diagnostic Test 
 
This research study includes exposure to radiation from diagnostic tests in addition to that which 
you would receive from standard care.  The risk of harm to the body from this radiation can be 
compared to risks from everyday activities.  For example, the risk of developing fatal cancer 
during your lifetime from this radiation is comparative to the risk of suffering a fatal car crash 
while driving 6,050 miles in an automobile.  The average household in the United States drives 
23,000 miles per year (2001 data). 
11.5 
Risks of Blood Drawing 
 
Risks associated with drawing blood is minimal discomfort and/or bruising.  Infection, excess 
bleeding, clotting, and/or fainting also are possible, although unlikely. Approximately 43 
tablespoons of blood collected through Week 48. 
 
12.0 
STUDY MANAGEMENT 
12.1 
Conflict of Interest 
Any investigator who has a conflict of interest with this study (patent ownership, royalties, or 
financial gain greater than the minimum allowable by their institution, etc.) must have the 
conflict reviewed by the UTSW COI Committee and IRB according to UTSW Policy on 
Conflicts of Interest.  All investigators will follow the University conflict of interest policy. 
12.2 Institutional Review Board (IRB) Approval and Consent 
It is expected that the IRB will have the proper representation and function in accordance with 
federally mandated regulations. The IRB must approve the consent form and protocol. 
 


Gilead IN-US-337-1811 
Version 3. 19/MAR/2016 
Protocol Number (SCCC-01416)  
______________________________________________________________________________ 
52 
In obtaining and documenting informed consent, the investigator should comply with the 
applicable regulatory requirement(s), and should adhere to Good Clinical Practice (GCP) and to 
ethical principles that have their origin in the Declaration of Helsinki. 
 
 
Before recruitment and enrollment onto this study, the subject will be given a full explanation of 
the study and will be given the opportunity to review the consent form. Each consent form must 
include all the relevant elements currently required by the FDA Regulations and local or state 
regulations. Once this essential information has been provided to the subject and the investigator 
is assured that the subject understands the implications of participating in the study, the subject 
will be asked to give consent to participate in the study by signing an IRB-approved consent 
form. 
 
Prior to a patient’s participation in the trial, the written informed consent form should be signed 
and personally dated by the subject  and by the person who conducted the informed consent 
discussion. 
12.3 
Required Documentation (for multi-site studies) 
Before the study can be initiated at any site, the following documentation must be provided to 
the HIV/AIDS Research Unit. 
 
 
A copy of the official IRB approval letter for the protocol and informed consent 
 
IRB membership list or Federal wide Assurance letter 
 
CVs and medical licensure for the principal investigator and any associate 
 
investigators who will be involved in the study 
 
Form FDA 1572 appropriately filled out and signed with appropriate 
 
documentation (NOTE: this is required if 4 holds the IND. Otherwise,  
the 
affiliate Investigator’s signature on the protocol is sufficient to ensure  
compliance) 
 
A copy of the IRB-approved consent form 
 
CAP and CLIA Laboratory certification numbers and institution lab normal values 
 
Executed clinical research contract 
 
 
12.3.1 Registration/Randomization Procedures 
 This study is not randomized. Subjects will obtain a screening number generated by REDCaps. 
Once eligibility is verified and reviewed by Project Director, the subject will be enrolled in 
REDCaps by site coordinator and an enrollment number will be generated. This will be the id for 
the subject during the study.  
  
All subjects must be registered with the Lead site (UT Southwestern) before enrollment to study. 
The coordinator at each site will contact Project Director, Tianna Petersen at 214-590-0611 to 
notify of enrollment. 
  
 Prior to enrollment, eligibility criteria must be confirmed with the Study Coordinator.   
 


Gilead IN-US-337-1811 
Version 3. 19/MAR/2016 
Protocol Number (SCCC-01416)  
______________________________________________________________________________ 
53 
A lead-in identifier for each site will be created. Each site will be assigned a number.   The first 
patient consented and enrolled at the first site will be subject 01-001-01. The second subject 
enrolled at the second site might be 02-003-02. 
 
New subjects will receive a number beginning with 001 upon study consent such that the first 
subject consented is numbered 001, the second subject consented receives the number 002, etc.  
 
Upon confirmation of eligibility and enrollment as per the afore-mentioned instructions, the 
subject will be assigned a secondary number in the order of enrollment. For example, subject 001 
will become 001-01 upon enrollment. If subject 002 screen fails, and subject 003 is the next 
subject enrolled, subject 003 will become 003-02 and so-on.  
 
Each newly consented subject should be numbered using the schema provided above. Upon 
registration, the registrar will assign the additional registration/randomization code according to 
the numbering schema outlined above, which should then be entered as the patient study id in 
Velos upon updating the status to enrolled. 
 
The numbering schema should clearly identify the site number; the sequential number of the 
subject enrolled as well as the status of the subjects enrolled so that the number of subjects 
consented versus the number of subjects actually enrolled may be easily identified.   
 
12.3.2 Data Management and Monitoring/Auditing 
  
 
REDCap is the UTSW institutional choice for the electronic data capture of case report forms for 
this and all Investigator Initiated Trials. REDCap will be used for electronic case report forms in 
accordance with requirements. 
 
Other institutions participating in this trial as sub-sites will be expected to enter data into 
REDCap and upload de-identified source materials when instructed by the study team to 
facilitate remote source to case report form verification.  
 
Regulatory: Regulatory data will be monitored for each site including documentation of Federal 
Wide Assurance by having each site provide copies for the central site to maintain. Copies of 
approved consent forms, including all amendments and protocol version changes, will be 
obtained throughout the study. A copy of the IRB approval letter will need to be provided by the 
site for activation and contract execution.  In addition, yearly approval of informed consent needs 
to be provided by the sites.  The central site will review changes made to the Informed Consent 
by each site by respective IRBs.  If changes are required by an IRB that impacts the Informed 
Consent content, then changes to the Informed Consent may be required.  Any changes to the 
protocol will require an amendment to the protocol.  
 
Monitoring: Monitoring visits will be conducted at each site to review informed consent 
documents to ensure appropriate consent has been obtained, including signature, date, and 
documentation of consenting process in source document.   The monitor will also review 


Gilead IN-US-337-1811 
Version 3. 19/MAR/2016 
Protocol Number (SCCC-01416)  
______________________________________________________________________________ 
54 
inclusion and exclusion criteria on every patient enrolled to insure that patients are enrolled that 
are appropriate.  Any enrollments that do not follow inclusion/exclusion criteria will be 
considered protocol violations.  Protocol deviations will include missed lab tests or visits.  The 
monitor will also review charts to verify all adverse events documented in the source have been 
reported on the adverse event log.  
A monthly call will be done by the central site to discuss recruitment goals, problems in 
recruitment, challenges in procedures, or other aspects of study implementation at each site.  
Safety: Adverse events will be reported by each site as described in the protocol. Serious 
Adverse Events will be reported by the site. Any serious adverse event(s) or adverse event(s) 
which changes the risk for the patient will be documented by a letter to the IRB.  
 
12.3.3 Method and Frequency of Analysis:  
Mamta Jain, MD will be responsible for the overall monitoring of data and safety for the study. 
The data collected at each site will be monitored by the Project Manager, Tianna Petersen.  Dr. 
William Lee will be the Safety Officer for the study and will review adverse events and serious 
adverse events to determine if causality to study drug exists. The Project Manager will be 
responsible for creating reports of unanticipated problems, adverse events, protocol deviations 
and violations to the IRB.  This study is not an IND study and no reporting of Adverse Events is 
required for the FDA.  
The study accrual, protocol deviations and violations, unanticipated problems, and overall safety 
of participants will be submitted to the IRB yearly.  
An interim analysis of data will be planned after 21 patients are enrolled or 1 year after the first 
patient is enrolled.  
 
12.3.4 Reporting Unanticipated Problems, Adverse Events, Protocol Deviations and 
Protocol Violations:  
The UTSW Simmons Cancer Center (SCC) Data Safety Monitoring Committee (DSMC) is 
responsible for monitoring data quality and patient safety for all UTSW SCC clinical trials.  As 
part of that responsibility, the DSMC reviews all local serious adverse events and unanticipated 
problems in real time as they are reported and reviews adverse events on a quarterly basis.  The 
quality assurance activity for the Clinical Research Office provides for periodic auditing of 
clinical research documents to ensure data integrity and regulatory compliance.  A copy of the 
DSMC plan is available upon request. 
 
The SCC DSMC meets quarterly and conducts annual comprehensive reviews of ongoing 
clinical trials, for which it serves as the DSMC of record. The QAC works as part of the DSMC 
to conduct regular audits based on the level of risk. Audit findings are reviewed at the next 
available DSMC meeting.  In this way, frequency of DSMC monitoring is dependent upon the 
level of risk.  Risk level is determined by the DSMC Chairman and a number of factors such as 
the phase of the study; the type of investigational agent, device or intervention being studied; and 
monitoring required to ensure the safety of study subjects based on the associated risks of the 
study. Protocol-specific DSMC plans must be consistent with these principles.  
 


Gilead IN-US-337-1811 
Version 3. 19/MAR/2016 
Protocol Number (SCCC-01416)  
______________________________________________________________________________ 
55 
The Project Manager will be responsible for monitoring at each site. She will develop a report of 
protocol deviations or violations. Problems observed at the site will be documented and the site 
staff will develop a corrective action plan if needed.  The Project Manager will verify that the 
plan is being implemented at the next site visit.  The site visits are anticipated to occur quarterly 
but may vary depending on enrollments at each site.  
The Project Manager will also have to verify specific milestones have been met in order for sites 
to obtain payment. 
Each Site Investigator will be responsible for reviewing the adverse events and serious adverse 
events at their site and determining the severity and relationship to study drug.  The Project 
Manager will compile all safety data and report to the DSMC quarterly or as required.  
 If a modification of the informed consent will need to occur due to safety concerns, each site   
will be sent a modification of the informed consent for approval by their IRBs. In addition, a 
letter describing the change in risk or safety will be given to each site for submission to their 
IRB.  All other adverse events or serious adverse events which do not change the risk or safety 
for the patient will be reported to the IRB yearly.  
 
Procedures and Time Frames for Communicating Outcomes:  The project manager will have 
30 days to complete a report of the findings from each site. This report will be given to each 
respective site and will be the basis of the yearly reporting for the IRB.  
 
Precautions for Maintaining Data Integrity:  The Project Manager will monitor each site to 
determine if the site is adhering to the conduct of the study. This will include review of informed 
consent process, verification of adherence to inclusion and exclusion criteria, verification of 
study visits being conducted during the time-frame outlined in the protocol, verification that all 
laboratory and imaging that is required by the study is conducted as dictated by the protocol.  
Any findings of non-compliance to informed consent,   inclusion/exclusion criteria, or collection 
of data at key time points such as SVR, PET scan, and failure to report adverse events or serious 
adverse events that are deemed by the site investigator to be causally related to study drug will 
be considered as a Protocol Violation. All other non-adherence to protocol will be protocol 
deviations. All data reported on case report forms will be verified by monitor against the source 
document. This will assure the validity and integrity of the data.  
 
12.3.5 Adherence to the Protocol 
Except for an emergency situation in which proper care for the protection, safety, and well-being 
of the study subject requires alternative treatment, the study shall be conducted exactly as 
described in the approved protocol.  
Emergency Modifications 
Investigators may implement a deviation from, or a change of, the protocol to eliminate an 
immediate hazard(s) to trial subjects without prior IRB approval.  
 
For any such emergency modification implemented, an IRB modification form must be 
completed within five (5) business days of making the change. 


Gilead IN-US-337-1811 
Version 3. 19/MAR/2016 
Protocol Number (SCCC-01416)  
______________________________________________________________________________ 
56 
Other Protocol Deviations/Violations 
All other planned deviations from the protocol must have prior approval by the Principal 
Investigator and the IRB. According to the IRB, a protocol deviation is any unplanned variance 
from an IRB approved protocol that:  
 
Is generally noted or recognized after it occurs 
 
Has no substantive effect on the risks to research participants 
 
Has no substantive effect on the scientific integrity of the research plan or the 
 
value of the data collected  
 
Did not result from willful or knowing misconduct on the part of the 
 
investigator(s).  
 
An unplanned protocol variance is considered a violation if the variance: 
 
Has harmed or increased the risk of harm to one or more research participants. 
 
Has damaged the scientific integrity of the data collected for the study. 
 
Results from willful or knowing misconduct on the part of the investigator(s). 
 
Demonstrates serious or continuing noncompliance with federal regulations, State 
 
laws, or University policies. 
 
If a deviation or violation occurs without prior approval from the Principal Investigator, please 
follow the guidelines below: 
 
Protocol Deviations: Personnel will report to any sponsor or data and safety monitoring 
committee in accordance with their policies. Deviations should be summarized and reported to 
the IRB at the time of continuing review. 
 
Protocol Violations: Study personnel should report violations within two (2) week of the 
investigator becoming aware of the event using the same IRB online mechanism used to report 
Unanticipated Problems.  
12.3.6 Amendments to the Protocol 
Should amendments to the protocol be required, the amendments will be originated and 
documented by the Principal Investigator.  A summary of changes document outlining proposed 
changes as well as rationale for changes, when appropriate, is highly recommended.  When an 
amendment to the protocol substantially alters the study design or the potential risk to the patient, 
a revised consent form might be required.  
 
The written amendment, and if required the amended consent form, must be sent to the IRB for 
approval prior to implementation.  
12.3.7 Record Retention 
Study documentation includes all Case Report Forms, data correction forms or queries, source 
documents, Sponsor-Investigator correspondence, monitoring logs/letters, and regulatory 
documents (e.g., protocol and amendments, IRB correspondence and approval, signed patient 
consent forms). 
 


Gilead IN-US-337-1811 
Version 3. 19/MAR/2016 
Protocol Number (SCCC-01416)  
______________________________________________________________________________ 
57 
Source documents include all recordings of observations or notations of clinical activities and all 
reports and records necessary for the evaluation and reconstruction of the clinical research study. 
 
Government agency regulations and directives require that the study investigator retain all study 
documentation pertaining to the conduct of a clinical trial. In the case of a study with a drug 
seeking regulatory approval and marketing, these documents shall be retained for at least two 
years after the last approval of marketing application in an International Conference on 
Harmonization (ICH) region. In all other cases, study documents should be kept on file until 
three years after the completion and final study report of this investigational study. 
12.3.8 Obligations of Investigators 
The Principal Investigator is responsible for the conduct of the clinical trial at the site in 
accordance with Title 21 of the Code of Federal Regulations and/or the Declaration of Helsinki. 
The Principal Investigator is responsible for personally overseeing the treatment of all study 
patients. The Principal Investigator must assure that all study site personnel, including sub-
investigators and other study staff members, adhere to the study protocol and all FDA/GCP/NCI 
regulations and guidelines regarding clinical trials both during and after study completion. 
 
The Principal Investigator at each institution or site will be responsible for assuring that all the 
required data will be collected and entered onto the Case Report Forms. Periodically, monitoring 
visits may be conducted and the Principal Investigator will provide access to his/her original 
records to permit verification of proper entry of data. At the completion of the study, all case 
report forms will be reviewed by the Principal Investigator and will require his/her final 
signature to verify the accuracy of the data. 
13.0 
REFERENCES 
1. 
Forghieri F, Luppi M, Barozzi P, et al. Pathogenetic mechanisms of hepatitis C virus-
 
induced B-cell lymphomagenesis. Clinical & developmental immunology 
 
2012;2012:807351. 
2. 
Peveling-Oberhag J, Arcaini L, Hansmann ML, Zeuzem S. Hepatitis C-associated B-cell 
 
non-Hodgkin lymphomas. Epidemiology, molecular signature and clinical management. 
 
Journal of hepatology 2013;59:169-77. 
3. 
Arcaini L, Merli M, Volpetti S, Rattotti S, Gotti M, Zaja F. Indolent B-cell lymphomas 
 
associated with HCV infection: clinical and virological features and role of antiviral 
 
therapy. Clinical & developmental immunology 2012;2012:638185. 
4. 
Kasama Y, Mizukami T, Kusunoki H, et al. B-cell-intrinsic hepatitis C virus expression 
 
leads to B-cell-lymphomagenesis and induction of NF-kappaB signalling. PloS one 
 
2014;9:e91373. 
5. 
Hermine O, Lefrere F, Bronowicki JP, et al. Regression of splenic lymphoma with villous 
 
lymphocytes after treatment of hepatitis C virus infection. The New England journal of 
 
medicine 2002;347:89-94. 
6. 
Vallisa D, Bernuzzi P, Arcaini L, et al. Role of anti-hepatitis C virus (HCV) treatment in 
 
HCV-related, low-grade, B-cell, non-Hodgkin's lymphoma: a multicenter Italian 
 
experience. Journal of clinical oncology : official journal of the American Society of 
 
Clinical Oncology 2005;23:468-73. 


Gilead IN-US-337-1811 
Version 3. 19/MAR/2016 
Protocol Number (SCCC-01416)  
______________________________________________________________________________ 
58 
7. 
Arcaini L, Vallisa D, Rattotti S, et al. Antiviral treatment in patients with indolent B-cell 
 
lymphomas associated with HCV infection: a study of the Fondazione Italiana Linfomi. 
 
Annals of oncology : official journal of the European Society for Medical Oncology / 
 
ESMO 2014;25:1404-10. 
8. 
Afdhal N, Zeuzem S, Kwo P, et al. Ledipasvir and sofosbuvir for untreated HCV 
 
genotype 1 infection. The New England journal of medicine 2014;370:1889-98. 
9. 
Gane EJ, Stedman CA, Hyland RH, et al. Nucleotide polymerase inhibitor sofosbuvir 
 
plus ribavirin for hepatitis C. The New England journal of medicine 2013;368:34-44. 
10. 
Kowdley KV, Gordon SC, Reddy KR, et al. Ledipasvir and sofosbuvir for 8 or 12 weeks 
 
for chronic HCV without cirrhosis. The New England journal of medicine 
 
2014;370:1879-88. 
11. 
Lawitz E, Poordad FF, Pang PS, et al. Sofosbuvir and ledipasvir fixed-dose combination 
 
with and without ribavirin in treatment-naive and previously treated patients with 
 
genotype 1 hepatitis C virus infection (LONESTAR): an open-label, randomised, phase 2 
 
trial. Lancet 2014;383:515-23. 
12. 
Zeuzem S, Dusheiko G, Salupere R, et al. Sofosbuvir +ribavirin for 12 or 24 weeks for 
 
patients with HCV gentoype 2 or 3: the VALENCE trial.  64th Annual Meeting of the 
 
American Association for the Study of Liver Diseases; 2013 Nov 1-5, 2013; Washington, 
 
D.C. 
13. 
Zeuzem S, Dusheiko GM, Salupere R, et al. Sofosbuvir and ribavirin in HCV genotypes 
 
2 and 3. The New England journal of medicine 2014;370:1993-2001. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
14.0 
APPENDICES 
14.1 
Appendix 1: Karnofsky Performance Status Scale 
100  
Normal, no complaints, no evidence of disease  
90  
Able to carry on normal activity, minor signs or symptoms of disease  
80  
Normal activity with effort, some signs or symptoms of disease  


Gilead IN-US-337-1811 
Version 3. 19/MAR/2016 
Protocol Number (SCCC-01416)  
______________________________________________________________________________ 
59 
70  
Cares for self. Unable to carry on normal activity or to do active work  
60  
Requires occasional assistance, but is able to care for most of his needs  
50  
Requires considerable assistance and frequent medical care  
40  
Disabled, requires special care and assistance  
30  
Severely disabled, hospitalization is indicated although death not imminent  
20  
Hospitalization necessary, very sick, active supportive treatment necessary  
10  
Moribund, fatal processes progressing rapidly.  
0  
Dead  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
14.2 
 Appendix 2.  Follicular Lymphoma International Prognostic Index 2 (FLIPI2) 
Calculator 
 
Prognostic score for untreated follicular lymphoma 
Applies at the time of first treatment. 
1. Sum the number of risk factors to calculate FLIPI-2 score 
Age: 
 < 60 years 
 60 years or older 


Gilead IN-US-337-1811 
Version 3. 19/MAR/2016 
Protocol Number (SCCC-01416)  
______________________________________________________________________________ 
60 
Serum beta 2 microglobulin: 
 Normal 
 Raised 
Hemoglobin: 
 12 g/dL or greater 
 < 12 g/dL 
Bone marrow involvement: 
 Absent 
 Present 
Longest diameter of largest involved node: 
 Less than 6 cm 
 6 cm or more 
FLIPI-2 score: 
 
2. Determine risk category and prognosis 
FLIPI-2 score 
FLIPI-2 risk category 
5 year PFS (%)1 
5 year PFS (%)2 
 
 
 
 
0 
Low risk 
80 
76 
1 - 2 
Intermediate risk 
51 
49 
3 - 5 
High risk 
19 
37 
 
 
 
 
1. 
Vallisa D, Bernuzzi P, Arcaini L, et al. Role of anti-hepatitis C virus (HCV) treatment in 
HCV-related, low-grade, B-cell, non-Hodgkin's lymphoma: a multicenter Italian 
experience. Journal of clinical oncology : official journal of the American Society of 
Clinical Oncology. 2005;23(3):468-473. 
2. 
Foster GR, Afdhal N, Roberts SK, et al. Sofosbuvir and Velpatasvir for HCV Genotype 2 
and 3 Infection. The New England journal of medicine. 2015;373(27):2608-2617. 
3. 
Feld JJ, Jacobson IM, Hezode C, et al. Sofosbuvir and Velpatasvir for HCV Genotype 1, 
2, 4, 5, and 6 Infection. The New England journal of medicine. 2015;373(27):2599-2607. 
4. 
Armstrong GL, Wasley A, Simard EP, McQuillan GM, Kuhnert WL, Alter MJ. The 
prevalence of hepatitis C virus infection in the United States, 1999 through 2002. Annals 
of internal medicine. 2006;144(10):705-714.