Clinical trial NCT01853618
Conditions: Heptocellular Cancer Biliary Tract Neoplasms Liver Cancer Hepatocellular Carcinoma Biliary Cancer
Keywords: Blocking of Immune Suppression Monoclonal Antibody Immunotherapy Ablative Therapy
Sponsor: National Cancer Institute (NCI)
Start date: 2013-05-02; Completion date: 2017-06-07
Enrollment: 61 participants; Allocation: NON_RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
Background:

\- Tremelimumab is a cancer treatment drug that helps the immune system recognize and destroy cancer cells. Researchers want to see if it can be used to treat advanced liver cancer. The drug will be given with one of two types of treatment for liver cancer. The first type, transarterial catheter chemoembolization (TACE), injects chemotherapy drugs into the tumor through the main blood vessel that is feeding it. That blood vessel is then closed off to help keep the drugs in the tumor longer. The second type, radiofrequency ablation (RFA), uses a heated probe to destroy the tumor tissue. Researchers want to study how safe and effective these treatments are with the study drug.

Objectives:

\- To test the safety and effectiveness of Tremelimumab with TACE or RFA for advanced liver cancer.

Eligibility:

\- Individuals at least 18 years of age who have advanced liver cancer that has not responded to other treatments.

Detailed description:
Background:

Worldwide, hepatocellular carcinoma (HCC) is the fifth most common malignancy with a median survival of 6-9 months. For patients with advanced disease sorafenib is the only approved drug and this has limited benefit.

Tremelimumab is a monoclonal antibody against cytotoxic T-lymphocyte-associated protein 4 (CTLA4). Anti-CTLA4 therapy has been shown to enhance anti-tumor immunity by blocking tumor-induced immune suppression of cytotoxic T cells.

Various tumor ablative procedures and techniques have been shown to result in immunogenic cell death and induction of a peripheral immune response. Both transarterial catheter chemoembolization (TACE) and radiofrequency ablation (RFA) have been shown to do this, as well as cryoablation and external beam radiation.

The underlying hypothesis of this study is that the effect of anti-CTLA4 treatment can be enhanced by TACE or RFA in patients with advanced hepatocellular carcinoma. We will also evaluate this in the context of cryoablation and radiation in hepatocellular carcinoma (HCC) and RFA in cholangiocarcinoma.

Objective:

To assess the safety and feasibility of combining Tremelimumab with trans-arterial catheter chemoembolization (TACE) radiofrequency ablation (RFA), or cryoablation in patients with advanced HCC.

Eligibility:

Histologically or cytologically confirmed diagnosis of HCC.

Childs-Pugh A/B7 cirrhosis only is allowed. If patient does not have cirrhosis, this limitation does not apply.

Barcelona Clinic Liver Cancer (BCLC) Stage B and C patients.

Patients must have disease that is not amenable to potentially curative resection, radiofrequency ablation, or liver transplantation.

Arms: arm 1: Escalating doses of Tremelimumab + Radiofrequency Ablation (RFA) or Transarterial Catheter Chemoembolization (TACE) arm 2: Tremelimumab + Radiofrequency Ablation (RFA) or Transarterial Catheter Chemoembolization (TACE) arm 3: Tremelimumab + Transarterial Catheter Chemoembolization (TACE) arm 4: Tremelimumab + Radiofrequency Ablation (RFA) or Transarterial Catheter Chemoembolization (TACE) arm 5: Tremelimumab + Cryoablation arm 6: Tremelimumab + Radiofrequency Ablation (RFA)
Interventions: intervention 1: Tremelimumab intervention 2: RFA intervention 3: TACE intervention 4: Cryoablation
Intervention descriptions: intervention 1: 3.5 mg/kg or 10 mg /kg intravenous (IV) every 4 weeks times 6 doses and then every 12 weeks for 2 years intervention 2: Performed on Day 36 intervention 3: Performed on Day 36 and may be repeated (as per standard of care) on months 3, 7, and 13, and every (q)6 months thereafter (if indicated) intervention 4: Performed on Day 36

Protocol documents:
Prot_SAP_000.pdf: 
Abbreviated Title: anti-CTLA4 & ablative therapy  
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Version Date: 08/14/2017 
Abbreviated Title: anti-CTLA4 & ablative therapy  
CC Protocol #:  13-C-0120 
Version Date:  08/14/2017 
Amendment: J 
NCT Number: NCT01853618 
Title: A Pilot Study of Tremelimumab – A Monoclonal Antibody against CTLA-4 – in 
combination with Trans-Arterial Catheter Chemoembolization (TACE), Radiofrequency 
Ablation (RFA), or Cryoablation in Subjects with Hepatocellular Carcinoma (HCC) or Biliary 
Tract Carcinomas (BTC) 
 
NCI Principal Investigator:        Tim Greten, MD A-F 
    Thoracic & GI Oncology Branch 
    National Cancer Institute 
    Building 10, Room 12N226 
    9000 Rockville Pike 
    Bethesda, MD 20892 
    240-760-6114 
    gretentf@mail.nih.gov   
NIH Associate Investigators:         Changqing Xie, MD, HB, NHLBI A-F 
                                                           Brad Wood MD, DRD/CC/NIH A,B,E,F 
 
     William D. Figg, PharmD, GMB/CCR/NCI E-F 
     Suzanne Fioravanti, RN, OCD/CCR/NCI A,B,C,E,F 
     Melissa Walker, RN, OCD/CCR/NCI A,B,C,E,F 
                             Seth Steinberg, PhD, BDMS, CCR, NCI E-F  
     Gregoire Yves Altan-Bonnet, PhD, CIP, NCIE-F 
                                                  
Referral Contact/ 
Study Coordinator:   
           Suzanne Fioravanti, RN, OCD, CCR, NCI 
     Building 10, Room 12N226 
     9000 Rockville Pike 
 
     Bethesda, MD 20892 
 
     240-760-6113  
 
     fioravas@mail.nih.gov 
 
Non-NIH Associate Investigators:  Firouzeh Korangy, PhD, Kelly Government Solutions E-F 
                                                           Ratnadeep Mukherjee, PhD, Fellow, CIP, NCIE-F 


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Investigators Roles:    A. Obtain information by intervening or interacting with living 
                                         individuals for research purposes 
                                    B. Obtaining identifiable private information about living individuals 
                                    C. Obtaining the voluntary informed consent of individuals to be subjects 
                                    D. Makes decisions about subject eligibility 
                                    E. Studying, interpreting, or analyzing identifiable private information or 
                                        data/specimens for research purposes 
                                    F. Studying, interpreting, or analyzing de-identified data or specimens for 
                                          research purposes 
                                    G. Some/all research activities performed outside NIH 
 
Investigational Agents:     
Drug Name: 
Tremelimumab  
IND Number: 
117537 
Sponsor: 
Center for Cancer Research, National Cancer Institute 
Manufacturer: 
MedImmune, Inc. 
 


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PRÉCIS 
Background:  
x Worldwide, hepatocellular carcinoma (HCC) is the fifth most common malignancy with a 
median survival of 6-9 months. For patients with advanced disease sorafenib is the only 
approved drug and this has limited benefit.   
x Tremelimumab is a monoclonal antibody against CTLA4. Anti-CTLA4 therapy has been 
shown to enhance anti-tumor immunity by blocking tumor-induced immune suppression 
of cytotoxic T cells.  
x Various tumor ablative procedures and techniques have been shown to result in 
immunogenic cell death and induction of a peripheral immune response.  Both trans-
arterial catheter chemoembolization (TACE) and radiofrequency ablation (RFA) have 
been shown to do this, as well as cryoablation and external beam radiation  
x The underlying hypothesis of this study is that the effect of anti-CTLA4 treatment can be 
enhanced by TACE or RFA in patients with advanced hepatocellular carcinoma. We will 
also evaluate this in the context of cryoablation and radiation in HCC and RFA in 
cholangiocarcinoma. 
Objective: 
x To assess the safety and feasibility of combining Tremelimumab with trans-arterial 
catheter chemoembolization (TACE) radiofrequency ablation (RFA) or cryoablation in 
patients with advanced HCC.  
 
Eligibility: 
x Histologically or cytologically confirmed diagnosis of HCC or biliary tract carcinoma 
(cohort E).   
x Childs-Pugh A/B7 cirrhosis only is allowed. If patient does not have cirrhosis, this 
limitation does not apply. 
x Barcelona Clinic Liver Cancer (BCLC) Stage B and C patients. 
x Patients must have disease that is not amenable to potentially curative resection, 
radiofrequency ablation, or liver transplantation. 
Design: 
x The proposed study is a pilot study of Tremelimumab - at a planned dose 10mg/kg/IV q 4 
weekly x 6 doses and then 1 dose every 12 weeks - in patients with advanced HCC or 
cholangiocarcinoma treated with ablative therapy for 2 years or until disease progression 
(as per immune-related RECIST criteria) whichever comes first. 
x The main study population is Cohort A as described below and these patients will be 
treated with either RFA or TACE. The decision on which treatment to administer (i.e. 
RFA vs. TACE) will be made in consultation with the interventional radiologists. The 
reason for this is that there are technical considerations (size and location of lesion, main 
portal vein occlusion etc.) which would make one procedure preferable over the other.  
x We will also enroll an additional cohort of up to N=20 patients (Cohort B) with liver-
confined disease for whom TACE is indicated as standard of care. These patients will 


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receive TACE in combination with Tremelimumab using the same schema. They will not 
receive RFA. 
x For Cohort A (BCLC Stage C patients): TACE or radiofrequency ablation (RFA) will be 
performed once only. 
x For Cohort B (BCLC Stage B patients): TACE may be repeated (as per standard of care) 
on months 3, 7, and 13, and q6 months thereafter (if indicated). 
x Cohort B will only be recruited following completion of the dose-escalation portion of 
Cohort A. 
x Dose escalation: Initially three patients will be treated at 3.5mg/kg (with subsequent 
dosing also at 3.5mg/kg) prior to enrolling to the10mg/kg dose level. If a single patient 
experiences dose-limiting toxicity (DLT) related to the combination of TACE/RFA and 
Tremelimumab this cohort will be expanded to N=6 as per a standard 3+3 design. If 
3.5mg/kg is established to be safe we will proceed to the 10mg/kg dose level. 
x Cohorts A+B: Following dose escalation up to N=40 patients will be treated at 10mg/kg 
(20 patients in Cohort A and 20 in Cohort B).  
x Subjects will no longer enroll onto Cohort C effective with amendment I. 
x Cohorts D-E: N=Up to 30 patients will be treated at 10mg/kg. 
- 
Evaluation period for Dose-limiting Toxicities (DLT) will extend for the first 8 weeks 
of the study.  Restaging CT /MRI scan every 8 weeks to evaluate TTP in target lesion. 
(Both standard RECIST and Immune-related Response Criteria [irRC] will be 
employed). 
- 
Once safety is established for the initial concept of combining anti-CTLA4 with 
ablative procedures (RFA and TACE), we will similarly explore feasibility of 
tremelimumab at the same dose and schedule in 2 additional cohorts (denoted D-E) 
evaluating tremelimumab in combination with cryoablation in HCC (cohort D) and 
with RFA in a cohort of patients with biliary tract carcinoma (cohort E). For these 
additional cohorts the dose (10mg/kg) and schedule of tremelimumab will be as per 
cohorts A and B. The timing of the interventional procedure will also be identical. 


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TABLE OF CONTENTS 
Précis ............................................................................................................................................... 3 
TABLE OF CONTENTS ................................................................................................................ 5 
1 
INTRODUCTION ................................................................................................................ 10 
1.1 
Study Objectives ............................................................................................................ 10 
1.1.1 
Primary:................................................................................................................... 10 
1.1.2 
Secondary:............................................................................................................... 10 
1.1.3 
Exploratory: ............................................................................................................ 10 
1.2 
Background and Rationale ............................................................................................. 10 
1.2.1 
HCC and the current therapeutic paradigm (radiofrequency ablation [RFA] trans-
arterial catheter chemoembolization [TACE] and sorafenib) ............................................... 10 
1.2.2 
Recent advances in immune-based approaches in solid tumor malignancies ......... 12 
1.2.3 
Immune response to interventional radiological treatments ................................... 13 
1.2.4 
Tremelimumab ........................................................................................................ 14 
1.2.5 
Justification for dose and schedule ......................................................................... 16 
1.2.6 
Rationale for Re-Induction ..................................................................................... 16 
1.2.7 
Rationale for Viral Hepatitis Studies and Specifically for Hepatitis B Surface 
Antigen and Hepatitis B Immune Monitoring ...................................................................... 17 
1.2.8 
Rationale for Amendment F .................................................................................... 17 
1.2.9 
Rationale for Amendment I .................................................................................... 20 
1.2.10 Rationale for Amendment J .................................................................................... 20 
2 
ELIGIBILITY ASSESSMENT AND ENROLLMENT ....................................................... 21 
2.1 
Eligibility Criteria .......................................................................................................... 21 
2.1.1 
Inclusion Criteria .................................................................................................... 21 
2.1.2 
Exclusion Criteria ................................................................................................... 22 
2.1.3 
Re-Induction Criteria (if applicable) ....................................................................... 23 
2.1.4 
Inclusion of Women and Minorities ....................................................................... 24 
2.1.5 
Recruitment Strategies ............................................................................................ 24 
2.2 
Screening evaluation ...................................................................................................... 24 
2.2.1 
History and Physical Examination .......................................................................... 24 
2.2.2 
Laboratory Evaluation ............................................................................................ 24 
2.2.3 
Histologic confirmation (at any time point prior to commencement) .................... 24 


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2.3 
Baseline Studies ............................................................................................................. 25 
2.3.1 
Imaging studies (obtained within 28 days prior to first dose) ................................ 25 
2.3.2 
Laboratory evaluation (obtained within 72 hours prior to first dose) ..................... 25 
2.3.3 
Laboratory evaluation (obtained within 28 days prior to first dose) ...................... 25 
2.3.4 
History and physical exam with vital signs (obtained within 1 week prior to first 
dose). 
25 
2.3.5 
Electrocardiogram (obtained within 28 days prior to first dose) ............................ 25 
2.4 
Registration Procedures.................................................................................................. 25 
3 
STUDY IMPLEMENTATION ............................................................................................ 25 
3.1 
Study Design .................................................................................................................. 25 
3.2 
Schedule ......................................................................................................................... 27 
3.3 
Cohort A ......................................................................................................................... 27 
3.3.1 
Definition ................................................................................................................ 27 
3.3.2 
Treatment ................................................................................................................ 27 
3.3.3 
Protocol Stopping Rules ......................................................................................... 28 
3.3.4 
Re-Induction ........................................................................................................... 29 
3.4 
Cohort B ......................................................................................................................... 29 
3.4.1 
Definition ................................................................................................................ 29 
3.4.2 
Treatment ................................................................................................................ 29 
3.5 
Cohort C ......................................................................................................................... 29 
3.6 
Cohorts D-E.................................................................................................................... 29 
3.7 
Dose Limiting Toxicities ................................................................................................ 30 
3.7.1 
Definition of Dose-limiting Toxicities (DLTs): ..................................................... 30 
3.7.2 
Exclusions to Dose Limiting Toxicities .................................................................. 30 
3.8 
Drug Administration ...................................................................................................... 31 
3.8.1 
Tremelimumab Drug Administration ..................................................................... 31 
3.8.2 
Monitoring of Dose Administration........................................................................ 31 
3.9 
Dosing Delays ................................................................................................................ 32 
3.9.1 
Dosing Delays/Dose Modifications: General Guidelines ....................................... 33 
3.9.2 
Toxicities Mandating Permanent Discontinuation of Tremelimumab.................... 33 
3.9.3 
Specific immune-mediated adverse reactions ......................................................... 34 
3.10 
Specific Procedures for TACE, RFA and Cryoablation ............................................. 38 
3.10.1 Transarterial chemoembolization............................................................................ 38 


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3.10.2 Radiofrequency ablation ......................................................................................... 38 
3.10.3 Cryoablation ............................................................................................................ 39 
3.11 
Study Calendar ........................................................................................................... 40 
3.12 
Criteria for Removal from Protocol Therapy and Off Study Criteria ........................ 44 
3.12.1 Criteria for removal from protocol therapy ............................................................ 44 
3.12.2 Criteria for Removal from Study ............................................................................ 44 
3.12.3 Off protocol therapy and Off Study Procedure ....................................................... 44 
4 
CONCOMITANT MEDICATIONS/MEASURES .............................................................. 44 
5 
BIOSPECIMEN COLLECTION .......................................................................................... 45 
5.1 
CORRELATIVE STUDIES FOR RESEARCH/PHARMACOKINETIC STUDIES ... 45 
5.2 
NCI Correlative Studies ................................................................................................. 47 
5.2.1 
Immune Monitoring (All cohorts) .......................................................................... 47 
5.2.2 
Liver autoantibody panel for autoimmune hepatitis (AIH) .................................... 48 
5.2.3 
Hepatitis serology and viral load ............................................................................ 48 
5.2.4 
MDSC functional assay .......................................................................................... 49 
5.2.5 
Optional Tumor Biopsy .......................................................................................... 49 
5.2.6 
TCR Beta Sequencing ............................................................................................. 50 
5.3 
MedImmune Planned Studies......................................................................................... 50 
5.3.1 
Pharmacokinetics .................................................................................................... 50 
5.3.2 
Immunogenicity ...................................................................................................... 50 
5.3.3 
T CELL Activation/ICOS expression ..................................................................... 50 
5.3.4 
Plasma-based assays for circulating receptors/ligands e.g. PDL1 .......................... 50 
5.4 
Sample Storage, Tracking and Disposition .................................................................... 51 
5.4.1 
Sample Data Collection .......................................................................................... 51 
5.4.2 
Sample Storage and Destruction ............................................................................. 51 
5.4.3 
Protocol Completion/Sample Destruction .............................................................. 52 
6 
DATA COLLECTION AND EVALUATION ..................................................................... 52 
6.1 
Data Collection ............................................................................................................... 52 
6.2 
Data Sharing Plans ......................................................................................................... 52 
6.2.1 
HUMAN DATA SHARING PLANS ..................................................................... 52 
6.3 
Response Criteria ........................................................................................................... 53 
6.3.1 
Definitions............................................................................................................... 53 
6.3.2 
Disease Parameters ................................................................................................. 53 


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6.3.3 
Methods for Evaluation of Measurable Disease ..................................................... 54 
6.3.4 
Response Criteria .................................................................................................... 55 
6.3.5 
Duration of Response .............................................................................................. 58 
6.4 
Modified immune-related response criteria (irRC) ........................................................ 58 
6.5 
Toxicity Criteria ............................................................................................................. 58 
7 
SAFETY REPORTING REQUIREMENTS/DATA AND SAFETY MONITORING PLAN
 
59 
7.1 
Definitions ...................................................................................................................... 59 
7.1.1 
Adverse Event ......................................................................................................... 59 
7.1.2 
Suspected adverse reaction ..................................................................................... 59 
7.1.3 
Unexpected adverse reaction .................................................................................. 59 
7.1.4 
Serious..................................................................................................................... 60 
7.1.5 
Serious Adverse Event ............................................................................................ 60 
7.1.6 
Disability ................................................................................................................. 60 
7.1.7 
Life-threatening adverse drug experience ............................................................... 60 
7.1.8 
Protocol Deviation (NIH Definition) ...................................................................... 60 
7.1.9 
Protocol Non-compliance (NIH Definition) ........................................................... 60 
7.1.10 Unanticipated Problem............................................................................................ 61 
7.2 
NCI-IRB and Clinical Director Reporting ..................................................................... 61 
7.2.1 
NCI-IRB and NCI CD Expedited Reporting of Adverse Events , and Deaths ....... 61 
7.2.2 
NCI-IRB Requirements for PI Reporting at Continuing Review ........................... 61 
7.2.3 
NCI-IRB Reporting of IND Safety Reports............................................................ 62 
7.3 
IND Sponsor Reporting Criteria .................................................................................... 62 
7.3.1 
Reporting Pregnancy ............................................................................................... 62 
7.4 
Safety Reporting criteria to the Pharmaceutical Collaborators ...................................... 63 
7.5 
Data and Safety Monitoring Plan ................................................................................... 63 
7.5.1 
Principal Investigator/Research Team .................................................................... 63 
7.5.2 
Sponsor Monitoring Plan ........................................................................................ 63 
8 
STATISTICAL CONSIDERATIONS.................................................................................. 64 
8.1 
Cohorts A and B ............................................................................................................. 64 
8.2 
Cohorts D- E................................................................................................................... 65 
8.3 
Secondary and Exploratory Analyses ............................................................................ 66 
8.4 
Accrual ........................................................................................................................... 66 


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9 
COLLABORATIVE AGREEMENTS ................................................................................. 66 
9.1 
COOPERATIVE RESEARCH AND DEVELOPMENT AGREEMENT (CRADA) ... 66 
9.2 
MATERIAL TRANSFER AGREEMENTS (MTA) ..................................................... 66 
10 HUMAN SUBJECTS PROTECTIONS ............................................................................... 66 
10.1 
Rationale For Subject Selection ................................................................................. 66 
10.2 
Participation of Children ............................................................................................ 67 
10.3 
Participation of Subjects Unable to Give Consent ..................................................... 67 
10.4 
Evaluation of Benefits and Risks/Discomforts ........................................................... 67 
10.4.1 Risks of exposure to ionizing radiation .................................................................. 67 
10.4.2 Risk of optional biopsy ........................................................................................... 67 
10.4.3 Other risks/benefits ................................................................................................. 67 
10.5 
Risks/Benefits Analysis .............................................................................................. 67 
10.6 
Consent and Assent Process and Documentation ....................................................... 68 
10.6.1 Telephone re-consent .............................................................................................. 68 
10.6.2 Informed consent of non-English speaking subjects .............................................. 68 
11 PHARMACEUTICAL INFORMATION ............................................................................. 69 
11.1 
Tremelimumab............................................................................................................ 69 
11.1.1 Investigational Product Dose Preparation ............................................................... 69 
11.1.2 Dose Calculation ..................................................................................................... 70 
11.1.3 Investigational Product Inspection .......................................................................... 70 
11.1.4 Dose Preparation Steps ........................................................................................... 70 
11.1.5 Investigational Product Accountability ................................................................... 71 
11.1.6 Reporting Product Complaints ................................................................................ 71 
12 REFERENCES ..................................................................................................................... 73 
13 APPENDICES ...................................................................................................................... 78 
13.1 
APPENDIX A:  Performance Status Criteria ............................................................. 78 
13.2 
Appendix B:  Child-Pugh classification system ......................................................... 79 
13.3 
Appendix C:  Modified immune-related response criteria (irRC) .............................. 80 
13.4 
Appendix D: MedImmune Sample Preparation Procedures ....................................... 82 


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1 
INTRODUCTION 
1.1 
STUDY OBJECTIVES 
1.1.1 Primary: 
 
To assess the safety and feasibility of combining Tremelimumab with trans-arterial catheter 
chemoembolization (TACE) or radiofrequency ablation (RFA) in patients with advanced HCC.  
1.1.2 Secondary:  
 
To evaluate clinical indicators of efficacy (response rate, time to tumor progression, overall 
survival) in patients with advanced HCC undergoing TACE or radiofrequency ablation (RFA) in 
combination with Tremelimumab.  
1.1.3 Exploratory: 
1.1.3.1 To evaluate changes in immune parameters as well as pharmacokinetics in the peripheral 
blood of patients with advanced HCC undergoing TACE or radiofrequency ablation 
(RFA) in combination with Tremelimumab 
1.1.3.2 Following amendment F we will evaluate safety and feasibility of combining 
Tremelimumab with cryoablation in patients with advanced HCC and radiofrequency 
ablation (RFA) in advanced intrahepatic cholangiocarcinoma. 
1.1.3.3 To evaluate changes in immune parameters as well as pharmacokinetics in the peripheral 
blood of patients with advanced HCC or intrahepatic cholangiocarcinoma undergoing 
TACE, radiofrequency ablation (RFA) or cryoablation in combination with 
Tremelimumab. 
1.2 
BACKGROUND AND RATIONALE 
1.2.1 HCC and the current therapeutic paradigm (radiofrequency ablation [RFA] trans-arterial 
catheter chemoembolization [TACE] and sorafenib) 
Worldwide, hepatocellular carcinoma (HCC) is the fifth most common malignancy with a 
median survival of 6-9 months1. The therapeutic paradigm – including the possible interventions 
and their indications – is outlined below. The approach to management has traditionally 
comprised of loco-regional strategies: surgery (partial resection or transplantation) or 
interventional radiologic procedures, such as chemoembolization or ablative techniques. 
Recently, sorafenib has been added to this paradigm and it is the only systemic drug therapy 
which has demonstrated a survival benefit in modern randomized studies.  
 
Table 1: Therapeutic paradigm for HCC 
Intervention 
Indication 
Potentially curative 
Partial Hepatectomy 
Limited liver disease with 
Yes 


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good reserve 
Transplantation 
1 lesion <5cm or 3 < 3cm 
Yes 
RFA 
Lesion to be ablated at least 
1cm and not greater than 5cm. 
Yes 
TACE 
Liver confined; no portal vein 
thrombosis 
No 
Sorafenib 
Metastatic disease 
No 
 
The most widely used staging system in HCC is the Barcelona Clinic Liver Cancer (BCLC) 
Staging system, the major advantage of which is that in addition to staging patients it also directs 
management2. The BCLC staging system is shown in Figure 1 below. 
 
 
Figure 1: Barcelona Clinic Liver Cancer (BCLC) staging classification and treatment schedule. 
 
For the proposed study we will not include patients for whom surgical resection or 
transplantation is a possibility. We will also exclude patients with isolated lesions for whom 


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RFA alone is possible, given the curative potential of that intervention. The target population 
will be those with advanced disease for whom the only available interventions are TACE or 
sorafenib.  
1.2.2 Recent advances in immune-based approaches in solid tumor malignancies 
The past two years have seen progress for immune-based approaches in solid tumor 
malignancies, with FDA approvals for these approaches in prostate cancer and melanoma3-5. In 
melanoma, anti-CTLA4 therapy has been shown to demonstrate a median survival benefit in two 
separate phase 3 studies, both of which were associated with long-term disease control in 
approximately one-fifth of patients. More recently, anti-PD1 therapy has demonstrated a similar 
degree of clinical activity not only in melanoma and kidney cancer but also in lung cancer, a 
disease type previously thought to be refractory to an immune approach. Appreciation of the role 
in developing tumors of immune-evasion has also been evidenced by its inclusion as one of the 
(updated) hallmarks of cancer6.  
Both anti-PD1 and anti-CTLA4 therapy enhance anti-tumor immunity by blocking tumor 
induced immune suppression of cytotoxic T cells and therefore exaggerating the immune 
activation that must first occur of its own accord and is thought to be the result of tumor neo-
antigens formed as a tumor progresses. The role of CTLA4 in inhibiting T-cell activation is 
represented in the schematic in Figure 2 below. CTLA4-mediated immune checkpoint is induced 
in T cells at the time of their initial response to antigen. The level of CTLA4 induction depends 
on the amplitude of the initial T cell receptor (TCR)-mediated signaling. After the TCR is 
triggered by antigen encounter, CTLA4 is transported to the cell surface. The stronger the 
stimulation through the TCR (and CD28), the greater the amount of CTLA4 that is deposited on 
the T cell surface. Therefore, CTLA4 functions as a signal dampener to maintain a consistent 
level of T cell activation in the face of widely varying concentrations and affinities of ligand for 
the TCR. 
 
 
Figure 2: CTLA4-mediated immune checkpoint is induced in T cells at the time of their initial 
response to antigen. (Pardoll. Nat Rev Cancer. 20127) 
 
Whilst these studies demonstrate the potential for anti-CTLA4 (or anti PD1) therapy to enhance 
the anti-tumor immune response already in process, it clearly does not work in the majority of 
patients. The question is whether the initial immune activation stage can be enhanced. The 
potential for this was intriguingly demonstrated in a recent publication by Postow et al who 


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reported a case of the so-called abscopal effect in a patient with melanoma treated with 
ipilimumab and radiotherapy8. Temporal associations were noted between tumor shrinkage and 
antibody responses to the cancer-testis antigen NY-ESO-1 in addition to changes in peripheral-
blood immune cells, and increases in antibody responses to other antigens after a patient being 
treated with anti-CTLA4 was then treated with external beam radiotherapy. The enhanced effect 
from anti-CTLA4 seen after radiation appears to have been due to a boost effect of tumor cell 
death and immune stimulation following deliverance of a tumor antigen load. It is this enhanced 
effect we wish to study in the context of interventional procedures for HCC.  
1.2.3 Immune response to interventional radiological treatments 
The aim of our proposed study is to enhance the antitumor immune response which has been 
shown to occur following interventional radiological treatments. The attractive aspect of this 
approach – especially in a disease as prevalent as HCC – is that it has the potential for enhancing 
the effect of treatments (both RFA and TACE) which have already been approved, have 
demonstrated survival benefit in randomized studies and are commonly performed throughout 
the community. Following RFA and TACE necrotic tumor results in the release of tumor 
antigens which are taken up by antigen-presenting cells (mainly dendritic cells) and which 
activate a tumor-specific immune response9. Ablated tumor tissue has been shown to promote 
dendritic cell maturation (and resultant T-cell stimulatory properties)10,11. This antigen release is 
potentially significant because, although ablative procedures are very effective in eradicating 
visible lesions, a tumor-specific immune response may prevent recurrent disease in addition to 
treating distant metastases. In other words, RFA and TACE have the potential to turn a patient’s 
tumor into an endogenous vaccine. 
Several studies have documented an increase in peripheral antitumor immunity following 
interventional radiological procedures, predominantly RFA10,12-15. This has been demonstrated 
both in animal models and in human studies12,14,15. Ayaru et al. evaluated the immune response 
in HCC patients (N=10) undergoing TACE16. They found that AFP-specific CD4-T cell 
responses were significantly expanded during (p < 0.0001) and after embolisation (p < 0.002). 
The development of higher frequencies of AFP-specific CD4 T cells after treatment were 
significantly associated with the induction of >50% necrosis of tumor and an improved clinical 
outcome (p < 0.007). Mizukoshi et al. measured cytotoxic T cell response to tumor associated 
antigens (TAA) in HCC patients undergoing treatment17. They measured the frequency of TAA-
specific T cells before and after HCC treatment by ELISPOT assay in 12 cases who received 
TACE, RFA or chemotherapy. The frequency of TAA-specific T cells was found to be increased 
in all patients. Furthermore, incubation of T cells with CTLA-4 antibodies resulted in an increase 
of the number of TAA-specific T cells. Dromi et al. evaluated the influence of subtotal RFA on 
tumor-specific immune response in a murine urothelial carcinoma (MB49) tumor model18. RFA 
resulted in enhanced systemic antitumor T-cell immune responses and tumor regression that was 
associated with increased dendritic cell infiltration into the remaining viable, non-ablated tumor.  
Hansler et al. assessed the specific cytotoxic T cell response in patients with malignant liver 
tumors (both metastatic colon cancer and HCC) which were treated with RFA. Significant 
tumor-specific cytotoxic T-cell stimulation was seen, with a dramatically increased tumor 
specific cytolytic activity of CD8(+) T cells against autologous liver and tumor lysate after 
RFA12.  Hiroishi et al. analyzed tumor-specific CD8(+) T-cell responses in twenty patients with 
HCC undergoing loco-regional therapy (either RFA or TACE)13. They found that the CD8(+) T-


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cell response was increased and, on multivariate analysis, the magnitude of the immune response 
was the only significant prognostic factor for a prolonged tumor-free interval (hazard ratio 0.342, 
P = 0.022).  
Despite this, only a few cases of spontaneous remission of metastases following RFA – the so-
called abscopal effect – have been reported, presumably because this immune response by itself 
is too weak to be clinically significant19-21. A number of studies have tried to boost this anti-
tumor immune response following ablation by combining with an immunomodulatory agent:  
Waitz et al. provided preclinical proof-of-concept for this in a mouse model of prostate cancer 
using CTLA-4 blockade to augment the immune response from cryoablation22. The combination 
therapy resulted in >80% of intratumoral CD8+ T cells being antigen-specific. The effect on 
secondary responses was assessed by injection of the secondary tumor on the opposite flank of 
the mouse on Day 2 following ablation. The growth of secondary tumors was found to be 
unaffected by cryoablation alone, but the combination treatment (anti-CTLA4 + RFA) was 
sufficient to slow growth or trigger rejection. In addition, secondary tumors were highly 
infiltrated by CD4+ T cells and CD8+ T cells, and there was a significant increase in the ratio of 
intratumoral T effector cells to T regulatory cells, compared with either RFA or anti-CTLA4 
alone. Johnson et al. sought to enhance the antitumor effect of RFA by combining it with huKS-
IL2 immunocytokine [tumor-specific monoclonal antibody fused to interleukin-2 (IL2)] in mice 
bearing CT26-KS colon adenocarcinoma. Mice were treated with RFA, huKS-IL2 via 
intratumoral injection, or combination therapy. Treatment of mice bearing s.c. tumors with RFA 
and huKS-IL2 resulted in significantly greater tumor growth suppression and enhanced survival 
compared with mice treated with either RFA or huKS-IL2 alone. When sub-therapeutic regimens 
of RFA or huKS-IL2 were used, tumors progressed in all treated mice. In contrast, the 
combination of RFA and immunocytokine resulted in complete tumor resolution in 50% of mice. 
Treatment of a tumor with RFA and intratumoral huKS-IL2 also showed antitumor effects 
against a distant untreated tumor. Tumor-free mice after treatment with RFA and huKS-IL2 
showed immunologic memory based on their ability to reject subsequent challenges of CT26-KS 
and the more aggressive parental CT26 tumors. Flow cytometry analysis of tumor-reactive T 
cells from mice with complete tumor resolution showed that treatment with RFA and huKS-IL2 
resulted in a greater proportion of cytokine-producing CD4 T cells and CD8 T cells compared 
with mice treated with RFA or huKS-IL2 alone.  den Brok et al. evaluated combination treatment 
of RFA plus TLR9 stimulation in B16 tumors and showed that the combination resulted in far 
more potent antitumor immune responses than either treatment modality alone23.  
1.2.4 Tremelimumab  
Tremelimumab (formerly CP-675,206) is a human IgG2 mAb directed against CTLA-4. 
Upon T cell activation, CTLA-4 expression acts to dampen immune responses by CTLA-4 
relocation to the cell surface in order to modulate and eventually switch off T cell activation. 
Tremelimumab blocks the inhibitory effect of CTLA-4, and therefore enhances T cell activation. 
The binding of CTLA-4 to its target ligands (B7.1 [CD80] and B7.2 [CD86]) provides a negative 
regulatory signal, which limits T cell activation. Blockade of B7 binding to CTLA-4 by anti-
CTLA-4 antibodies also results in markedly enhanced T cell activation and antitumor activity in 
animal models, including killing of established murine solid tumors and induction of protective 
antitumor immunity. 


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Anti-CTLA-4 therapy has recently been shown to be a validated approach to cancer treatment by 
the approval of the mAb ipilimumab in 2011 for the treatment of patients with metastatic 
melanoma, based on 2 Phase III studies that demonstrated a significant improvement on OS in 
the first- and second-line settings. In general, tumor response rates to anti-CTLA-4 therapy are 
low, approximately 10%, but the durable response or stable disease seen in a proportion of 
patients can lead to a significant prolongation of OS. In a large, single-arm Phase II 
Tremelimumab trial in patients with advanced refractory and/or relapsed melanoma, objective 
responses (primary endpoint) following Tremelimumab 15 mg/kg Q3M were observed in 16 of 
SDWLHQWV&,>@5HVSRQVHVZHUHGXUDEOHSUHVHQWDWPRQWKV 
from enrollment) in all 16 responders. A Phase III, open-label, randomized study comparing 
Tremelimumab 15 mg/kg Q3M (Arm A) to either dacarbazine or temozolomide (Arm B) in 
patients with advanced melanoma was terminated following a pre-specified interim futility 
analysis. At the time of database lock, the median OS (primary endpoint) was 12.58 months in 
Arm A and 10.71 months in Arm B (HR=1.1416, p=0.1272). 
The efficacy data for tremelimumab are consistent with those of the related – and FDA-
approved- anti-CTLA-4 antibody ipilimumab: tumor response rates are generally low 
(approximately 10%) but the responses observed are generally durable. The ipilimumab 
melanoma data clearly demonstrate that a small proportion of patients with an objective response 
and a small impact on PFS rates can lead to a significant prolongation of OS, and support 
development of this class of agent in other tumors. Although Phase II and Phase III studies of 
tremelimumab in metastatic melanoma failed to meet the primary endpoints of response rate and 
OS, respectively, the data clearly indicate activity of tremelimumab in melanoma, with response 
rates and median OS similar to those observed in the ipilimumab trials. However, in contrast to 
tremelimumab, there are no safety data for the use of ipilimumab in HCC. 
1.2.4.1 Clinical experience of Tremelimumab 
Tremelimumab has been evaluated in a number of clinical studies – and over 1000 patients – and 
demonstrated manageable toxicities24,25.  
The efficacy data for Tremelimumab are consistent with those of the related anti-CTLA-4 
antibody ipilimumab: tumor response rates are generally low (approximately 10%) but the 
responses observed are generally durable. The ipilimumab melanoma data clearly demonstrate 
that a small proportion of patients with an objective response and a small impact on PFS rates 
can lead to a significant prolongation of OS, and support development of this class of agent in 
other tumors. Although Phase II and Phase III studies of Tremelimumab in metastatic melanoma 
failed to meet the primary endpoints of response rate and OS, respectively, the data clearly 
indicate activity of Tremelimumab in melanoma, with response rates and median OS similar to 
those observed in the ipilimumab trials. 
The AE profile of Tremelimumab is consistent with that of ipilimumab, and with the 
pharmacology of the target. To date, no tumor type or stage appears to be associated with unique 
AEs (except for vitiligo, which appears to be confined to patients with melanoma). Events 
reported at a frequency oIDQGDVVHVVHGE\WKHLQYHVWLJDWRUDVUHODWHGWRWUHDWPHQWOLVWHGLQ
descending order of frequency) were diarrhea, rash, pruritus, fatigue, nausea, vomiting, anorexia, 
headache, abdominal pain, and colitis. 
1.2.4.2 Experience in Hepatitis/HCC 


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Tremelimumab has recently been shown to be safe in a study in HCC. Twenty-one patients with 
HCV-related HCC were treated with Tremelimumab intravenously at a dose of 15 mg/kg every 
90 days for two cycles. Toxicity was manageable with reported treatment-related adverse events 
among 80% of patients. Grade 3 or higher adverse events included 1 case of pruritus, 1 case of 
purpura, and 5 cases of elevated transaminases. There was preliminary evidence of efficacy. In 
an intention-to-treat analysis, investigators observed a median overall survival of 7.5 months and 
time to progression of 6.4 months as well as a reduction of hepatitis C virus (HCV) in the 
patients’ blood, which was also accompanied with objective enhancements of antiviral 
immunity. A significant and progressive decline in serum HCV viral load was observed (median 
values: baseline 3.78x10e5 copies/ml vs. day 120 3.02x10e4 copies/ml, P = .02; vs. day 210 
1.69x10e3 copies/ml, P = .04).  
1.2.5 Justification for dose and schedule 
There is safety data from ~70 patients treated with 10 mg/kg Q4 weeks and currently an ongoing 
study is collecting additional data on this dose and schedule. The proposed dose and schedule is 
informed by safety and efficacy data on Tremelimumab, and by data showing a relationship 
between exposure and survival in the advanced melanoma studies with Tremelimumab. The PK 
of Tremelimumab has been characterized in various clinical studies with more than 1,000 
patients treated with Tremelimumab to date. Tremelimumab has been administered at doses 
ranging from 3 to 15 mg/kg Q4W or Q12W. The PK of Tremelimumab was linear and dose-
proportional. The disposition of Tremelimumab exhibits biphasic elimination, with a long 
terminal phase half-life of ~20 days. In an early Phase 1/2 study (A3671002; Camacho et al, 
2009), patients with melanoma in the Phase 2 portion of the study were randomly assigned to 
Tremelimumab 15 mg/kg Q12W (n = 46) or Tremelimumab 10 mg/kg Q4W (n = 44). The 
overall AE frequency between the 2 schedules was comparable, albeit with fewer Grade 3-4 AEs 
(13%) in the less frequent dosing regimen (15 mg/kg Q12W) compared to the Q4W regimen 
(27%). The difference in Grade 3-4 AEs was largely due to differences in the incidence of 
*UDGHGLDUUKHDYV. 9%). However, all SAEs were manageable and reversible when 
appropriate intervention was applied. Efficacy results of this study showed similar response rates 
in each arm (10% for 10 mg/kg Q4W, 9% for 15 mg/kg Q12W) with no significant difference in 
OS. 
However, a retrospective analysis of data from Phase 2 and Phase 3 melanoma studies with15 
mg/kg Q12W Tremelimumab showed an improvement in the OS outcome for patients who 
achieved a higher exposure as measured by the area under the concentration-time curve from 
time 0 to 90 days (AUC90). Furthermore, pharmacokinetic simulations indicate that following 
Tremelimumab at 10 mg/kg Q4W, approximately 90% patients are expected to be above the 
target concentration aȝJP/) compared to ~50% with 15 mg/kg every Q12W dosing 
regimen.   Based on these data, MedImmune now proposes using a Tremelimumab dosing 
regimen of 10 mg/kg Q4W both for this study and across all other studies. 
1.2.6 Rationale for Re-Induction 
Re-treatment with Anti-CTLA-4 agent provide durable response or stable disease in patients with 
melanoma who initially respond to treatment but later progressed26,27 with some subjects 
achieved better overall response after re-induction4. No new types of toxicities observed after re-


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induction with safety profile consistent with induction profile.26,27 These findings support re-
treatment with immune checkpoint inhibitors after initial disease control. 
RFA or TACE are modalities inducing localized cell death and enhancing antitumor immune 
response28,29. To date it is unknown what type of treatment, RFA vs TACE is more 
immunogenic. By allowing the same patient to undergo TACE and RFA we will produce 
different immune stimulation and possibly enhance antitumor immune response. In addition, 
benefit of re-treatment with TACE or RFA is to provide a similar immune boost as revaccination 
treatment in cancer vaccine clinical trials. 
Combining TACE and RFA in HCC treatments has been atttemted in single centers small studies 
showing an improvement in OS without significant increase in side effects30,31. Larger 
randomized clinical trial of 189 patiens resulted in improvement in OS and recurrence free 
survival in RFA-Tace group relative to RFA group alone whithout significant differences in 
toxicity profiles.32 Findings from these studies confrim tolerability of combination. For definite 
conclusions on efficacy of combined interventional management larger clinical trials are needed. 
1.2.7 Rationale for Viral Hepatitis Studies and Specifically for Hepatitis B Surface Antigen and 
Hepatitis B Immune Monitoring 
Anti-HCV specific immune responses as well as a reduction in Hepatitis C viral load have been 
described in in patients with chronic HCV infection and HCC (decline in serum HCV viral load 
from median values: basal 3.78x10e5 copies/ml to median values on day 120 of 3.02x10e4 
copies/ml, p=0.02; vs. day 210 1.69x10e3 copies/ml, p=0.04); in addition three patients 
demonstrated a complete viral response for the duration of the follow-up33. 
The antiviral effect of CTLA-4 blockade in patients with chronic HBV infection is unknown. 
Hepatitis e antigen (HBeAg) is a marker of viral replication and infectivity that is usually 
associated with and active liver disease. Hepatitis B surface antigen (HBsAg) is a protein on the 
surface of the hepatitis B virus. Its presence identifies patients with chronic infection.   CTLA-4 
blockade in cynomolgus macaques enhanced antibody response to hepatitis B surface antigen 
(HBsAg)34. Interestingly, polymorphisms of CTLA-4 have been associated with chronic hepatitis 
B and C infection35,36. The mechanisms behind these events imply an existing link between 
CTLA-4 activity and hepatic viral pathogenesis that should be exploited in details for therapeutic 
benefit. The population of HCC patients with chronic hepatitis B virus (HBV) infection will 
provide an exceptional occasion to simultaneously test the anti-tumoral, immune and antiviral 
effect of tremelimumab. 
1.2.8 Rationale for Amendment F 
The purpose of amendment F is to add 3 additional patient cohorts (denoted C, D and E) of N=10 
patients each to evaluate additional globally used and potentially immunomodulative procedures 
(cryoablation and external beam radiation) in patients with HCC. We would also like to evaluate 
RFA plus tremelimumab in biliary tract carcinoma. The justification for each of these cohorts is 
as follows: 
Cohort C: SBRT plus tremelimumab in HCC (removed, effective with amendment I).  Several 
studies have documented an increase in peripheral antitumor immunity following radiation. It 
may even be the case that an intact immune system is critical for RT to exert its maximal 
antitumor effect. This was suggested by a mouse model of melanoma in which single-fraction 


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RT slowed the growth of small tumors in immune-competent but not immune-deficient mice37.  
The same authors also showed that in an animal model of breast cancer ablative RT of a primary 
tumor prevented the growth of metastatic tumor colonies in the lung, an effect that was 
dependent on the presence of CD8+ T cells. Other animal models have likewise displayed 
augmentation of systemic antitumor immunity following local RT38-40. The underlying 
mechanism appears to be that RT-induced necrosis results in the exposure of tumor antigens, 
thereby increasing the pool of intracellular peptides for cross-presentation41. Radiation has been 
shown to augment MHC-I expression by tumors, which is critical for antigen recognition by 
cognate CD8+ TCRs and which is known to be diminished in tumors as one of their escape 
mechanisms42. Tumor antigen processing and presentation on MHC-I molecules is dependent on 
expression of a protein called highmobility group box 1 (HMGB-1), a “danger signal” which 
binds toll-like receptor 4 (TLR4) on dendritic cells. In a pivotal study Apetoh et al. demonstrated 
that RT causes dying tumor cells to release HMGB-143. Intriguingly these authors also reported 
that in breast cancer patients undergoing radiation and chemotherapy the presence of a 
polymorphism in TLR4 – and by implication a less immunogenic drug-induced cell death – was 
associated with an inferior prognosis. Similarly, in esophageal cancer patients preoperative 
chemoradiation has been shown to increase cancer-specific T cell responses and serum levels of 
HMGB-1, the latter of which correlated with overall survival44.  
Despite this, only a few cases of spontaneous decrease of metastases following radiation – the 
so-called abscopal effect – have been reported. This is presumably because the immune response 
by itself is too weak to be clinically significant. A number of studies have tried to boost this anti-
tumor immune response following ablation by combining with an immunomodulatory agent: 
Dewan et al. evaluated RT in combination with anti-CTLA-4 antibody in two separate mouse 
models of breast and colorectal carcinoma45. The authors found that the combination of anti-
CTLA4 and RT achieved enhanced tumor response at the primary site (compared to either 
modality alone). in addition to an abscopal effect. (Interestingly this only occurred in 
fractionated versus single-dose RT). The frequency of CD8+ T cells showing tumor-specific 
IFN-gamma production was proportional to the absopal effect. Demaria et al. tested the 
combination of RT with CTLA-4 blockade in a breast cancer model (4T1) known to be poorly 
immunogenic46. Anti-CTLA4 alone did not have any effect on primary tumor growth or survival. 
RT was able to delay the growth of the primary irradiated tumor, but in the absence of anti-
CTLA4 survival was similar to that of control mice. In contrast, mice treated with RT + anti-
CTLA4 had a statistically significant survival advantage. The increased survival correlated with 
inhibition of lung metastases formation and required CD8+. 
Administering radiation therapy to the liver is not standard or conventional. With newer 
techniques however, this has been shown to be a safe strategy and to have palliative benefit in an 
incurable population. For example, Dr. Citrin – one of our associate investigators – has 
previously conducted a study employing hepatic radiation in colorectal cancer47. In that study 
patients received a total radiation dose of 32 Gy to sites of metastatic disease in the liver, 
delivered in 8-Gy courses (4 separate 2-Gy fractions) beginning one day after each vaccine boost 
(days 22–25, 36–39, 50–53, 64–67). The treatment was well tolerated, with the most common 
toxicity being a transient dermatologic reaction as a result of the vaccine used in the study. There 
ZHUHQRJUDGHWR[LFLWLHVDWWULEXWDEOHWRWKHWUHDWPHQWDQGVSHFLILFDOO\WKHUHZHUHQRJUDGH
hepatic toxicities. Other additional reports have documented the safety of SBRT to the liver at 
doses/schedules of 60 Gy/10 Fr and 50 Gy/4 Fr48; 36 to 60 Gy in 6 to 15 Gy per fraction (HCC, 
cholangio and colorectal cancer)49;  single doses of 17 to 30 Gy (median dose 24 Gy)50; median 


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dose per fraction and total dose of 3.6 Gy (2.0-13.0 Gy) and 55 Gy (30-80 Gy) in N=26patients 
with colorectal cancer51. 
Cohort D: Cryoablation and tremelimumab in HCC. Whilst RFA is the more traditional ablative 
strategy in HCC there is a growing use of cryoablation globally. In addition there is a growing 
body of data which suggests that it may be more effective52. At a minimum it appears to be 
equivalent in terms of safety and efficacy, as recently shown in a recent multicenter randomized 
study comparing the outcomes of percutaneous cryoablation with RFA for the treatment of 
HCC52. Three hundred and sixty patients with Child-Pugh class A or B cirrhosis and one or two 
+&&OHVLRQVFPWUHDWPHQWQDwYHZLWKRXWPHWDVWDVLVZHUHUDQGRPO\DVVLJQHGWRFU\RDEODWLRQ
(n=180) or RFA (n=180). The primary end-points were local tumor progression at 3 years after 
treatment, and safety. Local tumor progression rates at 1, 2, and 3 years were 3%, 7%, and 7% 
for cryoablation and 9%, 11%, and 11% for RFA, respectively (P=0.043). For lesions >3 cm in 
diameter, local tumor progression rate was significantly lower in cryoablation group versus RFA 
group (7.7% vs 18.2%, P=0.041). The 1-, 3-, and 5-year overall survival rates were 97%, 67% 
and 40%, for cryoablation and 97%, 66%, and 38% for RFA, respectively (P=0.747). The 1-, 3-, 
and 5-year tumor-free survival rates were 89%, 54%, and 35% in cryoablation group and 84%, 
50%, and 34% in RFA group, respectively (P=0.628). Major complications occurred in seven 
patients (3.9%) following cryoablation and in six patients (3.3%) following RFA (P=0.776). The 
conclusions of this study were that cryoablation appeared to be just as safe and feasible as 
radiofrequency or microwave ablation in HCC and is very commonly used across the world. 
Intriguingly – for our purposes - there is evidence that cryoablation may be better in terms of 
immune stimulation compared to other ablative strategies53. 
Cohort E: RFA in biliary tract carcinoma: Biliary tract carcinoma (BTC) is the second most 
common hepatobiliary cancer. For the majority of patients who present with or develop 
metastatic/ unresectable disease the modest standard therapy comprises Gemcitabine in 
combination with cisplatin based on the ABC-02 trial which demonstrated a median overall 
survival benefit of 11.7 v 8.1 months (P<0.001) in favor of  cisplatin–gemcitabine compared to 
gemcitabine alone54. There is no standard second-line treatment for biliary tract carcinomas.  
The most compelling argument in favor of testing immune-based strategies (and anti-PD1 
therapy in particular) in this disease is that chronic inflammation is the most common etiologic 
factor in the development of BTC. Recent studies have linked the increasing incidence of chronic 
hepatitis C virus infection with intrahepatic cholangiocarcinoma55, which may explain the 
increasing incidence of the intrahepatic subtype 56. In biliary tract cancer, the prevalence and 
prognostic relevance of infiltrating T-lymphocytes has been documented. Goeppert et al. 
evaluated immune cell infiltration in 375 cases of biliary tract cancer obtained following surgical 
resection57. Approximately half the patients had intraepithelial tumor infiltrating T cells (both 
CD4 and CD8) and this was associated with better survival. Further evidence of the importance 
of immune activation/suppression, this time specific to the PD1/PD-L1 axis, was provided by Ye 
et al. who evaluated the expression of B7-H1(PD-L1) and its receptor PD-1 in N=31 surgically 
resected cholangiocarcinoma tissues and the corresponding cancer adjacent tissues58. Expression 
of PD-L1 and PD-1 was found to be up-regulated in cholangiocarcinoma tissues compared with 
the cancer adjacent tissues. Tumor-related PD-L1 expression was significantly correlated with 
both tumor differentiation and pTNM stage and was inversely correlated with CD8+ tumor-
infiltrating lymphocytes. Similarly, Nakakubo et al. investigated the significance of tumor-
infiltrating immune cells in 110 surgically resected biliary tract cancer (gallbladder) specimens59. 


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They found high levels of CD4+ T cell (51.1%), CD8+ T cell (37.8%), NL cell (33.3%), and 
dendritic cell (48.9%) infiltration. CD4+ and CD8+ T cell infiltration correlated with decreasing 
tumour invasion, and high numbers of infiltrating DCs correlated with decreasing lymph-node 
tumour metastasis. Furthermore, increased infiltration of CD4+ and CD8+ T cells and DCs 
exhibited a significant correlation with prolonged survival. Because of these data, and coupled to 
the data summarized earlier for immune stimulation following RFA, we wish to treat a cohort of 
biliary tract carcinoma patients. 
1.2.9 Rationale for Amendment I 
The purpose of amendment I is to remove Cohort C. Given a range of factors - the number of 
variables in this study, the finding of interesting activity with ablative methods (commonly used 
in HCC) and the relative infrequency of SBRT in this disease – it was decided both scientifically 
and for patient safety reasons to focus and refine our research efforts. At this point we will not 
enroll to Cohort C but preferentially enroll HCC patients to either cohort B of this protocol or 
our new protocol (16-C-0135). Should we decide to evaluate SBRT in combination with immune 
modulating therapy in this population in the future it will only be done after an IRB amendment. 
1.2.10 Rationale for Amendment J 
The purpose of amendment J is to stop further tremelimumab treatment beyond 2 years if there is 
no evidence of disease progression. Currently patients would continue to receive tremelimumab 
treatment every 12 weeks until disease progression. The justification for this is as follows:  
1) Two-year-duration of immune checkpoint inhibitor treatment is adequate for disease treatment 
and control: early trials in melanoma allowed treatment until progression; then, 2-year duration 
was the maximal adopted by majority of clinical trials 60, 61, 62 and approved regimens. Such 
study design does not prevent patients from benefiting the most from immune checkpoint 
inhibitor treatment 63. Effectively, the discontinuation of immune checkpoint inhibitor after a 
predetermined duration is not associated with an increased risk of acquired resistances such as 
that described with cytotoxic chemotherapy 63. Few reports have examined the outcome in 
patients who achieved a response and stopped therapy after 2 to 3 years 64. Among them, 61 
(64%) stopped treatment after complete response and maintained their remission. Median 
duration of treatment was 23 months. Only 2 of the 61 patients who stopped treatment after 
complete response experienced disease progression. Many of those who did not achieve a 
complete response and whose disease progressed were able to respond to further immunotherapy 
64. The existence of the “tail on the curve” of survival in melanoma, and now other cancers, 
suggests that a subset of patients who discontinue treatment with one of these agents experience 
durable responses after therapy and do not need to be treated until progression. Presumably, the 
patient’s immune system has been engaged and is still monitoring and effectively suppressing 
the cancer. Nevertheless, re-challenging the tumor with the same immune checkpoint inhibitor 
even after a long stable period demonstrated a greater response and lesser adverse events 65. 
Thus, indefinite treatment may not be truly necessary, and a duration of not less than 1 year and 
not more than 2 years seems reasonable. 
2) Prolonged immune checkpoint inhibitor exposure has greater risks for potentially life-
threatening toxicities: despite important clinical benefits, immune checkpoint inhibition is 
associated with a unique spectrum of immune-related adverse events. Serious side effects are 
observed in less than 10% of patients, and typically emerge an average of 6 to 12 weeks after the 


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start of treatment 66,67. The risk of side effects increases with higher doses, and overall seems to 
increase with cumulative exposure. Moreover, as immunotherapies are being tested in 
combination, side effects tend to be additive. For example, the more common adverse effects are 
related to GI inflammation, which can be as minor as slight irritation or as severe as colitis, 
potentially even leading to perforation of the bowel. Those potentially life-threatening toxicities 
in the context of prolonged treatment may outweigh the benefits of indefinite immune 
checkpoint inhibitor therapy.  
Given above discussed justifications, it is decided both scientifically and for patient safety 
reasons to focus and refine our research efforts. At this point we will discontinue tremelimumab 
administration after 2 years if patient is experiencing responding to the treatment over 2 years, 
including stable disease, partial or complete remission.    
2 
ELIGIBILITY ASSESSMENT AND ENROLLMENT  
2.1 
ELIGIBILITY CRITERIA 
2.1.1 Inclusion Criteria 
2.1.1.1 Patients must have histopathological confirmation of hepatocellular carcinoma (HCC) or 
(Cohort E only) biliary tract carcinoma (BTC) by the Laboratory of Pathology of the 
NCI prior to entering this study OR histopathological confirmation of carcinoma in the 
setting of clinical and radiological characteristics which, together with the pathology, 
are highly suggestive of a diagnosis of HCC (or biliary tract carcinoma in Cohort E). 
Fibrolammelar variant is also allowed. For cohort E, the term BTC includes intra- or 
extrahepatic cholangiocarcinoma, gallbladder cancer or ampullary cancer, as long as 
there is an intrahepatic component amenable to RFA. 
2.1.1.2 Patients must have disease that is not amenable to potentially curative resection, 
transplantation or ablation. For Cohorts A and D patients must have progressed on, been 
intolerant to, or refused prior sorafenib therapy. Cohort E patients must have received at 
least one line of chemotherapy for BTC. 
2.1.1.3 Disease must be technically amenable to transhepatic arterial chemoembolization 
(TACE), radiofrequency ablation (RFA), or cryoablation. Each case will be discussed at 
GI tumor board with interventional radiology. Patients must have evaluable disease. 
2.1.1.4 If liver cirrhosis is present, patient must have a Child-Pugh A/B7 classification (see 
Appendix B section 12.2 ). 
2.1.1.5 Age >18 years  
2.1.1.6 Life expectancy of greater than 3 months. 
2.1.1.7 ECOG performance status 0-2 (see Appendix A section 12.1) 
2.1.1.8 Patients must have normal organ and marrow function as defined below: 
leukocytes 
>3,000/mcL 
absolute neutrophil count 
> 1,000/mcL 
platelets 
,000/mcL 
total bilirubin 
If cirrhosis present: Part of Child Pugh 


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22 
Version Date: 08/14/2017 
requirement 
,IQRFLUUKRVLV%LOLVKRXOGEH
xULN 
Serum albumin  
If cirrhosis present: Part of Child Pugh 
requirement 
,IQRFLUUKRVLVDOEXPLQVKRXOGEH
2.5g/dl 
Patients are eligible with ALT or AST up to 5 x ULN. 
creatinine 
<1.5X institution upper limit of 
normal 
OR 
creatinine clearance 
>45 mL/min/1.73 m2, as calculated 
below, for patients with creatinine 
levels above institutional normal 
 
2.1.1.9 Patients must have recovered from any acute toxicity related to prior therapy, including 
surgery.  Toxicity should be  grade 1 or returned to baseline. 
2.1.1.10 Patients must not have other invasive malignancies within the past 5 years (with the 
exception of non-melanoma skin cancers, non-invasive bladder cancer or localized 
prostate cancer for whom systemic therapy is not required). 
2.1.1.11 Patient must be able to understand and willing to sign a written informed consent 
document. 
2.1.2 Exclusion Criteria 
2.1.2.1 Patients who have had standard of care chemotherapy, large field radiotherapy, or major 
surgery must wait 2 weeks prior to entering the study. For recent experimental therapies 
a 28 day period of time must elapse before treatment. 
2.1.2.2  Patients who have undergone prior liver transplantation are ineligible. 
2.1.2.3 Patients with known brain metastases will be excluded from this clinical trial because of 
their poor prognosis and because they often develop progressive neurologic dysfunction 
that would confound the evaluation of neurologic and other adverse events. 
2.1.2.4 Uncontrolled intercurrent illness including, but not limited to, ongoing or active systemic 
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac 
arrhythmia (excluding insignificant sinus bradycardia and sinus tachycardia) or 
psychiatric illness/social situations that would limit compliance with study 
requirements.  
2.1.2.5 History of chronic autoimmune disease (e.g., Addison’s disease, multiple sclerosis, 
Graves’ disease, Hashimoto’s thyroiditis, rheumatoid arthritis, hypophysitis, etc.) with 
symptomatic disease within the 3 years before randomization. Note: Active vitiligo or a 
history of vitiligo will not be a basis for exclusion.  


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2.1.2.6 Dementia or significantly altered mental status that would prohibit the understanding or 
rendering of Information and Consent and compliance with the requirements of the 
protocol.  
2.1.2.7 Diverticulitis (either active or history of) within the past 2 years. Note that diverticulosis 
is permitted. 
2.1.2.8 Active or history of inflammatory bowel disease (colitis, Crohn’s), irritable bowel 
disease, celiac disease, or other serious, chronic, gastrointestinal conditions associated 
with diarrhea. Active or history of systemic lupus erythematosus or Wegener’s 
granulomatosis. 
2.1.2.9 Currently receiving immunosuppressive doses of steroids or other immunosuppressive 
medications (inhaled and topical steroids are permitted) 
2.1.2.10 History of sarcoidosis syndrome 
2.1.2.11 Patients should not be vaccinated with live attenuated vaccines within 1 month of 
starting Tremelimumab treatment. 
2.1.2.12 Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies) 
2.1.2.13 HIV-positive patients receiving anti-retroviral therapy are excluded from this study due 
to the possibility of pharmacokinetic interactions between antiretroviral medications 
and Tremelimumab. HIV positive patients not receiving antiretroviral therapy are 
excluded due to the possibility that Tremelimumab may worsen their condition and the 
likelihood that the underlying condition may obscure the attribution of adverse events. 
2.1.2.14 History of hypersensitivity reaction to human or mouse antibody products. 
2.1.2.15 Pregnancy and breast feeding are exclusion factors.  The effects of Tremelimumab on 
the developing human fetus are unknown.  Enrolled patients must agree to use adequate 
contraception (hormonal or barrier method of birth control; abstinence) prior to study 
entry, the duration of study participation and 3 months after the end of the treatment. 
Should a woman become pregnant or suspect she is pregnant while she or her partner is 
participating in this study, she should inform her treating physician immediately. 
2.1.2.16 Patients with unhealed surgical wounds for more than 30 days.  
2.1.3 Re-Induction Criteria (if applicable) 
2.1.3.1 Subjects must have entered the Maintenance Phase and are under ongoing maintenance 
treatment  
or  Subjects who stopped maintenance treatment because of a CR  
or  Subjects with an initial PR or CR or at least 3 months of SD on tumor assessment  
and  who subsequently have a confirmed and documented disease progression (per 
immune-related RECIST criteria). 
2.1.3.2 Patients are excluded from re-induction if they have experienced any related Dose-
limiting toxicities as described in Section 3.6, delayed dosing beyond 35 days due to 
Tremelimumab-related AEs, or have been taken off treatment due to toxicity as 
described in Section 3.8.3.  


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2.1.3.3 Patients who have progressed on initial therapy will not be considered for re-induction 
treatment. 
2.1.3.4 Tremelimumab Dose: Patients will be treated at the same dose of Tremelimumab as they 
previously received. For patients on Dose Level 1 who had already satisfied criteria for 
escalation to 10mg/kg they will be re-treated at 10mg/kg. 
2.1.3.5 The patient must – at the time of re-induction – satisfy all the eligibility criteria as set out 
in Sections 2.1.1 & 2.1.2. 
2.1.3.6 The patient must be discussed at GI Tumor Board, NCI and suitability for the 
interventional procedure (TACE or RFA) re-affirmed.  
Eligible patients will follow the same treatment criteria, evaluation plan and schedule as was 
previously described for the main part of the study, and doses may be delayed or modified as 
described in Section 3.8. There will be no limit to the number of additional re-inductions a 
patient may receive if the same efficacy and safety criteria described above are met, until 
intolerable toxicity or progressive disease necessitates ending the re-induction phase. 
2.1.4 Inclusion of Women and Minorities 
Men and women of all races and ethnic groups are eligible for this trial. 
2.1.5 Recruitment Strategies 
The study will be posted on the CCR website and on clinicaltrials.gov. 
2.2 
  SCREENING EVALUATION  
2.2.1 History and Physical Examination  
Complete history (including prior hormone use) and physical examination (including height, 
weight, vital signs, EKG, and performance status) will be conducted prior to starting study drug. 
2.2.2 Laboratory Evaluation 
x Hematological profile: CBC with differential and platelet count, PT, INR, aPTT, 
fibrinogen. 
x Biochemical profile: electrolytes, BUN, creatinine, AST, ALT, total bilirubin (including 
direct and indirect), calcium, phosphorus, albumin, magnesium, uric acid, amylase. 
x Serum or urine pregnancy test for female participants of childbearing age (in the absence 
of prior hysterectomy). Test to be performed within 72 hours prior to initiating treatment. 
2.2.3 Histologic confirmation (at any time point prior to commencement)  
A block or unstained slides of primary or metastatic tumor tissue will be required from each 
participant to confirm diagnosis with analysis being performed by the Laboratory of Pathology, 
NIH. As stated in the inclusion criteria above, histopathological confirmation of carcinoma may 
be sufficient. Fibrolammelar variant is also allowed. 


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2.3 
BASELINE STUDIES 
2.3.1 Imaging studies (obtained within 28 days prior to first dose)  
x CT scan of chest, abdomen and pelvis 
And/or 
x MRI liver  
2.3.2 Laboratory evaluation (obtained within 72 hours prior to first dose) 
If laboratory tests are done within 72 hours of Cycle 1 Day 1 they do not need to be repeated on 
Day 1. 
x Hematological profile: CBC with differential and platelet count, PT, INR, aPTT, 
fibrinogen. 
x Biochemical profile: electrolytes, BUN, creatinine, AST, ALT, total bilirubin (including 
direct and indirect), calcium, phosphorus, albumin, magnesium, uric acid, amylase. 
x Tumor marker profile: aFP or Ca19.9 (obtained within 7 days prior to first dose) 
2.3.3 Laboratory evaluation (obtained within 28 days prior to first dose) 
x Thyroid function tests (TSH, T3, T4) 
x Hepatitis B and/or C viral load and serology 
x HLA-A2 phenotype 
2.3.4 History and physical exam with vital signs (obtained within 1 week prior to first dose). 
2.3.5 Electrocardiogram (obtained within 28 days prior to first dose) 
2.4 
REGISTRATION PROCEDURES 
Authorized staff must register an eligible candidate with NCI Central Registration Office (CRO) 
within 24 hours of signing consent.  A registration Eligibility Checklist from the web site 
(http://home.ccr.cancer.gov/intra/eligibility/welcome.htm) must be completed and f sent via 
encrypted email to:  NCI Central Registration Office ncicentralregistration-l@mail.nih.gov.  
After confirmation of eligibility at Central Registration Office, CRO staff will call pharmacy to 
advise them of the acceptance of the patient on the protocol prior to the release of any 
investigational agents.  Verification of Registration will be forwarded electronically via e-mail to 
the research team.  A recorder is available during non-working hours.  
3 
STUDY IMPLEMENTATION 
3.1 
STUDY DESIGN 
- 
The proposed study is a pilot study of Tremelimumab - at a planned dose 10mg/kg/IV q 4 
weekly - in patients with advanced HCC treated with either TACE or RFA. 


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The initial study population is Cohort A as described below and these patients will be 
treated with either RFA or TACE. The decision on which treatment to administer (i.e. 
RFA vs. TACE) will be made in consultation with the interventional radiologists. The 
reason for this is that there are technical considerations (size and location of lesion, main 
portal vein occlusion etc.) which would make one procedure preferable over the other.  
 
 
Cohort 
Population 
Immune stimulative 
procedure 
Dose level 
(Trem) 
Planned N 
A 
Advanced HCC, 
BCLC Stage C 
RFA/TACE 
3.5mg/kg 
3-6 
10mg/kg 
20 
B 
Intermediate HCC, 
BCLC B 
TACE 
10mg/kg  
20 
 
- 
Transarterial chemoembolization is percutaneous procedure performed under general 
anesthesia or conscious sedation. (See 3.9.1 for details) 
- 
Patients undergoing trans-arterial chemoembolization, RFAor cryoablation are pre-
medicated with analgesics, antibiotics and anti-emetics per clinical standards. For details 
regarding each procedure please see 3.9. 
- 
We will also enroll an additional cohort of N=20 patients (Cohort B) with liver-confined 
disease for whom TACE is indicated as standard of care. These patients will receive 
TACE in combination with Tremelimumab using the same schema, although for these 
patients TACE may be repeated (as per standard of care). They will not receive RFA. 
- 
With protocol amendment F, it was proposed that once cohort A has demonstrated safety 
and feasibility for the combination of ablative treatment and tremelimumab in HCC, we 
will add 3 additional cohorts (C-E) to the study. However, with amendment I we have 
revised the study design to remove Cohort C, so only 2 cohorts, D and E, remain. For 
these cohorts, the schedule of administration for tremelimumab and the timing of the 
immune-stimulative procedure is identical to cohorts A and B, as summarized below.  
Cohort 
Population 
Immune 
stimulative 
procedure 
Dose level 
(Trem) 
Planned N 
D 
Advanced HCC, BCLC Stage 
C 
Cryoablation 
10mg/kg  
10 


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E 
Intrahepatic 
cholangiocarcinoma 
RFA 
10mg/kg 
20 
 
3.2 
SCHEDULE 
- 
Day 1: Tremelimumab IV every 4 weeks x 6 doses and then every 12 weeks for 2 years 
or until disease progression whichever comes first. 
- 
Day 36 [+/- 96 hours]: RFA or TACE. 
- 
Restaging CT /MRI scan every 8 weeks to evaluate TTP in target lesion. (Both standard 
RECIST and Immune-related Response Criteria [irRC] will be employed). 
- 
Dose: (Cohort A only): Initially three to six patients will be treated at 3.5mg/kg (with 
subsequent dosing also at 3.5mg/kg) prior to enrolling to the10mg/kg dose level. If a 
single patient experiences dose-limiting toxicity (DLT) related to the combination this 
cohort will be expanded to N=6 as per a standard 3+3 design. If 3.5mg/kg is established 
to be safe we will proceed to the 10mg/kg dose level. N=20 patients in cohort A will be 
treated at 10mg/kg. 
- 
For Cohort A (BCLC Stage C patients): TACE or radiofrequency ablation (RFA) will be 
performed once only. 
- 
For Cohort B (BCLC Stage B patients): TACE may be repeated (as per standard of care) 
on months 3, 7, and 13, and q6 months thereafter (if indicated). 
- 
Cohort B will only be recruited following completion of the dose-escalation portion of 
Cohort A. 
For Cohort E (BTC patients, status post prior chemotherapy with intrahepatic disease) RFA will 
be performed once only, also on Day 36 (+/- 96hrs). 
3.3 
COHORT A 
3.3.1 Definition 
The definition of Cohort A is as follows:  
 
Cohort A (N=23-26):  
x Advanced stage HCC, BCLC group C 
x Patients must have progressed on, been intolerant of prior sorafenib therapy. 
x Child Pugh A/B7  
x No available surgical option (i.e. transplantation or hepatic resection) or curative 
ablative option. 
x Disease amenable to either TACE or RFA 
3.3.2 Treatment 
Three patients will be treated at 3.5mg/kg (with subsequent dosing also at 3.5mg/kg i.e. no 
intrapatient dose escalation) prior to enrolling to the10 mg/kg dose level. If a single patient 
experiences dose-limiting toxicity (DLT) related to the combination of TACE/RFA and 


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Tremelimumab this cohort will be expanded to N=6 as per a standard 3+3 design. If 3.5mg/kg is 
established to be safe we will proceed to the 10 mg/kg dose level. N=20 patients will be treated 
at 10 mg/kg to evaluate the feasibility endpoint, provided no more than 2 of 3-6 patients have a 
DLT at this level. 
 
Dose level 
Tremelimumab dose (mg/kg) 
N 
1 
3.5 
3-6 
2 
10 
20 
  
- 
The 3.5 mg/kg cohort will have at least 3 patients to evaluate for toxicity to establish 
MTD for the combination of Tremelimumab with either TACE or RFA.  Three patients 
will be treated at this dose level.  The descriptions and grading scales found in the revised 
NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be 
utilized for AE reporting. If none of the three patients at the 3.5 mg/kg dose level 
experiences dose-limiting toxicity (DLT), accrual to DL2 will proceed to the 10mg/kg 
cohort.  If one of three patients treated at a dose level experiences DLT that is considered 
to be at least possibly related to the combination of Tremelimumab with either TACE or 
RFA, then three more patients will be enrolled at that same level.  If the incidence of 
DLT among those six patients is one in six, then we will proceed to 10 mg/kg.  If two or 
more of the six patients experience DLT, then the MTD is considered to have been 
exceeded.   
- 
Evaluation period for Dose-limiting Toxicities (DLT) will extend for the first 8 weeks of 
the study. 
- 
Following completion of the dose escalation portion of the study Tremelimumab will be 
administered at the MTD at the same schedule.  A total of 20 patients will be treated in 
cohort A at the MTD, not including those patients treated at the lower doses. 
- 
For patients on Dose Level 1 who have completed at least 16 weeks of protocol therapy, 
we will consider dose escalation to 10mg/kg if criteria for continuance of therapy are met 
and the patient does not have >Grade 2 toxicity attributable to tremelimumab. 
3.3.3 Protocol Stopping Rules 
This study will utilize the Common Terminology Criteria for Adverse Events (CTCAE) version 
4.0 for grading systemic toxicity. For safety reasons, the protocol will be temporarily halted 
pending discussions with the NCI IRB and Sponsor regarding necessary amendment for either of 
the following events: 
x One occurrence of grade 5 toxicity by the NCI-CTCAE version 4.0 attributable to the 
treatment regimen. 
x Two occurrences of grade 4 toxicity by the NCI-CTCAE version 4.0 attributable to the 
treatment regimen. 


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3.3.4 Re-Induction 
Patients who entered the maintenance phase and have confirmed PD (per immune-related 
RECIST criteria) during the maintenance treatment may be eligible to receive re-induction 
therapy using Tremelimumab at the assigned dose and schedule: i.e. 10mg/kg monthly for 6 
months followed by maintenance 3-monthly Tremelimumab. Patients who stopped maintenance 
treatment because of a CR and subsequently had confirmed PD (per immune-related RECIST 
criteria) are eligible to receive re-induction as well. Subjects with an initial PR or CR or SD for 
at least 3 months and subsequently have PD are also eligible for re-induction. As part of re-
induction they will also undergo the repeat ablative procedure on Day 36 (+/- 96hrs). This may 
be either an RFA or TACE depending on the opinion of the interventional radiologist. To be 
eligible for re-induction patients must satisfy the criteria stated in section 2.1.3. 
3.3.4.1 Tumor Biopsies 
If a patient opts to undergo re-induction therapy we would like to perform pre- and post-re-
induction tumor biopsies to better understand the role of emerging resistance to anti-CTLA4 
therapy. These would occur prior to re-induction (< 2 weeks prior to starting) and then during the 
interventional radiologic procedure.  
3.4 
COHORT B 
3.4.1 Definition 
The definition of Cohort B is as follows:  
Cohort B (N=20):                                        
x HCC, Barcelona Clinic Liver Cancer (BCLC) Stage B;  
x Child Pugh A/B7;  
x No available surgical (i.e. transplantation or hepatic resection) or curative ablative option. 
x Disease amenable to TACE 
3.4.2 Treatment 
The treatment schema for both cohorts is identical with the exception of the fact that in cohort B 
TACE may be repeated (as per standard of care) on months 3, 7, and 13, and q6 months 
thereafter (if indicated). 
Patients in Cohort B will only be recruited following completion of the dose-escalation portion 
of Cohort A and will be treated at the dose level which has been determined to be safe in that 
cohort. 
3.5 
COHORT C 
This cohort, designed to evaluate tremelimumab in combination with external beam radiation 
was removed with amendment I.  
3.6 
COHORTS D-E 
Once safety is established for the initial concept of combining anti-CTLA4 with ablative 
procedures (RFA and TACE), we will similarly explore feasibility of tremelimumab at the same 
dose and schedule in 2 additional cohorts (denoted D-E) evaluating tremelimumab in 


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30 
Version Date: 08/14/2017 
combination with cryoablation in HCC (cohort D) and with RFA in a cohort of patients with 
biliary tract carcinoma (cohort E).  
- 
For these additional cohorts, the dose (10mg/kg) and schedule of tremelimumab will be 
as per cohorts A and B. The timing of the interventional procedure will also be identical. 
- 
Cohort Definition: Cohort D will have the same definition as Cohort A above: 
Advanced stage HCC, BCLC group C 
Patients must have progressed on, been intolerant of prior sorafenib therapy. 
Child Pugh A/B7  
No available surgical option (i.e. transplantation or hepatic resection) or curative ablative 
option.  
Disease amenable to cryoablation 
- 
Cohort E will contain BTC patients as specified in the eligibility criteria. 
- 
For cohorts D-E no dose escalation will occur. All patients will receive tremelimumab at 
10mg/kg at the same schedule established as safe and feasible in Cohort A of the study. 
However, protocol stopping rules will apply as outlined in Section 3.3. 
3.7 
DOSE LIMITING TOXICITIES  
3.7.1 Definition of Dose-limiting Toxicities (DLTs): 
$'/7LVGHILQHGDVD*UDGHDGYHUVHGUXJUHDFWLRQ$'5DFFRUGLQJWRWKH1&,-CTCAE 
v4.0, that is possibly, probably, or definitely related to the combination of Tremelimumab with 
either TACE or RFA, occurring during the DLT evaluation period except for any of the 
following outlined in section 3.6.2. ADRs are defined in this trial as any AEs suspected to be 
related to Tremelimumab by the investigator.  Evaluation period for Dose-limiting Toxicities 
(DLT) will extend for the first 8 weeks of the study. 
Treatment-related SAE will be ascribed as related to drug except where a clear relationship to the 
underlying disease or recognized co-morbidities is evident. For this trial, the MTD is defined as 
the highest dose where < 2 of 6 subjects experience a DLT. 
3.7.2  Exclusions to Dose Limiting Toxicities 
x Grade 3 infusion-related reaction resolving within 6 hours and controlled with medical 
management.  
x  Any Grade 3/4 non-hem toxicity that occurs in the first 10 days after RFA or TACE and 
which is an expected toxicity of the procedure in the opinion of the PI. These symptoms 
include, but are not limited to, fevers/rigors, pain, fatigue and nausea. 
x Any grade 3 immune-mediated adverse event (including but not limited to Grade 3 
diarrhea, Grade 3 skin toxicity, or Grade 3 liver enzyme elevation) that improves to *UDGH
2 within 1 week of onset with supportive care (which may include systemic 
corticosteroids). 
x Nausea and vomiting Grade 3 will only be considered dose-limiting if it is refractory to 
anti-emetic therapy and unable to be corrected to Grade 1 or less within 48 hours. 


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x Grade 3 rise in creatinine, not corrected to Grade 1 or less after 2 liters of intravenous 
fluids within 24 hours, will be considered dose limiting.   
x 
Single laboratory values out of normal range that are unlikely related to trial treatment 
according to the investigator, do not have any clinical correlate, and resolve within 7 days 
with adequate medical management.  
x 
7UDQVLHQWKRXUV*UDGHIDWLJXHORFDOUHDFWLRQVKHDGDFKHQDXVHDHPHVLVWKDW
UHVROYHVWR*UDGH 
x  Grade 4 elevation in transaminase elevation that improves to *UDGHwithin 10 days of 
onset with supportive care.  
x Grade 3 endocrinopathy that is managed with or without systemic corticosteroid therapy 
and/or hormone replacement therapy and the following criteria are met: 
 The subject’s hormone levels are within normal limits 
 The subject is asymptomatic 
x Grade 3 inflammatory reaction attributed to a local antitumor response (eg, inflammatory 
reaction at sites of metastatic disease, lymph nodes, etc.) 
3.8 
DRUG ADMINISTRATION 
3.8.1 Tremelimumab Drug Administration 
The first day of dosing is considered Day 1. Each dose of investigational product should be 
administered using the following guidelines:  
1) Investigational product must be administered at room temperature (25°C) by controlled 
infusion at a rate of 250 mL/hr via an infusion pump into a peripheral vein. Prior to the 
start of the infusion, ensure that the bag contents are at room temperature to avoid an 
infusion reaction due to the administration of the solution at low temperatures. 
2) Investigational product must not be administered via IV push or bolus but as a slow IV 
infusion. The entire content of each IV bag will be infused using an infusion pump.  
3) The infusion lines should be attached only at time of use. Lines used for infusion during 
dose administration will need to be equipped with 0.22 or 0.2 ȝPLQ-line filters.  
4)  If there are no requirements to slow, interrupt, or permanently stop the infusion, the 
anticipated infusion time to deliver each dose (250 mL) is anticipated to be 
approximately 60 minutes. 
The duration of the investigational product administration will be recorded. 
3.8.2 Monitoring of Dose Administration  
Vital signs will be collected before investigational product infusion and at the completion of the 
infusion.  
As with any antibody, allergic reactions to dose administration are possible. Therefore, 
appropriate drugs and medical equipment to treat acute anaphylactic reactions must be 
immediately available, and study personnel must be trained to recognize and treat anaphylaxis, 
as per local institutional guidelines. 


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3.9 
DOSING DELAYS  
The following broad guidelines for dose delays apply to both of the planned dosages of 
Tremelimumab and are dependent on the clinical and laboratory assessment on the day of 
dosing. No dose reductions will be employed. Patients will either proceed or forgo treatment. 
Dosing may be delayed up to 14 days to allow recovery from treatment-related toxicity. For specific 
immune-mediated adverse reactions see Section 3.8.3 which will take precedence over this broad 
management guideline.  
 
Condition  
Management  
Onset of any toxicity  
 
Rule out alternative etiology  
In case of doubt, investigator should consult with study medical 
monitor promptly  
 
NCI CTCAE Grade 1  
 
Provide symptomatic treatment  
Possible topical steroids if applicable  
 
 
NCI CTCAE Grade 2  
 
Provide symptomatic treatment  
In the case of an immune-mediated adverse event do not give 
scheduled dose; dosing may be resumed once symptoms are 
resolved.  
Consider oral or IV steroids at the onset of symptoms. Taper 
steroid if symptoms improve.  
NCI CTCAE Grade 3  
 Start high-dose IV steroids at the onset of the symptoms  
 Provide symptomatic treatment  
 
 
 
NCI CTCAE Grade 4  
Start high-dose IV steroids at the onset of the symptoms  
Provide symptomatic treatment  
Permanent discontinuation 
a of Tremelimumab for all NCI 
CTCAE Grade 4 events (unless specific exemption stated 
elsewhere in protocol) 
 
Steroid refractory toxicity (no 
improvement after 5 days on high-
dose IV steroids) or relapse after 
reducing high-dose steroids  
Continue symptomatic treatment and steroids  
Possible infliximab 
b 5 mg/kg IV for GI toxicities unless 
contraindicated [consult with GI specialist]. Caution: rule out 
bowel perforation and refer to label before using infliximab  
For subjects with increased AST/ALT, or total bilirubin levels, 
consider mycophenolate mofetil  
 
ALT = alanine transaminase; AST = aspartate transaminase; GI = gastrointestinal; IV = intravenous; NCI CTCAE = 
National Cancer Institute Common Terminology Criteria for Adverse Events.  


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a Subjects will not receive any subsequent dose, but will remain on study and follow the other procedures required 
from the study (e.g., follow-up procedures, disease assessment scans, blood sample collections).  
b Use will result in discontinuation of treatment.  
During the study, subjects may require immunosuppressive medications such as steroids for 
management of underlying disease, treatment-related toxicity, or unrelated conditions. If symptoms 
UHVROYHGWR1&,&7&$(*UDGHTremelimumab dosing may be resumed during steroid taper. 
Subjects with adrenal insufficiency may take daily prednisone or equivalent therapy for their 
endocrinopathy while receiving Tremelimumab treatment. Topical and inhaled steroids in standard 
doses are allowed.  
3.9.1 Dosing Delays/Dose Modifications: General Guidelines  
3.9.1.1 Grade 1 or 2 Toxicity  
Treatment with Tremelimumab need not be interrupted, although for chronic low grade toxicity 
causing significant detrimental effect in patient’s well-being the PI may elect to delay/omit 
dosing at his discretion, in particular in the case of a suspected immune-mediated adverse event.   
3.9.1.2 Grade 3 Hematologic or Non-Hematologic Toxicity  
Hold Tremelimumab and re-HYDOXDWHXQWLOWR[LFLW\LPSURYHVWRJUDGHRUSUH-treatment 
baseline.  Treatment will be discontinued in patients who experience grade 3 non-hematologic 
toxicities felt to be drug-related.  
3.9.1.3 Grade 4 Non-Hematologic Toxicity  
Patients with clinical treatment-related grade 4 non-hematologic toxicity (except pulmonary 
embolism without significant hypoxia and hemodynamic instability) will be taken off treatment 
permanently. Unacceptable toxicities that have not resolved at time of “off treatment” must be 
followed until stabilization or resolution, at which time they will continue in follow up for 
survival.  
3.9.2 Toxicities Mandating Permanent Discontinuation of Tremelimumab 
As per the Investigator’s brochure the following criteria will result in permanent discontinuation 
of tremelimumab. 


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3.9.3 Specific immune-mediated adverse reactions 
Tremelimumab can result in severe and fatal immune-mediated adverse reactions due to T-cell 
activation and proliferation. These immune-mediated reactions may involve any organ system, 
however, the most common severe immune-mediated adverse reactions are enterocolitis, 
hepatitis, dermatitis (including toxic epidermal necrolysis), neuropathy, and endocrinopathy. The 
majority of these immune-mediated reactions initially manifest during treatment, however, a 
minority may occur weeks to months after discontinuation of Tremelimumab. Tremelimumab 
will be discontinued and systemic high-dose corticosteroid therapy initiated for severe immune-
mediated reactions. 
Patients will be assessed for signs and symptoms of enterocolitis, dermatitis, neuropathy and 
endocrinopathy and evaluate clinical chemistries including liver function tests and thyroid 
function tests at baseline and before each dose. 
 The following are anticipated immune-mediated adverse reactions for which specific guidance 
and management is outlined below. 
3.9.3.1 Gastrointestinal 
 


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35 
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3.9.3.2 Liver (Immune-mediated hepatitis) 
Tremelimumab can result in severe and fatal inflammation of the liver most commonly 
manifested as elevation of transaminases and hyperbilirubinemia. Liver enzymes and liver 
function tests (hepatic transaminase and bilirubin levels) will be evaluated and patients assessed 
for signs and symptoms of hepatitis before each dose of Tremelimumab. 
In patients who experience AST or ALT > 5.0 ULN and/or baseline or total bilirubin > 3.0 ULN 
liver biopsy should be considered as per standard of care investigation for automimmune 
hepatitis. 
Symptoms 
Immediate action 
Subsequent management 
Moderate 
$67RU$/7!WR
ULN 
and/or baseline (if this was 
abnormal). 
7RWDOELOLUXELQ!WR
ULN 
 
Withhold Tremelimumab 
5XOHRXWLQIHFWLRXVRU 
malignant causes 
,QFUHDVHIUHTXHQF\RIOLYHU
function test monitoring until 
resolution 
 
Symptoms resolve: 
Resume Tremelimumab if 
liver function tests are 2.5 
ULN 
or return to baseline and 
bilirubin level is 1.5 ULN or 
returns to baseline 
IF AST OR ALT 
CONTINUES TO 


Abbreviated Title: anti-CTLA4 & ablative therapy  
36 
Version Date: 08/14/2017 
ELEVATE TO >5.0 ULN 
OR 
TOTAL BILIRUBIN >3.0 
ULN, 
See management for ‘severe’ 
 
 
Symptoms 
Immediate action 
Subsequent management 
Severe 
$67RU$/7!8/1 
and/or 
7RWDOELOLUXELQ!8/1 
 
Hold Tremelimumab and re-
evaluate until toxicity 
LPSURYHVWRJUDGHRUSUH-
treatment baseline.  Treatment 
will be discontinued in 
patients who experience grade 
3 non-hematologic toxicities 
that do not resolve to grade 1 
or baseline within 4 weeks.  
Increase frequency of liver 
function 
test monitoring until 
resolution 
Administer systemic 
corticosteroid of 
1 to 2 mg/kg/day of 
prednisone 
or equivalent. 
Consider liver biopsy as per 
standard of care investigation 
for autoimmune hepatitis 
 
Symptoms resolve: 
When liver function tests 
show sustained improvement 
or return to baseline, initiate 
corticosteroid tapering and 
continue to taper over 1 month 
Consider alternative 
immunosuppressive therapy 
 
Symptoms Ongoing >1 
week: 
Consider alternative 
immunosuppressive therapy 
 
 
 
3.9.3.3 Skin: Immune-mediated dermatitis 
Symptoms 
Immediate action 
Subsequent management 
Moderate 
Non-localized rash (diffuse, 
<50% 
of skin surface) 
 
Withhold Tremelimumab 
Administer topical or systemic 
corticosteroids if there is no 
improvement of symptoms 
within 
1 week 
 
Symptoms resolve: 
Resume Tremelimumab if 
dermatitis resolves or 
improves to 
mild (localized) symptoms 
and systemic steroid dose is 
10 mg prednisone equivalent 
or less 
 
If symptoms worsen see 
management for ‘severe’ 


Abbreviated Title: anti-CTLA4 & ablative therapy  
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Symptoms 
Immediate action 
Subsequent management 
Severe 
Stevens-Johnson syndrome, 
toxic epidermal necrolysis, or 
rash complicated by full 
thickness dermal 
ulceration, or necrotic, 
bullous, or hemorrhagic 
manifestations 
Permanently d/c 
Tremelimumab 
Administer systemic 
corticosteroid 
therapy of 1 to 2 mg/kg/day of 
prednisone or equivalent 
 
Symptoms resolve: 
When dermatitis is controlled, 
corticosteroid tapering 
should occur over a period of 
at least 1 month 
 
 
 
3.9.3.4 Central/Peripheral nervous system 
Symptoms 
Immediate action 
Subsequent management 
Moderate 
Moderate symptoms, 
clinically 
detectable with no impact on 
activities 
of daily living (ADLs) 
 
Withhold Tremelimumab 
Introduce appropriate medical 
intervention 
 
Symptoms resolve: 
Resume Tremelimumab when 
symptoms resolve or return 
to baseline 
 
If symptoms worsen see 
management for ‘severe’ 
 
 
 
 
Symptoms 
Immediate action 
Subsequent management 
Severe 
Severe symptoms (impact on 
ADLs) or life threatening 
 
Permanently d/c 
Tremelimumab 
Institute appropriate medical 
intervention 
Consider the use of systemic 
corticosteroid of 1 to 2 
mg/kg/day of 
prednisone or equivalent 
 
 
Permanently d/c 
Tremelimumab 
Continue appropriate medical 
intervention 
 
 
3.9.3.5 Endocrine system 
Symptoms 
Immediate action 
Subsequent management 
Moderate 
Signs and/or symptoms of 
dysfunction 
Endocrinopathies requiring 
hormone 
Withhold Tremelimumab 
Evaluate endocrine function 
Consider radiographic 
pituitary gland 
imaging 
Symptoms resolve: 
Resume Tremelimumab when 
Patient is stable and symptoms 
are resolved or return 
to baseline 


Abbreviated Title: anti-CTLA4 & ablative therapy  
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replacement or medical 
intervention 
Adverse reactions requiring 
hospitalization, urgent medical 
intervention, or interfering 
with 
activities of daily living 
(including 
adrenal crisis) 
 
Continue to assess as 
indicated 
Withhold Tremelimumab in 
symptomatic 
patients 
Administer systemic 
corticosteroid 
therapy of 1 to 2 mg/kg/day of 
prednisone or equivalent 
Initiate appropriate 
hormone-replacement therapy 
 
Patient is stable on hormone-
replacement therapy 
(as indicated) 
Patient is receiving "7.5 mg 
prednisone or equivalent 
per day 
 
 
 
3.10 SPECIFIC PROCEDURES FOR TACE, RFA AND CRYOABLATION 
3.10.1 Transarterial chemoembolization  
Is percutaneous procedure performed under general anesthesia or conscious sedation. Access is 
obtained from the common femoral artery and selective catheterization of the superior 
mesenteric and celiac arteries is performed to define anatomy and hepatic arterial supply. 
Superselective catheterization of hepatic artery branches feeding the tumors is then performed 
followed by infusion of a chemotherapeutic mixture.  
Trans-arterial chemoembolization will be performed with drug eluding beads (DEB). In this 
case, 100mg of doxorubicin are loaded into 100-250 micron beads. The DEB are mixed with 
contrast and infused into the hepatic artery branches supplying the tumor. Patients undergoing 
trans-arterial chemoembolization are pre-medicated with analgesics, antibiotics and anti-emetics 
per clinical standards.  
3.10.2 Radiofrequency ablation 
Thermal ablation is a minimally invasive image guided procedure performed under general 
anesthesia or conscious sedation. Radiofrequency or microwave ablations are performed; the 
ablation zone includes the tumor and a safety margin of surrounding tissue. Thermal ablation 
therapy will be administered according to the manufacturer’s instructions of the device. The 
probe chosen varies depending on the type of thermal ablation, size of the tumor. The ablation 
probe will be inserted into the lesion, under image guidance.  After confirmation of appropriate 
positioning, the lesion will be heated typically for 10-15 minutes for RFA and 5-10 minutes for 
microwave, according to manufacturer’s guidelines. The time of ablation will depend on thermal 
ablation technique (RF vs. microwave) as well as the size of the ablation zone desired. The 
ablation time might also vary depending on proximity of critical structures, patient-specific 
anatomy or issues.  Depending on ablation zone size, several probes might be required with 
several heating times to achieve complete coverage of the desired ablation zone.  Balloon 
catheter may be used in cases where the tumor is adjacent to a hepatic vein to avoid “heat sync” 
where the ablation zone is cooled by the blood inflow. This catheter is typically inserted from the 
neck vein and is then placed into a hepatic vein. Hydrodissection may also be used in cases 
where the tumor is adjacent to a critical structure such as the heart or colon. These organs can 


Abbreviated Title: anti-CTLA4 & ablative therapy  
39 
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sustain damage from heating, therefore a catheter is inserted into the space separating them and 
the tumor and fluid (dextrose 5%) is administered during the ablation. 
3.10.3 Cryoablation  
The freeze zone of cryoablation effects depend upon the probe size and configuration as well as 
the nadir of the freeze cycle (dependent upon the specific cryogen). Two cryoablation systems 
are commercially available and FDA cleared for human use (Endocare / Healthtronics and Galil) 
Both use helium and argon gases to induce lethal temperatures locally.  
The systems require argon and helium gases which produce low temperatures upon phase change 
from gas to liquid. The cryotherapy equipment will be an argon-helium gas system using 1.6mm 
or 2.4 mm cryoprobes (Endocare, Inc., Irvine, CA) or 0.049 inches = 18 gauge = 1.3 mm 
cryoprobes (Galil).  The ice-ball diameters for these probes may vary according to the tissue and 
blood supply, but their freeze lengths should be comparable to the RFA system (10-30 mm).  Ice-
ball diameters refer to the outer 0°C margin, but cytotoxic temperatures (e.g., < -20 to -40 °C) 
are known to occur 3-5 mm behind visualized ice margins.  A 10- 20 minute freeze, followed by 
a 5-10 minute thaw, and a 10-20 minute re-freeze produce visible ice and necrosis by rapid and 
slow mechanisms (dehydration and vascular stasis). The specific times depend upon the 
temperatures and potentially the temperatures of any remote thermometry used to asse4ss 
temperature at the margin of a freeze. Rapid intracellular ice formation causes irreversible cell 
death. Cell membrane dysfunction occurs below -10 degrees C, leading to intracellular ice 
formation, disrupting organelles. During thawing, osmolar shifts cause cellular swelling and 
rupture. Apoptosis and vascular stasis may also play a role in cell death by freezing.  
The probes are placed into the tumor(s) by ultrasound, CT or MRI guidance. Up to 8 
simultaneous probes may be placed sequentially for simultaneous treatment (different from 
current monopolar RFA). 1 % lidocaine is applied to the subcutaneous tissues down to the organ 
of interest. The helium and argon gases are hooked up to the system, and the cryotherapy 
machine and software are relatively automatic at this point with the freeze, thaw, refreeze cycles 
as described above. The process is monitored with ultrasound and CT scans as clinically required 
for standard operating procedures described by the manufacturers.
 


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3.11 STUDY CALENDAR  
 
 
Pre-
study 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 
Cycle 5 
Cycle 6 
Every 
12 
weeks 
for 2 
years or 
until 
PD 
Off 
Treat
ment 
l 
 
FUn 
 
Day 
 
1 
8 
15 
22 
1 
8 (day 36) 
15 
22 
1 
8 
15 
22 
1 
8 
15 
22 
1 
8 
15 
22 
1 
8 
15 
22 
 
 
 
Tremelimumaba 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
RFA/TACE/ 
/Cryoablation b 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed consent  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
and concomitant 
meds 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
 
Adverse event 
evaluation  
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
 
Physical exam  
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
 
Vital signsi  
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
 
Height  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight  
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
Performance  
Status  
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
 
CBC 
w/differential,c  
Platelets  
X 
X X X X X X X X X X X X X X X X X X X X X X X X 
X 
X 
 


Abbreviated Title: anti-CTLA4 & ablative therapy  
41 
Version Date: 08/14/2017 
PT, INR, PTT,c  
X 
X X X X X X X X X X X X X X X X X X X X X X X X 
X 
X 
 
Thyroid Panelc 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
Serum chemistryc 
X 
X X X X X X X X X X X X X X X X X X X X X X X X 
X 
X 
 
Serum aFP or Ca 
19.9, hepatitis 
serologyd 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
HLA-A2 
Phenotyping 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ECG 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Restaging 
radiologic 
Evaluatione 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
Tumor biopsyf,m 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xm 
 
 
Immune 
monitoringj 
 
X 
 
 
 
X X 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Pharmacokinetic 
studiesg 
 
X X X 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Immunogenicityh 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
Liver 
autoantibody 
panel 
(autoimmune 
hepatitis) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tumor-specific 
Į)3UHVSRQVHV 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
MDSC functional 
assay 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Hepatitis serology 
and viral load 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
T cell 
activation/ICOS 
expression 
(PBMC) 
X 
 
 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 


Abbreviated Title: anti-CTLA4 & ablative therapy  
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Version Date: 08/14/2017 
a: Tremelimumab: Dose as assigned  
b: RFA/TACE/cryoablation on day 35 +/- 96 hrs. 
c: Acute, hepatic and mineral panels, uric acid and amylase. If laboratory tests done within 72 hours of Cycle 1 Day 1 they do not need to be 
repeated on Day 1.Thyroid Panel and Hepatitis Serologies do not need to be repeated on Day 1 if done within the last 28 days. For all labs a ‘+/- 
48hrs’ window applies, with the exception of those needed to determine proceeding with treatment. Labs may be performed outside of NIH. Once 
patients are in the every 12 week phase, weekly labs only need to be completed after their dose of tremelimumab for the 28 day period during the 
12 weeks.  
d: For Hepatitis B: HBV viral load; Anti-HBc Antibody, Anti-HBe Antibody, HBeAg and quantitative HepB Ag, HBV specific immune response. 
For Hepatitis C: HCV viral load, anti-HCV Antibody titer.  
e: Restaging CT /MRI scan every 8 weeks to evaluate TTP in target lesion. Post cycle 6 restaging will occur every 8 weeks. 
f: An optional tumor biopsy may  be performed at baseline and at the time of the ablative therapy for analysis of immune infiltration. 
g: pre-infusion and immediately post infusion. Day 8 and 15 for local patients only (optional research blood).  
h:  pre-infusion. 
i: Vitals may be done +/- 30 minutes at required timepoints. If patients are local or still post op procedure. 
j: Immune monitoring +/- 7 days. 
k: As indicated in section 9.3 , all subjects will be offered the opportunity to complete an NIH Advance Directive form.  This should be done 
preferably at baseline but can be done at any time during the study as long as the capacity to do so is retained.  The completion of the form is 
strongly recommended, but is not required. 
1: The off treatment visits/labs will occur if patient is agreeable to coming back and physically able to return for the visit. This visit should occur 
around day 30 post the last dose of study drug. If toxicities cause discontinuation of therapy, patients will be followed until resolution 
of toxicity to at least Grade 1. If the patient cannot return to the Clinical Center for this visit, a request will be made to collect required clinical 
labs from a local physician or laboratory.  If this is not possible, patients may be assessed by telephone for symptoms 
Plasma-based 
assays for 
circulating 
receptors/ligands 
e.g. PDL1 
X 
X 
 
 
 
X X 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
NIH Advance 
Directive Formk 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Annual telephone 
contact 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 


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m: An optional tumor biopsy may be obtained 2 weeks prior starting re-induction treatment.   
n: Follow-up will be annual telephone contact to assess survival status.  Every attempt will be made to contact patient/subject 
including: contacting referring physician, contacting emergency contact patient identified on admission, checking SSDI (Social 
Security Death Index)


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3.12 CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF STUDY CRITERIA 
3.12.1 Criteria for removal from protocol therapy 
Prior to removal from the study, effort must be made to have all subjects complete a safety visit 
approximately 30 days following the last dose of study therapy 
In the absence of treatment delays due to adverse events, treatment may continue until one of the 
following criteria applies: 
x Disease progression (per immune-related response criteria) 
x Completion of 2 years’ protocol therapy with tremelimumab 
x Intercurrent illness that prevents further administration of treatment 
x Unacceptable adverse event(s) 
x Participant requests to be withdrawn from active therapy 
x Investigator discretion 
x Positive pregnancy test 
x Delayed recovery from toxicity that prevents re-treatment in d 28 days of scheduled 
therapy  
x Completed end of treatment safety visit 
3.12.2 Criteria for Removal from Study 
x Death 
x Investigator discretion 
x Participant requests to be withdrawn from study  
x PI decision to close the study 
3.12.3 Off protocol therapy and Off Study Procedure 
Authorized staff must notify Central Registration Office (CRO) when a subject is taken off 
protocol therapy and when a subject is taken off-study. A Participant Status Updates Form from 
the web site (http://home.ccr.cancer.gov/intra/eligibility/welcome.htm) main page must be 
completed and sent via encrypted email to:  NCI Central Registration Office  
ncicentralregistration-l@mail.nih.gov. 
4 
CONCOMITANT MEDICATIONS/MEASURES 
All routine and appropriate supportive care (including blood products) will be provided during 
this study, as clinically indicated, and in accordance with the standard of care practices.  Clinical 
judgment should be utilized in the treatment of any AE experienced by the patient. 
Information on all concomitant medications, administered blood products, as well as 
interventions occurring during the study must be recorded on the patient’s eCRF.   


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Version Date: 08/14/2017 
5 
BIOSPECIMEN COLLECTION 
5.1 
CORRELATIVE STUDIES FOR RESEARCH/PHARMACOKINETIC STUDIES  
The correlative studies which we wish to perform are outlined below and summarized in the 
table. A description of each test including a brief statement of rationale and processing 
information is made below. 
 
Test/assay 
Volume blood 
(approx) 
Type of 
tube 
Collection point 
(+/- 48hrs) 
Location of 
specimen analysis 
Immune- 
monitoring 
120mls (for 
PBMC) 
EDTA 
C1D1, C2D1, 
C2D8 (D36) (or 
corresponding 
day+7 after 
TACE/RFA/ 
cryoablation will 
be optional) 
C3D1, C4D1, 
every 12 weeks 
until PD 
Figg Lab 
5-10mls (for 
serum) 
EDTA 
PK 
3mls 
SST 
C1D1 (pre-
infusion and 
immediately post-
infusion*), C1D8 
(local only), 
C1D15 (local 
only),  
C2D1 (pre-
infusion and 
immediately post-
infusion*),  
C3D1 (pre-
infusion and 
immediately post-
infusion*), and  
End-of-treatment 
(EOT)  
 
*Immediately 
post-infusion PK 
samples should 
be collected 
within 
approximately 15 
minutes. Dose 1: 
pre-infusion, 
immediately post 
MedImmune/Intertek 
Alta 


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Version Date: 08/14/2017 
Test/assay 
Volume blood 
(approx) 
Type of 
tube 
Collection point 
(+/- 48hrs) 
Location of 
specimen analysis 
infusion, C1D8 
(local only), and 
C1D15 (local 
only) 
Dose 2 and 
thereafter: pre-
infusion, 
immediately post 
infusion 
EOT 
Immunogenicity 
4mls 
SST 
C1D1 (pre-
infusion), C2D1 
(pre-infusion), 
C3D1 (pre-
infusion), C4D1, 
Every 3 months, 
End-of-treatment 
(EOT)  
MedImmune/PPD 
ANA  
4mls 
SST 
Baseline and 
C4D1 
CC Department of 
Laboratory Medicine 
(DLM) 
AMA & 
Liver/kidney 
microsomal 
antibody 
4 mL 
SST 
Baseline and 
C4D1 
CC DLM will send to 
Mayo Labs 
Tumor-specific 
responses (e.g. 
Į)3 
20mls 
EDTA 
C1D1, C2D1, 
C3D1, C4D1, 
every 12 weeks 
until PD 
Greten Lab 
CFSE-proliferation 
T cells 
5mls 
EDTA 
C1D1, C2D1, 
C3D1, C4D1, 
every 12 weeks 
until PD 
Greten Lab 
MDSC functional 
assay 
20mls  
EDTA 
C1D1, C2D1, 
C3D1, C4D1, 
every 12 weeks 
until PD 
Greten Lab 
Hepatitis B & C 
viral load 
8mls 
SST 
Baseline and q28 
days. 
CC Department of 
Transfusion Medicine 
T cell 
activation/ICOS 
expression 
(PBMC) 
10 mL 
EDTA 
Baseline (both 
screening and 
preinfusion C1D1 
if possible), 
C1D15, C2D1, 
MedImmune/Covance 


Abbreviated Title: anti-CTLA4 & ablative therapy  
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Version Date: 08/14/2017 
Test/assay 
Volume blood 
(approx) 
Type of 
tube 
Collection point 
(+/- 48hrs) 
Location of 
specimen analysis 
C3D1, C4D1, 
every 12 weeks 
until PD 
Plasma-based 
assays for 
circulating 
receptors/ligands 
e.g. PDL1 
6mls 
EDTA 
Baseline, pre-
infusion every 
cycle C1D1, 
C2D1, C2D8 
(D36), C3D1, 
C3D8 (if seen in 
clinic), D85, 
every 12 weeks 
until PD and 
EOT. 
MedImmune 
Optional tumor 
biopsy 
NA 
NA 
Baseline and at 
time of ablative 
procedure 
Pathology 
 
5.2 
NCI CORRELATIVE STUDIES 
5.2.1 Immune Monitoring (All cohorts) 
We will analyze PBMC for quantitative and functional changes of effector cells as well as 
analyze sera for cytokines and chemokines. The effect on (i) CD4 T cell number and activity, (ii) 
CD8 T cell number and activity, (iii) NK cell number and activity, (iv) Treg number, (vi) 
MDSC: frequency + functional assay, (vii) selected cytokines in serum, and (viii) the detection 
of HCC-associated antigens using ELISPOT assay.  
Patients will undergo blood sampling (c.120mls blood) on the time points outlined in the table 
(+/- 48 hrs). Blood will initially be sent to the Figg laboratory for barcoding and processing. On 
certain occasions the blood may also be brought to the Greten lab for processing and analysis.  
For  Dr. Figg’s Blood Processing Core (BPC): 
Please e-mail Julie Barnes at Julie.barnes@nih.gov and Paula Carter pcartera@mail.nih.gov at 
least 24 hours before transporting samples (the Friday before is preferred). 
For sample pickup, page 102-11964. 
For immediate help, call 240-760-6180 (main blood processing core number) or, if no answer, 
240-760-6190 (main clinical pharmacology lab number). 
For questions regarding sample processing, contact Julie Barnes by e-mail or at 240-760-6044.. 
PBMC will be isolated by Ficoll density centrifugation. Aliquots of 1 x 107 PBMC/tube will be 
individually frozen – after initial handling and processing at the Figg laboratory. 


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5.2.2 Liver autoantibody panel for autoimmune hepatitis (AIH) 
AIH is a chronic disorder characterized by progressive hepatocellular loss and cell-mediated 
immunologic attack. Histologic inflammation is present and is usually accompanied by fibrosis, 
which can progress to cirrhosis and liver failure. AIH accounts for 11% to 23% of chronic liver 
disease in North America and about 6% of liver transplants in the United States.  
The AIH Diagnostic Panel includes tests for actin (smooth muscle) antibody, antinuclear 
antibodies (ANAs), and liver/kidney microsome antibody (LKM-1). ANAs and actin antibody 
are associated with type 1 AIH, the most common form in the United States, while LKM-1 
antibody is associated with type 2 AIH, more commonly found in Europe and in some South 
American countries. The panel also includes mitochondrial antibody, which can help 
differentiate AIH from PBC. Given that autoimmune hepatitis is a potential complication of 
immune checkpoint inhibition we will perform this panel of autoimmune antibodies to 
investigate this. Samples will be collected at baseline and on D85 approximately. These antibody 
titers are exploratory and will not be used to guide therapy in the absence of clinical correlation. 
5.2.3 Hepatitis serology and viral load 
As mentioned in the background section the phase II study of Tremelimumab in HCC showed 
significant anti-HCV immune response with progressive decline in serum HCV viral load 
(median values: basal 3.78x10e5 copies/ml vs. day 120 3.02x10e4 copies/ml, p=0.02; vs. day 
210 1.69x10e3 copies/ml, p=0.04). Therefore, for all viral hepatitis patients we will measure 
viral load and antibody titers at baseline and every 30 days. For patients with chronic HBV 
infection, in addition to the studies already described, we plan to: 
- 
determine HBsAg concentrations in serum  
- 
determine HBeAg (in HBeAg positive patients) 
- 
determine HBsAg fractions (small, middle, large HBsAg) 
- 
determine HBV specific Tcell responses 
These studies will be performed on samples obtained at baseline and every 28 days (collection 
point +/-48 hours). Samples with be processed by CC Department of Laboratory medicine.  For 
HBsAg and Hepatitis B specific immune response, samples will be processed by the Department 
of Gastroenterology, Hannover Medical School, Germany.  
With Amendment E the NCI Thoracic and GI Oncology Branch will release coded serum 
samples collected in conventional “CryoTubes” in association with this protocol to: 
Heiner Wedemeyer 
Department of Gastroenterology 
Hannover Medical School 
Carl Neuberg Strasse 1 
30625 Hannover 
Germany 
for HBsAg and Hepatitis B specific immune response, as will be specified in NCI Material 
Transfer Agreement #38376-14.   


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Specimens will be labeled with the study identifier only and will be shipped to the address 
above, either on dry ice or at ambient temperatures as required by the type of sample to be 
analyzed. Tumor-VSHFLILFĮ)3UHVSRQVHV 
Frequency of AFP-specific CD4+ T cells will be analyzed using the interferon (IFN)-[gamma] 
cytokine secretion assay as previously described68. In brief, PBMCs will be resuspended in 
medium cultured in duplicate with the following peptides: AFP137-145 (PLFQVPEPV), AFP249-258 
(KVNFTEIQKL), and AFP364-373 (QLAVSVILRV) or an irrelevant control peptide (SIINFEKL). 
Recombinant interleukin-2 (25 IU/mL) will be added on day 2 of culture. After 7 days, PBMCs 
will be re-stimulated with the same peptide and incubated for 5 hours at 37°C and IFN-[gamma] 
secretion by CD4+ T cells analyzed by IFN-[gamma] capture assay. Live gating on CD4+ T cells 
will be performed until up to 100,000 events were acquired. Only AFP responses >0.1% of CD4+ 
T cells will be considered positive. 
5.2.4 MDSC functional assay 
Freshly isolated PBMC will be labeled with CSFE and stimulated with CD2/CD3/CD28 beads in 
the presence/absence of L-NMMA and NorNOHA. In control experiments CD14 depleted 
PBMC will be stimulated under the same conditions. Proliferative response of T cells will be 
assessed by FACS analysis (Serafini et al. Journal of Experimental Medicine (2006) 203: 2691). 
5.2.5 Optional Tumor Biopsy 
An optional tumor biopsy may be performed at baseline and at the time of the ablative therapy 
for analysis of immune infiltration. Tumor Tissue will be processed by the Department of 
Pathology, NCI. 
NIH (Dr. David Kleiner). Two core biopsies will be attempted. For each specimen obtained the 
core will be divided in two parts for Surgical Pathology and frozen preservation. If for some 
reason only one core is able to be obtained, the core will be divided, with half submitted to 
Surgical Pathology and half used for PD studies. 
1) Formalin-fixed. 
i. 
The half fixed in 10% formalin will be submitted to Surgical Pathology, 
CCR/NCI (Bldg 10, 2N212).  
ii. 
The specimens will have routine H&E stains made as well as 5 additional 
unstained sections.  
2) Frozen-preservation 
i. 
Two 1.5 ml cryogenic vials (obtained from Greten lab) will be labeled with the 
patient’s name, accession number (HP#) and date using a waterproof sharpie.  
ii. 
The isotherm flask (Greten lab) will be filled with liquid nitrogen on the morning 
of the procedure and will be available together with the cryogenic vials for pick 
up from there when radiology page the contact person to collect the specimens. 
iii. 
Once the biopsy is ready, the half-core to be cryopreserved will be transferred into 
an empty 1.5-mL cryogenic vial with the use of sterile, pre-chilled (in dry ice) 
disposable tweezers. 


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iv. 
The vial with specimen will be immediately dropped into liquid nitrogen 
contained in an isotherm flask.  
v. 
The frozen half will be transferred in the isotherm flask to the protocol-specified 
location for that particular analysis.  
5.2.6 TCR Beta Sequencing 
With Amendment H the NCI Thoracic and GI Oncology Branch will release coded tumor and 
PBMC samples collected in association with this protocol to: 
Lara Gruye 
Adaptive Biotechnologies 
1551 Eastlake Ave E #200,  
Seattle, WA 98102 
(855) 466-8667 
For TCR (cell receptor) gene usage may be quantitated in samples using conventional 
sequencing techniques of the T cell receptor variable region of the beta chain as will be specified 
in NCI Material Transfer Agreement #pending. Fewer than 100 genes will be analyzed. 
5.3 
MEDIMMUNE PLANNED STUDIES 
All samples will be processed and cryopreserved in the Figg laboratory. Transfer in batch to 
Medimmune/vendor facilities for further analysis will occur at a later date. Please also see 
Appendix D: MedImmune Sample Preparation Procedures. 
5.3.1 Pharmacokinetics 
The time points for PK sampling are described in the table in section 5 above. A validated 
enzyme-linked immunosorbent assay (ELISA) will be used for the quantitative determination of 
Tremelimumab in human serum.  
5.3.2 Immunogenicity  
The time points for the assessment of anti-Tremelimumab antibodies are described in the table in 
section 5 above. A validated electrochemiluminescence assay (ECLA) using a Meso Scale 
Discovery (MSD) platform will be used for the detection of anti-drug antibodies against 
Tremelimumab in human serum.  
5.3.3 T CELL Activation/ICOS expression  
The number and subsets of T cells as well as other immune cells will be evaluated in PBMC by 
flow cytometry. The activation status of T cells will also be assessed in the same study. Whole 
blood samples will be collected pre-infusion at baseline (screening and D1), D8, D29, D57 and 
D85.  Samples will be processed to PBMC and stored frozen until time of analysis. Additionally, 
absolute lymphocyte count at baseline and in response to Tremelimumab treatment will be 
evaluated for any relationship with treatment outcome. 
5.3.4 Plasma-based assays for circulating receptors/ligands e.g. PDL1  
Plasma samples are to be collected at the time points listed directly into plastic 6 ml lavender 
vacutainer tube with EDTA as anticoagulant.  2-3 ml of obtained plasma are to be aliquoted (1 


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ml each) and frozen. Samples may be analyzed for circulating levels of soluble factors such as 
CRP, cytokines, and chemokines. They may include but are not limited to soluble CTLA-4, 
soluble PD-L1, soluble B7.1/B7.2, soluble IL-6R, vascular endothelial growth factor, fibroblast 
growth factor, IL-1 IL-2, IL-4, IL-6, IL-8, IL-10, cancer biomarkers (alpha fetoprotein, 
carcinoembryonic antigen, cancer antigen 125, prostate specific antigen, soluble mesothelin-
related protein [SMRP]), granzyme B, IFN, C-X-C motif chemokine 10 (CXCL10), suppressor 
of cytokine signaling 3 (SOCS3), a proliferation inducing ligand, B-cell activating factor, 
insulin-like growth factor (IGF)-1, IGF-2,  and autoantibodies to host and tumor antigens and 
explore their association with Tremelimumab treatment and clinical outcome.   
5.4 
SAMPLE STORAGE, TRACKING AND DISPOSITION 
Samples will be ordered in CRIS and tracked through a Clinical Trial Data Management system.  
Should a CRIS screen not be available, the CRIS downtime procedures will be followed.  All 
samples will be sent to Dr. Figg’s lab for processing and storage until they are distributed to Dr. 
Greten’s lab, Dr. Altan-Bonnet’s lab or MedImmune for sample analysis as described in the 
protocol.  Samples will not be sent outside NIH without IRB notification and an executed MTA.  
All specimens obtained in the protocol are used as defined in the protocol. Any specimens that 
are remaining at the completion of the protocol will be stored in the conditions described below. 
The study will remain open so long as sample or data analysis continues.  Samples from 
consenting subjects will be stored until they are no longer of scientific value or if a subject 
withdraws consent for their continued use, at which time they will be destroyed. The PI will 
report any loss or destruction of samples to the NCI IRB as soon as he is made aware of such 
loss. 
If the patient withdraws consent the participant’s data will be excluded from future distributions, 
but data that have already been distributed for approved research use will not be able to be 
retrieved. 
5.4.1 Sample Data Collection 
All samples sent to the Blood Processing Core (BPC) will be barcoded, with data entered and 
stored in the LABrador (aka LabSamples) utilized by the BPC. This is a secure program, with 
access to LABrador limited to defined Figg lab personnel, who are issued individual user 
accounts. Installation of LABrador is limited to computers specified by Dr. Figg. These 
computers all have a password restricted login screen. All Figg lab personnel with access to 
patient information annually complete the NIH online Protection of Human Subjects course.  
LABrador creates a unique barcode ID for every sample and sample box, which cannot be traced 
back to patients without LABrador access. The data recorded for each sample includes the 
patient ID, name, trial name/protocol number, time drawn, cycle time point, dose, material type, 
as well as box and freezer location. Patient demographics associated with the clinical center 
patient number are provided in the system. For each sample, there are notes associated with the 
processing method (delay in sample processing, storage conditions on the ward, etc.). 
5.4.2 Sample Storage and Destruction 
Barcoded samples are stored in barcoded boxes in a locked freezer at either -20 or -80qC 
according to stability requirements.  These freezers are located onsite in the BPC and offsite at 


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NCI Frederick Central Repository Services in Frederick, MD. Visitors to the laboratory are 
required to be accompanied by laboratory staff at all times.  
Access to stored clinical samples is restricted. Samples will be stored until requested by a 
researcher named on the protocol. All requests are monitored and tracked in LABrador. All 
researchers are required to sign a form stating that the samples are only to be used for research 
purposes associated with this trial (as per the IRB approved protocol) and that any unused 
samples must be returned to the BPC. It is the responsibility of the NCI Principal Investigator to 
ensure that the samples requested are being used in a manner consistent with IRB approval. 
5.4.3 Protocol Completion/Sample Destruction 
x The PI will report destroyed samples to the IRB if samples become unsalvageable 
because of environmental factors (ex. broken freezer or lack of dry ice in a shipping 
container) or if a patient withdraws consent. Samples will also be reported as lost if they 
are lost in transit between facilities or misplaced by a researcher.  Freezer problems, lost 
samples or other problems associated with samples will also be reported to the IRB, the 
NCI Clinical Director, and the office of the CCR, NCI. 
6 
DATA COLLECTION AND EVALUATION  
6.1 
DATA COLLECTION 
The PI will be responsible for overseeing entry of data into an in-house password protected 
electronic system (C3D) and ensuring data accuracy, consistency and timeliness. The principal 
investigator, associate investigators/research nurses and/or a contracted data manager will assist 
with the data management efforts. All data obtained during the conduct of the protocol will be 
kept in secure network drives or in approved alternative sites that comply with NIH security 
standards. Primary and final analyzed data will have identifiers so that research data can be 
attributed to an individual human subject participant. 
End of study procedures: Data will be stored according to HHS, FDA, and NIH Intramural 
Records Retention Schedule regulations as applicable.  
Loss or destruction of data: Should we become aware that a major breach in our plan to protect 
subject confidentiality and trial data has occurred, the IRB will be notified. 
6.2 
DATA SHARING PLANS 
6.2.1 HUMAN DATA SHARING PLANS 
Human data generated in this research will be shared for future research as follows: 
 
De-identified data in an NIH-funded or approved public repository 
 
Identified data in BTRIS 
Data will be shared through: 
 
An NIH-funded or approved public repository: clinicaltrials.gov 
 
BTRIS 
 
Publication and/or public presentations. 


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Data will be shared at the time of publication or shortly thereafter. 
6.3 
RESPONSE CRITERIA 
For the purposes of this study, patients should be re-evaluated for response every 8 weeks.  In 
addition to a baseline scan, confirmatory scans should also be obtained 4-8 weeks following 
initial documentation of objective response. 
Response and progression will be evaluated in this study using the new international criteria 
proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline 
(version 1.1) [Eur J Ca 45:228-247, 2009].  Changes in the largest diameter (unidimensional 
measurement) of the tumor lesions and the shortest diameter in the case of malignant lymph 
nodes are used in the RECIST criteria. 
6.3.1 Definitions 
6.3.1.1 Evaluable for toxicity  
All patients will be evaluable for toxicity from the time of their first treatment with 
Tremelimumab. 
6.3.1.2 Evaluable for objective response  
Only those patients who have measurable disease present at baseline, have received at least one 
cycle of therapy, and have had their disease re-evaluated will be considered evaluable for 
response.  These patients will have their response classified according to the definitions stated 
below.  (Note:  Patients who exhibit objective disease progression prior to the end of cycle 1 will 
also be considered evaluable.) 
6.3.2 Disease Parameters 
6.3.2.1 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 by chest x-ray, as >10 mm with CT 
scan, or >10 mm with calipers by clinical exam.  All tumor measurements must be recorded in 
millimeters (or decimal fractions of centimeters). 
6.3.2.2 Malignant lymph nodes  
To be considered pathologically enlarged and measurable, a lymph node must be >15 mm in 
short axis when assessed by CT scan (CT scan slice thickness recommended to be no greater 
than 5 mm).  At baseline and in follow-up, only the short axis will be measured and followed. 
6.3.2.3 Non-measurable disease   
All other lesions (or sites of disease), including small lesions (longest diameter <10 mm or 
SDWKRORJLFDOO\PSKQRGHVZLWKWRPPVKRUWD[LVDUHFRQVLGHUHGQRQ-measurable 
disease.  Bone lesions, leptomeningeal disease, ascites, pleural/pericardial effusions, 
lymphangitis cutis/pulmonitis, inflammatory breast disease, and abdominal masses (not followed 
by CT or MRI), are considered as non-measurable. 
Note:  Cystic lesions that meet the criteria for radiographically defined simple cysts should not 
be considered as malignant lesions (neither measurable nor non-measurable) since they are, by 
definition, simple cysts. 


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‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable lesions, 
if they meet the definition of measurability described above. However, if non-cystic lesions are 
present in the same patient, these are preferred for selection as target lesions. 
6.3.2.4 Target lesions   
All measurable lesions up to a maximum of 2 lesions per organ and 5 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), be representative of all involved organs, but in addition should be those 
that lend themselves to reproducible repeated measurements.  It may be the case that, on 
occasion, the largest lesion does not lend itself to reproducible measurement in which 
circumstance the next largest lesion which can be measured reproducibly should be selected.  A 
sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target 
lesions will be calculated and reported as the baseline sum diameters.  If lymph nodes are to be 
included in the sum, then only the short axis is added into the sum.  The baseline sum diameters 
will be used as reference to further characterize any objective tumor regression in the measurable 
dimension of the disease. 
6.3.2.5 Non-target lesions   
All other lesions (or sites of disease) including any measurable lesions over and above the 5 
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, absence, or in rare cases 
unequivocal progression of each should be noted throughout follow-up.  
6.3.3 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 4 weeks 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 unless the lesion(s) being followed cannot be 
imaged but are assessable by clinical exam. 
6.3.3.1 Clinical lesions  
Clinical lesions will only be considered measurable when they are superficial (e.g., skin nodules 
and palpable lymph nodes) and t10 mm diameter as assessed using calipers (e.g., skin nodules).  
In the case of skin lesions, documentation by color photography, including a ruler to estimate the 
size of the lesion, is recommended.  
6.3.3.2 Chest x-ray 
Lesions on chest x-ray are acceptable as measurable lesions when they are clearly defined and 
surrounded by aerated lung.  However, CT is preferable.  
6.3.3.3 Conventional CT and MRI  
This guideline has defined measurability of lesions on CT scan based on the assumption that CT 
slice thickness is 5 mm or less.  If CT scans have slice thickness greater than 5 mm, the 


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minimum size for a measurable lesion should be twice the slice thickness.  MRI is also 
acceptable in certain situations (e.g. for body scans).   
Use of MRI remains a complex issue.  MRI has excellent contrast, spatial, and temporal 
resolution; however, there are many image acquisition variables involved in MRI, which greatly 
impact image quality, lesion conspicuity, and measurement.  Furthermore, the availability of 
MRI is variable globally.  As with CT, if an MRI is performed, the technical specifications of the 
scanning sequences used should be optimized for the evaluation of the type and site of disease.  
Furthermore, as with CT, the modality used at follow-up should be the same as was used at 
baseline and the lesions should be measured/assessed on the same pulse sequence.  It is beyond 
the scope of the RECIST guidelines to prescribe specific MRI pulse sequence parameters for all 
scanners, body parts, and diseases.  Ideally, the same type of scanner should be used and the 
image acquisition protocol should be followed as closely as possible to prior scans.  Body scans 
should be performed with breath-hold scanning techniques, if possible. 
6.3.3.4 Ultrasound   
Ultrasound is not useful in assessment of lesion size and should not be used as a method of 
measurement.  Ultrasound examinations cannot be reproduced in their entirety for independent 
review at a later date and, because they are operator dependent, it cannot be guaranteed that the 
same technique and measurements will be taken from one assessment to the next.  If new lesions 
are identified by ultrasound in the course of the study, confirmation by CT or MRI is advised.  If 
there is concern about radiation exposure at CT, MRI may be used instead of CT in selected 
instances. 
6.3.3.5 Endoscopy, Laparoscopy   
The utilization of these techniques for objective tumor evaluation is not advised.  However, such 
techniques may be useful to confirm complete pathological response when biopsies are obtained 
or to determine relapse in trials where recurrence following complete response (CR) or surgical 
resection is an endpoint. 
6.3.3.6 Cytology, Histology  
These techniques can be used to differentiate between partial responses (PR) and complete 
responses (CR) in rare cases (e.g., residual lesions in tumor types, such as germ cell tumors, 
where known residual benign tumors can remain). 
The cytological confirmation of the neoplastic origin of any effusion that appears or worsens 
during treatment when the measurable tumor has met criteria for response or stable disease is 
mandatory to differentiate between response or stable disease (an effusion may be a side effect of 
the treatment) and progressive disease. 
6.3.4 Response Criteria 
6.3.4.1 Evaluation of Target Lesions 
Complete Response (CR): Disappearance of all target lesions.  Any pathological lymph nodes 
(whether target or non-target) must have reduction in short axis to <10 mm. 
Partial Response (PR): At least a 30% decrease in the sum of the diameters of target lesions, 
taking as reference the baseline sum of diameters. 


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Progressive Disease (PD): At least a 20% increase in the sum of the diameters of target lesions, 
taking as reference the smallest sum on study (this includes the baseline sum if that is the 
smallest on study).  In addition to the relative increase of 20%, the sum must also demonstrate an 
absolute increase of at least 5 mm.  (Note:  the appearance of one or more new lesions is also 
considered progressions). 
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum of diameters while on study. 
6.3.4.2 Evaluation of Non-Target Lesions 
Complete Response (CR): Disappearance of all non-target lesions and normalization of tumor 
marker level.  All lymph nodes must be non-pathological in size (<10 mm short axis). 
Note:  If tumor markers are initially above the upper normal limit, they must normalize for a 
patient to be considered in complete clinical response. 
Non-CR/Non-PD: Persistence of one or more non-target lesion(s) and/or maintenance of tumor 
marker level above the normal limits. 
Progressive Disease (PD): Appearance of one or more new lesions and/or unequivocal 
progression of existing non-target lesions.  Unequivocal progression should not normally trump 
target lesion status.  It must be representative of overall disease status change, not a single lesion 
increase.     
Although a clear progression of “non-target” lesions only is exceptional, the opinion of the 
treating physician should prevail in such circumstances, and the progression status should be 
confirmed at a later time by the review panel (or Principal Investigator). 
6.3.4.3 Evaluation of Best Overall Response 
The best overall response is the best response recorded from the start of the treatment until 
disease progression/recurrence (taking as reference for progressive disease the smallest 
measurements recorded since the treatment started).  The patient's best response assignment will 
depend on the achievement of both measurement and confirmation criteria. 
 
For Patients with Measurable Disease (i.e., Target Disease) 
Target 
Lesions 
Non-Target 
Lesions 
New 
Lesions 
Overall 
Response 
Best Overall Response when 
Confirmation is Required* 
CR 
CR 
No 
CR 
>4 wks. Confirmation** 
CR 
Non-
CR/Non-PD 
No 
PR 
>4 wks. Confirmation** 
CR 
Not 
evaluated 
No 
PR 
PR 
Non-
CR/Non-
PD/not 
evaluated 
No 
PR 
SD 
Non-
CR/Non-
No 
SD 
Documented at least once >4 
wks. from baseline** 


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Target 
Lesions 
Non-Target 
Lesions 
New 
Lesions 
Overall 
Response 
Best Overall Response when 
Confirmation is Required* 
PD/not 
evaluated 
PD 
Any 
Yes or 
No 
PD 
no prior SD, PR or CR 
Any 
PD*** 
Yes or 
No 
PD 
Any 
Any 
Yes 
PD 
* 
See RECIST 1.1 manuscript for further details. 
** 
Only for non-randomized trials with response as primary endpoint. 
*** 
In exceptional circumstances, unequivocal progression in non-target 
lesions may be accepted as disease progression. 
Note: Patients with a global deterioration of health status requiring 
discontinuation of treatment without objective evidence of disease 
progression at that time should be reported as “symptomatic 
deterioration.”  Every effort should be made to document the objective 
progression even after discontinuation of treatment. 


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For Patients with Non-Measurable Disease (i.e., Non-Target Disease) 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD* 
Not all evaluated 
No 
not evaluated 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
* ‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since 
SD is increasingly used as an endpoint for assessment of efficacy in some trials 
so to assign this category when no lesions can be measured is not advised 
 
6.3.5 Duration of Response 
6.3.5.1 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 progressive disease is objectively documented. 
 
6.3.5.2 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, 
including the baseline measurements.  
6.4 
MODIFIED IMMUNE-RELATED RESPONSE CRITERIA (IRRC) 
Modified immune-related response criteria (irRC) will also be employed in this study. This new 
classification is based on the recent learning from clinical studies with cancer immunotherapies 
that even if some new lesions appear at the beginning of a treatment or if the total tumor burden 
does not increase substantially, tumor regressions or stabilizations might still occur later. The 
irRC were created using bi-dimensional measurements (as previously widely used in the World 
Health Organization criteria). For this trial, the concepts of the irRC are combined with RECIST 
1.1 to come up with the modified irRC.  Please refer to Appendix C section 12.3 for further 
details. 
6.5 
TOXICITY CRITERIA 
The following adverse event management guidelines are intended to ensure the safety of each 
patient while on the study.  The descriptions and grading scales found in the revised NCI 
Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be utilized for AE 
reporting.  All appropriate treatment areas should have access to a copy of the CTCAE version 
4.0.  A copy of the CTCAE version 4.0 can be downloaded from the CTEP web site 


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(http://ctep.cancer.gov).  All appropriate treatment areas should have access to a copy of the 
CTEP Active Version of CTCAE. 
7 
SAFETY REPORTING REQUIREMENTS/DATA AND SAFETY MONITORING 
PLAN   
7.1 
DEFINITIONS 
7.1.1 Adverse Event 
An adverse event is defined as any reaction, side effect, or untoward event that occurs during the 
course of the clinical trial associated with the use of a drug in humans, whether or not the event 
is considered related to the treatment or clinically significant. For this study, AEs will include 
events reported by the patient, as well as clinically significant abnormal findings on physical 
examination or laboratory evaluation. A new illness, symptom, sign or clinically significant 
laboratory abnormality or worsening of a pre-existing condition or abnormality is considered an 
AE.   
All AEs, including clinically significant abnormal findings on laboratory evaluations, regardless 
of severity, will be followed until return to baseline or stabilization of event. Serious adverse 
events that occur more than 30 days after the last administration of investigational 
agent/intervention and have an attribution of at least possibly related to the agent/intervention 
should be recorded and reported as per sections 7.2, 7.3, and 7.4.   
An abnormal laboratory value will be considered an AE if the laboratory abnormality is 
characterized by any of the following: 
x 
Results in discontinuation from the study 
x 
Is associated with clinical signs or symptoms  
x 
Requires treatment or any other therapeutic intervention 
x 
Is associated with death or another serious adverse event, including hospitalization.  
x 
Is judged by the Investigator to be of significant clinical impact 
x 
If any abnormal laboratory result is considered clinically significant, the investigator will 
provide details about the action taken with respect to the test drug and about the patient’s 
outcome. 
7.1.2 Suspected adverse reaction 
Suspected adverse reaction means any adverse event for which there is a reasonable possibility 
that the drug caused the adverse event. For the purposes of IND safety reporting, ‘reasonable 
possibility’ means there is evidence to suggest a causal relationship between the drug and the 
adverse event. A suspected adverse reaction implies a lesser degree of certainty about causality 
than adverse reaction, which means any adverse event caused by a drug. 
7.1.3 Unexpected adverse reaction 
An adverse event or suspected adverse reaction is considered “unexpected” if it is not listed in 
the investigator brochure or is not listed at the specificity or severity that has been observed; or, 


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if an investigator brochure is not required or available, is not consistent with the risk information 
described in the general investigational plan or elsewhere in the current application. 
"Unexpected”, also refers to adverse events or suspected adverse reactions that are mentioned in 
the investigator brochure as occurring with a class of drugs or as anticipated from the 
pharmacological properties of the drug, but are not specifically mentioned as occurring with the 
particular drug under investigation. 
7.1.4 Serious  
An Unanticipated Problem or Protocol Deviation is serious if it meets the definition of Serious 
Adverse Event or if it compromises the safety, welfare or rights of subjects or others. 
7.1.5 Serious Adverse Event 
An adverse event or suspected adverse reaction is considered serious if in the view of the 
investigator or the sponsor, it results in any of the following: 
x 
Death 
x 
A life-threatening adverse drug experience 
x 
Inpatient hospitalization or prolongation of existing hospitalization 
x 
Persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions 
x 
A congenital anomaly/birth defect. 
x 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered a serious adverse drug experience when, based upon 
appropriate medical judgment, they may jeopardize the patient or subject and may require 
medical or surgical intervention to prevent one of the outcomes listed in this definition. 
7.1.6 Disability 
 A substantial disruption of a person’s ability to conduct normal life functions. 
7.1.7 Life-threatening adverse drug experience 
Any adverse event or suspected adverse reaction that places the patient or subject, in the view of 
the investigator or sponsor, at immediate risk of death from the reaction as it occurred, i.e., it 
does not include a reaction that had it occurred in a more severe form, might have caused death. 
7.1.8 Protocol Deviation (NIH Definition) 
Any change, divergence, or departure from the IRB approved research protocol. 
7.1.9 Protocol Non-compliance (NIH Definition) 
The failure to comply with applicable NIH Human Research Protections Program (HRPP) 
policies, IRB requirements, or regulatory requirements for the protection of human research 
subjects.  


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7.1.10 Unanticipated Problem 
Any incident, experience, or outcome that: 
x  Is unexpected in terms of nature, severity, or frequency in relation to  
(a) the research risks that are described in the IRB-approved research protocol and informed 
consent document; Investigator’s Brochure or other study documents, and 
(b) the characteristics of the subject population being studied; AND 
x Is related or possibly related to participation in the research; AND 
x Suggests that the research places subjects or others at a greater risk of harm (including 
physical, psychological, economic, or social harm) than was previously known or 
recognized. 
7.2 
NCI-IRB AND CLINICAL DIRECTOR REPORTING 
7.2.1 NCI-IRB and NCI CD Expedited Reporting of Adverse Events , and Deaths 
The Protocol PI will report in the NIH Problem Form to the NCI-IRB and NCI Clinical Director: 
x All deaths, except deaths due to progressive disease  
x All Protocol Deviations 
x All Unanticipated Problems 
x All non-compliance 
Reports must be received within 7 days of PI awareness via iRIS. 
7.2.2 NCI-IRB Requirements for PI Reporting at Continuing Review 
The protocol PI will report to the NCI-IRB:  
1. A summary of all protocol deviations in a tabular format to include the date the deviation 
occurred, a brief description of the deviation and any corrective action. 
2. A summary of any instances of non-compliance 
3. A tabular summary of the following adverse events: 
x All Grade 2 unexpected events that are possibly, probably or definitely related to the 
research;  
x All Grade 3 and 4 events that are possibly, probably or definitely related to the 
research;  
x All Grade 5 events regardless of attribution;  
x All Serious Events regardless of attribution.  
NOTE: Grade 1 events are not required to be reported.  


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7.2.3 NCI-IRB Reporting of IND Safety Reports 
Only IND Safety Reports that meet the definition of an unanticipated problem will need to be 
reported to the NCI IRB. 
7.3 
IND SPONSOR REPORTING CRITERIA  
An investigator must immediately report to the sponsor using the mandatory MedWatch form 
3500a any serious adverse event, whether or not considered drug related, including those listed in 
the protocol or investigator brochure and must include an assessment of whether there is a 
reasonable possibility that the drug caused the event.  
 
All Grade 5 (fatal) events (except death due to progressive disease) must be reported via 
email within 24 hours.  A complete report must be submitted within one business day.  
 
All other serious adverse events including deaths due to progressive disease must be 
reported within one business day 
Study endpoints that are serious adverse events (e.g. all-cause mortality) must be reported in 
accordance with the protocol unless there is evidence suggesting a causal relationship between 
the drug and the event (e.g. death from anaphylaxis).  In that case, the investigator must 
immediately report the death to the sponsor. 
Events will be submitted to the Center for Cancer Research (CCR) at: CCRsafety@mail.nih.gov 
and to the CCR PI and study coordinator. 
7.3.1 Reporting Pregnancy  
7.3.1.1 Maternal exposure 
If a patient becomes pregnant during the course of the study, the study treatment should be 
discontinued immediately and the pregnancy reported to the Sponsor. The potential risk of 
exposure of the fetus to the Tremelimumab should be documented in box B5 of the MedWatch 
form “Describe Event or Problem”. 
Pregnancy itself is not regarded as an SAE. However, as patients who become pregnant on study 
risk intrauterine exposure of the fetus to Tremelimumab which may be teratogenic, the CCR is 
requesting that pregnancy should be reported in an expedited manner as Grade 3 “Pregnancy, 
puerperium and perinatal conditions - Other (pregnancy)” under the Pregnancy, puerperium and 
perinatal conditions SOC.  
Congenital abnormalities or birth defects and spontaneous miscarriages should be reported and 
handled as SAEs. Elective abortions without complications should not be handled as AEs. The 
outcome of all pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, 
normal birth, or congenital abnormality) should be followed up and documented. 
If any pregnancy occurs in the course of the study, then the investigator should inform the 
Sponsor within 1 day, i.e., immediately, but no later than 24 hours of when he or she becomes 
aware of it. 
The designated Sponsor representative will work with the investigator to ensure that all relevant 
information is provided to the Sponsor within 1 to 5 calendar days for SAEs and within 30 days 
for all other pregnancies. 
The same timelines apply when outcome information is available. 


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7.3.1.2 Paternal exposure 
Male patients should refrain from fathering a child or donating sperm during the study and for 3 
months after the last dose of Tremelimumab. 
Pregnancy of the patient’s partner is not considered to be an AE. However, the outcome of all 
pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, normal birth, or 
congenital abnormality) occurring from the date of the first dose until 3 months after the last 
dose of Tremelimumab should, if possible, be followed up and documented. 
 
  
7.4 
SAFETY REPORTING CRITERIA TO THE PHARMACEUTICAL COLLABORATORS 
All safety reports must be reported in the defined timelines to CCRsafety@mail.nih.gov.  
The CCR Office of Regulatory Affairs will send all reports to the MedImmune at: 
MedImmune or designee (PharmaNet/i3, LLC) contact information:  
Patient Safety PharmaNet/i3, LLC  
MedImmune  
One MedImmune Way  
Gaithersburg, MD 20878  
Fax: +1 301 398 4205 
7.5 
DATA AND SAFETY MONITORING PLAN 
7.5.1 Principal Investigator/Research Team  
The clinical research team will meet on a regular basis when patients are being actively treated 
on the trial to discuss each patient. Decisions about dose level enrollment and dose escalation if 
applicable will be made based on the toxicity data from prior patients.  
All data will be collected in a timely manner and reviewed by the principal investigator or a lead 
associate investigator. Adverse events will be reported as required above. Any safety concerns, 
new information that might affect either the ethical and or scientific conduct of the trial, or 
protocol deviations will be immediately reported to the IRB using iRIS and to the Sponsor.  
The principal investigator will review adverse event and response data on each patient to ensure 
safety and data accuracy. The principal investigator will personally conduct or supervise the 
investigation and provide appropriate delegation of responsibilities to other members of the 
research staff.  
7.5.2 Sponsor Monitoring Plan 
As a sponsor for clinical trials, FDA regulations require the CCR to maintain a monitoring 
program. The CCR’s program allows for confirmation of: study data, specifically data that could 
affect the interpretation of primary study endpoints; adherence to the protocol, regulations, and 
SOPs; and human subjects protection. This is done through independent verification of study 
data with source documentation focusing on: 
x Informed consent process 


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x Eligibility confirmation 
x Drug administration and accountability 
x Adverse events monitoring 
x Response assessment. 
The monitoring program also extends to multi-site research when the CCR is the coordinating 
center. 
This trial will be monitored by personnel employed by an NCI contractor. Monitors are qualified 
by training and experience to monitor the progress of clinical trials. Personnel monitoring this 
study will not be affiliated in any way with the trial conduct. 
8 
STATISTICAL CONSIDERATIONS   
The primary objective of this pilot study is to determine if it is feasible to administer three doses 
of Tremelimumab to patients with hepatocellular carcinoma (HCC) and to determine clinical 
efficacy in several cohorts of patients. Secondary objectives include examining a variety of 
immunologic parameters prior to treatment and after treatment to determine if there is evidence 
of patients exhibiting an immune response to treatment, to assess safety and toxicity and to 
determine the feasibility of administering 3 doses of tremelimumab in addition to RFA in 
patients with biliary tract cancer. 
8.1 
COHORTS A AND B 
Relative to the feasibility endpoint, this will be decided in Cohorts A and B; all patients enrolled 
into Cohorts A and B at the 10 mg/kg dose level will be considered as one group for feasibility 
evaluation. Feasibility will be evaluated in the first 20 evaluable patients enrolled in in these two 
cohorts on this trial at the 10mg/kg dose level following a dose-escalation phase of 3-6 patients 
treated at 3.5mg/kg dose level. The safety of the 10 mg/kg dose level will be evaluated in the 
first 3-6 patients treated at that dose. If there are 2 or more DLTs among the first 3-6 patients 
treated at this level, then accrual would stop. Regarding feasibility, it would be desirable if the 
fraction of patients who could receive three doses of the monoclonal antibody were consistent 
with 80% or higher and greater than 50%. With 20 evaluable patients, if there are 14 or more 
patients who are able to receive three doses of the monoclonal antibody, then there is a 5.8% 
probability of this being true if the true probability of an individual patient being able to receive 
this much antibody were 50% and there is a 91.3% probability of this being true if the true 
probability for an individual were 80%. Thus, 14 or more out of 20 patients receiving three doses 
of antibody would provide strong evidence that it is feasible to administer this antibody in a 
substantial fraction of patients, consistent with 80% or more and this would be considered a 
successful outcome for the trial. 
Prior to amendment G, administration of three doses has been determined to be feasible based on 
the first 20 total patients enrolled and the feasibility evaluation was considered to have ended at 
that point. Evaluations for clinical efficacy will be the primary objective from this point forward. 
With amendment G, there will be 20 patients enrolled in cohort A at 10mg/kg (10 receiving RFA 
and 10 receiving TACE).  
Each of these sub-cohorts will be evaluated for efficacy as follows. In each sub-cohort of 10 
patients the trial will have 82% power to rule out 15% 6 month as the proportion stable at 6 


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months in favor of 50% being stable at 6 months, with each evaluation assuming that a one-sided 
0.10 significance level exact binomial test would be performed. If there are 3 patients in 10 who 
are able to have stable disease at a 6 month evaluation, then the lower one-sided 90% confidence 
bound for 3/10 is 11.6% (the two sided 80% confidence interval extends from 11.6% to 55.2%). 
Similarly, with 4 in 10 with stable disease at 6 months, the lower one-sided 90% confidence 
bound for 4/10 is 18.8% (the two sided 80% confidence interval extends from 18.8% to 64.6%). 
Thus, in Cohort A, 3 or 4 patients out of 10 attaining stable disease at 6 months with either 
TACE or RFA would rule out 10-15% as the fraction who would do so, with 90% one sided 
confidence.  The results from the two sub-cohorts of cohort A treated at 10 mg/kg may also have 
their results combined in an exploratory fashion to report their overall efficacy.   
Also by Amendment G, cohort B will be expanded to allow 20 evaluable patients to be enrolled 
for efficacy. With this number of patients, this cohort will have 97% power to rule out 15% as 
the proportion stable at 6 months in favor of 50% being stable at 6 months, with the evaluation 
assuming that a one-sided 0.10 significance level exact binomial test would be performed. If 
there are 6 patients in 20 who are able to have stable disease at a 6 month evaluation, then the 
lower one-sided 90% confidence bound for 6/20 is 16.6% (the two sided 80% confidence 
interval extends from 16.6% to 46.7%). Thus, in cohort B, having 6 or greater patients attaining 
stable disease at 6 months would rule out 15% as the fraction who would do so, with 90% one-
sided confidence.   
8.2 
COHORTS D- E 
With amendment F, one additional cohort of N=10 patients will be added to explore the immune 
effects of combining tremelimumab with cryoablation (Cohorts  D) and one cohort with RFA in 
a BTC population. Thus, there will be 2 new cohorts added at this time for a total of 20 
additional patients. Results to date from cohorts A and B suggest that the overall procedure is 
very likely to meet its feasibility goal since 9/10 patients have done so as of the date this 
amendment was constructed. As a result, the goal of the two new cohorts is to determine in a 
preliminary fashion if the treatment proposed in each cohort is able to offer clinical benefit to 
patients. Data on similar patients suggests a median time to progression of approximately 2 
months, and approximately 10-15% would have stable disease at 6 months. It would be a very 
meaningful improvement if the treatment proposed could be associated with results which were 
consistent with 50% of patients having stable disease at 6 months. With the goal of keeping the 
trial small, in each cohort of 10 patients the trial will have 82% power to rule out 15% as the 
proportion stable at 6 months in favor of 50% being stable at 6 months, with each evaluation 
assuming that a one-sided 0.10 significance level exact binomial test would be performed. As a 
practical matter, 10 patients will be enrolled in each of the two cohorts and if there are 3 patients 
in 10 who are able to have stable disease at a 6 month evaluation, then the lower one-sided 90% 
confidence bound for 3/10 is 11.6% (the two sided 80% confidence interval extends from 11.6% 
to 55.2%). Similarly, with 4 in 10 with stable disease at 6 months, the lower one-sided 90% 
confidence bound for 4/10 is 18.8% (the two sided 80% confidence interval extends from 18.8% 
to 64.6%). Thus, in any given cohort, 3 or 4 patients attaining stable disease at 6 months would 
rule out 10-15% as the fraction who would do so, with 90% one sided confidence.  
With amendment G, cohort E (cholangiocarcinoma patients) will be expanded to a total of 20 
patients. This cohort will have 97% power to rule out 15% as the proportion stable at 6 months in 
favor of 50% being stable at 6 months, with the evaluation assuming that a one-sided 0.10 
significance level exact binomial test would be performed. If there are 6 patients in 20 who are 


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able to have stable disease at a 6 month evaluation, then the lower one-sided 90% confidence 
bound for 6/20 is 16.6% (the two sided 80% confidence interval extends from 16.6% to 46.7%). 
Thus, in cohort E, having 6 or greater patients attaining stable disease at 6 months would rule out 
15% as the fraction who would do so, with 90% one-sided confidence. 
In addition to evaluations of response and 6 month disease stabilization, Kaplan-Meier curves for 
progression free survival (PFS) will be constructed based on each of cohorts A, B, and E.  
8.3 
SECONDARY AND EXPLORATORY ANALYSES 
In all cohorts, the actual levels of changes of immune parameters will also be determined, and 
the fractions that are noted to have a change in the parameter values which would be considered 
immune responses will be reported. These will be considered secondary and exploratory 
analyses. Exploratory analyses may also be done informally comparing results for those 
receiving one procedure with another, e.g. RFA vs. TACE.  In cohort B, 20 patients are expected 
to be enrolled (following amendment G); the same types of analyses are anticipated, but will be 
considered very tentative and hypothesis generating in view of the small numbers of patients to 
be evaluated. 
Safety and toxicity will also be evaluated and addressed by tabulating and monitoring the grades 
of toxicity experienced by patients in the study. 
At the conclusion of the trial, the clinical results and the immune parameter results may be used 
to arrive at an overall judgment involving which cohort or cohorts may merit expansion or 
further evaluation in subsequent trials. 
8.4 
ACCRUAL  
It is expected that up to 2 patients per month may be able to enroll onto this trial.  Cohort A may 
theoretically enroll a maximum of 26 evaluable patients at both dose levels combined, and there 
also may be 20 evaluable patients in cohort B, 10 in cohort D, and 20 in cohort E. The accrual 
ceiling for the protocol will be set at 90 patients to allow for a small number of inevaluable 
patients. Thus, it is expected that 48-60 months may be needed to accrue all patients onto this 
trial. 
9 
COLLABORATIVE AGREEMENTS 
9.1 
COOPERATIVE RESEARCH AND DEVELOPMENT AGREEMENT (CRADA) 
A CRADA (02853) is in place with MedImmune, Inc. for supply of the investigational agent.  
9.2 
MATERIAL TRANSFER AGREEMENTS (MTA) 
MTA (38376-14) is in place with Hannover Medical School 
MTA (40860-16) is in place with Adaptive Biotechnologies 
10 HUMAN SUBJECTS PROTECTIONS  
10.1 RATIONALE FOR SUBJECT SELECTION 
Subjects treated on this study, will be individuals with advanced hepatocellular carcinoma 
(HCC), which has recurred (or persisted) after appropriate standard treatment.  Individuals of any 
race or ethnic group will be eligible for this study.  Eligibility assessment will be based solely on 
the patient’s medical status.  Recruitment of patients onto this study will be through standard 
CCR mechanisms.  No special recruitment efforts will be conducted. 


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10.2 PARTICIPATION OF CHILDREN 
Individuals under the age of 18 will not be eligible to participate in this study because they are 
unlikely to have hepatocellular or biliary tract carcinoma, and because of unknown toxicities in 
pediatric patients. 
10.3 PARTICIPATION OF SUBJECTS UNABLE TO GIVE CONSENT 
Adults unable to give consent are excluded from enrolling in the protocol.  However, re-consent 
may be necessary and there is a possibility, though unlikely, that subjects could become 
decisionally impaired. For this reason and because there is a prospect of direct benefit from 
research participation (section 10.5), all subjects  will be offered the opportunity to fill in their 
wishes for research and care, and assign a substitute decision maker on the “NIH Advance 
Directive for Health Care and Medical Research Participation” form so that another person can 
make decisions about their medical care in the event that they become incapacitated or 
cognitively impaired during the course of the study. Note: The PI or AI will contact the NIH 
Ability to Consent Assessment Team for evaluation.  For those subjects that become 
incapacitated and do not have pre-determined substitute decision maker, the procedures 
described in MEC Policy 87-4 for appointing a surrogate decision maker for adult subjects who 
are (a) decisionally impaired, and (b) who do not have a legal guardian or durable power of 
attorney, will be followed. 
10.4 EVALUATION OF BENEFITS AND RISKS/DISCOMFORTS 
10.4.1 Risks of exposure to ionizing radiation  
This research study involves three CT guided biopsies collected for research purposes only.  
Subjects undergoing three optional biopsy collection will be exposed to 2.3 rem.  This amount of 
radiation is below the guideline of 5 rem per year allowed for adult research subjects by the NIH 
Radiation Safety Committee. 
10.4.2 Risk of optional biopsy  
All care will be taken to minimize risks that may be incurred by tumor sampling.  However, 
there are procedure-related risks (such as bleeding, infection and visceral injury) that will be 
explained fully during informed consent. 
10.4.3 Other risks/benefits 
The potential benefit to a patient that goes onto study is a reduction in the bulk of their tumor 
which may or may not have favorable impact on symptoms and/or survival.  Potential risks 
include the possible occurrence of any of a range of side effects which are listed in the Consent 
Document.  The procedure for protecting against or minimizing risks will be to medically 
evaluate patients on a regular basis as described. 
10.5 RISKS/BENEFITS ANALYSIS 
For patients with hepatocellular carcinoma and biliary cancer, median survival is in the range of 
6 months. It is possible that treatment on this protocol may reduce tumor burden or lessen 
symptoms caused by the cancer. While treatment on this protocol may not individually benefit 
subjects. The knowledge gained from this study may help others in the future who have 
hepatocellular carcinoma.   Potential risks include the possible occurrence of any of a range of 
side effects listed.  If patients suffer any physical injury as a result of the biopsies, immediate 


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medical treatment is available at the NIH’s Clinical Center in Bethesda, Maryland.  Although no 
compensation is available, any injury will be fully evaluated and treated in keeping with the 
benefits or care to which patients are entitled under applicable regulations. 
10.6 CONSENT AND ASSENT PROCESS AND DOCUMENTATION 
Patients will meet with an associate or principal investigator on the trial in the GI oncology 
Clinic, during the initial evaluation for this study.  During that meeting, the investigator will 
inform patients of the purpose, alternatives, treatment plan, research objectives and follow-up of 
this trial.  The investigator will then provide a copy of the IRB-approved informed consent 
document that is included in this protocol.  The patient will be allowed to take as much time as 
he wishes, in deciding whether or not he wishes to participate.  If a prolonged period of time 
expires during the decision making process (several weeks, as an example), it may be necessary 
to reassess the patient for protocol eligibility. The original signed consent goes to Medical 
Records; copy placed in research record (NIH policy). 
All patients must have a signed informed consent form and an on-study (confirmation of 
eligibility) form filled out and signed by a participating investigator before entering on the study. 
10.6.1 Telephone re-consent  
The informed consent document will be sent to the subject.  An explanation of the study will be 
provided over the telephone after the subject has had the opportunity to read the consent form.  
The subject will sign and date the informed consent. A witness to the subject’s signature will 
sign and date the consent. 
The original informed consent document will be sent back to the consenting investigator who 
will sign and date the consent form with the date the consent was obtained via telephone.   
A fully executed copy will be returned via mail for the subject’s records. 
The informed consent process will be documented on a progress note by the consenting 
investigator and a copy of the informed consent document and note will be kept in the subject’s 
research record. 
10.6.2 Informed consent of non-English speaking subjects 
If there is an unexpected enrollment of a research participant for whom there is no translated 
extant IRB approved consent document, the principal investigator and/or those authorized to 
obtain informed consent will use the Short Form Oral Consent Process as described in MAS 
Policy M77-2, OHSRP SOP 12, 45 CFR 46.117 (b) (2), and 21 CFR 50.27 (b) (2)).  The 
summary that will be used is the English version of the extant IRB approved consent document.  
Signed copies of both the English version of the consent and the translated short form will be 
given to the subject or their legally authorized representative and the signed original will be filed 
in the medical record. 
Unless the PI is fluent in the prospective subject’s language, an interpreter will be present to 
facilitate the conversation (using either the long translated form or the short form). Preferably 
someone who is independent of the subject (i.e., not a family member) will assist in presenting 
information and obtaining consent. Whenever possible, interpreters will be provided copies of 
the relevant consent documents well before the consent conversation with the subject (24 to 48 
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We request prospective IRB approval of the use of the short form process for non-English 
speaking subjects and will notify the IRB at the time of continuing review of the frequency of the 
use of the Short Form. 
11 PHARMACEUTICAL INFORMATION   
11.1 TREMELIMUMAB 
Tremelimumab is a human IgG2 anti-CTLA-4 mAb that is being developed as an 
immunotherapeutic agent for various cancers. Tremelimumab will be supplied by MedImmune. 
 
Investigational Product  
Manufacturer  
Concentration and 
Formulation as Supplied  
Tremelimumab  
MedImmune  
Formulated at a nominal 
concentration of 20 mg/mL in 
20 mM histidine/histidine 
hydrochloride, 222 mM 
trehalose dihydrate, 0.02% 
(w/v) polysorbate 80, and 0.27 
mM disodium edetate dihydrate 
(EDTA), pH 5.5.  
 
Tremelimumab is to be administered as an IV solution of 10 mg/kg at a rate of 250 mL/hr, 
followed by observation for 60 minutes.  
 
11.1.1 Investigational Product Dose Preparation  
Tremelimumab is supplied as a sterile IV solution, filled in 20 mL clear glass vials with a rubber 
stopper and aluminum seal. Each vial contains 20 mg/mL (with a nominal fill of 20 mL 
accounting to 400 mg/vial) of Tremelimumab, in an isotonic solution at pH 5.5. Vials containing 
Tremelimumab must be stored in the refrigerator at 2-8
oC. The 20 mg/mL solution will be 
diluted into a saline bag for IV infusion. Vials containing Tremelimumab may be gently inverted 
for mixing, but should not be shaken. 
For dose preparation steps, the following ancillary items are required:  
x IV infusion bags of 0.9% sodium chloride injection (250 mL size). Saline bags must be 
latex-free and can be made of polyvinyl chloride (PVC) or polyolefins (e.g. 
polyethylene), manufactured with bis (2-ethylhexyl) phthalate (DEHP) or DEHP-free.  
 
x IV infusion lines made of PVC/DEHP or PVC/tri octyl trimellitate (TOTM) or 
polyethylene or polyurethane. All DEHP-containing or DEHP-free lines are acceptable. 
Lines should FRQWDLQDRUȝPLQ-line filter. The in-line filter can be made of 


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polyethersulfone (PES) or polyvinylidene fluoride DRF (PVDF). Lines containing 
cellulose-based filters should not be used with Tremelimumab.  
x Catheters/infusion sets made of polyurethane or fluoropolymer with silicone and stainless 
steel and/or PVC components.  
x Syringes made of polypropylene and latex-free. Polycarbonate syringes should not be 
used with Tremelimumab.  
x Needles made of stainless steel.  
11.1.2 Dose Calculation  
The subject’s weight (in kilograms) must be measured prior to each dosing for dose calculation. 
Measurements can be taken in street clothes without shoes and a calibrated scale must be used 
for all measurements.  
The dose will be calculated at each dosing visit using the following formula:  
Dose (mL) = [subject weight (kg) × dose level (10 mg/kg)] drug concentration (20 mg/mL)  
The corresponding volume of investigational product should be rounded to the nearest tenth of a 
mL (0.1 mL). Each vial contains a small amount of overage and the overage should be utilized as 
much as possible before using another vial.  
The number of vials required for dose preparation is the next greatest whole number of vials 
from the following formula: Number of vials = Dose (mL) ÷ 20 (mL/vial) 
11.1.3 Investigational Product Inspection  
Each vial selected for dose preparation should be inspected.  
If there are any defects noted with the investigational product, the investigator and site monitor 
should be notified immediately. Refer to the Product Complaint section (10.1.6) for further 
instructions.  
During the inspection if the solution is not clear or any turbidity, discoloration or particulates are 
observed, notify your site monitor and store the vial(s) in QUARANTINE at refrigerated (2-8ºC) 
temperature for drug accountability and potential future inspection.  
Notify the IXRS that the unusable vials are damaged. The IXRS will indicate the replacement 
vials. Select appropriate replacement vials for the preparation of the subject’s dose, and perform 
the same inspection on the newly selected vials. For accountability, record the total number of 
vials removed from site inventory. Used vials should be held for accountability purposes at 
ambient storage temperature. 
11.1.4 Dose Preparation Steps  
Tremelimumab does not contain preservatives and any unused portion must be discarded. 
Preparation of Tremelimumab and preparation of the IV bag are to be performed aseptically. 
Total in-use storage time for the prepared final IV bag should not exceed 24 hours at 2-8°C or 4 
hours at room temperature (25°C). However, it is recommended that the prepared final IV bag be 
stored in the dark at 2-8°C until needed. The refrigerated infusion solutions in the prepared final 


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IV bag should be equilibrated at room temperature for about 2 hours prior to administration. If 
storage time exceeds these limits, a new dose must be prepared from new vials.  
The investigational product manager or qualified personnel will be responsible for preparing the 
IV doses using the following steps:  
1) Select the IXRS-assigned number of vials of investigational product required to prepare the 
subject’s dose.  
2) All investigational product vials should be equilibrated to room temperature for 30 minutes 
prior to dose preparation.  
3) To prepare the IV bag, first, calculate the dose volume of investigational product required. 
Second, remove the volume of 0.9% sodium chloride IV solution equivalent to the calculated 
dose volume of investigational product from the IV bag. Lastly, add the calculated dose volume 
of investigational product to the IV bag. Gently mix the solution in the bag by inverting up and 
down. Avoid shaking the IV bag to prevent foaming.  
Example: A subject weighing 85 kg will require 42.5 mL (3 vials) of investigational product. 
Remove 42.5 mL of saline from the commercial IV bag. Add the 42.5 mL of investigational 
product to the IV bag and gently mix by inverting up and down. 
Tremelimumab should be stored at refrigerated temperatures (2°C to 8°C), and should not be 
frozen.  
Labels will be prepared in accordance with Good Manufacturing Practice (GMP). 
11.1.5 Investigational Product Accountability  
The investigator’s or site’s designated investigational product manager is required to maintain 
accurate investigational product accountability records. Upon completion of the study, copies of 
investigational product accountability records will be returned to MedImmune. All unused 
investigational product will be returned to a MedImmune-authorized depot or disposed of upon 
authorization by MedImmune. 
11.1.6 Reporting Product Complaints  
Any defects with the investigational product must be reported immediately to the MedImmune 
Product Complaint Department by the site with further notification to the site monitor. All 
defects will be communicated to MedImmune and investigated further with the Product 
Complaint Department. During the investigation of the product complaint, all investigational 
products must be stored at labeled conditions unless otherwise instructed.  
Product defects may be related to component, product, or packaging and labeling issues. The list 
below includes, but is not limited to, descriptions of product complaints that should be reported.  
Component Issue: Defect in container or dosing mechanism of the investigational product. The 
component defect may be damaged, missing, or broken. Component examples include vials, 
stoppers, caps, spray barrels, spray nozzles, or plungers.  
 
Product Issue: Defect in the product itself. The product appearance has visual imperfections 
such as foreign particles, crystallization, discoloration, turbidity, insufficient volume, or anything 
that does not apply to the product description.  


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Packaging/Labeling Issue: Defect in the packaging or labeling of the product. The packaging or 
labeling defects may be damaged or unreadable, or the label may be missing.  
 
When reporting a product complaint, site staff must be prepared to provide the following 
information:  
1) Customer information: reporter name, address, contact number, and date of complaint  
2) Product information: product name, packaging kit number or lot number, expiry date, and 
clinical protocol number  
3) Complaint information: complaint issue category and description  
 
MedImmune contact information for reporting product complaints:  
Email: productcomplaints@medimmune.com  
Phone: +1-301-398-2105 +1-877-MEDI-411 (+1-877-633-4411)  
Fax: +1-301-398-8800  
Mail: MedImmune, LLC Attn: Product Complaint Department One MedImmune Way, 
Gaithersburg, MD USA 20878 
 


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29. 
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Peng ZW, Zhang YJ, Chen MS, et al. Radiofrequency ablation with or without 
transcatheter arterial chemoembolization in the treatment of hepatocellular carcinoma: a 
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hepatology 2013;59:81-8. 
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Keler T, Halk E, Vitale L, et al. Activity and safety of CTLA-4 blockade combined with 
vaccines in cynomolgus macaques. J Immunol 2003;171:6251-9. 
35. 
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antigen-4 polymorphisms and serum tumor necrosis factor-alpha and interferon-gamma levels in 
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European Histamine Research Society  [et al] 2011;60:1071-8. 
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Lee Y, Auh SL, Wang Y, et al. Therapeutic effects of ablative radiation on local tumor 
require CD8+ T cells: changing strategies for cancer treatment. Blood 2009;114:589-95. 
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Blanquicett C, Saif MW, Buchsbaum DJ, et al. Antitumor efficacy of capecitabine and 
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mediated through p53. Cancer Res 2003;63:1990-3. 
40. 
Demaria S, Ng B, Devitt ML, et al. Ionizing radiation inhibition of distant untreated 
tumors (abscopal effect) is immune mediated. International journal of radiation oncology, 
biology, physics 2004;58:862-70. 
41. 
Reits EA, Hodge JW, Herberts CA, et al. Radiation modulates the peptide repertoire, 
enhances MHC class I expression, and induces successful antitumor immunotherapy. The 
Journal of experimental medicine 2006;203:1259-71. 
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Sharma A, Bode B, Wenger RH, et al. gamma-Radiation promotes immunological 
recognition of cancer cells through increased expression of cancer-testis antigens in vitro and in 
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43. 
Apetoh L, Ghiringhelli F, Tesniere A, et al. Toll-like receptor 4-dependent contribution 
of the immune system to anticancer chemotherapy and radiotherapy. Nat Med 2007;13:1050-9. 
44. 
Suzuki Y, Mimura K, Yoshimoto Y, et al. Immunogenic tumor cell death induced by 
chemoradiotherapy in patients with esophageal squamous cell carcinoma. Cancer Res 
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45. 
Dewan MZ, Galloway AE, Kawashima N, et al. Fractionated but not single-dose 
radiotherapy induces an immune-mediated abscopal effect when combined with anti-CTLA-4 
antibody. Clin Cancer Res 2009;15:5379-88. 
46. 
Demaria S, Kawashima N, Yang AM, et al. Immune-mediated inhibition of metastases 
after treatment with local radiation and CTLA-4 blockade in a mouse model of breast cancer. 
Clin Cancer Res 2005;11:728-34. 
47. 
Gulley JL, Madan RA, Tsang KY, et al. A pilot safety trial investigating a vector-based 
vaccine targeting carcinoembryonic antigen in combination with radiotherapy in patients with 
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48. 
Hiraki M, Nishimura J, Ohtsuka M, et al. Impact of stereotactic body radiotherapy on 
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49. 
Nouhaud E, Crehange G, Cueff A, et al. Stereotactic Body radiation therapy for liver 
tumors with or without rotational intensity modulated radiation therapy. BMC research notes 
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50. 
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Radiation oncology 2013;8:175. 
51. 
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responses for hepatocellular carcinoma and metastatic colorectal liver tumours. The British 
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52. 
Wang C, Wang H, Yang W, et al. A multicenter randomized controlled trial of 
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Ye Y, Zhou L, Xie X, Jiang G, Xie H, Zheng S. Interaction of B7-H1 on intrahepatic 
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13 APPENDICES 
13.1 APPENDIX A:  PERFORMANCE STATUS CRITERIA 
ECOG Performance Status Scale 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Description 
0 
Normal activity.  Fully active, able 
to carry on all pre-disease 
performance without restriction. 
100 
Normal, no complaints, no 
evidence of disease. 
90 
Able to carry on normal activity; 
minor signs or symptoms of 
disease. 
1 
Symptoms, but ambulatory.  
Restricted in physically strenuous 
activity, but ambulatory and able to 
carry out work of a light or 
sedentary nature (e.g., light 
housework, office work). 
80 
Normal activity with effort; some 
signs or symptoms of disease. 
70 
Cares for self, unable to carry on 
normal activity or to do active 
work. 
2 
In bed <50% of the time.  
Ambulatory and capable of all self-
care, but unable to carry out any 
work activities.  Up and about more 
than 50% of waking hours. 
60 
Requires occasional assistance, 
but is able to care for most of 
his/her needs. 
50 
Requires considerable assistance 
and frequent medical care. 
3 
In bed >50% of the time.  Capable 
of only limited self-care, confined 
to bed or chair more than 50% of 
waking hours. 
40 
Disabled, requires special care and 
assistance. 
30 
Severely disabled, hospitalization 
indicated.  Death not imminent. 
4 
100% bedridden.  Completely 
disabled.  Cannot carry on any self-
care.  Totally confined to bed or 
chair. 
20 
Very sick, hospitalization 
indicated. Death not imminent. 
10 
Moribund, fatal processes 
progressing rapidly. 
5 
Dead. 
0 
Dead. 
 


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13.2 APPENDIX B:  CHILD-PUGH CLASSIFICATION SYSTEM 
 
 
 
 
 
 


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13.3 APPENDIX C:  MODIFIED IMMUNE-RELATED RESPONSE CRITERIA (IRRC) 
 
This new classification is based on the recent learning from clinical studies with cancer 
immunotherapies that even if some new lesions appear at the beginning of a treatment or if the 
total tumor burden does not increase substantially, tumor regressions or stabilizations might still 
occur later. The irRC were created using bi-dimensional measurements (as previously widely 
used in the World Health Organization criteria). For this trial, the concepts of the irRC are 
combined with RECIST 1.1 to come up with the modified irRC.  
 
For modified irRC, only target and measurable lesions are taken into account. In contrast to the 
RECIST 1.1 criteria, the modified irRC criteria (a) require confirmation of both progression and 
response by imaging at 6 weeks after initial imaging and (b) do not necessarily score the 
appearance of new lesions as progressive disease if the sum of lesion diameters of target lesions 
(minimum of 10 mm per lesion, maximum of 5 target lesions, maximum of 2 per organ) and 
PHDVXUDEOHQHZOHVLRQVGRHVQRWLQFUHDVHE\ 
The same method of assessment and the same technique should be used to characterize each 
identified and reported target lesion(s) at baseline, during the trial, and at the end of trial visit. 
All measurements should be recorded in metric notation. The modified irRC based on RECIST 
1.1 are displayed below.  
 
 
 
 
 
 
 


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Overall Responses Derived from Changes in Index, Non-Index, and New Lesions 
 
 


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13.4 APPENDIX D: MEDIMMUNE SAMPLE PREPARATION PROCEDURES 
 
Serum- SST Tube 
1. Draw maximum volume of blood into gold top SST tube (s). Record time of collection. 
2. Gently invert 5 times. 
3. Allow the blood to clot for 30 minutes at room temperature. 
4. Centrifuge within 2 hours of collection at 1100 -1300 g for 15 minutes. 
5. Transfer serum into labeled cryovials.  
6. Immediately freeze the cryovials upright at -20ºC or colder. 
7. Store at -20ºC or colder until shipment on dry ice. 
 
 
Plasma- K2 EDTA Tube 
1.  Draw maximum volume of blood into lavender top K2 EDTA tube(s). Record time of 
collection 
2. Gently invert 8 to 10 times. 
3. Centrifuge within 2 hours of collection at 1100 -1300 g for 10 minutes. 
4. Transfer plasma into labeled cryovials. 
5. Immediately freeze the cryovials upright at -20ºC or colder. 
6. Store at -20ºC or colder until shipment on dry ice. 
 
Tube Label should include: 
1. Patient Identifier  
2. Sample ID (Serum 1, Cycle 1, Day 1etc.) 
3. Sample type (plasma, serum) 
4. Sample volume  
5. Collection time  
6. Barcode (if this system is available) 

ICF_001.pdf: 
MEDICAL RECORD 
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY 
• 
Adult Patient or 
• Parent, for Minor Patient 
INSTITUTE: 
National Cancer Institute 
STUDY NUMBER: 
13-C-0120 
PRINCIPAL INVESTIGATOR: 
Tim Greten, M.D. 
STUDY TITLE:  
A Pilot Study of Tremelimumab - A Monoclonal Antibody Against CTLA-4 in 
Combination with either Trans-Arterial Catheter Chemoembolization (TACE), 
Radiofrequency Ablation (RFA), or Cryoablation in Subjects with Hepatocellular 
Carcinoma (HCC) or Biliary Tract Carcinomas (BTC) 
 
 
Continuing Review Approved by the IRB on 06/10/19 
Amendment Approved by the IRB on 09/14/17 (J) 
Date posted to web:  06/19/19 
Standard 
PATIENT IDENTIFICATION 
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY 
• 
Adult Patient or 
• Parent, for Minor Patient 
NIH-2514-1 (07-09) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent (1) 
 
 
INTRODUCTION 
We invite you to take part in a research study at the National Institutes of Health (NIH). 
First, we want you to know that: 
Taking part in NIH research is entirely voluntary.  
You may choose not to take part, or you may withdraw from the study at any time.  In 
either case, you will not lose any benefits to which you are otherwise entitled.  However, 
to receive care at the NIH, you must be taking part in a study or be under evaluation for 
study participation. 
You may receive no benefit from taking part.  The research may give us knowledge that 
may help people in the future. 
Second, some people have personal, religious or ethical beliefs that may limit the kinds of 
medical or research treatments they would want to receive (such as blood transfusions).  If you 
have such beliefs, please discuss them with your NIH doctors or research team before you agree 
to the study. 
Now we will describe this research study.  Before you decide to take part, please take as much 
time as you need to ask any questions and discuss this study with anyone at NIH, or with family, 
friends or your personal physician or other health professional.   
Why is this study being done?  
This research is being done to study the effectiveness of the combination of the drug 
Tremelimumab with trans-arterial catheter chemoembolization (TACE), radiofrequency ablation 
(RFA) or cryoablation. 
Tremelimumab is an experimental drug that has not been approved by the U.S. Food and Drug 
Administration (FDA). TACE, RFA and cryoablation are standard procedures that are used to 
treat tumors.  


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research 
Study 
STUDY NUMBER:13-C-0120 
CONTINUATION: page 2 of 12 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
 
If you receive TACE a small catheter will be placed into the artery at the groin and 
chemotherapy will be injected directly into the liver. A material which closes off the vessels 
supplying blood to the tumor is also injected. If you receive RFA you will be put to sleep and a 
needle will directly be placed into the tumor and your tumor will be burnt (or part of it). If you 
receive Cryoablation you will be put to sleep and a needle will be put directly into the tumor and 
the tumor will be frozen (or part of it). Once it is determined which procedure you will receive 
your doctor will explain the procedure in full detail. 
Although Tremelimumab is not approved by the FDA, it has been evaluated in a number of 
clinical studies, and over 1000 patients, most of whom had melanoma. Tremelimumab is similar 
in how it works to another drug (called ipilimumab) which was recently approved by the FDA. 
Tremelimumab has been tested in a small group of patients with liver cancer or hepatocellular 
cancer (HCC) and in general was well tolerated. It has not been tested however in combination 
with TACE, RFA or cryoablation, which is the main goal of this study. 
Why are you being asked to take part in this study? 
You are being asked to take part in this study because you have advanced hepatocellular cancer 
(HCC) or biliary tract cancer that has not responded to other types of therapy, and your doctor 
has determined that you are not a candidate for liver transplantation. 
How many people will take part in this study?  
About 90 people will take part in this study. 
Description of Research Study   
Before you begin the study 
Before you begin this study, you will have several exams and tests to make sure you are eligible 
for this study.  The exams and tests are part of regular cancer care and may be done even if you 
do not join the study.  If you recently had some of the tests, they may not need to be repeated. 
The research team will explain these exams and tests to you. You will have: 
x History and physical exam 
x Review of current medications and past treatments 
x Blood work 
x Urine laboratory tests 
x Tumor measurements using special x-rays called computerized tomography (CT or CAT 
scans) or magnetic resonance imaging (MRI) of your chest, stomach, and pelvis areas 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research 
Study 
STUDY NUMBER:13-C-0120 
CONTINUATION: page 3 of 12 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
 
x A heart test called an electrocardiogram or ECG to check your heart 
x Urine or blood pregnancy test 
During the study 
If the exams, tests and procedures show that you can be in the study, and you choose to take part, 
then you will begin treatment.  
Treatment involves receiving Tremelimumab through a vein (IV) once every 4 weeks and then 
once every 12 weeks for 2 years’ total. Treatment can be stopped before completion of 2 years’ 
therapy if your disease shows clear evidence of growth or your body is no longer tolerating the 
treatment. A 4-week time-period is called a cycle. In this study, there are six initial cycles 
followed by maintenance.  
On the first day of every cycle you will receive the following: 
x History and physical exam 
x Review of current medications and treatments 
x Routine and research blood tests. The purposes of the research blood tests will be to see if 
there is evidence that your immune system has become ‘activated’ by the treatment. 
x Urine laboratory tests 
x Receive Tremelimumab  
On the first day of every week during cycles 1 through 6 you will receive the following: 
x Routine blood tests 
x History and physical exam 
x Review of current medications and treatments 
During your second cycle (within 4 days of Day 36), you will receive the TACE, RFA, SBRT or 
cryoablation procedure. The procedure that you will receive at this time is based on the size and 
location of your tumor as well as other conditions that will be discussed by the study doctors.  
Every 8 weeks, you will have tumor measurements using special x-rays called computerized 
tomography (CT or CAT scans) or magnetic resonance imaging (MRI) of your chest, stomach, 
and pelvis. 
While you are in the maintenance phase of the study if it is confirmed that your disease has 
progressed you may be eligible to receive re-induction therapy using Tremelimumab. This option 
will be discussed with you by your study doctor. 
 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research 
Study 
STUDY NUMBER:13-C-0120 
CONTINUATION: page 4 of 12 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
 
When you are finished taking the drugs (treatment) 
After you have finished taking the study drugs, you will be asked to return to clinic within 4 
weeks for a safety follow up visit.   At this visit, you will be asked questions about your health, 
get a physical exam and undergo routine and research blood and urine tests. If you have any 
unresolved drug related health issues, you will be followed until you feel better.  If you are 
unable to return for this visits, we will obtain the information from you by telephone. After that 
we will contact you by phone once a year.  
Birth Control 
If you are a woman who is breast feeding or pregnant, you may not take part in the study because 
we don’t know how this medicine would affect your baby or your unborn child. If you are a 
woman who can become pregnant, or are the partner of a woman who can become pregnant, you 
will need to practice an effective form of birth control before starting study treatment, during 
study treatment, and for 3 months after you finish study treatment. In addition, male subjects 
should not donate sperm during the study and for 3 months after the last dose of study therapy. If 
you think that you or your partner is pregnant, you should tell your study doctor or nurse at once.   
Effective forms of birth control include:  
• abstinence  
x intrauterine device (IUD) 
• hormonal [birth control pills, injections, or implants] 
• tubal ligation 
• vasectomy 
Risks or Discomforts of Participation 
If you choose to take part in this study, there is a risk that: 
x You may lose time at work or home and spend more time in the hospital or doctor’s 
office than usual 
x You may be asked sensitive or private questions which you normally do not discuss.  
There is also a risk that you could have side effects from the study drug.  Here are important 
points about side effects: 
x The study doctors do not know who will or will not have side effects. 
x Some side effects may go away soon, some may last a long time, or some may never go 
away. 
x Some side effects may interfere with your ability to have children. 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research 
Study 
STUDY NUMBER:13-C-0120 
CONTINUATION: page 5 of 12 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
 
Here are important points about how you and the study doctor can make side effects less of a 
problem: 
x Tell the study doctor if you notice or feel anything different so they can see if you are 
having any symptoms. 
x The study doctor may be able to treat some side effects. 
Below we show the most common and the most serious side effects that researchers know about. 
There might be other side effects that researchers do not yet know about. If important new side 
effects are found, the study doctor will discuss these with you. 
Risks from study therapy  
All Participants 
Tremelimumab: 
The following are side effects that have been associated with Tremelimumab: 
x Diarrhea 
x Rash 
x Pruritus (itching) 
x Fatigue 
x Nausea 
x Vomiting 
x Anorexia (loss of appetite) 
x Headache 
x Abdominal Pain 
x Auto-immune changes to the pituitary gland leading to hormonal changes. 
x Inflammation of the part of the intestine known as the colon which can lead to infection, 
blood in the stools and abdominal pain. This is also known as ‘colitis’.  Colitis has the 
potential to be life threatening and require prolonged hospitalizations. As part of its 
management it may require treatment with steroids which may place you at increased risk 
for severe infections.  
x Inflammation of the liver which is also known as hepatitis. In extreme cases this may 
result in liver failure and death.   
x Occasionally you can also get a skin rash related to the treatment and this can also result 
in severe and life threatening symptoms.  
x Problems related to Tremelimumab infusion 
x There is a remote chance that you may have a serious allergic reaction (anaphylaxis) to 
Tremelimumab. Anaphylaxis may cause a serious drop in blood pressure, difficulty in 
breathing, severe hives, and sometimes death. Your doctor will monitor you very closely 
after you receive the Tremelimumab, and will have medications available to treat any 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research 
Study 
STUDY NUMBER:13-C-0120 
CONTINUATION: page 6 of 12 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
 
allergic reactions that might occur. Less serious allergic reactions, such as skin rash with 
or without itching and swelling, may also occur within hours to days after receiving the 
Tremelimumab. These effects usually get better without treatment. 
x There is a remote chance that you may develop new allergies to previously exposed 
substances, other than Tremelimumab. For example, it is possible that you could develop 
an allergy to shellfish or IV contrast while taking Tremelimumab. These allergies may be 
severe and life threatening. 
Risks from Blood Collection  
Side effects of blood draws include pain and bruising in the area where the needle was placed, 
lightheadedness, and rarely, fainting. When large amounts of blood are collected, low red blood 
cell count (anemia) can develop. 
Risks from Biopsy  
This procedure usually causes only brief discomfort at the site from which the biopsy is taken.  
Rarely, infection or bleeding may occur at the needle site. 
Tumor biopsies will be done by a specialist using the CT scanner or ultrasound machine to guide 
the biopsy needle into the tumor to ensure accuracy. To collect the research biopsies, you will be 
exposed to 3 CT scans. This radiation exposure is not required for your medical care and is for 
research purposes only. The amount of radiation you will receive in this procedure is 2.3 rem 
which is below the guideline of 5 rem per year allowed for research subjects by the NIH 
Radiation Safety Committee.  The average person in the United States receives a radiation 
exposure of 0.3 rem per year from natural sources, such as the sun, outer space, and the earth's 
air and soil.  If you would like more information about radiation, please ask the investigator for a 
copy of the pamphlet, An Introduction to Radiation for NIH Research Subjects. 
TACE Procedure (Cohort A/B) 
Likely 
Less Likely 
Rare but Serious 
x Abdominal pain 
x Fever 
x Nausea and/or vomiting 
x Abdominal fluid buildup 
(Ascites) 
x Bleeding (at catheter 
insertion site) 
x Allergy to iodine contrast 
agent  
x Liver failure 
x Kidney failure 
x Liver abscess formation  
x Stomach or duodenal ulcer 
x Pancreatitis 
x Cholecystitis (irritation of 
the gall bladder) 
x Arterial injury at catheter 
insertion site 
 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research 
Study 
STUDY NUMBER:13-C-0120 
CONTINUATION: page 7 of 12 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
 
RFA Procedure (Cohorts A/B/E) 
The risks from the radiofrequency or microwave ablation procedure itself include a small chance 
of bleeding, injury to the normal liver tissue, and re-growth of the tumor.  An infection, called an 
abscess, can develop in the treated tumor, and may require antibiotics and/or putting a temporary 
tube in the abscess to drain it.  There should be minimal discomfort from the ablation procedure 
itself during the ablation procedure, because you will be “asleep” under general anesthesia.  The 
length of time you will need to be in the hospital will vary but will be estimated by your doctors. 
This will be discussed with you in greater detail prior to the procedure. 
Cryoablation (Cohort D only) 
The risks from cryoablation procedure itself include a small chance of bleeding, injury to the 
normal liver tissue, and re-growth of the tumor.  Nerve damage may result. Completely frozen 
nerves can cause motor weakness or numbness in the area supplied by the nerves.  There should 
be minimal discomfort from the cryoablation procedure itself during the procedure, because you 
will be “asleep” under general anesthesia.  Following percutaneous cryotherapy, you should be 
able to resume your usual activities within one to three days. If you have had open cryoablation, 
you should be able to resume your usual activities within seven to 10 days. You should avoid 
lifting heavy objects for at least 72 hours. This will be discussed with you in greater detail prior 
to the procedure. 
Potential Benefits of Participation 
Are there benefits to taking part in this study?  
The aim of this study is to see if this experimental treatment will cause your tumors to shrink.  
We do not know if you will receive personal, medical benefit from taking part in this study.  
These potential benefits could include shrinking of your tumor or lessening of your symptoms, 
such as pain, that are caused by the cancer.  Because there is not much information about the 
drug’s effect on your cancer, we do not know if you will benefit from taking part in this study, 
although the knowledge gained from this study may help others in the future who have cancer.   
Alternative Approaches or Treatments 
What other choices do I have if I do not take part in this study?  
 
Instead of being in this study, you have these options: 
x Getting treatment or care for your cancer without being in a study 
x Taking part in another study 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research 
Study 
STUDY NUMBER:13-C-0120 
CONTINUATION: page 8 of 12 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
 
x Getting comfort care, also called palliative care.  This type of care helps reduce pain, 
tiredness, appetite problems and other problems caused by the cancer.  It does not treat 
the cancer directly.  Instead, it tries to improve how you feel.  Comfort care tries to keep 
you as active and comfortable as possible. 
Please talk to your doctor about these and other options. 
Research Subject’s Rights 
What are the costs of taking part in this study?  
If you choose to take part in the study, the following will apply, in keeping with the NIH policy: 
x 
You will receive study treatment at no charge to you. This may include 
surgery, medicines, laboratory testing, x-rays or scans done at the 
Clinical Center, National Institutes of Health (NIH), or arranged for you 
by the research team to be done outside the Clinical Center, NIH if the 
study related treatment is not available at the NIH.  
x 
There are limited funds available to cover the cost of some tests and 
procedures performed outside the Clinical Center, NIH.  You may have 
to pay for these costs if they are not covered by your insurance company. 
x 
Medicines that are not part of the study treatment will not be provided or 
paid for by the Clinical Center, NIH. 
x 
Once you have completed taking part in the study, medical care will no 
longer be provided by the Clinical Center, NIH. 
Will your medical information be kept private?  
We will do our best to make sure that the personal information in your medical record will be 
kept private.  However, we cannot guarantee total privacy.  Organizations that may look at 
and/or copy your medical records for research, quality assurance, and data analysis include: 
 
x The National Cancer Institute (NCI) and other government agencies, like the Food and 
Drug Administration (FDA), which are involved in keeping research safe for people. 
x National Cancer Institute Institutional Review Board. 
x Qualified representatives from MedImmune, Inc., the pharmaceutical company who 
produces Tremelimumab. 
Stopping Therapy  
Your doctor may decide to stop your therapy for the following reasons: 
x if he/she believes that it is in your best interest 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research 
Study 
STUDY NUMBER:13-C-0120 
CONTINUATION: page 9 of 12 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
 
x if your disease comes back during treatment 
x if you have side effects from the treatment that your doctor thinks are too severe 
x if new information shows that another treatment would be better for you 
x if you become pregnant 
In this case, you will be informed of the reason therapy is being stopped. 
You can stop taking part in the study at any time. However, if you decide to stop taking part in 
the study, we would like you to talk to the study doctor and your regular doctor first. 
If you decide at any time to withdraw your consent to participate in the trial, we will not collect 
any additional medical information about you. However, according to FDA guidelines, 
information collected on you up to that point may still be provided to MedImmune, Inc. or 
designated representatives. If you withdraw your consent and leave the trial, any samples of 
yours that have been obtained for the study and stored at the NCI can be destroyed upon request. 
However, any samples and data generated from the samples that have already been distributed to 
other researchers or placed in the research databases cannot be recalled and destroyed. 
Conflict of Interest 
The National Institutes of Health (NIH) reviews NIH staff researchers at least yearly for conflicts 
of interest.  This process is detailed in a Protocol Review Guide.  You may ask your research 
team for a copy of the Protocol Review Guide or for more information.  Members of the research 
team who do not work for NIH are expected to follow these guidelines but they do not need to 
report their personal finances to the NIH. 
Members of the research team working on this study may have up to $15,000 of stock in the 
companies that make products used in this study.  This is allowed under federal rules and is not a 
conflict of interest.  
The National Institutes of Health and the research team for this study are using Tremelimumab 
developed by MedImmune, Inc. through a joint study with your researchers and the company.   
The company also provides financial support for this study. 
Optional Biopsy  
An optional tumor biopsy may be performed at baseline and at the time of the RFA or TACE 
and, if applicable, prior to re-induction. These are optional biopsies which you do not have to 
undergo. If performed, the tissue will be studied to see if any immune cells have entered the 
tumor. The biopsy to be performed is exclusively for research purposes and will not benefit you.  
It might help other people in the future.  The decision to participate in this part of the research is 
optional, and no matter what you decide to do, it will not affect your care. You will be given the 
opportunity to sign a separate consent at the time of the biopsy. 
 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research 
Study 
STUDY NUMBER:13-C-0120 
CONTINUATION: page 10 of 12 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
 
Use of Specimens and Data for Future Research  
To advance science, it is helpful for researchers to share information they get from studying 
human samples.  They do this by putting it into one or more scientific databases, where it is 
stored along with information from other studies. A researcher who wants to study the 
information must apply to the database and be approved.  Researchers use specimens and data 
stored in scientific databases to advance science and learn about health and disease.   
We plan to keep some of your specimens and data that we collect and use them for future 
research and share them with other researchers. We will not contact you to ask about each of 
these future uses.  These specimens and data will be stripped of identifiers such as name, address 
or account number, so that they may be used for future research on any topic and shared broadly 
for research purposes. Your specimens and data will be used for research purposes only and will 
not benefit you.  It is also possible that the stored specimens and data may never be used.  
Results of research done on your specimens and data will not be available to you or your doctor.  
It might help people who have cancer and other diseases in the future.   
If you do not want your stored specimens and data used for future research, please contact us in 
writing and let us know that you do not want us to use your specimens and/or data.  Then any 
specimens that have not already been used or shared will be destroyed and your data will not be 
used for future research. However, it may not be possible to withdraw or delete materials or data 
once they have been shared with other researchers. 
 


MEDICAL RECORD 
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY 
• 
Adult Patient or 
• Parent, for Minor Patient 
STUDY NUMBER: 13-C-0120 
CONTINUATION: page 11 of 12 pages 
 
PATIENT IDENTIFICATION 
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH 
STUDY (Continuation Sheet) 
• 
Adult Patient or 
• Parent, for Minor Patient 
NIH-2514-1 (07-09) 
P.A.:  09-25-0099 
 
File in Section 4:  Protocol Consent 
 
 
 
OTHER PERTINENT INFORMATION 
1. 
Confidentiality.  When results of an NIH research study are reported in medical journals 
or at scientific meetings, the people who take part are not named and identified.  In most cases, 
the NIH will not release any information about your research involvement without your written 
permission.  However, if you sign a release of information form, for example, for an insurance 
company, the NIH will give the insurance company information from your medical record.  This 
information might affect (either favorably or unfavorably) the willingness of the insurance 
company to sell you insurance. 
The Federal Privacy Act protects the confidentiality of your NIH medical records.  However, you 
should know that the Act allows release of some information from your medical record without 
your permission, for example, if it is required by the Food and Drug Administration (FDA), 
members of Congress, law enforcement officials, or authorized hospital accreditation 
organizations. 
2. 
Policy Regarding Research-Related Injuries.  The Clinical Center will provide short-
term medical care for any injury resulting from your participation in research here.  In general, 
no long-term medical care or financial compensation for research-related injuries will be 
provided by the National Institutes of Health, the Clinical Center, or the Federal Government.  
However, you have the right to pursue legal remedy if you believe that your injury justifies such 
action. 
3. 
Payments.  The amount of payment to research volunteers is guided by the National 
Institutes of Health policies.  In general, patients are not paid for taking part in research studies at 
the National Institutes of Health.  Reimbursement of travel and subsistence will be offered 
consistent with NIH guidelines. 
4. 
Problems or Questions.  If you have any problems or questions about this study, or 
about your rights as a research participant, or about any research-related injury, contact the 
Principal Investigator, Tim Greten, M.D., Building 10, Room 12N226, Telephone:  240-760-
6114. You may also call the Clinical Center Patient Representative at 301-496-2626. If you have 
any questions about the use of your specimens or data for future research studies, you may also 
contact the Office of the Clinical Director, Telephone:  240-760-6070.  
5. 
Consent Document.  Please keep a copy of this document in case you want to read it 
again. 


MEDICAL RECORD 
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY 
• 
Adult Patient or 
• Parent, for Minor Patient 
STUDY NUMBER: 13-C-0120 
CONTINUATION: page 12 of 12 pages 
 
PATIENT IDENTIFICATION 
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH 
STUDY (Continuation Sheet) 
• 
Adult Patient or 
• Parent, for Minor Patient 
NIH-2514-1 (07-09) 
P.A.:  09-25-0099 
 
File in Section 4:  Protocol Consent 
 
 
 
 
 
COMPLETE APPROPRIATE ITEM(S) BELOW: 
A. Adult Patient’s Consent 
B. Parent’s Permission for Minor Patient. 
I have read the explanation about this study 
and have been given the opportunity to discuss 
it and to ask questions.  I hereby consent to 
take part in this study. 
I have read the explanation about this study 
and have been given the opportunity to discuss 
it and to ask questions.  I hereby give 
permission for my child to take part in this 
study.   
(Attach NIH 2514-2, Minor’s Assent, if 
applicable.) 
 
  
  
 
 
 
Signature of Adult Patient/ 
Legal Representative 
Date 
Signature of Parent(s)/ Guardian Date 
 
 
Print Name 
 
 
Print Name 
C. Child’s Verbal Assent (If Applicable) 
The information in the above consent was described to my child and my child agrees to 
participate in the study. 
 
  
  
 
Signature of Parent(s)/Guardian 
Date 
Print Name 
THIS CONSENT DOCUMENT HAS BEEN APPROVED FOR USE  
FROM JUNE 10, 2019 THROUGH JUNE 24, 2020.  
 
 
 
 
 
 
 
 
Signature of Investigator 
Date 
Signature of Witness 
Date 
 
 
Print Name 
 
 
Print Name