Clinical trial NCT03111732
Conditions: Biliary Tract Neoplasms Cholangiocarcinoma Bile Duct Cancer Liver Cancer Gallbladder Cancer
Keywords: Immune-Based Strategies Anti-PD1 Therapy Chronic Inflammation Combination Chemotherapy
Sponsor: National Cancer Institute (NCI)
Start date: 2017-06-14; Completion date: 2021-11-08
Enrollment: 11 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Background:

Biliary tract cancers are rare but they are serious. Researchers want to see if a certain drug helps the immune system fight cancer cells. The drug is called pembrolizumab. It may work even better with two chemotherapy drugs that are widely used to treat gastrointestinal cancers.

Objective:

To study if pembrolizumab given with capecitabine and oxaliplatin (CAPOX) increases the time it takes for a person's biliary tract cancer to get worse.

Eligibility:

People age 18 and older with previously treated biliary tract cancer that has spread to other parts of the body

Design:

Participants will be screened with tests as part of their regular cancer care.

Each study cycle is 3 weeks.

For 6 cycles, participants will:

Get pembrolizumab and oxaliplatin on day 1 of each cycle. They will be given in an intravenous (IV) catheter.

Take capecitabine by mouth for 2 weeks then have 1 week without it.

Participants will complete a patient diary.

Starting with cycle 7, participants will get only pembrolizumab. They will get it once every 3 weeks.

On day 1 of every cycle, participants will have:

Physical exam

Review of symptoms and how well they do normal activities

Blood tests

Every 9 weeks, they will have a scan.

Participants may have tumor samples taken.

Participants will have a final visit about 1 month after they stop the study drug. After that, they will be contacted by phone or email yearly.

Detailed description:
Background:

* The most compelling argument in favor of testing immune-based strategies (and anti-Programmed cell death protein 1 (PD1) therapy in particular) in biliary tract cancers (BTC) is that chronic inflammation appears to be the most common etiologic factor in the development of biliary tract cancer.
* Single-agent activity has been shown for PD1-directed therapy in BTC. Given the potential for oxaliplatin-induced immunogenic cell death we would like to evaluate the combination of capecitabine and oxaliplatin (CAPOX) chemotherapy with pembrolizumab.

Objective:

To determine the 5-month progression free survival (PFS) of Pembrolizumab in combination with CAPOX in patients with advanced biliary tract carcinoma.

Eligibility:

* Histologically confirmed diagnosis biliary tract carcinoma 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 biliary tract carcinoma.
* Patients must have at least one prior chemotherapeutic regimen.
* Patients must have disease that is not amenable to potentially curative resection.
* No prior treatment with oxaliplatin.

Design:

The proposed study is a phase II study of Pembrolizumab in combination with CAPOX in patients with advanced biliary tract carcinoma

Arms: arm 1: Pembrolizumab plus Oxaliplatin plus Capecitabine
Interventions: intervention 1: Pembrolizumab (MK-3475) intervention 2: Oxaliplatin intervention 3: Capecitabine
Intervention descriptions: intervention 1: 200 mg will be administered as an IV infusion on Day 1 of each 21 day cycle intervention 2: 130mg/m(2) IV Infusion will be administered as an IV infusion on Day 1 of cycles 1-6 intervention 3: 750 mg/m(2) will be administered orally twice a day on Days 1-14 of cycles 1-6

Protocol documents:
Prot_SAP_000.pdf: 
Abbreviated Title: CAPOX Pembrolizumab in BTC  
Version Date: 03/19/2020 
1 
Abbreviated Title: CAPOX Pembrolizumab in BTC 
CC Protocol #: 17C0082 G 
Version Date: 03/19/2020 
NCT Number: NCT03111732 
Title: A Phase 2 Study of Pembrolizumab, a Monoclonal Antibody Against PD-1, in 
Combination with Capecitabine and Oxaliplatin (CAPOX) in Subjects with Advanced Biliary 
Tract Carcinoma (BTC) 
 
NCI Principal Investigator:         Tim Greten, MD  
     Thoracic & GI Malignancies Branch 
     National Cancer Institute 
     Building 10, Room 2B38B 
     9000 Rockville Pike 
     Bethesda, MD 20892 
     240-760-6114  
     gretentf@mail.nih.gov  
 
Investigational Agents:     
None 
Commercial Agents:  
Pembrolizumab (Keytruda) 
Capecitabine  
Oxaliplatin 


Abbreviated Title: CAPOX Pembrolizumab in BTC  
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PRÉCIS  
Background: 
• The most compelling argument in favor of testing immune-based strategies (and anti-PD1 
therapy) in biliary tract cancers (BTC) is that chronic inflammation appears to be the 
most common etiologic factor in the development of biliary tract cancer.  
• Single-agent activity has been shown for PD1-directed therapy in BTC. Given the 
potential for oxaliplatin-induced immunogenic cell death we would like to evaluate the 
combination of CAPOX chemotherapy with pembrolizumab.  
Objective: 
• To determine the 5-month PFS of Pembrolizumab in combination with CAPOX in 
patients with advanced biliary tract carcinoma. 
Eligibility: 
• Histologically confirmed diagnosis biliary tract carcinoma 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 biliary tract 
carcinoma.  
• Patients must have at least one prior chemotherapeutic regimen. 
• Patients must have disease that is not amenable to potentially curative resection. 
• No prior treatment with oxaliplatin. 
Design: 
• The proposed study is a phase II study of Pembrolizumab in combination with CAPOX in 
patients with advanced biliary tract carcinoma. 
 
 


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TABLE OF CONTENTS  
PRÉCIS .......................................................................................................................................... 2 
TABLE OF CONTENTS ................................................................................................................ 3 
1. 
INTRODUCTION .................................................................................................................. 8 
1.1 
Study Objectives .............................................................................................................. 8 
1.1.1 
Primary Objective: .................................................................................................... 8 
1.1.2 
Secondary Objectives: .............................................................................................. 8 
1.1.3 
Exploratory Objectives: ............................................................................................ 8 
1.2 
Background and Rationale ............................................................................................... 8 
1.2.1 
Biliary tract cancer/Cholangiocarcinoma: current standard of care. ........................ 8 
1.2.2 
Immune-based approaches in gastrointestinal malignancies .................................... 9 
1.2.3 
Inflammation and predisposition to biliary tract carcinoma. .................................. 10 
1.2.4 
Immunogenicity of biliary tract carcinoma. ............................................................ 10 
1.2.5 
Translational immune-based efforts in BTC........................................................... 13 
1.2.6 
Pembrolizumab ....................................................................................................... 15 
1.2.7 
Rationale for Dose Selection/Regimen/Modification ............................................. 17 
1.2.8 
CAPOX in biliary tract carcinomas ........................................................................ 18 
2 
ELIGBILITY ASSESSMENT AND ENROLLMENT ........................................................ 18 
2.1 
Eligibility Criteria .......................................................................................................... 18 
2.1.1 
Inclusion Criteria .................................................................................................... 18 
2.1.2 
Exclusion Criteria ................................................................................................... 19 
2.1.3 
Recruitment Strategies ............................................................................................ 20 
2.2 
Screening Evaluation...................................................................................................... 20 
2.3 
Registration Procedures.................................................................................................. 21 
2.3.1 
Treatment Assignment Procedures (For registration purposes only): .................... 21 
2.4 
Baseline Evaluation ........................................................................................................ 22 
3 
STUDY IMPLEMENTATION ............................................................................................ 22 
3.1 
Study Design .................................................................................................................. 22 
3.2 
Schedule ......................................................................................................................... 23 
3.3 
Drug Administration ...................................................................................................... 23 
3.3.1 
Pembrolizumab ....................................................................................................... 23 
3.3.2 
CAPOX ................................................................................................................... 23 
3.4 
Dosing Delays and Modifications .................................................................................. 24 


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3.4.1 
General guidance .................................................................................................... 24 
3.4.2 
Dose Modifications for Hematologic Toxicity ....................................................... 24 
3.4.3 
Dose Modifications for Neutropenia for Capecitabine and Oxaliplatin ................. 24 
Grade 2 ...................................................................................................................................... 24 
1.0 ≤ ANC < 1.5 x 109/L .......................................................................................................... 24 
Platelets > 50 - < 75 x 109/L ..................................................................................................... 24 
Grade 3 ...................................................................................................................................... 24 
0.5 ≤ ANC < 1.0 x 109/L .......................................................................................................... 24 
3.4.4 
Capecitabine ............................................................................................................ 25 
3.4.5 
Oxaliplatin............................................................................................................... 25 
3.4.6 
Pembrolizumab ....................................................................................................... 26 
3.5 
Study Calendar ............................................................................................................... 31 
3.6 
Criteria for Removal from Protocol Therapy and Off Study Criteria ............................ 33 
3.6.1 
Criteria for Removal from Protocol Therapy.......................................................... 33 
3.6.2 
Off-Study Criteria ................................................................................................... 33 
3.6.3 
Off-Study Procedure ............................................................................................... 34 
4 
CONCOMITANT MEDICATIONS/MEASURES .............................................................. 34 
4.1 
Supportive Care Guidelines ........................................................................................... 34 
4.1.1 
Pneumonitis: ........................................................................................................... 34 
4.1.2 
Diarrhea/Colitis ....................................................................................................... 34 
4.1.3 
Type 1 diabetes mellitus ......................................................................................... 35 
4.1.4 
Hypophysitis ........................................................................................................... 35 
4.1.5 
Hepatic .................................................................................................................... 36 
4.1.6 
Renal Failure or Nephritis ....................................................................................... 36 
5 
BIOSPECIMEN COLLECTION .......................................................................................... 37 
5.1 
Correlative Studies for Research .................................................................................... 37 
5.2 
NCI Correlative Studies ................................................................................................. 38 
5.2.1 
Immune monitoring ................................................................................................ 38 
5.2.2 
Tumor Biopsy ......................................................................................................... 39 
5.2.3 
Tumor tissue analysis .............................................................................................. 39 
5.3 
Sample Storage, Tracking and Disposition .................................................................... 40 
5.3.1 
Samples Managed by Dr. Figg’s Blood Processing Core (BPC)............................ 40 
5.3.2 
Procedures for Storage of Tissue Specimens in the Laboratory of Pathology ....... 41 


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5.3.3 
Procedures for storage of specimens in the Laboratory of Dr. Greten ................... 41 
5.3.4 
Protocol Completion/Sample Destruction .............................................................. 42 
5.4 
Samples for Genetic/Genomic Analysis ........................................................................ 42 
5.4.1 
Privacy and Confidentiality of medical information/biological specimens ............ 42 
5.4.2 
Management of Results........................................................................................... 42 
6 
DATA COLLECTION AND EVALUATION ..................................................................... 42 
6.1 
Data Collection ............................................................................................................... 42 
6.2 
Data Sharing Plans ......................................................................................................... 43 
6.2.1 
Human Data Sharing Plan ....................................................................................... 43 
6.2.2 
Genomic Data Sharing Plan .................................................................................... 43 
6.3 
Response Criteria ........................................................................................................... 44 
6.3.1 
Definitions............................................................................................................... 44 
6.3.2 
Disease Parameters ................................................................................................. 44 
6.3.3 
Methods for Evaluation of Measurable Disease ..................................................... 45 
6.3.4 
Response Criteria .................................................................................................... 47 
6.3.5 
Duration of Response .............................................................................................. 49 
6.4 
Modified immune-related response criteria (irRC) ........................................................ 49 
6.5 
Toxicity Criteria ............................................................................................................. 49 
7 
NIH REPORTING REQUIREMENTS/DATA AND SAFETY MONITORING PLAN .... 50 
7.1 
Definitions ...................................................................................................................... 50 
7.2 
OHSRP Office of Compliance and Training / IRB Reporting ....................................... 50 
7.2.1 
Expedited Reporting ............................................................................................... 50 
7.2.2 
IRB Requirements for PI Reporting at Continuing Review ................................... 50 
7.3 
NCI Clinical Director Reporting .................................................................................... 50 
7.4 
NIH Required Data and Safety Monitoring Plan ........................................................... 50 
7.5 
Safety Reporting Criteria to the Pharmaceutical Collaborator (Merck) ........................ 50 
7.5.1 
Auditing and Monitoring. ....................................................................................... 50 
7.5.2 
Safety Reports. ........................................................................................................ 51 
8 
STATISTICAL CONSIDERATIONS.................................................................................. 51 
9 
COLLABORATIVE AGREEMENTS ................................................................................. 52 
9.1 
Cooperative Research and Development Agreement (CRADA) ................................... 52 
9.2 
Material Transfer Agreement ......................................................................................... 52 
10 HUMAN SUBJECTS PROTECTIONS ............................................................................... 52 


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10.1 
Rationale For Subject Selection ................................................................................. 52 
10.2 
Participation of Children ............................................................................................ 52 
10.3 
Participation of subjects unable to give consent ......................................................... 52 
10.4 
Evaluation of Benefits and Risks/Discomforts for all participants ............................ 53 
10.4.1 Risk of Optional Biopsy.......................................................................................... 53 
10.4.2 Risks of exposure to ionizing radiation .................................................................. 53 
10.4.3 Research Blood Collection Risks............................................................................ 53 
10.4.4 Other Risks.............................................................................................................. 53 
10.4.5 Benefits ................................................................................................................... 53 
10.5 
Consent Process and Documentation ......................................................................... 53 
10.5.1 Re-Consent via Telephone ...................................................................................... 53 
11 PHARMACEUTICAL INFORMATION ............................................................................. 54 
11.1 
Pembrolizumab ........................................................................................................... 54 
11.1.1 Packaging and Labeling Information ...................................................................... 54 
11.1.2 Stability and Handling of Drug Product ................................................................. 55 
11.1.3 Clinical Supplies Disclosure ................................................................................... 55 
11.1.4 Storage and Handling Requirements ...................................................................... 56 
11.1.5 Returns and Reconciliation ..................................................................................... 56 
11.2 
Oxaliplatin .................................................................................................................. 56 
11.2.1 Toxicity ................................................................................................................... 56 
11.2.2 Formulation ............................................................................................................. 57 
11.2.3 Preparation .............................................................................................................. 57 
11.2.4 General .................................................................................................................... 58 
11.2.5 Stability and Storage ............................................................................................... 58 
11.2.6 Administration procedures ...................................................................................... 58 
11.2.7 Incompatibilities ..................................................................................................... 59 
11.3 
CAPECITABINE ....................................................................................................... 59 
11.3.1 Source ..................................................................................................................... 59 
11.3.2 Toxicity ................................................................................................................... 59 
11.3.3 Formulation and preparation ................................................................................... 61 
11.3.4 Stability and Storage ............................................................................................... 61 
11.3.5 Administration procedures ...................................................................................... 61 
11.3.6 Incompatibilities ..................................................................................................... 62 


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12 REFERENCES ..................................................................................................................... 63 
13 APPENDICES ...................................................................................................................... 69 
13.1 
Appendix A-Performance Status Criteria ................................................................... 69 
13.2 
Appendix B- Modified Immune-Related Response Criteria (irRC) ........................... 70 
13.3 
Appendix C PATIENT’S MEDICATION DIARY ________________________... 72 
 


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1. INTRODUCTION 
1.1 
STUDY OBJECTIVES 
1.1.1 Primary Objective: 
• To determine the 5-month PFS of Pembrolizumab in combination with capecitabine and 
oxaliplatin chemotherapy (CAPOX) in patients with advanced biliary tract carcinoma. 
1.1.2 Secondary Objectives: 
• To determine the safety, tolerability and feasibility of Pembrolizumab in combination 
with capecitabine and oxaliplatin chemotherapy (CAPOX) in patients with advanced 
biliary tract carcinoma. 
• To evaluate the response rate and overall survival in patients with advanced biliary tract 
cancer during and following treatment with Pembrolizumab in combination with 
capecitabine and oxaliplatin chemotherapy (CAPOX) in patients with advanced biliary 
tract carcinoma. 
1.1.3 Exploratory Objectives: 
• To measure changes in PDL1 expression in the tumors of patients with advanced biliary 
tract cancer following treatment with capecitabine and oxaliplatin chemotherapy 
(CAPOX) in patients with advanced biliary tract carcinoma. 
• To measure changes in immune parameters in the peripheral blood and tumors in patients 
with advanced biliary tract cancer following treatment with Pembrolizumab in 
combination with capecitabine and oxaliplatin chemotherapy (CAPOX) in patients with 
advanced biliary tract carcinoma. 
1.2 
BACKGROUND AND RATIONALE 
1.2.1 Biliary tract cancer/Cholangiocarcinoma: current standard of care. 
The term biliary tract carcinoma (BTC) refers primarily to cancers which develop in the 
gallbladder and intra- and extra-hepatic biliary ductal system, although periampullary tumors are 
often considered part of this group as well. BTC is a relatively uncommon diagnosis, and 
randomized studies are few and far between. Among the new cases of BTC that are diagnosed 
every year in the United States, there are approximately 6500 cases of gallbladder carcinoma, 
3000 
cases 
of 
extrahepatic 
cholangiocarcinoma, 
and 
3000 
cases 
of 
intrahepatic 
cholangiocarcinoma[1].  
As is the case for most solid tumors, surgical resection is the only curative approach for patients 
with BTC, although recurrence rates are high and the majority of patients who initially present 
with the disease are not resectable. Patients with periampullary tumors or extrahepatic 
cholangiocarcinomas commonly present with localized disease – primarily because of the early 
development of jaundice – and are more likely to be operable. In contrast, complete surgical 
resection of intrahepatic cholangiocarcinomas is rarely feasible with clear margins. Gallbladder 
carcinoma is frequently identified incidentally at the time of cholecystectomy for presumed 
cholelithiasis, in which case re-exploration and further extended resection is usually advised[2]. 
For metastatic or unresectable disease the modest standard of care for BTC comprises 
gemcitabine in combination with cisplatin chemotherapy, based on the ABC-02 trial in which a 


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total of 410 patients with unresectable locally advanced or metastatic disease were randomly 
assigned to receive gemcitabine with or without cisplatin[3]. Median progression-free and 
overall survival were superior in the combination arm (8.0 versus 5.0 months and 11.7 versus 8.1 
months, respectively; P<0.001), with the benefit seen consistently across the BTC subtypes. For 
patients who progress following first-line therapy there is no outright standard second-line option 
and therapy is usually an extrapolation from agents used in pancreatic or other gastrointestinal 
cancers[4]. Clearly, there is an unmet need here to improve the treatment options at every stage 
for patients diagnosed with this relatively uncommon cancer type.  
1.2.2 Immune-based approaches in gastrointestinal malignancies  
The past number of years have seen much progress for immune-based approaches in solid tumor 
malignancies, with FDA approvals for various strategies, including dendritic cell vaccination 
(prostate cancer) as well as so-called immune checkpoint inhibition, targeting CTLA4 or the 
PD1/PDL1axis (melanoma, lung, kidney cancer)[5-7]. These latter therapies in particular have 
generated enormous excitement across the entire field of oncology, providing real and major 
benefit to a significant minority of patients, as well as teaching us a great deal about the immune 
system in our efforts to predict who will benefit from treatment. Appreciation of the role of 
immune-evasion in developing tumors was evidenced by its inclusion as one of the (updated) 
hallmarks of cancer[8]. The next steps seem to be clear, at least in outline, with current attempts 
in the clinic focusing on identifying those patients who will or will not respond to treatment 
while at the same time expanding the proportion of patients in each cancer type who can 
experience the real and dramatic benefits seen with immune-based approaches. The next frontier 
is for these treatments to prove themselves, even in principle, in diseases which have thus far 
proved relatively refractory. So far, with some notable exceptions, this has unfortunately 
included cancers of the gastrointestinal tract, including BTC. One of the first studies evaluating 
and showing impressive results of PD1/PDL1-directed therapy was disappointing from a GI 
cancer viewpoint[9]. There were no responses in any of cohorts containing patients with 
colorectal (N=18), pancreatic (N=14) and gastric (N=7) cancer. Similarly, negative results for GI 
cancers were seen both in other studies of anti-PD1 therapy and also CTLA4 inhibition[10-12]. 
The notable exceptions to this disappointing, preliminary experience, have been in mismatch 
repair-deficient colorectal cancer – where exceptional responses to PD-1 inhibition have been 
seen – and also hepatocellular carcinoma[13, 14]. The former situation results in a marked 
increase in the non-synonymous mutagenic burden within tumors, thereby – presumably – 
increasing the likelihood that a tumor-specific neoantigen is generated which is recognized by 
the immune system[15]. This of course is relevant for any tumor type which happens to have a 
high mutagenic burden, either because of inherited or acquired mismatch repair deficiency - 
resulting in a degree of microsatellite instability (MSI-hi) – or other factors. In the study by Le et 
al. MSI-hi non-colorectal cancers also responded excellently well and in melanoma and non-
small cell lung cancer mutagenic burden has been associated with benefit to immune checkpoint 
inhibition[16, 17]. The findings of activity of anti-PD1 therapy in HCC are particularly apt for 
cholangiocarcinoma however, given their overlapping etiology and the common basis of both 
tumor types in inflammation. In BTC itself, emerging data suggests clinical activity with 
immune checkpoint inhibition in the clinic and, though very preliminary, is encouraging, 
particularly in the context of the underlying rationale for why this should be the case[18, 19].  


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1.2.3 Inflammation and predisposition to biliary tract carcinoma. 
The causative link and similarity between inflammation and cancer development stretches back 
to the 19th century observations of Rudolph Virchow and, indeed, even two millennia earlier than 
that to the time of the first physicians[20]. Chronic inflammation can greatly facilitate cancer 
development and progression through a number of means, culminating in the development of an 
immunosuppressed microenvironment, whereby host anti-tumor immunity is evaded or 
inhibited[21]. This broad and sometimes paradoxical relationship between cancer and 
inflammation is particularly relevant in BTC, a cancer – like HCC, the other, more prevalent 
primary liver cancer – whose main associated predisposing conditions have chronic 
inflammation as their common underlying pathological denominator. Although the majority of 
patients with BTC will have no identifiable cause on an individual basis, strong associations 
exist between BTC and various disparate inflammatory conditions[22]. The dominant known risk 
factor for gallbladder carcinoma is cholelithiasis-induced chronic inflammation[23], whereas – 
worldwide – infestation of the biliary ducts by parasites or persistent hepatolithiasis are 
important predisposing factors for intrahepatic cholangiocarcinoma[24]. In the US and Europe 
primary biliary cirrhosis and sclerosing cholangitis are all established risk factors for BTC, as are 
causes of intrahepatic inflammation – hepatitis, diabetes, obesity for example – whose 
importance in the etiology of intrahepatic cholangiocarcinoma is being increasingly 
appreciated[25]. Recent studies have linked liver disease associated with the increasing incidence 
of chronic hepatitis C virus infection with intrahepatic cholangiocarcinoma[26], which may 
explain in part the increasing occurrence of this subtype (intrahepatic type) of biliary tract 
cancer[27]. For established cancer the Glasgow prognostic score (GPS), an inflammation-based 
prognostic score, has been shown to predict for postoperative outcome for BTC[28]. 
The finding of an immune role in the etiology of BTC is important because it raises the 
possibility of an immune-based remedy in at least a proportion of patients. This is not only 
relevant for established cancer but also in the long antecedent period of inflammation and pre-
malignancy where the opportunity for prevention exists. It has been shown that cholangiocytes 
have the ability to present antigens and can activate a subset of lymphocytes called Natural Killer 
T (NKT) cells[29]. Primary sclerosing cholangitis (PSC) and primary biliary cirrhosis (PBC) are 
characterized by a marked hepatic mononuclear infiltration, but this is also a feature of other 
chronic liver diseases, including environmentally-driven conditions such as alcoholic 
cirrhosis[30]. As stated above, all of these conditions increase the risk of developing BTC[31]. In 
PSC, a marked CD4+ and CD8+ T-cell infiltration in portal tracts and around bile ducts is 
seen[32]. Interestingly, it seems that the pattern of antigen-driven clonal expansion of T cells 
may vary according to the underlying predisposing condition, with distinct T-cell receptor (TCR) 
signatures reflective of different antigenic repertoires[30]. This was suggested by Liaskou et al. 
who performed high-throughput sequencing of the TCR beta chain complementarity-determining 
region 3 of liver-infiltrating T cells in samples derived from patients with primary sclerosing 
cholangitis, primary biliary cirrhosis and alcoholic cirrhosis[30]. These analyses revealed the 
presence of distinct disease-associated clonotypes which differed by degree. For example, in 
alcohol-related disease, a pronounced oligoclonal nature of liver infiltrating T cells was 
observed, in contrast to a higher diversity amongst T-cells infiltrating PSC.  
1.2.4 Immunogenicity of biliary tract carcinoma. 
The success of immune checkpoint inhibition is dependent first and foremost upon the presence 
of an already existing endogenous anti-tumor immune response, which can then be amplified or 


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disinhibited. In the absence of initial immune recognition this class of agents won’t be effective, 
as – by definition – there will be no adaptive resistance or suppression to overcome. Spontaneous 
immune responses do occur in established BTC. This was illustrated in dramatic fashion by 
Rosenberg and colleagues who performed whole-exome-sequencing on the resected tumor of a 
patient with metastatic chemo-refractory cholangiocarcinoma in order to identify mutations 
which could serve as neo-antigens[33]. By generating tandem minigene (TMG) constructs of 
each of the mutations and co-culturing with expanded populations of the isolated tumor 
infiltrating lymphocytes (TIL), they were able to identify a clonal population of CD4+ T helper 1 
(T(H)1) cells which were reactive to a mutation in erbb2 interacting protein (ERBB2IP) in the 
tumor. Via adoptive transfer of enriched populations of these cells, cultured ex-vivo, the 
investigators could produce persistent tumor regression. This case confirms that tumor-
associated antigen (TAA)-provoked immune responses do occur in cholangiocarcinoma as well 
as illustrating that, in principle, the exact nature of this response can be isolated by currently 
available technologies, quantitatively enhanced, enriched, and then administered back to the 
patient with therapeutic effect[33]. Beyond the proof of concept however, the wider relevance of 
this case to cholangiocarcinoma is uncertain. It was notable in this patient that only 26 
nonsynonymous mutations were identified in the tumor, a relatively low number in comparison 
to, for example, UV-associated melanoma or cigarette-induced lung cancer, where a much 
greater mutagenic burden appears to increase the chances of generating an epitope or epitopes 
capable of inciting a strongly reactive immune response. Cholangiocarcinoma in general is not a 
highly mutated cancer. For example, in 239 cases of BTC in whom whole-exome sequencing 
was performed the median numbers of non-silent somatic mutations across the ICC (N=137 
cases), ECC (N=74 cases) and gallbladder cancer (N=28 cases) subtypes were 39, 35 and 64, 
respectively[34]. Interestingly, in that analysis, a small proportion (5.9%) of cases were 
identified as having a very high number of mutations (median no. = 641), 5 of whom had defects 
in the mismatch-repair apparatus. We have seen already that this population of MSI-hi tumors 
respond excellently well to anti-PD1 therapy[35]. Also, of special interest in this analysis was 
that via unsupervised clustering of global gene expression levels, determined by transcriptome 
sequencing, four molecular subgroups of BTC were elucidated which could be divided into 
prognostic categories. The group which had the poorest prognosis demonstrated enrichment for 
genes involved in the immune system and cytokine activity. The hypermutated tumors were part 
of this cluster and expression of immune checkpoint molecules, including PD-L1, was 
significantly higher in this poor outcome group. This suggests that in addition to the pro-
tumorigenic effects of inflammation, escape from immunity is achieved by the tumor – at least in 
a significant proportion of cases – via the upregulation of targetable (and now FDA-approved) 
strategies. 
Perhaps the best indicator of an already existing, but possibly suppressed, antitumor immunity is 
the presence of immune cells which have already migrated to the tumor. Tumor infiltrating 
lymphocytes (TIL) have been shown in a variety of non-GI cancers to be prognostic as well as 
predictive of efficacy in immune and non-immune therapeutic approaches[36-39]. In melanoma, 
the presence of T-cell-infiltration, particularly those with high CD8 T-cell content, are more 
likely to be associated with PD-L1 expression in tumor cells – making them more susceptible to 
anti-PD1/PDL1 treatment – and an improved prognosis[39]. The presence of TIL has likewise 
been shown to be a favorable prognostic factor in a variety of GI cancers such as colorectal 
cancer and pancreatic cancer[40-42]. Recent evidence has highlighted the link between overall 
mutagenic burden, immune reactivity and – in the case of UV-associated melanoma, cigarette-


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12 
induced lung and MMR-deficient colon cancer especially – dramatic responses to immune 
checkpoint inhibition. However, Tran and colleagues have recently suggested that the 
relationship is more nuanced than that, with the finding – through the same TMG approach 
mentioned above – of immunoreactive TIL even in the setting of low burden mutational 
burden[43]. These investigators found that in patients with gastrointestinal cancers whose tumors 
had, as expected, a low mutation burden (range 10-155) T-cell responses against at least one 
somatic mutation were still present and identifiable in nine out of ten cases.  
In BTC, the prevalence and prognostic relevance of infiltrating T-lymphocytes has also been 
documented. Sabbatino et al. evaluated lymphocyte infiltration (as well as HLA and PDL1 
expression in 27 cases of ICC[44]. All tumor specimens had TIL, and this correlated – as one 
would expect – with HLA expression. Nakakubo et al. investigated the significance of tumor-
infiltrating immune cells in 110 surgically resected biliary tract cancer (gallbladder) 
specimens[45]. They found high levels of CD4+ T cell (51.1%), CD8+ T cell (37.8%), NK cell 
(33.3%), and dendritic cell (48.9%) infiltration. CD4+ and CD8+ T cell infiltration correlated 
with decreasing tumor invasion, and high numbers of infiltrating DCs correlated with decreasing 
lymph-node tumor metastasis. Furthermore, increased infiltration of CD4+ and CD8+ T cells and 
DCs exhibited a significant correlation with prolonged survival. In a similar analysis, Goeppert 
et al. evaluated immune cell infiltration in 375 cases of biliary tract cancer obtained following 
surgical resection[46]. Approximately half the patients had some degree of intraepithelial CD8 T 
cell tumor infiltration and this – in addition to other inflammatory infiltrate – decreased with 
increasing stage of disease. The presence of intraepithelial tumor-infiltrating CD4+ T 
lymphocytes as well as CD8+ T lymphocytes correlated significantly with a longer overall 
survival in BTC patients. Interestingly, patients who had higher total regulatory T lymphocyte 
counts had a better survival outcome. The prognostic value of Tregs in other GI tumor types, 
especially colorectal cancer, has been variable in terms of whether it was a favorable or adverse 
factor[47]. In cholangiocarcinoma cell lines it has been shown that down-regulation of FOXP3 
inhibits tumor cell invasion by reducing the quantity of MMP-9 and MMP-2 as well as 
immunosuppressive cytokines (IL-10 and TGF-b1) produced by the tumor cells leading to better 
T-cell survival, suggesting that FOXP3 plays an important role in the evolution of the malignant 
phenotype[48].  
It was also of note in the large sample analyzed by Goeppert et al that differences were observed 
in the composition of inflammatory infiltrate by anatomical subtype with comparatively less 
CD8+ infiltration in intrahepatic disease relative to extrahepatic disease and gallbladder cancer. 
Indeed, the prognostic significance of the presence of intraepithelial T and B lymphocytes 
pertained only to these subtypes and not to intrahepatic cholangiocarcinoma. The potential 
difference in inflammatory infiltrate according to anatomical subtype noted by Goeppert et al. is 
intriguing, but perhaps not surprising given the differences in molecular derangement or gene 
expression, different cell of origin as well as in incidence, risk factors and indeed outcome[49, 
50]. Although clinically the anatomical subtypes are treated the same (surgical resection if 
technically feasible, gemcitabine-based chemotherapy, radiation) this paradigm has evolved 
more through expediency and clinical trial design or enrollment issues rather than being driven 
by biological considerations. As we move into the immunotherapeutic era we will need to pay 
more attention to this, perhaps by stratification measures to ensure that enough patients in each 
subtype are treated. 


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13 
Given that antigen-specific adaptive responses are brokered by MHC class 1-presentation of 
tumor peptide to T cells, it has been reported by many investigators across many disease types 
that one method of immune evasion is achieved by virtue of changes in expression or 
downregulation of MHC I[51-53]. Indeed, downregulation of MHC I expression is more 
frequently observed in advanced disease stages and tumors which are poorly differentiated[54, 
55]. 
Goeppert et al. analyzed the impact of the expression of MHC I on patient survival in BTC as 
well as the quantitative and qualitative relationship of this factor to tumor-infiltrating immune 
cell types[56]. They evaluated a large cohort of patients (N=334), including extrahepatic (n=129) 
and intrahepatic cholangiocarcinomas (n=146), as well as adenocarcinomas of the gallbladder 
(n=59). In addition, 71 high-grade biliary intraepithelial lesions (BilIN 3) were included. MHC I 
expression was assessed semi-quantitatively and broadly divided into two groups of high and 
low expression patterns, roughly half in half (47.6% Vs 52.4%).There was a trend for higher 
MHC I expression in lower Union for International Cancer Control (UICC) stages (P=0.074) and 
in particular biliary intraepithelial neoplasia (BilIN) 3, where significantly higher MHC I 
expression levels were seen compared to invasive tumors (P=0.004) in addition to a significant 
association between high MHC I expression and low tumor grade. There was also an association 
between MHC I expression and the number of tumor-infiltrating immune cells. Interestingly, the 
investigators found that the associations differed by anatomical subtype. The association between 
inflammatory infiltrate and MHC I expression for the whole cohort pertained to ECC, whereas in 
ICC, MHC I expression was correlated significantly only with the number of tumor-infiltrating 
CD8+ T cells. In GBAC, the smallest cohort, a significant correlation of MHC I expression was 
only seen for CD68+ macrophages. Higher MHC I expression on tumor cells was also 
significantly associated with longer overall survival with patients exhibiting strong MHC I 
expression having an improved median overall survival of 28 months (versus 20 months for low 
expression; P=0.006). Looking at the subtypes the investigators found in their analysis that the 
prognostic significance of MHC I expression on tumor cells, although not reaching statistical 
significance, was by trend stronger in ECC and GBAC compared with ICC, again suggesting that 
mechanisms of immune escape may vary with anatomical subtype.  
PD-L1 expression in tumors, induced by interferon-gamma, has been shown to predict for 
response to PD1-inhibtion[57]. The relationship is not absolute and additional factors exist in the 
tumor microenvironment which contribute to the immunosuppression and dictate the manner of 
response. Nevertheless, PDL1 expression is likely to be the first companion diagnostic to make it 
into clinical practice as a predictive test of benefit to checkpoint inhibition. In BTC Ye et al. 
evaluated the expression of B7-H1 (PD-L1) and its ligand PD-1 in N=31 surgically resected 
cases in addition to the corresponding cancer adjacent tissues[58]. 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. In the analysis by Sabbatino et al. 8 of 27 ICC cases expressed PD-L1[44].  
1.2.5 Translational immune-based efforts in BTC 
There is a paucity of randomized clinical trials for BTC, no doubt because of the relative rarity of 
this tumor type. In addition, the cholangiocarcinoma-specific phase 2 studies which are available 
to patients tend towards the evaluation of chemotherapeutic combinations (e.g. FOLFIRINOX or 
gemcitabine + nab-Paclitaxel) which have already shown efficacy in other indications, and the 


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14 
usefulness of which investigators are attempting to assert in BTC. As a result of this, progress in 
BTC has seemed to lag behind that of other, more common solid tumors, with a dearth of studies 
evaluating new and innovative drugs. Traditionally, BTC patients could for the most part only 
access clinical trials in the phase 1 setting. With the advent of immune-based approaches, this 
paradigm shows signs of change, with less emphasis on the initial dose-escalation phase of drug 
development - important mainly for dose limiting toxicity (DLT) determination in the evaluation 
of cytotoxic agents - in favor of large, basket studies allowing multi-histology cohorts, such as 
the initial anti-PD1 studies[59, 60], in which pure DLT-determination in the first 28days is less 
crucial. Table 2 shows the currently open and accruing studies employing an immune-based 
approach currently available on clinicaltrials.gov and which are specific to BTC or have BTC 
explicitly stated as an eligible histology.  
In terms of published or presented clinical data for immune approaches in BTC the experience in 
the literature is dominated by peptide vaccines, most commonly directed against mucin protein 1 
(MUC1) or Wilm’s Tumor protein 1 (WT1)[61]. These small studies have been well tolerated 
without showing a strong clinical signal of efficacy[62, 63]. For example, Aruga and colleagues 
conducted a small phase I clinical trial evaluating multiple-peptide vaccination for patients with 
advanced BTC[64]. The vaccine selected comprised three cancer-testis antigens that were 
identified using cDNA microarray technology coupled with laser microdissection and which 
were found to be overexpressed in nearly 100% of BTC. Patients were vaccinated on a 
continuous basis even if their disease had progressed. Peptide-specific T cell immune responses 
were observed in all patients and stable disease, prolonged in a couple of cases and associated 
with increased CXCR3+CCR4- T cells, was observed in 5 of 9 patients. The median PFS and OS 
of 3.4 and 9.7 months respectively. The same investigators had earlier tested a different four-
peptide vaccine, similarly well tolerated observing peptide-specific T-cell immune responses in 
seven of nine patients and clinical responses – including two instances of minor response not 
reaching PR criteria - observed in six of nine patients[65]. Dendritic-cell based vaccines have 
also been evaluated, most commonly in combination with standard modalities, such as surgical 
resection and/or chemoradiation, and which complicates assessment of efficacy[66, 67].  
The published or presented experience with immune checkpoint inhibitors is very preliminary. 
Documented response to anti-CTLA4 therapy (with tremelimumab) has been seen, interestingly 
manifesting as a delayed response after initial progression of disease[18]. The early data for anti-
PD1 inhibition (pembrolizumab) has been recently presented, showing encouraging evidence of 
efficacy (17% partial response rate) in BTC, and which seems broadly in line with use of this 
agent in other solid tumor studies where no pre-selection based on PD-L1 expression or MSI 
status was performed[19].  
One of the great advantages and promises of immune-based approaches is the potential role for 
their combination with standard therapies, either cytotoxic agents which have immune-
modulatory effects or strategies such as radiation or interventional radiologic procedures, in 
whom participation of the immune system has been shown to be a determinant in how they 
work[68]. Certain chemotherapeutics can activate rather than suppress the immune system and 
that a robust immune response is a necessary component determining tumor response[69]. 
Gemcitabine is a nucleoside analogue that is part of the standard treatment, and probably the 
most common chemotherapeutic agent used in BTC[3, 70]. The immune effects of gemcitabine 
have been studied perhaps more than for any other drug used in GI cancer. Its effects on the 
immune system are diverse[68]. With regard to BTC Koido et al. demonstrated that in ICC cells 


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15 
isolated from a patient with malignant ascites immunogenic modulation of the cells could be 
induced by gemcitabine with upregulation of MHC class I and II, calreticulin – a modulator or 
immunogenic cell death – MUC1 and WT1 mRNA[71]. Interestingly, the authors found that 
gemcitabine also induced up-regulation of immunosuppressive PDL1, suggesting a potential 
rationale for combination therapy. Ablative therapies are occasionally employed in the 
management of BTC, although with a much smaller role than in HCC for example. Following 
RFA, tumor antigens from necrotic tumor are taken up by antigen-presenting cells (mainly DCs), 
activating tumor-specific immune responses[72, 73]. Ablated tumor tissue promotes DC 
maturation[74, 75]. A tumor-specific immune response may prevent recurrent disease in addition 
to treating distant metastases. Several preclinical and clinical studies have documented an 
increase in peripheral immunity following ablation[74, 76-79]. We are currently conducting a 
study evaluating subtotal RFA in combination with anti-CTLA4 therapy (NCT01853618) in 
patients with HCC and BTC. Provisionally, this approach is feasible and safe, with some early 
evidence of efficacy, which needs to be confirmed with more patient numbers and more mature 
follow-up[80].  
1.2.6 Pembrolizumab 
Pembrolizumab is a potent and highly selective humanized monoclonal antibody (mAb) of the 
immunoglobulin G4 (IgG4)/kappa isotype designed to directly block the interaction between PD-
1 and its ligands, programmed cell death ligand 1 (PD-L1) and programmed cell death ligand 2 
(PD-L2). This blockade enhances functional activity of the target lymphocytes to facilitate tumor 
regression and ultimately immune rejection. 
On 04-Sep-2014, the United States (U.S.) Food and Drug Administration (FDA) granted 
accelerated approval to KEYTRUDA® for treatment of subjects with unresectable or metastatic 
melanoma and disease progression following treatment with ipilimumab (IPI) and, if BRAF 
V600 mutation positive, a BRAF inhibitor. The recommended dose of KEYTRUDA is 2 mg/kg 
administered as an intravenous (IV) infusion over 30 minutes every 3 weeks (Q3W) until disease 
progression or unacceptable toxicity. This indication was approved based on tumor response rate 
and durability of response (data cutoff date 18-Oct-2013) observed in a total of 411 IPI-
refractory plus IPI-naïve melanoma subjects enrolled in P001 and treated with 1 of 3 dose 
regimens of pembrolizumab (2 mg/kg Q3W, 10 mg/kg Q3W, or 10 mg/kg every 2 weeks 
[Q2W]). An improvement in survival or disease-related symptoms had not yet been established 
at the time of the FDA filing. 
On October 24, 2016, the U.S. Food and Drug Administration approved pembrolizumab 
(KEYTRUDA, Merck & Co., Inc.) for the treatment of patients with metastatic non-small cell 
lung cancer (NSCLC) whose tumors express PD-L1 as determined by an FDA-approved test. 
This was the first FDA approval of a checkpoint inhibitor for first-line treatment of lung cancer. 
This approval also expanded the indication in second-line treatment of lung cancer to include all 
patients with PD-L1-expressing NSCLC. 
The FDA approval added the following indications for pembrolizumab: 
• 
Patients with metastatic NSCLC whose tumors have high PD-L1 expression (Tumor 
Proportion Score [TPS] greater than or equal to 50%) as determined by an FDA-approved 
test, with no EGFR or ALK genomic tumor aberrations, and no prior systemic 
chemotherapy treatment for metastatic NSCLC. 


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• 
Patients with metastatic NSCLC whose tumors express PD-L1 (TPS greater than or equal 
to 1%) as determined by an FDA-approved test, with disease progression on or after 
platinum-containing chemotherapy. Patients with EGFR or ALK genomic tumor 
aberrations should have disease progression on FDA-approved therapy for these 
aberrations prior to receiving pembrolizumab. 
Approval was based on results of two randomized, controlled trials that demonstrated 
statistically significant improvements in progression-free survival (PFS) and overall survival 
(OS) for patients randomized to pembrolizumab compared with chemotherapy. 
In a trial of 305 patients who had no prior treatment for metastatic NSCLC and TPS greater than 
or equal to 50%, those who received pembrolizumab (200 mg every 3 weeks) had a significant 
improvement in PFS (HR 0.50 [95% CI: 0.37, 0.68]; p<0.001) with a median PFS of 10.3 
months versus 6.0 months for those receiving platinum-based chemotherapy. A pre-specified 
interim analysis demonstrated a statistically significant improvement in OS for patients 
randomized to pembrolizumab as compared with chemotherapy (HR 0.60 [95% CI: 0.41, 0.89]; 
p<0.005). 
In a three-arm trial of 1033 patients who were previously treated for metastatic NSCLC with a 
TPS greater than or equal to 1%, those randomized to pembrolizumab 2 mg/kg every 3 weeks 
(HR 0.71 (95% CI: 0.58, 0.88]; p<0.001) or pembrolizumab 10 mg/kg every 3 weeks (HR 0.61 
[95% CI: 0.49, 0.75]; p<0.001) had an improved OS compared with patients receiving docetaxel. 
The median survival was 10.4 months in the pembrolizumab 2 mg/kg arm, 12.7 months in the 
pembrolizumab 10 mg/kg arm, and 8.5 months in the docetaxel arm. 
The recommended dose and schedule of pembrolizumab for NSCLC is 200 mg intravenously 
every three weeks. 
1.2.6.1 Nonclinical Pharmacology 
Pembrolizumab binds to human and Cynomolgus monkey PD-1 with comparable affinity and 
blocks the binding of human and Cynomolgus monkey PD-1 to PD-L1 and PD-L2 with 
comparable potency. Pembrolizumab does not cross-react with dog, rat, or mouse PD-1. 
Pembrolizumab does not bind immunoglobulin superfamily members cluster of differentiation 
28 (CD28), cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), or inducible T-cell co-
stimulator (ICOS). 
Pembrolizumab strongly enhances T-lymphocyte immune responses in cultured blood cells from 
healthy human donors, cancer subjects, and nonhuman primates. In T-cell activation assays using 
human donor blood cells, the half-maximal effective concentration (EC50) has been 
approximately 0.1 to 0.3 nM. In addition to interleukin-2 (IL-2), tumor necrosis factor alpha 
(TNFα), interferon gamma (IFNɣ), and levels of other cytokines were found to be modulated by 
pembrolizumab. The antibody potentiates existing immune responses only in the presence of 
antigen and does not nonspecifically activate T-cells. In the in vitro peripheral blood 
mononuclear cell (PBMC) and whole blood cytokine release assays, the cytokine levels induced 
by pembrolizumab were low and comparable to those induced by trastuzumab. Pembrolizumab 
does not induce antibody-dependent cell-mediated cytotoxicity (ADCC) or complement-
dependent cytotoxicity (CDC). 


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Using anti–murine PD-1 surrogate antibodies, PD-1 blockade has been shown to significantly 
inhibit tumor growth in a variety of syngeneic murine tumor models. In these experiments in 
mice, anti–PD-1 therapy is synergistic with chemotherapeutic agents such as gemcitabine and 5-
fluorouracil (5-FU), and combination therapy results in increased complete tumor regression 
rates in vivo. Studies also revealed that immunosuppressive doses of dexamethasone included in 
combination with agents used in standard-of-care treatment for NSCLC do not reduce the anti-
tumor efficacy of an anti–murine PD-1 surrogate antibody. 
1.2.7 Rationale for Dose Selection/Regimen/Modification  
An open-label Phase I trial (Protocol 001) was conducted to evaluate the safety and clinical 
activity of single agent pembrolizumab. The dose escalation portion of this trial evaluated three 
dose levels, 1 mg/kg, 3 mg/kg, and 10 mg/kg, administered every 2 weeks (Q2W) in subjects 
with advanced solid tumors. All three dose levels were well tolerated, and no dose-limiting 
toxicities were observed. This first in human study of pembrolizumab showed evidence of target 
engagement and objective evidence of tumor size reduction at all dose levels (1 mg/kg, 3 mg/kg 
and 10 mg/kg Q2W). No MTD was identified. Recent data from other clinical studies within the 
pembrolizumab program has shown that a lower dose of pembrolizumab and a less frequent 
schedule may be sufficient for target engagement and clinical activity. 
PK data analysis of pembrolizumab administered Q2W and Q3W showed slow systemic 
clearance, limited volume of distribution, and a long half-life. Pharmacodynamic data (IL-2 
release assay) suggested that peripheral target engagement is durable (>21 days). This early PK 
and pharmacodynamic data provides scientific rationale for testing a Q2W and Q3W dosing 
schedule.  
A population pharmacokinetic analysis was performed using serum concentration time data from 
476 patients. Within the resulting population PK model, clearance and volume parameters of 
pembrolizumab were found to be dependent on body weight. The relationship between clearance 
and body weight, with an allometric exponent of 0.59, was within the range observed for other 
antibodies and would support both body weight normalized dosing or a fixed dose across all 
body weights. Pembrolizumab has been found to have a wide therapeutic range based on the 
melanoma indication. The differences in exposure for a 200 mg fixed dose regimen relative to a 
2 mg/kg Q3W body weight-based regimen are anticipated to remain well within the established 
exposure margins of 0.5 – 5.0 for pembrolizumab in the melanoma indication. The exposure 
margins are based on the notion of similar efficacy and safety in melanoma at 10 mg/kg Q3W vs. 
the proposed dose regimen of 2 mg/kg Q3W (i.e. 5-fold higher dose and exposure). The 
population PK evaluation revealed that there was no significant impact of tumor burden on 
exposure. In addition, exposure was similar between the NSCLC and melanoma indications. 
Therefore, there are no anticipated changes in exposure between different indication settings. 
The rationale for further exploration of 2 mg/kg and comparable doses of pembrolizumab in 
solid tumors is based on: 1) similar efficacy and safety of pembrolizumab when dosed at either 2 
mg/kg or 10 mg/kg Q3W in melanoma patients, 2) the flat exposure-response relationships of 
pembrolizumab for both efficacy and safety in the dose ranges of 2 mg/kg Q3W to 10 mg/kg 
Q3W, 3) the lack of effect of tumor burden or indication on distribution behavior of 
pembrolizumab (as assessed by the population PK model) and 4) the assumption that the 
dynamics of pembrolizumab target engagement will not vary meaningfully with tumor type. 


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The choice of the 200 mg Q3W as an appropriate dose for the switch to fixed dosing is based on 
simulations performed using the population PK model of pembrolizumab showing that the fixed 
dose of 200 mg every 3 weeks will provide exposures that 1) are optimally consistent with those 
obtained with the 2 mg/kg dose every 3 weeks, 2) will maintain individual patient exposures in 
the exposure range established in melanoma as associated with maximal efficacy response and 3) 
will maintain individual patients exposure in the exposure range established in melanoma that 
are well tolerated and safe.  
A fixed dose regimen will simplify the dosing regimen to be more convenient for physicians and 
to reduce potential for dosing errors. A fixed dosing scheme will also reduce complexity in the 
logistical chain at treatment facilities and reduce wastage. 
1.2.8 CAPOX in biliary tract carcinomas 
For metastatic or unresectable disease the modest standard of care for BTC comprises 
gemcitabine in combination with cisplatin chemotherapy, based on the ABC-02 trial in which a 
total of 410 patients with unresectable locally advanced or metastatic disease were randomly 
assigned to receive gemcitabine with or without cisplatin[3]. Median progression-free and 
overall survival were superior in the combination arm (8.0 versus 5.0 months and 11.7 versus 8.1 
months, respectively; P<0.001), with the benefit seen consistently across the BTC subtypes. For 
patients who progress following first-line therapy there is no outright standard second-line option 
and therapy is usually an extrapolation from agents used in pancreatic or other gastrointestinal 
cancers[4]. The choice in this study of CAPOX as an acceptable chemotherapy component is an 
extrapolation of the wide use of oxaliplatin/5FU-based combinations in all GI cancers. The use 
of capecitabine (as opposed to infusional 5-FU) has the added convenience of not requiring 
continuous IV infusion. 
2 
ELIGBILITY ASSESSMENT AND ENROLLMENT 
2.1 
ELIGIBILITY CRITERIA 
2.1.1 Inclusion Criteria 
2.1.1.1 Patients must have histopathological confirmation of 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 biliary tract carcinoma. The term BTC includes intra- or extrahepatic 
cholangiocarcinoma, gallbladder cancer or ampullary cancer. 
2.1.1.2 Patients must have disease that is not amenable to potentially curative resection. 
Patients must have received, been intolerant of or refused at least one line of 
chemotherapy.  
2.1.1.3 Patients must have at least one focus of measurable metastatic disease per RECIST 1.1. 
(Section 6.3). 
2.1.1.4 Patients must have at least one focus of metastatic disease that is amenable to pre- and 
on-treatment biopsies. Ideally the biopsied lesion should not be one of the target 
measurable lesions, although this can be up to the discretion of the investigators. 
2.1.1.5 Age >18 years  
2.1.1.6 ECOG performance status 0-1 (see Appendix A) 


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2.1.1.7 Patients must have normal organ and marrow function as defined below: 
leukocytes 
>3,000/mcL 
absolute neutrophil count 
> 1,000/mcL 
platelets 
≥ 100,000/mcL 
total bilirubin 
≤ 2 xULN 
Serum albumin  
≥ 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 for patients with 
creatinine levels above institutional 
normal 
2.1.1.8 Patients must have recovered from any acute toxicity related to prior therapy, including 
surgery. Toxicity should be ≤ grade 1 or returned to baseline. 
2.1.1.9 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). 
2.1.1.10 Patient must be able to understand and willing to sign a written informed consent 
document. 
2.1.1.11 The effects of Pembrolizumab in combination with Capecitabine and Oxaliplatin on the 
developing human fetus are unknown. For this reason, women of child-bearing potential 
and men must agree to use adequate contraception (hormonal or barrier method of birth 
control; abstinence) prior to study entry, for the duration of study participation and up to 
120 days after the last dose of the drug. 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 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. 
2.1.2.2 Previous treatment with immune checkpoint inhibitors. 
2.1.2.3 Patients who have undergone prior liver transplantation are ineligible. 
2.1.2.4 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. 
2.1.2.5 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. 
2.1.2.6 History of (non-infectious) pneumonitis that required steroids, evidence of interstitial 
lung disease or active, non-infectious pneumonitis. 


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2.1.2.7 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.  
2.1.2.8 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  
2.1.2.9 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. 
2.1.2.10 Currently receiving immunosuppressive doses of steroids or other immunosuppressive 
medications (inhaled and topical steroids are permitted) 
2.1.2.11 History of sarcoidosis syndrome. 
2.1.2.12 Known history of active tuberculosis. 
2.1.2.13 Patients should not be vaccinated with live attenuated vaccines within 1 month of 
starting pembrolizumab treatment. 
2.1.2.14 Active hepatitis B or C infection. 
2.1.2.15 HIV-positive patients receiving anti-retroviral therapy are excluded from this study due 
to the possibility of pharmacokinetic interactions between antiretroviral medications 
and pembrolizumab. HIV positive patients not receiving antiretroviral therapy are 
excluded due to the possibility that pembrolizumab may worsen their condition and the 
likelihood that the underlying condition may obscure the attribution of adverse events. 
2.1.2.16 History of hypersensitivity reaction to human or mouse antibody products. 
2.1.2.17 Female patients who are pregnant or breastfeeding. Because there is an unknown but 
potential risk for adverse events in nursing infants secondary to treatment of the mother 
with Pembrolizumab in combination with Capecitabine and Oxaliplatin, breastfeeding 
should be discontinued.  
2.1.2.18 Patients with unhealed surgical wounds for more than 30 days.  
2.1.2.19 Prior therapy with oxaliplatin 
2.1.3 Recruitment Strategies 
The study may be abstracted into a plain language announcement posted on NIH websites, 
including www.clinicaltrials.gov and the CCR website, and on NIH social media platforms. 
Outside providers and colleagues may directly refer patients for screening into this study. 
2.2 
SCREENING EVALUATION 
Studies should be done within 28 days prior to enrollment unless otherwise noted below. 
Note:  Screening evaluation testing/procedures are conducted under the separate screening 
protocol, 01-C-0129 (Eligibility Screening and Tissue Procurement for the NIH Intramural 
Research Program Clinical Protocols). 


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• Complete medical history (including prior hormone use) and physical examination (including 
height, weight, vital signs, EKG, and ECOG performance status). 
• Laboratory Evaluation 
o Hematological profile: CBC with differential and platelet count.  
o Biochemical profile: electrolytes, BUN, creatinine, AST, ALT, total and direct 
bilirubin, calcium, phosphorus, albumin, magnesium,  
o Serum or urine pregnancy test for female participants of childbearing age (in the 
absence of prior hysterectomy).  
o HIV, Hepatitis B and C serology and/or viral load  
o TB testing (if clinically indicated) 
• CT or PET of chest, abdomen and pelvis (or MRI abdomen) 
• Histologic confirmation (at any time point prior to enrollment). 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. If there is no 
available tumor sample, biopsy will be performed to confirm the diagnosis.  
2.3 
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 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. 
2.3.1 Treatment Assignment Procedures (For registration purposes only): 
Cohorts 
Number 
Name 
Description 
1 
1 
Subjects with advanced biliary tract carcinoma 
Arms 
Number Name 
Description 
1 
1 
Pembrolizumab + Oxaliplatin + Capecitabine 
Arm assignment 
Subjects in Cohort 1 will be directly assigned to Arm 1. 


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2.4 
BASELINE EVALUATION 
Tests done at screening do not need to be repeated on baseline if performed in designated time 
frame. 
Within 28 days prior to first dose: 
• CT or PET of chest, abdomen and pelvis (or MRI abdomen)  
• Electrocardiogram  
• HLA phenotype (any time prior to first dose) 
• Optional tumor biopsy for research 
Within 7 days prior to first dose: 
• History and physical exam with vital signs  
Within 72 hours prior to first dose: 
• Serum or urine pregnancy test for female participants of childbearing age (in the 
absence of prior hysterectomy).  
3 
STUDY IMPLEMENTATION 
3.1 
STUDY DESIGN 
The proposed study is a phase II study of Pembrolizumab in combination with CAPOX in 
patients with advanced biliary tract carcinoma. 
 
Group 
N 
PEMBROLIZUMAB 
CapOx 
Previously 
treated BTC 
19 
Day 1: Pembrolizumab 
200mg IV, 30 minutes. 
q-3-weekly until PD 
Day 1: Oxaliplatin 130mg/m2 IV 
over 2 hours  
Days 1–14: Capecitabine 750 mg/m2 
twice daily PO.  
q-3-weekly for 18 weeks 
 


Abbreviated Title: CAPOX Pembrolizumab in BTC  
Version Date: 03/19/2020 
23 
 
 
 
3.2 
SCHEDULE 
Pembrolizumab and Oxaliplatin should be administered on Day 1 of cycles 1-6. Pembrolizumab 
should be infused first and Oxaliplatin should be given at least 30 minutes after Pembrolizumab. 
Capecitabine should be administered orally with first dose the evening of Day 1 of cycles 1-6 
and last dose the morning of day 14 of cycles 1-6, given as intermittent treatment.  
Cycle length is 3 weeks (consisting of 2 weeks of capecitabine treatment followed by 1 week 
without capecitabine treatment).  
Starting in cycle 7, Pembrolizumab should be administered alone on Day 1, continuing once 
every 3 weeks until disease progression.  
Each cycle may start up to 3 days before or after the scheduled Day 1 due to administrative 
reasons. 
3.3 
DRUG ADMINISTRATION 
3.3.1 Pembrolizumab  
Pembrolizumab 200 mg will be administered as a 30-minute IV infusion on Day 1 of each cycle. 
Every effort should be made to target infusion timing to be as close to 30 minutes as possible. 
However, a window of -5 minutes and +10 minutes is permitted (i.e., infusion time is 25 – 40 
mins). Please see section 11.1.2 for preparation instructions. 
3.3.2 CAPOX  
Capecitabine should be administered at a dose of 750 mg/m2 PO every 12 hours (+/- 4 hours 
window is allowed) (equivalent to a total daily dose of 1500 mg/m2). Doses will be rounded 
downward to the nearest 150 mg. Patients will begin Capecitabine dosing on the first day of 
cycles 1-6 and will continue to receive Capecitabine for 14 days. Patients will be instructed to 
take Capecitabine with food. No morning dose should be taken on day 1 of the cycle and no 
D1  
CAPOX 
Screen 
CT Scan 
q9W 
BIOPSY 1 
Stop CAPOX 
Continue Pemb q21d 
until PD 
Immune- 
monitoring 
BIOPSY 2 
D22  
CAPOX 
D43  
CAPOX 
D64 
CAPOX 
D85  
CAPOX 
D106  
CAPOX 
Pemb 
 Pemb 
 Pemb 
 Pemb 
 Pemb 
 Pemb 


Abbreviated Title: CAPOX Pembrolizumab in BTC  
Version Date: 03/19/2020 
24 
evening dose should be taken on day 14 of the cycle. Patents will complete and return Patient’s 
Diary (Appendix C). 
Oxaliplatin should be administered on D1 of cycles 1-6 at a dose of 130mg/m² IV Infusion in 
500mls Glucose 5% over 2 hours. Please see section 11.2.3 for preparation instructions. 
Premedication with ondansetron 8mg and dexamethasone 8mg will be given 15-30 mins prior to 
infusion. 
3.4 
DOSING DELAYS AND MODIFICATIONS 
3.4.1 General guidance 
If, in the opinion of the investigator, a toxicity is considered to be due solely to one drug (e.g. 
hand-foot syndrome secondary to capecitabine, neurotoxicity due to oxaliplatin), the dose of the 
other drug does not require modification.  
When, at the beginning of a treatment cycle, treatment delay related to either oxaliplatin or 
capecitabine treatment alone is indicated, both oxaliplatin and capecitabine treatment should be 
delayed (except in the case of oxaliplatin-related neurological adverse events). Treatment should 
only be restarted when the requirements for restarting both oxaliplatin and capecitabine are met, 
or when oxaliplatin has to be discontinued but the requirements for restarting capecitabine alone 
are met.  
Dose modifications for isolated abnormal hematologic lab values will be based on hematological 
parameters at start of a treatment cycle. There is no scheduled sampling during a treatment cycle 
and thus, no scheduled collection of nadir values.  
If capecitabine must be discontinued permanently due to toxicity, the patient may continue on 
oxaliplatin alone. If the patient has SD or better on study, and both capecitabine and oxaliplatin 
are stopped prematurely for toxicity, the PI may consider continuing pembrolizumab. 
3.4.2 Dose Modifications for Hematologic Toxicity 
Capecitabine 
is 
not 
expected 
to 
worsen 
or 
unduly 
prolong 
episodes 
of 
neutropenia/granulocytopenia. The next treatment cycle can only start if hematologic toxicity has 
recovered to grade ≤ 1. No dose reductions or interruptions will be required for anemia (non-
hemolytic) as it can be satisfactorily managed by transfusions. 
3.4.3 Dose Modifications for Neutropenia for Capecitabine and Oxaliplatin 
 
 
Grade 2  
1.0 ≤ ANC < 1.5 x 109/L 
Platelets > 50 - < 75 x 109/L 
Grade 3  
0.5 ≤ ANC < 1.0 x 109/L 
Platelets > 10 - < 50 x 109/L 
Grade 4  
ANC < 0.5 x 109/L 
Platelets < 10 x 109/L 
1st 
occurrence  
No dose adjustment  
Capecitabine 75% of original 
dose + oxaliplatin 100 mg/m2  
Capecitabine 50% of 
original dose + 
oxaliplatin 85 mg/m2  
2nd 
occurrence  
No dose adjustment  
Capecitabine 75% of original 
dose + oxaliplatin 85 mg/m2  
Stop treatment 
permanently  
3rd 
occurrence  
No dose adjustment  
Stop treatment permanently 
unless it is in the best interest 
of the patient to treat with 
Not applicable  


Abbreviated Title: CAPOX Pembrolizumab in BTC  
Version Date: 03/19/2020 
25 
 
Grade 2  
1.0 ≤ ANC < 1.5 x 109/L 
Platelets > 50 - < 75 x 109/L 
Grade 3  
0.5 ≤ ANC < 1.0 x 109/L 
Platelets > 10 - < 50 x 109/L 
Grade 4  
ANC < 0.5 x 109/L 
Platelets < 10 x 109/L 
capecitabine monotherapy at 
75% of original dose  
3.4.4 Capecitabine 
Given that capecitabine is an FDA-approved agent, dose adjustments and management will be as 
per standard of care, as outlined in the package insert. Capecitabine will be withheld in cases of 
Grade 2 or greater hand-foot syndrome or mucositis that do not respond to medical management. 
Capecitabine will be restarted after the symptoms improved to Grade 1. The dose of 
Capecitabine may be adjusted in the event of recurrent Grade 2 or greater hand-foot syndrome, 
neutropenia, or other Capecitabine toxicities that have not been attributed to other study agents. 
Summary of management of common Capecitabine toxicities  
Toxicity  
Capecitabine dose modification  
Grade 2 hand foot syndrome  
Interrupt until ≤ grade 1. May then restart capecitabine at 
full dose. For second occurrence, hold capecitabine until ≤ 
grade 1, then restart capecitabine one dose level lower 
(75% of starting dose first occurrence, 50% of the starting 
dose the second occurrence, discontinue the third 
occurrence).  
Grade 3 hand foot syndrome  
Interrupt until ≤ grade 1. Then restart capecitabine one 
dose level lower (75% of starting dose first occurrence, 
50% of the starting dose the second occurrence, 
discontinue the third occurrence).  
*Dose reductions for capecitabine  
1. Starting dose  
2. 75% of the starting dose  
3. 50% of the starting dose 
3.4.5 Oxaliplatin  
3.4.5.1 Peripheral neuropathy 
Oxaliplatin is consistently associated with two types of peripheral neuropathy, which includes 
paresthesia and dysesthesias of the hands, feet, and peri-oral region. Patients treated with 
oxaliplatin in this study will be counseled to avoid cold drinks and exposure to cold water or air, 
especially for 3 to 5 days following oxaliplatin administration. 
3.4.5.1.1 Neurologic Toxicity Scale for Oxaliplatin Dose Adjustments 
Description 
Grade 
1st occurrence 
2nd occurrence 
3rd occurrence 
Paresthesia/dysesthesias that 
do not interfere with function  
1 
no dose reduction  
no dose reduction  no dose reduction  
Paresthesia/dysesthesias, 
interfering with function, but 
not activities of daily living 
(ADL)  
2 
no dose reduction  
no dose reduction  100 mg/m2  


Abbreviated Title: CAPOX Pembrolizumab in BTC  
Version Date: 03/19/2020 
26 
Description 
Grade 
1st occurrence 
2nd occurrence 
3rd occurrence 
Paresthesia/dysesthesias b 
with pain or with functional 
impairment that also 
interfere with ADL  
3 
no dose reduction  
100 mg/m2  
Stop treatment 
permanently  
Persistent 
paresthesia/dysesthesias that 
are disabling or life-
threatening  
4 
Stop treatment 
permanently  
Stop treatment 
permanently  
Stop treatment 
permanently  
ACUTE: (during or after the 2-hour 
infusion) laryngopharyngeal 
dysesthesias  
increase duration 
of next infusion to 
6 hours  
N/A  
N/A  
 
3.4.5.2 Laryngopharyngeal dysesthesias 
An unusual laryngopharyngeal dysesthesia, a loss of sensation of breathing (acute respiratory 
distress) without any objective evidence of respiratory distress (hypoxia, laryngospasm, or 
bronchospasm), also has been observed. This neurotoxicity may be induced or exacerbated upon 
exposure to cold. 
If a patient develops laryngopharyngeal dysesthesia, the patient’s oxygen saturation should be 
evaluated via a pulse oximeter and, if normal, reassurance, a benzodiazepine or other anxiolytic 
agent should be considered and the patient should be observed in the clinic until the episode has 
resolved. The oxaliplatin infusion may then be continued at 1/3 the rate. Because this syndrome 
may be associated with the rapidity of oxaliplatin infusion, subsequent doses of oxaliplatin 
should be administered as 6-hour infusions (instead of the normal 2-hour infusion). 
Patients on oxaliplatin should not receive cold drinks or ice chips on Day 1 of each cycle as this 
may exacerbate oral or throat dysesthesias, as well as laryngopharyngeal dysesthesia. 
3.4.5.3 Allergic reactions 
For Grade 1 or 2 acute hypersensitivity reactions, no dose modification of oxaliplatin is required 
if, in the investigator’s opinion, it is in the patient’s best interest to continue. Pre-medication with 
dexamethasone 20 mg IV, diphenhydramine 50 mg IV, and one of the following: cimetidine 300 
mg IV, ranitidine 50 mg IV, or famotidine 20 mg IV 30 minutes prior to study drug 
administration is suggested. If an allergic reaction persists into the next cycle, administer 50 mg 
dexamethasone PO 12 hours and 6 hours prior to administration of oxaliplatin. 
For Grade 3 or 4 acute hypersensitivity reactions, treatment with oxaliplatin should be 
discontinued. 
3.4.6 Pembrolizumab  
The following broad guidelines for dose delivery schedule delays and alternations apply to 
pembrolizumab and are dependent on the clinical and laboratory assessment on the day of 
dosing. Pembrolizumab can be delivered within 72 hours of planned interval to accommodate 
scheduling issues/logistics.  
Based on the mechanism of action of pembrolizumab leading to T-cell activation and 
proliferation, there is the possibility of observing irAEs during the conduct of this study. 


Abbreviated Title: CAPOX Pembrolizumab in BTC  
Version Date: 03/19/2020 
27 
Potential irAEs may be similar to those seen with the use of ipilimumab, BMS-936558 (anti-PD-
1 mAb), and BMS-936559 (anti-PD-L1 mAb) and may include immune-mediated enterocolitis, 
dermatitis, hepatitis (hepatotoxicity), and endocrinopathies[6, 59, 60]. These AEs are 
inflammatory in nature and can affect any organ.  
Subjects should be monitored for signs and symptoms of irAEs. In the absence of an alternate 
etiology (e.g., infection or PD), an immune-related etiology should be considered for signs or 
symptoms of enterocolitis, dermatitis, hepatitis, and endocrinopathy. In addition to the dose 
modifications shown in Table 1, it is recommended that management of irAEs follow the 
guidelines outlined for ipilimumab[81]. These guidelines recommend the following: 
1. Subjects should be evaluated to identify any alternative etiology 
2. In the absence of clear alternative etiology, all events of an inflammatory nature should 
be considered to be immune-related 
3. Symptomatic and topical therapy should be considered for low grade events (all Grade 1 
events, dermatologic and pruritus Grade 2 events). 
4. Systemic corticosteroids should be considered for a persistent low-grade event or for a 
more severe event  
5. More potent immunosuppressives should be considered for events not responding to 
systemic steroids (e.g., infliximab, mycophenolate, etc.). 
Dose modifications will not be required for AEs that are clearly not attributed to pembrolizumab 
(such as an accident) or for laboratory abnormalities that are not deemed to be clinically 
significant, or which are ascribable to CAPOX. Dose reductions of pembrolizumab are not 
permitted. 
General guidelines regarding dose modification are provided in Table 1. All toxicities will be 
graded according to NCI CTCAE v4.0. 
Dosing interruptions are permitted in the case of medical / surgical events or logistical reasons 
not related to study therapy (e.g., elective surgery, unrelated medical events, patient vacation, 
and/or holidays). Subjects should be placed back on study therapy within 3 weeks of the 
scheduled interruption. The reason for interruption should be documented in the patient's study 
record. 


Abbreviated Title: CAPOX Pembrolizumab in BTC  
Version Date: 03/19/2020 
28 
Table 1: Dose Modification Guidelines for Drug-Related Adverse Events, version 10-22-2017 
General instructions: 
1. Corticosteroid taper should be initiated upon AE improving to Grade 1 or less and continue to taper over at least 4 weeks. 
2. For situations where pembrolizumab has been withheld, pembrolizumab can be resumed after AE has been reduced to Grade 1 or 0 and 
corticosteroid has been tapered. Pembrolizumab should be permanently discontinued if AE does not resolve within 12 weeks of last dose or 
corticosteroids cannot be reduced to ≤10 mg prednisone or equivalent per day within 12 weeks.  
3. For severe and life-threatening irAEs, IV corticosteroid should be initiated first followed by oral steroid. Other immunosuppressive treatment 
should be initiated if irAEs cannot be controlled by corticosteroids. 
 
 
Immune-related 
AEs 
Toxicity grade or 
conditions 
(CTCAEv4.0) 
Action taken to 
pembrolizumab 
irAE management with 
corticosteroid and/or other 
therapies  
Monitor and follow-up  
Pneumonitis  
Grade 2 
Withhold  
• Administer corticosteroids (initial 
dose of 1-2 mg/kg prednisone or 
equivalent) followed by taper 
 
• 
Monitor participants for signs and 
symptoms of pneumonitis 
• 
Evaluate participants with suspected 
pneumonitis with radiographic imaging and 
initiate corticosteroid treatment 
• 
Add prophylactic antibiotics for 
opportunistic infections 
Grade 3 or 4, or 
recurrent Grade 2 
Permanently 
discontinue 
Diarrhea / Colitis  Grade 2 or 3 
Withhold 
• Administer corticosteroids (initial 
dose of 1-2 mg/kg prednisone or 
equivalent) followed by taper 
 
• 
Monitor participants for signs and symptoms 
of enterocolitis (i.e., diarrhea, abdominal 
pain, blood or mucus in stool with or 
without fever) and of bowel perforation 
(i.e., peritoneal signs and ileus). 
• 
Participants with ≥ Grade 2 diarrhea 
suspecting colitis should consider GI 
consultation and performing endoscopy to 
rule out colitis.  
• 
Participants with diarrhea/colitis should be 
advised to drink liberal quantities of clear 
fluids.  If sufficient oral fluid intake is not 
feasible, fluid and electrolytes should be 
substituted via IV infusion. 
Grade 4 
Permanently 
discontinue 
AST / ALT 
elevation or 
Grade 2 
Withhold 
• Administer corticosteroids (initial 
dose of 0.5- 1 mg/kg prednisone or 
equivalent) followed by taper 
• 
Monitor with liver function tests (consider 
weekly or more frequently until liver 
enzyme value returned to baseline or is 


Abbreviated Title: CAPOX Pembrolizumab in BTC  
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29 
Immune-related 
AEs 
Toxicity grade or 
conditions 
(CTCAEv4.0) 
Action taken to 
pembrolizumab 
irAE management with 
corticosteroid and/or other 
therapies  
Monitor and follow-up  
Increased 
bilirubin 
Grade 3 or 4  
Permanently 
discontinue 
• Administer corticosteroids (initial 
dose of 1-2 mg/kg prednisone or 
equivalent) followed by taper 
stable 
Type 1 diabetes 
mellitus (T1DM) 
or 
Hyperglycemia 
 
Newly onset 
T1DM or  
Grade 3 or 4 
hyperglycemia 
associated with 
evidence of β-cell 
failure 
Withhold 
• Initiate insulin replacement 
therapy for participants with 
T1DM  
• Administer anti-hyperglycemic in 
participants with hyperglycemia  
 
• 
Monitor participants for hyperglycemia or 
other signs and symptoms of diabetes. 
Hypophysitis 
Grade 2 
Withhold 
• Administer corticosteroids and 
initiate hormonal replacements as 
clinically indicated.   
 
• 
Monitor for signs and symptoms of 
hypophysitis (including hypopituitarism and 
adrenal insufficiency)  
Grade 3 or 4  
Withhold or 
permanently 
discontinue1  
Hyperthyroidism  
Grade 2 
Continue  
• Treat with non-selective beta-
blockers (e.g., propranolol) or 
thionamides as appropriate  
• 
Monitor for signs and symptoms of thyroid 
disorders.  
 
Grade 3 or 4  
Withhold or  
permanently 
discontinue1 
Hypothyroidism 
Grade 2-4 
Continue  
• Initiate thyroid replacement 
hormones (e.g., levothyroxine or 
liothyroinine) per standard of care 
• 
Monitor for signs and symptoms of thyroid 
disorders.  
 
Nephritis and 
Renal 
dysfunction 
Grade 2 
Withhold  
• Administer corticosteroids 
(prednisone 1-2 mg/kg or 
equivalent) followed by taper. 
• 
Monitor changes of renal function 
 
Grade 3 or 4  
Permanently 
discontinue 
Myocarditis 
Grade 1 or 2 
Withhold 
• Based on severity of AE 
administer corticosteroids 
• 
Ensure adequate evaluation to confirm 
etiology and/or exclude other causes 


Abbreviated Title: CAPOX Pembrolizumab in BTC  
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30 
Immune-related 
AEs 
Toxicity grade or 
conditions 
(CTCAEv4.0) 
Action taken to 
pembrolizumab 
irAE management with 
corticosteroid and/or other 
therapies  
Monitor and follow-up  
Grade 3 or 4 
Permanently 
discontinue 
 
All other 
immune-related 
AEs 
Intolerable/ 
persistent Grade 2 
Withhold 
• Based on type and severity of AE 
administer corticosteroids  
• 
Ensure adequate evaluation to confirm 
etiology and/or exclude other causes 
 
Grade 3 
Withhold or 
discontinue based 
on the type of 
event.  Events that 
require 
discontinuation 
include and not 
limited to:  
Gullain-Barre 
Syndrome, 
encephalitis 
Grade 4 or 
recurrent Grade 3  
Permanently 
discontinue 
1. Withhold or permanently discontinue pembrolizumab is at the discretion of the investigator or treating physician.   
NOTE:  
For participants with Grade 3 or 4 immune-related endocrinopathy where withhold of pembrolizumab is required, pembrolizumab may be resumed 
when AE resolves to ≤ Grade 2 and is controlled with hormonal replacement therapy or achieved metabolic control (in case of T1DM).   
 
 


Abbreviated Title: CAPOX Pembrolizumab in BTC  
Version Date: 03/19/2020 
31 
3.5 
STUDY CALENDAR 
 
Screening 
Baseline 
Cycles 1-65 
Cycle 7- to 
PD5 
EOT9 
Follow 
Up10 
Pembrolizumab 1 
 
 
X 
X 
 
 
Oxaliplatin2 
 
 
X 
 
 
 
Capecitabine3 
 
 
X 
 
 
 
Informed consent  
X 
 
 
 
 
 
Medical history 4  
X 
X 
 
 
 
 
Concomitant meds 
 
 
X 
X 
 
 
Adverse event 
evaluation  
 
 
X 
X 
X 
 
Physical exam 4 
X 
X 
X 
X 
X 
 
Vital signs4 
X 
X 
X 
X 
X 
 
Height  
X 
 
 
 
 
 
Weight4 
X 
 
X 
X 
 
 
Performance  
Status4  
X 
 
X 
X 
X 
 
CBC w/differential, 
Platelets 4 
X 
 
X13 
X13 
X 
 
PT, INR, PTT, 
Fibrinogen 
 
 
X13 
X13 
X 
 
Serum chemistry 4, 
12 
X 
 
X13 
X13 
X 
 
HIV, Hepatitis B 
and C serology 
and/or viral load  
X 
 
 
 
 
 
HLA  
 
X 
 
 
 
 
Thyroid Panel 
 
 
X13 
X13 
X 
 
TB testing (if 
clinically indicated) 
X 
 
 
 
 
 
Serum or urine 
pregnancy test4 
X 
X 
 
 
 
 


Abbreviated Title: CAPOX Pembrolizumab in BTC  
Version Date: 03/19/2020 
32 
 
Screening 
Baseline 
Cycles 1-65 
Cycle 7- to 
PD5 
EOT9 
Follow 
Up10 
Tumor markers: 
aFP, CEA or Ca 
19.94 
 
 
X13 
X13 
 
 
EKG4 
X 
X 
 
 
 
 
Confirmation of dx 
by NCI LP 
X 
 
 
 
 
 
Restaging 
radiologic 
Evaluation4  
X 
X 
X6 
X6 
 
 
Optional Tumor 
biopsy 
 
X 
X7 
 
 
 
Immune monitoring 
11 
 
 
X 
X 
 
 
Blood for TCR beta 
sequencing14 
 
 
X 
X 
 
 
Advance Directive8 
 
X 
 
 
 
 
Annual telephone 
contact 
 
 
 
 
 
X 
1 200 mg of Pembrolizumab will be administered as a 30-minute IV infusion Day 1 of each 
cycle. 
2 Oxaliplatin will be administered on D1 of each cycle at a dose of 130mg/m² IV 
3 Capecitabine will be administered at a dose of 750 mg/m2 PO every 12 hours. Doses will be 
rounded downward to the nearest 150 mg. Patients will begin Capecitabine dosing on the Day 1 
of each cycle and will continue to receive Capecitabine for 14 days. 
4 Tests performed at screening do not need to be repeated on baseline or Cycle 1 Day 1 if 
performed in designated time frame  
5 Each cycle is 21 days. Trial treatment may be administered up to 3 days before or after the 
scheduled Day 1 of each cycle due to administrative reasons.  
6 CT/PET/MRI of chest abdomen and pelvis. Restaging scans every 9 weeks +/- 7 days. 
7 Performed on cycle 3 Day 1 only +/- 7 days 
8 As indicated in section 10.3, 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. 


Abbreviated Title: CAPOX Pembrolizumab in BTC  
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33 
9 The off-treatment visits/labs will occur if patient is agreeable to coming back and physically 
able to return for the visit. This visit may 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. 
10 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)  
11 Immune monitoring on Day 1 of cycles 1-4, then every 12 weeks until PD, +/-48 hours’ time 
window applies  
12 Electrolytes, BUN, creatinine, AST, ALT, total and direct bilirubin, calcium, phosphorus, 
albumin, magnesium, uric acid, amylase. Uric acid and amylase do not need to be done on 
screening 
13 Within 48 hours prior to study drug 
14 D1 of each cycle until PD, +/-48 hours’ time window applies 
3.6 
CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF STUDY CRITERIA 
Prior to removal from study, effort must be made to have all subjects complete a safety visit 
approximately 30 days following the last dose of study therapy 
3.6.1 Criteria for Removal from Protocol Therapy 
Treatment may continue until one of the following criteria applies: 
• Disease progression (per immune-related response criteria). 
• Intercurrent illness that prevents further administration of treatment 
• Unacceptable toxicity as defined in section 3.4 
• Participant requests to be withdrawn from active therapy 
• General or specific changes in the patient's condition render the patient unacceptable for 
further treatment in the judgment of the investigator 
• Delayed recovery from toxicity that prevents re-treatment in ≤ 28 days of scheduled 
therapy  
• Investigator discretion 
• Positive pregnancy test 
3.6.2 Off-Study Criteria 
• Participant requests to be withdrawn from study 
• Investigator discretion 
• Death 
• PI decision to end the study 


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34 
3.6.3 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. 
4.1 
SUPPORTIVE CARE GUIDELINES 
Subjects should receive appropriate supportive care measures as deemed necessary by the 
treating investigator. Suggested supportive care measures for the management of adverse events 
with potential immunologic etiology are outlined below. Where appropriate, these guidelines 
include the use of oral or intravenous treatment with corticosteroids as well as additional anti-
inflammatory agents if symptoms do not improve with administration of corticosteroids. Note 
that several courses of steroid tapering may be necessary as symptoms may worsen when the 
steroid dose is decreased. For each disorder, attempts should be made to rule out other causes 
such as metastatic disease or bacterial or viral infection, which might require additional 
supportive care. The treatment guidelines are intended to be applied when the investigator 
determines the events to be related to pembrolizumab.  
Note: if after the evaluation the event is determined not to be related, the investigator does not 
need to follow the treatment guidance (as outlined below).  
It may be necessary to perform conditional procedures such as bronchoscopy, endoscopy, or skin 
photography as part of evaluation of the event.  
4.1.1 Pneumonitis:  
• For Grade 2 events, treat with systemic corticosteroids. When symptoms improve to 
Grade 1 or less, steroid taper should be started and continued over no less than 4 weeks. 
• For Grade 3-4 events, immediately treat with intravenous steroids. Administer additional 
anti-inflammatory measures, as needed. 
• Add prophylactic antibiotics for opportunistic infections in the case of prolonged steroid 
administration. 
4.1.2 Diarrhea/Colitis  
• Subjects should be carefully monitored for signs and symptoms of enterocolitis (such as 
diarrhea, abdominal pain, blood or mucus in stool, with or without fever) and of bowel 
perforation (such as peritoneal signs and ileus).  
• All subjects who experience diarrhea/colitis should be advised to drink liberal quantities 
of clear fluids. If sufficient oral fluid intake is not feasible, fluid and electrolytes should 


Abbreviated Title: CAPOX Pembrolizumab in BTC  
Version Date: 03/19/2020 
35 
be substituted via IV infusion. For Grade 2 or higher diarrhea, consider GI consultation 
and endoscopy to confirm or rule out colitis. 
• For Grade 2 diarrhea/colitis, administer oral corticosteroids.  
• For Grade 3 or 4 diarrhea/colitis, treat with intravenous steroids followed by high dose 
oral steroids.  
• When symptoms improve to Grade 1 or less, steroid taper should be started and 
continued over no less than 4 weeks. 
4.1.3 Type 1 diabetes mellitus  
• (if new onset, including diabetic ketoacidosis [DKA]) or ≥ Grade 3 Hyperglycemia, if 
associated with ketosis (ketonuria) or metabolic acidosis (DKA) 
• For T1DM or Grade 3-4 Hyperglycemia 
• Insulin replacement therapy is recommended for Type I diabetes mellitus and for Grade 
3-4 hyperglycemia associated with metabolic acidosis or ketonuria.  
• Evaluate patients with serum glucose and a metabolic panel, urine ketones, glycosylated 
hemoglobin, and C-peptide.  
4.1.4 Hypophysitis 
• For Grade 2 events, treat with corticosteroids. When symptoms improve to Grade 1 or 
less, steroid taper should be started and continued over no less than 4 weeks. 
Replacement of appropriate hormones may be required as the steroid dose is tapered. 
• For Grade 3-4 events, treat with an initial dose of IV corticosteroids followed by oral 
corticosteroids. When symptoms improve to Grade 1 or less, steroid taper should be 
started and continued over no less than 4 weeks. Replacement of appropriate hormones 
may be required as the steroid dose is tapered. 
• Hyperthyroidism or Hypothyroidism  
• Thyroid disorders can occur at any time during treatment. Monitor patients for changes in 
thyroid function (at the start of treatment, periodically during treatment, and as indicated 
based on clinical evaluation) and for clinical signs and symptoms of thyroid disorders. 
• Grade 2 hyperthyroidism events (and Grade 2-4 hypothyroidism) 
o In hyperthyroidism, non-selective beta-blockers (e.g. propranolol) are suggested as 
initial therapy. 
o In hypothyroidism, thyroid hormone replacement therapy, with levothyroxine or 
liothyronine, is indicated per standard of care. 
4.1.4.1 Grade 3-4 hyperthyroidism  
Treat with an initial dose of IV corticosteroid followed by oral corticosteroids. When symptoms 
improve to Grade 1 or less, steroid taper should be started and continued over no less than 4 
weeks. Replacement of appropriate hormones may be required as the steroid dose is tapered. 


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4.1.5 Hepatic 
• For Grade 2 events, monitor liver function tests more frequently until returned to baseline 
values (consider weekly). 
Treat with IV or oral corticosteroids 
• For Grade 3-4 events, treat with intravenous corticosteroids for 24 to 48 hours.  
• When symptoms improve to Grade 1 or less, a steroid taper should be started and 
continued over no less than 4 weeks. 
4.1.6 Renal Failure or Nephritis 
• For Grade 2 events, treat with corticosteroids. 
• For Grade 3-4 events, treat with systemic corticosteroids. 
• When symptoms improve to Grade 1 or less, steroid taper should be started and 
continued over no less than 4 weeks.  
Management of Infusion Reactions: Signs and symptoms usually develop during or shortly after 
drug infusion and generally resolve completely within 24 hours of completion of infusion.  
Table 2 below shows treatment guidelines for subjects who experience an infusion reaction 
associated with administration of pembrolizumab (MK-3475). 
Table 2: Treatment guidelines for those who experience infusion reaction associated with 
pembrolizumab. 
NCI CTCAE Grade 
Treatment 
Premedication at subsequent 
dosing 
Grade 1 
Mild 
reaction; 
infusion 
interruption 
not 
indicated; 
intervention not indicated 
Increase monitoring of vital signs as 
medically indicated until the subject is 
deemed medically stable in the opinion of 
the investigator. 
None 
Grade 2 
Requires infusion interruption but 
responds promptly to symptomatic 
treatment 
(e.g., 
antihistamines, 
NSAIDS, narcotics, IV fluids); 
prophylactic 
medications 
indicated for < =24 hrs. 
Stop Infusion and monitor symptoms. 
Additional appropriate medical therapy may 
include but is not limited to: 
IV fluids 
Antihistamines 
NSAIDS 
Acetaminophen 
Narcotics 
Increase monitoring of vital signs as 
medically indicated until the subject is 
deemed medically stable in the opinion of 
the investigator. 
If symptoms resolve within one hour of 
stopping drug infusion, the infusion may be 
restarted at 50% of the original infusion rate 
Subject may be pre-medicated 
1.5h (± 30 minutes) prior to 
infusion 
of 
pembrolizumab 
(MK-3475) with: 
 
Diphenhydramine 50 mg po (or 
equivalent 
dose 
of 
antihistamine). 
 
Acetaminophen 500-1000 mg 
PO (or equivalent dose of 
antipyretic). 


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NCI CTCAE Grade 
Treatment 
Premedication at subsequent 
dosing 
(e.g., from 100 mL/hr. to 50 mL/hr.). 
Otherwise dosing will be held until 
symptoms resolve and the subject should be 
pre-medicated for the next scheduled dose. 
Subjects who develop Grade 2 toxicity 
despite adequate premedication should 
be 
permanently 
discontinued 
from 
further trial treatment administration. 
Grades 3 or 4 
Grade 3: 
Prolonged 
(i.e., 
not 
rapidly 
responsive 
to 
symptomatic 
medication 
and/or 
brief 
interruption 
of 
infusion); 
recurrence of symptoms following 
initial 
improvement; 
hospitalization indicated for other 
clinical 
sequelae 
(e.g., 
renal 
impairment, pulmonary infiltrates) 
Grade 4: 
Life-threatening; 
pressor 
or 
ventilatory support indicated 
Stop Infusion. 
Additional appropriate medical therapy may 
include but is not limited to: 
IV fluids 
Antihistamines 
NSAIDS 
Acetaminophen 
Narcotics 
Oxygen 
Pressors 
Corticosteroids 
Epinephrine 
 
Increase monitoring of vital signs as 
medically indicated until the subject is 
deemed medically stable in the opinion of 
the investigator. 
Hospitalization may be indicated. 
Subject is permanently discontinued 
from 
further 
trial 
treatment 
administration. 
No subsequent dosing 
Appropriate resuscitation equipment should be available in the room and a physician readily available during the 
period of drug administration. 
 
 
5 
BIOSPECIMEN COLLECTION 
5.1 
CORRELATIVE STUDIES FOR RESEARCH 
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. 


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Test/assay 
Volume 
blood 
(approx.) 
Type 
of 
tube 
Collection 
point 
(+/- 48hrs) 
Location of specimen 
analysis2 
Immune- monitoring 120mls (for 
PBMC) 
EDTA 
See Study 
Calendar 3.5 
Greten Lab 
5-10mls (for 
serum) 
EDTA 
Immune cell 
infiltration (e.g. 
CD3+ CD4/8 cells 
etc.) as well as other 
surface markers 
such as PD-L1. 
Optional tumor 
biopsy 
NA 
Baseline and Cycle 
3 Day 1 +/- 7 days 
Greten Lab 
RNA Nanostring 
analysis 
(nCounterPan 
Cancer Immunology 
Profile)  
Optional tumor 
biopsy 
 
Cycle 3 Day 1 +/- 
7 days 
Greten Lab  
TCR beta 
sequencing. 
Optional tumor 
biopsy 
 
Cycle 3 Day 1 +/- 
7 days 
Adaptive 
Biotechnologies1. 
TCR beta 
sequencing. 
PBMC 
EDTA, 5 
ml 
See Study 
Calendar 3.5 
Adaptive 
Biotechnologies1  
 
1 Lara Gruye, Adaptive Biotechnologies, 1551 Eastlake Ave E #200, Seattle, WA 98102 (855) 
466-8667. Coded linked samples without key will be sent to Adaptive Biotechnologies. 
2 Blood samples will initially be sent to the Figg laboratory for barcoding and storage.  
5.2 
NCI CORRELATIVE STUDIES 
5.2.1 Immune monitoring 
• 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 tumor-associated antigens using tetramer assay.  
• Patients will undergo blood sampling (c.120mls blood) on the time points outlined in the 
Study Calendar 3.5. 12 purple EDTA tubes will be used. 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.  
• 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.  


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5.2.2 Tumor Biopsy 
An optional tumor biopsy will be performed at baseline for analysis of PD-L1 expression as well 
as other factors such as immune infiltration. We will also attempt an optional CT guided biopsy 
at a subsequent timepoint (after 6 weeks) if the patient is willing and the procedure can be 
performed safely. Tumor Tissue will be processed by the Department of Pathology, NCI, NIH 
(Dr. David Kleiner). Two core biopsies will be the 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 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. 
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.  
5.2.3 Tumor tissue analysis 
Tumor samples from biopsies will be send to the pathology for cancer evaluation, only leftover 
samples will be used for research.  
(i) IHC will be performed on tumor tissue for assessment of immune cell infiltration (e.g. CD3+ 
CD4/8 cells etc.) as well as other surface markers such as PD-L1. 
(ii) Tumor samples will also be used for Nanostring analysis (nCounterPan Cancer Immunology 
Profile) and TCR beta sequencing. 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 is specified in Material Transfer Agreement between NCI and Adaptive 
Biotechnologies. Fewer than 100 genes will be analyzed. For TCR Beta Sequencing 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. 


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5.3 
SAMPLE STORAGE, TRACKING AND DISPOSITION 
Samples will be ordered in CRIS Screens 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 Blood Processing Core (BPC) for processing and storage until they 
are distributed to Dr. Greten’s lab sample analysis as described in the protocol. Samples will not 
be sent outside NIH without appropriate approvals and/or agreements, if required.  
5.3.1 Samples Managed by Dr. Figg’s Blood Processing Core (BPC)  
5.3.1.1 BPC contact information  
Please e-mail at NCIBloodcore@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 NCIBloodcore@mail.nih.gov. 
5.3.1.2 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.  
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.). 
Sample bar-codes are linked to patient demographics and limited clinical information. This 
information will only be provided to investigators listed on this protocol, via registered use of the 
LABrador. It is critical that the sample remains linked to patient information such as race, age, 
dates of diagnosis and death, and histological information about the tumor, in order to correlate 
genotype with these variables 
5.3.1.3 Sample Storage  
Barcoded samples are stored in barcoded boxes in a locked freezer at either -20 or -80°C 
according to stability requirements. These freezers are located onsite in the BPC and offsite at 
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 


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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 NIH Intramural 
IRB approval. 
Following completion of this study, samples will remain in storage as detailed above. Access to 
these samples will only be granted following NIH Intramural IRB approval of an additional 
protocol, granting the rights to use the material. 
If, at any time, a patient withdraws from the study and does not wish for their existing samples to 
be utilized, the individual must provide a written request. Following receipt of this request, the 
samples will be destroyed (or returned to the patient, if so requested). 
The PI will record any loss or unanticipated destruction of samples as a deviation. Reports will 
be made per the requirements of section 7.2. 
5.3.2 Procedures for Storage of Tissue Specimens in the Laboratory of Pathology 
Tissues designated for clinical diagnostics are transported to the Laboratory of Pathology (LP) 
where they are examined grossly and relevant portions are fixed, embedded in paraffin and 
sectioned and stained for diagnostic interpretation. Unutilized excess tissues are stored for up to 
three months, in accordance with College of American Pathologists/Joint Commission on 
Accreditation of Healthcare Organizations (CAP/JCAHO) guidelines, and then discarded. 
Following completion of the diagnostic workup, the slides and tissue blocks are stored 
indefinitely in the LP’s clinical archives. All specimens are catalogued and retrieved utilizing the 
clinical laboratory information systems, in accordance with CAP/JCAHO regulations. The use of 
any stored specimens for research purposes is only allowed when the appropriate IRB approval 
has been obtained. In some cases, this approval has been obtained via the original protocol on 
which the patient was enrolled. 
5.3.3 Procedures for storage of specimens in the Laboratory of Dr. Greten 
Patient samples, collected for the purpose of research under IRB approved protocols where Dr 
Greten is Principal Investigator, may be archived in the Dr Greten laboratory. All data associated 
with archived clinical research samples is entered into the web-based NCI Labmatrix database, 
centralized system with access controlled via centralized login. Access to this database is limited 
to Dr Greten research staff, requiring individual login and password. All staff in the Dr Greten 
laboratory have received annually updated NIH/CIT training and maintain standards of computer 
security. 
The data recorded for each sample may include the patient ID, trial name/protocol number, date 
drawn/collected, treatment cycle/post-transplant time point, cell source (e.g. peripheral blood, 
marrow, tissue) as well as box and freezer location. All received samples will receive a unique 
bar code number, which will be added to the sample NCI Labmatrix database. 
Samples are stored in freezers at -80°C (sera, plasma, tissue samples) or under liquid nitrogen 
(cells), according to stability requirements. These freezers are located onsite at the Dr 
Greten laboratory. Access to samples from a protocol for research purposes will be by 
permission of the Principal Investigator. 
Contact information: 
Sophie Wang 


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Building 10 Rm 3B44 
Phone: 240-858-3218 
E-mail: sophie.wang@nih.gov 
5.3.4 Protocol Completion/Sample Destruction 
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 in 
sections above. 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.  
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. 
The PI will record any loss or unanticipated destruction of samples as a deviation. Reports will 
be made per the requirements of section 7.2. 
5.4 
SAMPLES FOR GENETIC/GENOMIC ANALYSIS 
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. Fewer than 100 genes will be 
analyzed. For TCR Beta Sequencing the NCI Thoracic and GI Oncology Branch will release 
coded tumor and PBMC samples to Adaptive Biotechnologies.  
5.4.1 Privacy and Confidentiality of medical information/biological specimens 
Fresh tumor and blood samples will be stored in a minus 80-degree freezer. Initially the samples 
of each patient will be sent to Dr. Figg’s lab (5.3.1). At no time will patient’s names be used on 
the blood and tissue samples. The molecular studies will be performed at the Adaptive 
Biotechnologies, 1551 Eastlake Ave E #200, Seattle, WA 98102 (855) 466-8667. Subject’s 
genetic data will be deposited in a database such as dbGaP. Although there is controlled access 
to such a database, such a submission carries theoretical risks of revealing the identity of the 
subject. This is discussed in the consent. 
5.4.2 Management of Results 
There are not going to be incidental findings in this study and the results of molecular studies 
will not be communicated to the patient.  
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 Labmatrix 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. 


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All adverse events, including clinically significant abnormal findings on laboratory evaluations, 
regardless of severity, will be followed until return to baseline or stabilization of event.  
Document AEs from the first study intervention, Study Day 1 of Cycle 1 through 30 days after 
the subject received the last study drug administration. Beyond 30 days after the last 
intervention, only adverse events which are serious and related to the study intervention need to 
be recorded.  
An abnormal laboratory value will be recorded in the database as an AE only if the laboratory 
abnormality is characterized by any of the following: 
• 
Results in discontinuation from the study 
• 
Is associated with clinical signs or symptoms  
• 
Requires treatment or any other therapeutic intervention 
• 
Is associated with death or another serious adverse event, including hospitalization.  
• 
Is judged by the Investigator to be of significant clinical impact 
• 
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. 
Grade 1 adverse events will not be recorded. 
End of study procedures: Data will be stored according to HHS, FDA regulations and NIH 
Intramural Records Retention Schedule 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, this will be reported expeditiously per 
requirements in section 7.2.1.  
6.2 
DATA SHARING PLANS 
6.2.1 Human Data Sharing Plan 
I will share coded, linked human data generated in this research for future research  
− in a NIH-funded or approved public repository clinicaltrials.gov, dbGaP 
− in BTRIS 
− with approved outside collaborators under appropriate agreements 
− in publication and/or public presentations 
at the time of publication or shortly thereafter. 
6.2.2 Genomic Data Sharing Plan 
Unlinked genomic data will be deposited in public genomic databases such as dbGaP in 
compliance with the NIH Genomic Data Sharing Policy. 


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6.3 
RESPONSE CRITERIA 
For the purposes of this study, patients should be re-evaluated for response every 9 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)[82]  and Modified Immune-related response criteria (irRC) Appendix B. 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 
Evaluable for toxicity: All patients will be evaluable for toxicity from the time of their first 
treatment with pembrolizumab. 
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.) 
Evaluable Non-Target Disease Response: Patients who have lesions present at baseline that are 
evaluable but do not meet the definitions of measurable disease, have received at least one cycle 
of therapy, and have had their disease re-evaluated will be considered evaluable for non-target 
disease. The response assessment is based on the presence, absence, or unequivocal progression 
of the lesions.  
6.3.2 Disease Parameters 
Measurable disease: Measurable lesions are defined as those that can be accurately measured in 
at least one dimension (longest diameter to be recorded) as >20 mm 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). 
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. 
Non-measurable disease. All other lesions (or sites of disease), including small lesions (longest 
diameter <10 mm or pathological lymph nodes with ≥10 to <15 mm short axis), are considered 
non-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. 
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. 
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. 
Clinical lesions: Clinical lesions will only be considered measurable when they are superficial 
(e.g., skin nodules and palpable lymph nodes) and ≥10 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.  
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.  
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 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. 


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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. 
PET-CT: At present, the low dose or attenuation correction CT portion of a combined PET-CT is 
not always of optimal diagnostic CT quality for use with RECIST measurements. However, if 
the site can document that the CT performed as part of a PET-CT is of identical diagnostic 
quality to a diagnostic CT (with IV and oral contrast), then the CT portion of the PET-CT can be 
used for RECIST measurements and can be used interchangeably with conventional CT in 
accurately measuring cancer lesions over time. Note, however, that the PET portion of the CT 
introduces additional data which may bias an investigator if it is not routinely or serially 
performed.  
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. 
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. 
Tumor markers: Tumor markers alone cannot be used to assess response. If markers are initially 
above the upper normal limit, they must normalize for a patient to be considered in complete 
clinical response. Specific guidelines for both CA-125 response (in recurrent ovarian cancer) and 
PSA response (in recurrent prostate cancer) have been published[83-85]. In addition, the 
Gynecologic Cancer Intergroup has developed CA-125 progression criteria which are to be 
integrated with objective tumor assessment for use in first-line trials in ovarian cancer[86]. 
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. 
FDG-PET: While FDG-PET response assessments need additional study, it is sometimes 
reasonable to incorporate the use of FDG-PET scanning to complement CT scanning in 
assessment of progression (particularly possible 'new' disease). New lesions on the basis of FDG-
PET imaging can be identified according to the following algorithm:  


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a. Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of PD 
based on a new lesion. 
b. No FDG-PET at baseline and a positive FDG-PET at follow-up: If the positive FDG-PET 
at follow-up corresponds to a new site of disease confirmed by CT, this is PD. If the 
positive FDG-PET at follow-up is not confirmed as a new site of disease on CT, 
additional follow-up CT scans are needed to determine if there is truly progression 
occurring at that site (if so, the date of PD will be the date of the initial abnormal FDG-
PET scan). If the positive FDG-PET at follow-up corresponds to a pre-existing site of 
disease on CT that is not progressing on the basis of the anatomic images, this is not PD. 
c. FDG-PET may be used to upgrade a response to a CR in a manner similar to a biopsy in 
cases where a residual radiographic abnormality is thought to represent fibrosis or 
scarring. The use of FDG-PET in this circumstance should be prospectively described in 
the protocol and supported by disease-specific medical literature for the indication. 
However, it must be acknowledged that both approaches may lead to false positive CR 
due to limitations of FDG-PET and biopsy resolution/sensitivity. 
 Note: A ‘positive’ FDG-PET scan lesion means one which is FDG avid with an uptake greater 
than twice that of the surrounding tissue on the attenuation corrected image. 
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. 
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 


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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-
PD/not 
evaluated 
No 
SD 
Documented at least once >4 
wks. from baseline** 
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 on what is evidence of a new lesion. 
** 
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. 


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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. 
 
For Patients with Non-Measurable Disease (i.e., Non-Target Disease) 
 
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 B, 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 
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 
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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 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm#ctc_40).  
7 
NIH REPORTING REQUIREMENTS/DATA AND SAFETY MONITORING PLAN 
7.1 
DEFINITIONS 
Please refer to definitions provided in Policy 801: Reporting Research Events found here. 
7.2 
OHSRP OFFICE OF COMPLIANCE AND TRAINING / IRB REPORTING 
7.2.1 Expedited Reporting  
Please refer to the reporting requirements in Policy 801: Reporting Research Events and Policy 
802 Non-Compliance Human Subjects Research found here. Note: Only IND Safety Reports that 
meet the definition of an unanticipated problem will need to be reported per these policies. 
7.2.2 IRB Requirements for PI Reporting at Continuing Review 
Please refer to the reporting requirements in Policy 801: Reporting Research Events found here.  
7.3 
NCI CLINICAL DIRECTOR REPORTING  
Problems expeditiously reported to the OHSRP in iRIS will also be reported to the NCI Clinical 
Director.  A separate submission is not necessary as reports in iRIS will be available to the 
Clinical Director. 
In addition to those reports, all deaths that occur within 30 days after receiving a research 
intervention should be reported via email to the Clinical Director unless they are due to 
progressive disease.   
To report these deaths, please send an email describing the circumstances of the death to Dr. 
Dahut at NCICCRQA@mail.nih.gov within one business day of learning of the death. 
7.4 
NIH REQUIRED DATA AND SAFETY MONITORING PLAN  
The clinical research team will meet on a regular basis when patients are being actively treated 
on the trial to discuss each patient.  
All data will be collected in a timely manner and reviewed by the principal investigator or a lead 
associate investigator. Events meeting requirements for expedited reporting as described in 
section 7.2.1 will be submitted within the appropriate timelines.  
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 
SAFETY REPORTING CRITERIA TO THE PHARMACEUTICAL COLLABORATOR (MERCK) 
7.5.1 Auditing and Monitoring.  
With reasonable advance notice and at reasonable times, during and after the completion of the 
Protocol, NCI will permit Collaborator or its designee(s) to access the NIH Clinical Center to 
audit the conduct of the research, as well as to audit source documents containing Raw Data, to 


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the extent necessary to verify compliance with FDA Good Clinical Practice (International 
Conference on Harmonization (ICH) E6: “Good Clinical Practice: Consolidated Guidance; 62 
Federal Register 25, 691 (1997)) and the Protocol(s)”. 
7.5.2 Safety Reports. 
The Principal Investigator will report to Merck all SAEs which involve death or a life-
threatening event which are deemed to be possibly, probably, or definitely related to 
Pembrolizumab within two (2) calendar days of receipt of these events by the Principal 
Investigator. 
The Principal Investigator will use its best efforts to report other SAEs whether or not related to 
Pembrolizumab to the Collaborator within six (6) calendar days of receipt of these events by the 
Principal Investigator. Adverse Event reports of cancer will be provided to Merck when the 
Principal Investigator receives them. The Collaborator Global Safety department will receive 
Adverse Experience Reports, from the Principal Investigator via fax (215-993-1220) or secure 
email (aer_mailbox@merck.com). Data exchange of individual adverse event reports exchanged 
will be confirmed within one (1) business day. If confirmation is not received, then the Principal 
Investigator will contact Collaborator to determine if the original report needs to be re-sent.  
8 
STATISTICAL CONSIDERATIONS  
The primary objective of this study is to determine in a preliminary, limited size trial whether 
Pembrolizumab in combination with CAPOX is associated with a 5-month progression free 
probability, which exceeds 25% when used to treat patients with biliary tract cancer.  
Based on our analysis of data from previous trials of patients with similar eligibility requirements 
the median progression free survival in biliary tract carcinoma is 2.5 months. This translates to 
25% without progressive disease at 5 months following an exponential failure model. Based on 
these results, it would be useful to demonstrate whether Pembrolizumab in combination with 
CAPOX is able to be associated with a median PFS of 5 months, which would correspond to 
50% of patients having stable disease at 5 months. The trial will be conducted using a two-stage 
optimal design (Simon R, Controlled Clinical Trials, 10:1-10, 1989). In order to attempt to 
determine if the agent offers any improvement, using alpha=0.10 and beta =0.10 as acceptable 
error probabilities, the trial will target 50% as the desirable proportion of patients who are still 
without progression at the five-month evaluation (p1=0.50), and will be considered inadequate if 
only a fraction consistent with 20% are without progression by the same evaluation time 
(p0=0.20). 
Initially, 10 patients will be enrolled and evaluated for progression. Enrollment will be 
temporarily halted after the 10th patient has been accrued, unless we know that 3 patients have 
passed the 5-month point without progression. If 3 or more of the first 10 patients enrolled have 
not progressed at the 5-month evaluation, then accrual will continue until a total of 17 patients 
have been entered. If, among the first 10 patients accrued, 0 to 2 are able to be progression-free 
at the 5-month evaluation, then no further patients will be enrolled after such a determination has 
been made. If 6 or more of the total cohort of 17 patients have been found to be progression-free 
at 5 months, then this will indicate an adequate progression free probability to justify further 
consideration of Pembrolizumab in combination with CAPOX in this population of patients. On 
the other hand, if 3 to 5 of 17 are progression-free at 5 months, this will be considered 


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insufficient. Under the null hypothesis (20% progression free at 5 months), the probability of 
being able to stop accrual after 10 patients have been evaluated at 5 months is 68%.  
In addition to evaluation of the proportion of patients that are progression-free at 5 months, the 
progression-free survival for patients will also be analyzed via a Kaplan-Meier curve. This curve 
will be compared informally to other published results in similar patients. As well, the overall 
response rate will be reported, and the overall survival will be reported using a Kaplan-Meier 
curve. It is anticipated that up to 10 patients per year will be able to enroll onto this protocol. 
Thus, it is expected that accrual of up to 17 total patients can be completed in approximately 2 
years. In order to allow for a small number of unevaluable patients, the accrual ceiling will be set 
at 19 patients. 
To evaluate the response rate, proportion of patients obtaining CR and PR per RECIST 1.1 
criteria of all evaluable patients will be analyzed.  
To address safety, tolerability and feasibility of Pembrolizumab in combination with CAPOX 
chemotherapy, adverse events will be tabulated by grade according to CTCAE and analyzed and 
reported descriptively. 
9 
COLLABORATIVE AGREEMENTS 
9.1 
COOPERATIVE RESEARCH AND DEVELOPMENT AGREEMENT (CRADA) 
A CRADA (03145) is in place with Merck for the supply of the commercial agent 
pembrolizumab. 
9.2 
MATERIAL TRANSFER AGREEMENT 
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 biliary tract carcinoma, 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. 
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 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 
decisional impaired. For this reason and because there is a prospect of direct benefit from 
research participation (section 10.4), 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 


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Ability to Consent Assessment Team (ACAT) for evaluation as needed for the following: an 
independent assessment of whether an individual has the capacity to provide consent; assistance 
in identifying and assessing an appropriate surrogate when indicated; and/or an assessment of the 
capacity to appoint a surrogate. For those subjects that become incapacitated and do not have 
pre-determined substitute decision maker, the procedures described in NIH HRPP SOP 14E for 
appointing a surrogate decision maker for adult subjects who are (a) decisional 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 FOR ALL PARTICIPANTS 
10.4.1 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. 
10.4.2 Risks of exposure to ionizing radiation  
This research study involves two CT guided biopsies collected for research purposes only. 
Subjects undergoing two optional biopsy collections will be exposed to 1.5 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. 
10.4.3 Research Blood Collection Risks 
Risks of blood draws include pain and bruising in the area where the needle is placed, 
lightheadedness, and rarely, fainting. When large amounts of blood are collected, low red blood 
cell count (anemia) can develop.  
10.4.4 Other Risks 
Potential risks include the possible occurrence of any of a range of side effects which are listed 
in section 11 and in the Consent Document. The procedure for protecting against or minimizing 
risks will be to medically evaluate patients on a regular basis as described. 
10.4.5 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.  
10.5 CONSENT PROCESS AND DOCUMENTATION 
The procedures and tests involved in this study and the associated risks, discomforts and benefits 
of these processes, will be carefully explained to the patient and a signed informed consent 
document will be obtained prior to entry onto the study. 
For the optional biopsies for research in the protocol, the patient will consent at the time of the 
procedure with the original form going to Medical Records and a copy placed in the research 
record. If the patient refuses the optional biopsy at that time, the refusal will be documented in 
the medical record and in the research record. 
10.5.1 Re-Consent via Telephone 
Consent via telephone may only be used when re-consent is required, and the patient is not 
scheduled to come for a clinic visit in a timely fashion. 


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Telephone consent will be obtained and documented per OHSRP/IRBO and CCR policies and 
procedures. 
11 PHARMACEUTICAL INFORMATION  
Pembrolizumab (Keytruda) is approved for the treatment of patients with metastatic melanoma, 
NSCLC and HNSCC.  
Oxaliplatin is approved for the treatment of patients with advanced colon and colorectal cancer. 
Capecitabine is approved for the treatment of patients with adjuvant colon, metastatic colorectal 
and metastatic breast cancer. 
None of these drugs are approved for the treatment of patients with advanced biliary tract 
carcinoma, the use in the current protocol. The investigation is not intended to support a new 
indication for use or any other significant changes to labeling or advertising in any of the 
commercial agents used on the study. The investigation does not involve a route of 
administration or dosage level in use in a patient population or other factor that significantly 
increases the risks (or decreases the acceptability of the risks) associated with the use of the drug 
products.  
11.1 PEMBROLIZUMAB 
The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution and usage of 
investigational product in accordance with the protocol and any applicable laws and regulations. 
Clinical Supplies will be provided by Merck as summarized in Table 3. 
Table 3: Product Descriptions 
Product Name & Potency 
Dosage Form 
Pembrolizumab 50 mg 
Lyophilized Powder for Injection 
Pembrolizumab 100 mg/ 4mL 
Solution for Injection 
11.1.1 Packaging and Labeling Information 
Clinical supplies will be affixed with a clinical label in accordance with regulatory requirements. 
11.2.1 Drug Product  
Pembrolizumab (MK-3475) Solution for Infusion, 100 mg/ 4 mL vial 
Pembrolizumab (MK-3475) Solution for Infusion is a sterile, non-pyrogenic aqueous solution 
supplied in single-use Type I glass vial containing 100 mg/4 mL of pembrolizumab (MK-3475). 
The product is preservative-free solution which is essentially free of extraneous particulates. 
Cap color of MK-3475 (Pembrolizumab) 100 mg vials: 
Both red and salmon color caps may be used. Though the cap color may be different, the product 
inside the vial is the same MK-3475 drug product. 


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11.1.2 Stability and Handling of Drug Product 
Pembrolizumab (MK-3475) Solution for Infusion, 100 mg/ 4 mL vial: pembrolizumab (MK-
3475) Solution for Infusion vials should be stored at refrigerated conditions (2 – 8 °C) and 
protected from light. 
Note: vials should be stored in the original box to ensure the drug product is protected from light. 
Pembrolizumab (MK-3475) infusion solutions should be prepared in 0.9% Sodium Chloride 
Injection, USP (normal saline) or regional equivalent or 5% Dextrose Injection, USP (5% 
dextrose) or regional equivalent and the final concentration of pembrolizumab (MK-3475) in the 
infusion solutions should be between 1 mg/mL and 10 mg/mL.  
Please note, the preferred diluent is 0.9% Sodium Chloride and 5% dextrose is only permissible 
if normal saline is not available. 
Local guidelines should be followed for collection of diluent information such as manufacturer, 
lot and expiry. When the diluent is provided by Merck, the drug accountability log should be 
used for collection of diluent information. 
Pembrolizumab (MK-3475) SHOULD NOT BE MIXED WITH OTHER DILUENTS.  
Pembrolizumab (MK-3475) solutions may be stored at room temperature for a cumulative time 
of up to 4 hours. This includes room temperature storage of admixture solutions in the IV bags 
and the duration of infusion 
In addition, IV bags may be stored under refrigeration at 2 °C to 8 °C (36 °F to 46 °F) for up to 
20 hours. If refrigerated, allow the IV bags to come to room temperature prior to use.  
Parenteral drug products should be inspected visually for particulate matter and discoloration 
prior to administration. Discard the drug product vial if extraneous particulate matter other than 
translucent to white proteinaceous particles is observed. 
Sites should follow their SOPs for drug transport and delivery, with all possible effort to 
minimize agitation of the drug product between the pharmacy and the clinic 
• Do not use PEMBROLIZUMAB (MK-3475) if discoloration is observed. 
• DO NOT SHAKE OR FREEZE THE VIAL(S). 
• DO NOT ADMINISTER THE PRODUCT AS AN (INTRAVENOUS (IV) PUSH OR 
BOLUS). 
• DO NOT COMBINE, DILUTE OR ADMINISTER IT AS AN INFUSION WITH 
OTHER MEDICINAL PRODUCTS. 
• Any departure from the guidance listed in this manual, must be discussed with sponsor 
11.1.3 Clinical Supplies Disclosure 
This trial is open-label; therefore, the subject, the trial site personnel, the Sponsor and/or 
designee are not blinded to treatment. Drug identity (name, strength) is included in the label text; 
random code/disclosure envelopes or lists are not provided. 


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11.1.4 Storage and Handling Requirements 
Clinical supplies must be stored in a secure, limited-access location under the storage conditions 
specified on the label.  
Receipt and dispensing of trial medication must be recorded by an authorized person at the trial 
site. 
Clinical supplies may not be used for any purpose other than that stated in the protocol. 
11.1.5 Returns and Reconciliation 
The investigator is responsible for keeping accurate records of the clinical supplies received from 
Merck or designee, the amount dispensed to and returned by the subjects and the amount 
remaining at the conclusion of the trial.  
Upon completion or termination of the study, all unused and/or partially used investigational 
product will be destroyed at the site per institutional policy. It is the Investigator’s responsibility 
to arrange for disposal of all empty containers, provided that procedures for proper disposal 
have been established according to applicable federal, state, local and institutional guidelines and 
procedures, and provided that appropriate records of disposal are kept. 
11.2 OXALIPLATIN  
Oxaliplatin will be supplied by the local pharmacy using supply purchased from commercial 
sources. 
11.2.1 Toxicity  
The most common side effects of oxaliplatin include:  
• neutropenia, anemia, thrombocytopenia, hypertension, diarrhea, nausea, vomiting, 
constipation, oral mucositis, abdominal pain, anorexia, fatigue, injection site reactions, 
alopecia and dehydration 
• Potentially serious toxicities include: 
• Grade 3/4 hypersensitivity, including anaphylactic/anaphylactoid reactions, to oxaliplatin 
has been observed in 2-3% of colon cancer patients. These reactions are usually managed 
with standard epinephrine, corticosteroid, antihistamine therapy, and require 
discontinuation of therapy or desensitization protocol for continuation of therapy. 
• Peripheral sensory neuropathy (acute ≤ 14 days and persistent > 14 days) was reported in 
adjuvant patients treated with ELOXATIN as part of FOLFOX with a frequency of 92% 
(all grades) and 13% (grade 3). At the 28-day follow-up after the last treatment cycle, 
60% of all patients had any grade (Grade 1=40%, Grade 2=16%, Grade 3=5%) peripheral 
sensory neuropathy decreasing to 39% at 6-month follow-up (Grade 1=31%, Grade 
2=7%, Grade 3=1%) and 21% at 18 months of follow-up (Grade 1=17%, Grade 2=3%, 
Grade 3=1%). 
• Overall, neuropathy was reported in patients previously untreated for advanced colorectal 
cancer in 82% (all grades) and 19% (grade 3/4), and in the previously treated patients in 
74% (all grades) and 7% (grade 3/4) events. Information regarding reversibility of 
neuropathy was not available from the trial for patients who had not been previously 
treated for colorectal cancer. 


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• Reversible Posterior Leukoencephalopathy Syndrome (RPLS, also known as PRES, 
Posterior Reversible Encephalopathy Syndrome) has been observed in clinical trials (< 
0.1%) and postmarketing experience. Signs and symptoms of RPLS could be headache, 
altered mental functioning, seizures, abnormal vision from blurriness to blindness, 
associated or not with hypertension. Diagnosis of RPLS is based upon confirmation by 
brain imaging. 
• Pulmonary Toxicity. oxaliplatin has been associated with pulmonary fibrosis (<1% of 
study patients), which may be fatal. The combined incidence of cough and dyspnea was 
7.4% (any grade) and < 1% (grade 3) with no grade 4 events in the oxaliplatin plus 
infusional 5-fluorouracil/leucovorin arm compared to 4.5% (any grade) and no grade 3 
and 0.1% grade 4 events in the infusional 5- fluorouracil/leucovorin alone arm in 
adjuvant colon cancer patients. In this study, one patient died from eosinophilic 
pneumonia in the oxaliplatin combination arm. The combined incidence of cough, 
dyspnea and hypoxia was 43% (any grade) and 7% (grade 3 and 4) in the oxaliplatin plus 
5-fluorouracil/leucovorin arm compared to 32% (any grade) and 5% (grade 3 and 4) in 
the irinotecan plus 5-fluorouracil/leucovorin arm of unknown duration for patients with 
previously untreated colorectal cancer. In case of unexplained respiratory symptoms such 
as non-productive cough, dyspnea, crackles, or radiological pulmonary infiltrates, 
ELOXATIN should be discontinued until further pulmonary investigation excludes 
interstitial lung disease or pulmonary fibrosis. 
• Hepatotoxicity as evidenced in the adjuvant study, by increase in transaminases (57% vs. 
34%) and alkaline phosphatase (42% vs. 20%) was observed more commonly in the 
oxaliplatin combination arm than in the control arm. The incidence of increased bilirubin 
was similar on both arms. Changes noted on liver biopsies include: peliosis, nodular 
regenerative hyperplasia or sinusoidal alterations, perisinusoidal fibrosis, and veno-
occlusive lesions. Hepatic vascular disorders should be considered, and if appropriate, 
should be investigated in case of abnormal liver function test results or portal 
hypertension, which cannot be explained by liver metastases 
11.2.2 Formulation 
11.2.2.1 Powder 
ELOXATIN is supplied in single-use vials containing 50 mg or 100 mg of oxaliplatin as a 
sterile, preservative-free lyophilized powder for reconstitution. Lactose monohydrate is also 
present as an inactive ingredient. 
11.2.2.2 Solution 
ELOXATIN is supplied in single-use vials containing 50 mg, 100 mg or 200 mg of oxaliplatin as 
a sterile, preservative-free, aqueous solution at a concentration of 5 mg/ml. Water for Injection, 
USP is present as an inactive ingredient. 
11.2.3 Preparation 
11.2.3.1 Powder 
Reconstitution or final dilution must never be performed with a sodium chloride solution or other 
chloride containing solutions. 


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The lyophilized powder is reconstituted by adding 10 mL (for the 50 mg vial) or 20 mL (for the 
100 mg vial) of Water for Injection, USP or 5% Dextrose Injection, USP. Do not administer the 
reconstituted solution without further dilution. The reconstituted solution must be further diluted 
in an infusion solution of 250-500 mL of 5% Dextrose Injection, USP. 
After reconstitution in the original vial, the solution may be stored up to 24 hours under 
refrigeration [2-8°C (36-46°F)]. After final dilution with 250-500 mL of 5% Dextrose Injection, 
USP, the shelf life is 6 hours at room temperature [20-25°C (68-77°F)] or up to 24 hours under 
refrigeration [2-8°C (36-46°F)]. 
ELOXATIN is not light sensitive. 
11.2.3.2 Solution 
Do not freeze and protect from light the concentrated solution. 
A final dilution must never be performed with a sodium chloride solution or other chloride 
containing solutions. 
The solution must be further diluted in an infusion solution of 250-500 mL of 5% Dextrose 
Injection, USP. 
After dilution with 250-500 mL of 5% Dextrose Injection, USP, the shelf life is 6 hours at room 
temperature [20-25°C (68-77°F)] or up to 24 hours under refrigeration [2-8°C (36-46°F)]. 
After final dilution, protection from light is not required. 
ELOXATIN is incompatible in solution with alkaline medications or media (such as basic 
solutions of 5-fluorouracil) and must not be mixed with these or administered simultaneously 
through the same infusion line. The infusion line should be flushed with 5% Dextrose Injection, 
USP prior to administration of any concomitant medication. 
11.2.4 General 
Parenteral drug products should be inspected visually for particulate matter and discoloration 
prior to administration and discarded if present. 
Needles or intravenous administration sets containing aluminum parts that may come in contact 
with oxaliplatin should not be used for the preparation or mixing of the drug. Aluminum has 
been reported to cause degradation of platinum compounds. 
11.2.5 Stability and Storage  
Powder for solution for infusion: 
Store under normal lighting conditions at 25°C (77°F); excursions permitted to 15-30°C (59-
86°F). 
Concentrate for solution for infusion: 
Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F). Do not freeze and protect from 
light (keep in original outer carton). 
11.2.6 Administration procedures 
Please see section 3.3.2.2. 


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11.2.7 Incompatibilities  
No specific cytochrome P-450-based drug interaction studies have been conducted. No 
pharmacokinetic interaction between 85 mg/m2 oxaliplatin and 5-fluorouracil/leucovorin has 
been observed in patients treated every 2 weeks. Increases of 5-fluorouracil plasma 
concentrations by approximately 20% have been observed with doses of 130 mg/m2 oxaliplatin 
dosed every 3 weeks. Because platinum-containing species are eliminated primarily through the 
kidney, clearance of these products may be decreased by co-administration of potentially 
nephrotoxic compounds; although, this has not been specifically studied. 
11.3 CAPECITABINE  
Chemical Name: 5’-deoxy-5-fluoro-N-[(pentyloxy) carbonyl]-cytidine  
Other Names: xeloda  
Classification: Fluoropyrimidine carbamate  
M.W.: 359.35 
11.3.1 Source  
Capecitabine will be supplied by the local pharmacy using supply purchased from commercial 
sources. 
11.3.2 Toxicity  
Most common adverse reactions (≥30%) were diarrhea, hand-and-foot syndrome, nausea, 
vomiting, abdominal pain, fatigue/weakness, and hyperbilirubinemia. Other adverse reactions, 
including serious adverse reactions, have been reported. 
Pooled Phase 3 Colorectal Trials: Percent Incidence of Adverse Reactions in ≥5% of 
Patients 
Adverse Event 
Capecitabine (n=596) 
Total 
% 
Grade 3 
% 
Grade 4 
% 
Number of Patients With > One Adverse Event 
96 
52 
9 
Body System/Adverse Event 
GI 
55 
13 
2 
Diarrhea 
Nausea 
43 
4 
– 
Vomiting 
27 
4 
<1 
Stomatitis 
25 
2 
<1 
Abdominal Pain 
35 
9 
<1 
Gastrointestinal Motility Disorder 
10 
<1 
– 
Constipation 
14 
1 
<1 
Oral Discomfort 
10 
– 
– 
Upper GI Inflammatory Disorders 
8 
<1 
– 
Gastrointestinal Hemorrhage 
6 
1 
<1 


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Adverse Event 
Capecitabine (n=596) 
Total 
% 
Grade 3 
% 
Grade 4 
% 
Number of Patients With > One Adverse Event 
96 
52 
9 
Body System/Adverse Event 
Ileus 
6 
4 
1 
Skin and Subcutaneous 
54 
17 
NA 
Hand-and-Foot Syndrome 
Dermatitis 
27 
1 
– 
Skin Discoloration 
7 
<1 
– 
Alopecia 
6 
– 
– 
General 
42 
4 
– 
Fatigue/Weakness 
Pyrexia 
18 
1 
– 
Edema 
15 
1 
– 
Pain 
12 
1 
– 
Chest Pain 
6 
1 
– 
Neurological 
10 
– 
– 
Peripheral Sensory Neuropathy 
Headache 
10 
1 
– 
Dizziness* 
8 
<1 
– 
Insomnia 
7 
– 
– 
Taste Disturbance 
6 
1 
– 
Metabolism 
26 
3 
<1 
Appetite Decreased 
Dehydration 
7 
2 
<1 
Eye 
13 
– 
– 
Eye Irritation 
Vision Abnormal 
5 
– 
– 
Respiratory 
14 
1 
– 
Dyspnea 
Cough 
7 
<1 
1 
Pharyngeal Disorder 
5 
– 
– 
Epistaxis 
3 
<1 
– 
Sore Throat 
2 
– 
– 
Musculoskeletal 
10 
2 
– 
Back Pain 
Arthralgia 
8 
1 
– 


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Adverse Event 
Capecitabine (n=596) 
Total 
% 
Grade 3 
% 
Grade 4 
% 
Number of Patients With > One Adverse Event 
96 
52 
9 
Body System/Adverse Event 
Vascular 
Venous Thrombosis 
 
8 
 
3 
 
<1 
Psychiatric 
 
5 
 
– 
 
– 
Mood Alteration 
Depression 
5 
– 
– 
Infections 
Viral 
 
5 
 
<1 
 
– 
Blood and Lymphatic 
80 
2 
<1 
Anemia 
Neutropenia 
13 
1 
2 
Hepatobiliary 
Hyperbilirubinemia 
48 
18 
5 
– Not observed 
* Excluding vertigo 
NA = Not Applicable 
11.3.3 Formulation and preparation  
Tablets: 150 mg and 500 mg 
XELODA is supplied as biconvex, oblong film-coated tablets for oral administration. Each light 
peach-colored tablet contains 150 mg capecitabine and each peach-colored tablet contains 500 
mg capecitabine. The inactive ingredients in XELODA include: anhydrous lactose, 
croscarmellose sodium, hydroxypropyl methylcellulose, microcrystalline cellulose, magnesium 
stearate and purified water. The peach or light peach film coating contains hydroxypropyl 
methylcellulose, talc, titanium dioxide, and synthetic yellow and red iron oxides. 
11.3.4 Stability and Storage  
Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F). KEEP TIGHTLY 
CLOSED. 
Care should be exercised in the handling of XELODA. XELODA tablets should not be cut or 
crushed. Procedures for the proper handling and disposal of anticancer drugs should be 
considered. Any unused product should be disposed of in accordance with local requirements, or 
drug take back programs. Several guidelines on the subject have been published. 
11.3.5 Administration procedures 
Please see section 3.3.2.1 


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11.3.6 Incompatibilities  
• Anticoagulants: Monitor anticoagulant response (INR or prothrombin time) frequently in 
order to adjust the anticoagulant dose as needed. 
• Phenytoin: Monitor phenytoin levels in patients taking XELODA concomitantly with 
phenytoin. The phenytoin dose may need to be reduced. 
• Leucovorin: The concentration of 5-fluorouracil is increased and its toxicity may be 
enhanced by leucovorin.  
• CYP2C9 substrates: Care should be exercised when XELODA is co-administered with 
CYP2C9 substrates.  
• Food reduced both the rate and extent of absorption of capecitabine.  
.  


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13 APPENDICES 
13.1 APPENDIX A-PERFORMANCE STATUS CRITERIA 
ECOG Performance Status Scale 
Grade 
Descriptions 
0 
Normal activity. Fully active, able 
to 
carry 
on 
all 
pre-disease 
performance without restriction. 
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). 
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. 
3 
In bed >50% of the time. Capable 
of only limited self-care, confined 
to bed or chair more than 50% of 
waking hours. 
4 
100% 
bedridden. 
Completely 
disabled. Cannot carry on any 
self-care. Totally confined to bed 
or chair. 
5 
Dead. 
 


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13.2 APPENDIX B- 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 
measurable new lesions does not increase by ≥ 20%.  
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.  
 
 
 
 
 
 
 


Abbreviated Title: CAPOX Pembrolizumab in BTC  
Version Date: 03/19/2020 
71 
 
Overall Responses Derived from Changes in Index, Non-Index, and New Lesions 
 
 


Abbreviated Title: CAPOX Pembrolizumab in BTC  
Version Date: 03/19/2020 
72 
13.3 APPENDIX C PATIENT’S MEDICATION DIARY ________________________ 
Cycle___________________ 
Patient’s ID ___________________ 
INSTRUCTIONS TO THE PATIENT: 
1. Complete one form for each cycle of treatment 
2. You will take capecitabine _________mg twice a day. You should take the tablets with food at 
approximately the same time each day. 
3. Dose: ____________150 mg  ______________ 500 mg 
4. Record the date, the number of tablets that you took, and when you took them. 
5. If you have any comments or notice any side effects, please record them in the comments column. 
6. Please bring this form and your bottles of capecitabine when you come for your clinic visits. 
Day 
Date 
Time of 
AM 
Dose 
# of Tablets Taken 
150 mg       500mg 
Time of 
PM 
Dose 
# of Tablets Taken 
150 mg       500mg 
Comments 
1 
 
 
 
 
 
 
 
 
2 
 
 
 
 
 
 
 
 
3 
 
 
 
 
 
 
 
 
4 
 
 
 
 
 
 
 
 
5 
 
 
 
 
 
 
 
 
6 
 
 
 
 
 
 
 
 
7 
 
 
 
 
 
 
 
 
8 
 
 
 
 
 
 
 
 
9 
 
 
 
 
 
 
 
 
10 
 
 
 
 
 
 
 
 
11 
 
 
 
 
 
 
 
 
12 
 
 
 
 
 
 
 
 
13 
 
 
 
 
 
 
 
 
14 
 
 
 
 
 
 
 
 
Patient’s signature:     ___________________________________________________ 

ICF_001.pdf: 
PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 03/19/2020
Page 1 of 17
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
PRINCIPAL INVESTIGATOR:  Tim Greten, M.D.
STUDY TITLE:
A Phase 2 Study of Pembrolizumab, a Monoclonal Antibody Against PD-
1, in Combination with Capecitabine and Oxaliplatin (CAPOX) in Subjects with Advanced Biliary 
Tract Carcinoma (BTC)
STUDY SITE:  National Institutes of Health Clinical Center
Cohort: Affected patient 
Consent Version:  03/19/2020
WHO DO YOU CONTACT ABOUT THIS STUDY? 
Tim Greten, MD, by phone at 240-760-6114 or email Tim.greten@nih.gov 
This consent form describes a research study and is designed to help you decide if you would like 
to be a part of the research study.  
You are being asked to take part in a research study at the National Institutes of Health (NIH). 
Members of the study team will talk with you about the information described in this document. 
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). Take the time needed 
to ask any questions and discuss this study with NIH staff, and with your family, friends, and 
personal health care providers. Taking part in research at the NIH is your choice.
If the individual being asked to participate in this research study is not able to give consent to be 
in this study, you are being asked to give permission for this person as their decision-maker. The 
term “you” refers to you as the decision-maker and/or the individual being asked to participate in 
this research, throughout the remainder of this document. 
IT IS YOUR CHOICE TO TAKE PART IN THE STUDY
You may choose not to take part in this study for any reason. If you join this study, you may change 
your mind and stop participating in the study at any time and for any reason. In either case, you 
will not lose any benefits to which you are otherwise entitled. However, to be seen at the NIH, you 
must be taking part in a study or are being considered for a study. If you do choose to leave the 
study, please inform your study team to ensure a safe withdrawal from the research.  
WHY IS THIS STUDY BEING DONE?
The purpose of this study is to investigate whether Pembrolizumab given in combination with 
capecitabine and oxaliplatin (CAPOX) increases the time it takes for your disease to get worse. 
Pembrolizumab targets a protein on tumor cells called PD-1. PD-1 normally maintains the balance 
of the immune system. In cancer, PD-1 helps tumors evade detection and elimination by the 
immune system. Pembrolizumab may increase the immune system’s ability to identify and destroy 
cancer cells. 
IRB NUMBER: 17C0082
IRB APPROVAL DATE: 04/29/2020


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 03/19/2020
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MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
Oxaliplatin and 5FU-based Capecitabine are chemotherapy medications widely used to treat 
different types of gastrointestinal cancer. 
Pembrolizumab, capecitabine and oxaliplatin are all approved by the Food and Drug 
Administration (FDA) to treat various types of cancer. However, none of the drugs has been 
approved for use in biliary tract cancer. 
WHY ARE YOU BEING ASKED TO TAKE PART IN THIS STUDY?
You are being asked to participate in this study because you have been diagnosed with previously 
treated biliary tract cancer that has spread to other parts of your body.
HOW MANY PEOPLE WILL TAKE PART IN THIS STUDY? 
About 19 people will take part in this study.
DESCRIPTION OF RESEARCH STUDY
Before you begin the study
Before you begin this study, you will need to have the following exams and tests to make sure you 
are eligible for this study. The exams and tests are part of regular cancer care. These tests will be 
done under a separate consent. 

A review of any past or current medical conditions, medicines you are taking and cancer 
history.

Physical examination, including vital signs, height and weight

Electrocardiogram (ECG) to evaluate your heart.

Review of your symptoms and your ability to perform your normal activities.

Imaging Assessments – either a computed tomographic scan (CT or PET) that produces a 
picture of your body using a small amount of radiation or magnetic resonance imaging 
(MRI) that uses a magnetic field to produce an image of your chest, abdomen and pelvis. 

You will have blood drawn (about 3 tablespoon) for:
o
routine blood tests to find out if you are anemic, have low blood counts, your blood is 
clotting normally and if your liver, thyroid, kidneys, and other organs are working well.
o
tests for HIV, Hepatitis B and Hepatitis C.
o
tests for tuberculosis if you have symptoms that indicate you might have the disease.

Routine urine test.

Pregnancy serum or urine test if you are a woman who can have children.

You will be asked to provide a sample of your tumor from a previous surgery so that we 
may confirm your diagnosis. If you do not have one, you will need to have a biopsy of your 
tumor.
IRB NUMBER: 17C0082
IRB APPROVAL DATE: 04/29/2020


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
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MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
During the study
Drug administration and schedule
Pembrolizumab and oxaliplatin will be administered to you through an IV (intravenous catheter, a 
small plastic tube that is put into a vein, usually in your arm) on Day 1 of each cycle (1 cycle = 3 
weeks) for 6 cycles (18 weeks). While taking oxaliplatin, you should avoid cold drinks and 
exposure to cold water or air, especially for the first 3 – 5 days after receiving it.
You also will start take orally Capecitabine on Day 1 of each cycle and continue for two weeks 
followed by one week without capecitabine treatment, for 6 cycles (18 weeks). Capecitabine 
should be taken with meals every 12 hours starting with the evening dose of on day 1 of each cycle 
and ending with the morning dose on day 14 of each cycle. If you need to take your capecitabine 
earlier than scheduled or you missed the dose, you can take it in the time period of +/- 4 hours of 
scheduled time. You will be given a Patient’s Diary to complete for each cycle. In the diary, you 
will be asked to record date, time and missing doses. Please bring the diary with you at every study 
visit. 
Beginning with cycle 7, you will have only Pembrolizumab infusions once every 3 weeks until 
your disease get worse.
Ongoing Procedures during each treatment cycle 
While you are on the treatment, on the first day of every cycle you will have tests done:

Physical exam and vital signs

Review of your symptoms and your ability to perform your normal activities.

Routine blood tests (about 3 tablespoons) to find out if you are anemic, have low blood 
counts, your blood is clotting normally and if your liver, thyroid, kidneys, and other organs 
are working well.

Research blood tests (about 9 tablespoons).
Additional Procedures every 9 weeks:

Imaging Assessments – either a CT scan or PET or MRI of chest, abdomen and pelvis
Research tests
In addition to the tests that we will conduct to determine whether you are having side effects or if 
you are responding to the study therapy, we will also collect samples from you for purposes of 
research only. These studies include:

Blood samples to study the effects of therapy on your immune system will be collected 
during every cycle.

Optional tumor biopsies: procedures using a needle to remove a piece of tissue or a sample 
of cells from your body so that it can be analyzed in a laboratory and is used to diagnose 
or evaluate the cancer. We may ask you to allow us to perform two biopsies: before start 
of the treatment and around day 1 of cycle 3, but these biopsies are optional and you will 
IRB NUMBER: 17C0082
IRB APPROVAL DATE: 04/29/2020


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 03/19/2020
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MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
be asked to sign a separate consent if you agree to have them. Please see page 9 for the 
risks of biopsy. 

Genetic testing – Your tissue will help us study how genes might play a role in biliary tract 
cancer. The testing will be limited so to genes that are not known to cause diseases; 
therefore, we will not share the results of these research tests with you.
When you are finished taking the drugs (treatment)
You will be invited for follow up safety visit approximately 1 month after the last day you take the 
study drug. At these visits, you will have the following tests: 

Physical exam and vitals

Review of your symptoms and your ability to perform your normal activities.

Routine blood tests (about 3 tablespoons) to find out if you are anemic, have low blood 
counts, your blood is clotting normally and if your liver, kidneys, and other organs are 
working well.
After that, we will contact you by telephone or email yearly to determine your health status and to 
find out about any new cancer treatments that you have begun.
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 4 months after you finish study treatment. In addition, male subjects should not 
donate sperm during the study and for 4 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 
•
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:

You may lose time at work or home and spend more time in the hospital or doctor’s 
office than usual

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. 
IRB NUMBER: 17C0082
IRB APPROVAL DATE: 04/29/2020


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 03/19/2020
Page 5 of 17
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
Here are important points about side effects:

The study doctors do not know who will or will not have side effects.

Some side effects may go away soon, some may last a long time, or some may never go 
away.

Some side effects may interfere with your ability to have children.
Here are important points about how you and the study doctor can make side effects less of a 
problem:

Tell the study doctor if you notice or feel anything different so they can see if you are 
having any symptoms.

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.
What side effects or risks can I expect from being in this study?
Risk associated with Pembrolizumab
Pembrolizumab works by helping your immune system to fight your cancer.
However, pembrolizumab can also cause your immune system to attack normal organs and tissues 
in your body and can affect the way they work, which can result in side effects. These side effects 
may be serious (i.e., causing hospitalization or be life-threatening), may result in death, and/or may 
occur after you stop taking pembrolizumab. These side effects can affect more than one of your 
normal organs and tissues at the same time.
Very Common. Out of 100 people who receive pembrolizumab, 20 or more people may have 
the following: 
Itching of the skin
Loose or watery stools
Cough
Common. Out of 100 people who receive pembrolizumab, at least 5 but less than 20 people 
may have the following:
Joint pain
Rash
Fever
Back pain
Pain in your belly
Loss of skin color
IRB NUMBER: 17C0082
IRB APPROVAL DATE: 04/29/2020


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 03/19/2020
Page 6 of 17
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
Not enough thyroid hormone, so you may feel tired, gain weight, feel cold, or have infrequent 
or hard stools (hypothyroidism)
Low levels of salt in the blood that may cause you to feel tired, feel confused, have a 
headache, have muscle cramps, and/or feel sick to your stomach (hyponatremia).
Uncommon. Out of 100 people who receive pembrolizumab, at least 1 but less than 5 people 
may have the following:
Inflammation of the lungs, so you may feel short of breath and cough (pneumonitis).
Too much thyroid hormone, so you may feel anxious, feel angry, have trouble sleeping, feel 
weak, tremble, sweat, feel tired, have loose and watery stools (hyperthyroidism). 
Infusion reaction, where you may feel dizzy or faint, feel flushed, get a rash, have a fever, 
feel short of breath, experience a decrease in your blood pressure at the time of receiving 
your infusion (IV) or just after, or have pain at the site of infusion.
Inflammation of the bowels/gut, which may cause severe pain in your belly with loose or 
watery stools, and black, tarry, sticky stools or stools with blood or mucus (colitis).
Inflammation of the skin so you may have peeling of the skin, itchiness, and/or skin redness. 
The skin inflammation (i.e peeling, itching and redness) could also be widespread throughout 
your body. More severe skin reactions may involve the inside of your mouth, the surface of 
your eye and genital areas, and/or may cause the top layer of your skin to peel from all over 
your body which can cause severe infection (Severe skin reactions, including Stevens-
Johnson syndrome/or toxic epidermal necrolysis).
Rare. Out of 100 people who receive pembrolizumab, less than 1 person may have the 
following:
Inflammation of the nerves that may cause pain, weakness, or tingling in your hands and feet, 
and may spread to your legs, arms, and upper body, leading to severe muscle weakness and 
possible temporary paralysis (Guillain-Barré syndrome).
Inflammation of the muscles, so you may feel weak or have pain in your muscles (myositis) 
Inflammation of the pancreas (a gland in your abdomen that controls sugar levels), so you 
may have severe pain in the top part of your belly that may move to your back, feel sick to 
your stomach, and have vomiting that gets worse when you eat (pancreatitis). 
Inflammation of the eye, so you may have eye redness, blurred vision, sensitivity to light, 
eye pain, see floaters or have headaches (uveitis).
Inflammation of the liver that may make you feel sick to your stomach and vomit, feel like 
not eating, feel tired, have a mild fever, pain in the right side of your belly, yellow eyes and 
skin, and dark urine (hepatitis).
Inflammation of the pituitary gland (a gland in the head), which may cause you to feel sick 
to your stomach or have headaches, changes in your behavior, double vision, few to no 
menstrual cycles, weakness, vomiting and dizziness, or fainting (hypophysitis).
IRB NUMBER: 17C0082
IRB APPROVAL DATE: 04/29/2020


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 03/19/2020
Page 7 of 17
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
Adrenal glands (glands on top of the kidneys) that may not make enough hormone, which 
could cause tiredness, weight loss, muscle weakness, feeling faint, having joint, muscle, and 
belly aches, nausea, vomiting, loose or watery stools, fever, salt craving, and sometimes 
darkening of the skin like a suntan (adrenal insufficiency).
Type 1 diabetes, a condition that can cause too much sugar in your blood, feeling thirstier 
than usual, frequent urination, and weight loss. You are likely to need regular insulin shots.
Inflammation of the kidney so you may pass less urine or have cloudy or bloody urine, 
swelling and low back pain (nephritis). 
Inflammation of the middle layer of your heart wall that may cause your heart to have 
difficulty pumping blood throughout your body, which can cause chest pain, shortness of 
breath, and swelling of the legs. You may experience a fast or irregular heartbeat that may 
cause dizziness or fainting (myocarditis). 
Inflammation of the thyroid gland, an organ that makes and stores thyroid hormones. This 
condition may lead to change in your heart rate, blood pressure, body temperature, and the 
rate at which food is converted into energy (thyroiditis). 
A condition that may make you feel weak and tired and may cause drooping of the eyelids, 
blurred or double vision, difficulty swallowing, slurred speech, weakness in your arms and 
legs, or difficulty breathing (myasthenic syndrome/myasthenia gravis including 
exacerbation). 
The formation of small clusters of immune cells (called granulomas) in parts of your body 
such as your lymph nodes, eyes, skin, or lungs (sarcoidosis).
Inflammation of the brain with confusion and fever. This may also include disorientation, 
memory problems, seizures (fits), changes in personality and behavior, difficulty speaking, 
weakness or loss of movement in some parts of your body, and loss of consciousness 
(encephalitis).
Inflammation of the spinal cord with pain, numbness, tingling, or weakness in the arms or 
legs, bladder or bowel problems including needing to urinate more frequently, urinary 
incontinence, difficulty urinating, and constipation (myelitis).
Additionally, since pembrolizumab was approved in September 2014, the following side effects 
have been reported by people receiving pembrolizumab. These side effects were voluntarily 
reported from a group of people of unknown size. It is not possible to estimate the frequency of 
this side effect:
Inflammation of the joints which may include joint pain, stiffness and/or swelling (arthritis)
Severe responses of the immune system that cause the body to attack its own blood cells, 
spleen, liver, lymph nodes, skin and brain. This may include fever, rash, inflammation of the 
liver, yellowing of the skin, an enlarged liver and spleen, low blood counts, and enlarged 
lymph nodes. The nervous system may also be affected and cause confusion, seizures, and 
even coma (hemophagocytic lymphohistiocytosis).
IRB NUMBER: 17C0082
IRB APPROVAL DATE: 04/29/2020


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 03/19/2020
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MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
Changes in eyesight, eye pain, whitish patches on the skin and hearing loss (Vogt-Koyanagi-
Harada syndrome).
If you have had an allogeneic stem cell transplant (a procedure in which a person receives 
blood-forming stem cells from a donor), you may experience graft versus host disease 
(GVHD), which may include diarrhea, skin rashes, and liver damage, after receiving 
pembrolizumab. Sometimes this condition can lead to death.
If you have had a solid organ transplant (for example, if you have received a kidney or heart 
transplant), you may experience rejection of the transplanted organ. Your doctor will monitor 
you and should tell you what signs and symptoms you should report depending on the type 
of organ transplant that you have had.
Risk associated with Capecitabine
Very Common: 
Swelling of the body
Blisters on the skin
Redness, pain or peeling of palms and soles
Pain
Diarrhea, loss of appetite, nausea, vomiting
Sores in mouth which may cause difficulty swallowing
Fever
Anemia which may require blood transfusions
Infection, especially when white blood cell count is low
Bruising, bleeding
Feeling of "pins and needles" in arms and legs
Tiredness
Less Common: 
Blurred vision, dry or itchy eyes
Muscle spasms, body aches
Abnormal heartbeat
Restlessness, irritability
Swelling of face, fingers and lower legs
Constipation
Difficulty with balancing
IRB NUMBER: 17C0082
IRB APPROVAL DATE: 04/29/2020


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 03/19/2020
Page 9 of 17
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
Rare:
Allergic reaction which may cause rash, low blood pressure, wheezing, shortness of breath, 
swelling of the face or throat
Difficulty speaking, walking or seeing
Internal bleeding which may cause blood in vomit or black tarry stools
Damage to the heart
Risk associated with Oxaliplatin
Very Common: 
Anemia which may require blood transfusion
Diarrhea, nausea, vomiting, constipation, loss of appetite
Tiredness
Bruising, bleeding
Infection, especially when white blood cell count is low
Numbness and tingling of the arms and legs
Feeling of "pins and needles" in arms and legs
Pain
Fever, cough
Less Common: 

Blood clot which may cause swelling, pain, or shortness of breath

Abnormal heartbeat which may cause fainting

Hearing loss

Dry eye, mouth, skin

Swelling and redness of the eye

Blurred vision with chance of blindness

Visual loss

Problem with eyelid

Fluid in the belly

Heartburn, passing gas

Difficulty walking, opening mouth, talking, with balance and hearing, smelling, eating, 
sleeping, emptying the bladder
IRB NUMBER: 17C0082
IRB APPROVAL DATE: 04/29/2020


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 03/19/2020
Page 10 of 17
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY

Swelling of the body which may cause shortness of breath

Blockage of the airway which may cause shortness of breath, cough, wheezing

Bleeding from multiple sites including vaginal bleeding, bleeding of the testis, or 
bleeding of the brain

Internal bleeding which may cause black tarry stool, blood in vomit or urine, or coughing 
up blood

Damage to organs which may cause shortness of breath

Sores in throat or mouth which may cause difficulty swallowing

Chills

Swelling and redness at the site of the medication injection

Liver damage which may cause yellowing of eyes and skin

Kidney damage which may require dialysis

Allergic reaction which may cause rash, low blood pressure, wheezing, shortness of 
breath, swelling of the face or throat

Weight gain, weight loss, dehydration

Dizziness, headache

Changes in taste, voice

Abnormal body movement including the eye and eyelid

Stroke which may cause paralysis, weakness

Inability to move shoulder or turn head

Muscle weakness

Seizure

Worry, confusion, depression

Increased urination

Stuffy nose, shortness of breath, hiccups, sinus problems

Scarring of the lungs

Hair loss, itching, rash, hives

Increased sweating, flushing, hot flashes

High blood pressure

Low blood pressure which may cause feeling faint
Rare:
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IRB APPROVAL DATE: 04/29/2020


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 03/19/2020
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MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY

Redness, pain or peeling of palms and soles

Brain damage, Reversible Posterior Leukoencephalopathy Syndrome, which may cause 
headache, seizure, blindness
Risks from Blood collection:
Local pain, bruising, bleeding, blood clot formation, and, in rare instances, an infection might 
occur at the site where blood is drawn. There is also the possibility of dizziness or fainting while 
your blood is being drawn. 
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.
The tumor biopsy will be done by a specialist using a CT scanner to guide the biopsy needle into 
the tumor to ensure accuracy. To collect the research biopsies, you will be exposed to two 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 1.5 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.
POTENTIAL BENEFITS OF PARTICIPATION
Are there benefits to taking part in this study?
The aim of this study is to find out whether the experimental treatment increases the time it takes 
biliary tract cancer to worsen. 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:

Getting treatment or care for your cancer without being in a study

Taking part in another study

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.
IRB NUMBER: 17C0082
IRB APPROVAL DATE: 04/29/2020


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 03/19/2020
Page 12 of 17
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
Please talk to your doctor about these and other options.
STOPPING THERAPY
Your doctor may decide to stop your therapy for the following reasons:

if he/she believes that it is in your best interest

if your disease comes back during treatment

if you become pregnant

if you have side effects from the treatment that your doctor thinks are too severe

if your treatment is delayed for more than 28 days

if new information shows that another treatment would be better for you

if he/she decided to close the study
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 Pine Pharmaceuticals, the 
Center for Cancer Research, NCI 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 therapies developed 
by Merck through a joint study with your researchers and the company. The company also provide 
financial support for this study. 
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 
IRB NUMBER: 17C0082
IRB APPROVAL DATE: 04/29/2020


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 03/19/2020
Page 13 of 17
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
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. 
We may put your research data in a large database for broad sharing with the research community. 
These databases are commonly called data repositories. These data repositories might or might not 
be located at the NIH. The information in this database could include but is not limited to genetic 
information, ethnicity and sex. If your individual research data is placed in one of these 
repositories, it will not be labeled with your name or other information that could be used to easily 
identify you, and only qualified researchers will be able to look at your data. These researchers 
must receive prior approval from individuals or committees to access the data.
In addition to the use and sharing of your specimens and data described above, we might remove 
any information from your specimens and data that can identify you such as name, address, or 
medical record number, and then use the specimens and data for additional research studies at the 
NIH or other places. If we do this, we might not contact you to ask your permission or otherwise 
inform you.
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.
Genomic Data Sharing
As part of this research study, we will put your genomic data in a large database for broad sharing 
with the research community. These databases are commonly called data repositories. The 
information in this database will include but is not limited to genetic information, race and 
ethnicity, and sex.  If your individual data are placed in one of these repositories, they will be 
labeled with a code and not with your name or other information that could be used to easily 
identify you, and only qualified researchers will be able to access them. These researchers must 
receive prior approval from individuals or committees with authority to determine whether these 
researchers can access the data.
Summary information about all of the participants included in this study (including you) is being 
placed in a database and will be available through open access. That means that  researchers and 
non-researchers will be able to access summary information about all the participants included in 
the study, or summary information combined from multiple studies, without applying for 
permission. The risk of anyone identifying you with this information is very low.
IRB NUMBER: 17C0082
IRB APPROVAL DATE: 04/29/2020


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 03/19/2020
Page 14 of 17
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
NIH policies require that genomic data be placed in a repository for sharing. Therefore, we cannot 
offer you a choice of whether your data will be shared.  If you do not wish to have your data placed 
in a repository, you should not enroll in this study.
COMPENSATION, REIMBURSEMENT, AND PAYMENT
Will you receive compensation for participation in the study?
Some NIH Clinical Center studies offer compensation for participation in research. The amount 
of compensation, if any, is guided by NIH policies and guidelines.
You will not receive compensation for participation in this study. 
Will you receive reimbursement or direct payment by NIH as part of your participation?
Some NIH Clinical Center studies offer reimbursement or payment for travel, lodging or meals 
while participating in the research. The amount, if any, is guided by NIH policies and guidelines.
On this study, the NCI will cover the cost for some of your expenses.  Some of these costs may 
be paid directly by the NIH and some may be reimbursed after you have paid.  Someone will 
work with you to provide more information. 
Will taking part in this research study cost you anything? 
NIH does not bill health insurance companies or participants for any research or related clinical 
care that you receive at the NIH Clinical Center. 

If some tests and procedures performed outside the NIH Clinical Center, you may have to 
pay for these costs if they are not covered by your insurance company.

Medicines that are not part of the study treatment will not be provided or paid for by the 
NIH Clinical Center.

Once you have completed taking part in the study, medical care will no longer be provided 
by the NIH Clinical Center.  
CLINICAL TRIAL REGISTRATION AND RESULTS REPORTING
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required 
by U.S. Law. This Web site will not include information that can identify you. At most, the Web 
site will include a summary of the results. You can search this Web site at any time.
CONFIDENTIALITY PROTECTIONS PROVIDED IN THIS STUDY  
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:

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.

National Institutes of Health Intramural Institutional Review Board
IRB NUMBER: 17C0082
IRB APPROVAL DATE: 04/29/2020


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 03/19/2020
Page 15 of 17
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
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.
If we share your specimens or data with other researchers, in most circumstances we will remove 
your identifiers before sharing your specimens or data. You should be aware that there is a slight 
possibility that someone could figure out the information is about you. 
Further, the information collected for this study is protected by NIH under a Certificate of 
Confidentiality and the Privacy Act. 
Certificate of Confidentiality
To help us protect your privacy, the NIH Intramural Program has received a Certificate of 
Confidentiality (Certificate). With this certificate, researchers may not release or use data or 
information about you except in certain circumstances.  
NIH researchers must not share information that may identify you in any federal, state, or local 
civil, criminal, administrative, legislative, or other proceedings, for example, if requested by a 
court.  
The Certificate does not protect your information when it:  
1. is disclosed to people connected with the research, for example, information may be used 
for auditing or program evaluation internally by the NIH; or 
2. is required to be disclosed by Federal, State, or local laws, for example, when information 
must be disclosed to meet the legal requirements of the federal Food and Drug 
Administration (FDA); 
3. is for other research;
4. is disclosed with your consent. 
The Certificate does not prevent you from voluntarily releasing information about yourself or your 
involvement in this research. 
The Certificate will not be used to prevent disclosure to state or local authorities of harm to self or 
others including, for example, child abuse and neglect, and by signing below you consent to those 
disclosures. Other permissions for release may be made by signing NIH forms, such as the Notice 
and Acknowledgement of Information Practices consent.
Privacy Act
The Federal Privacy Act generally protects the confidentiality of your NIH medical records we 
collect under the authority of the Public Health Service Act.  In some cases, the Privacy Act 
protections differ from the Certificate of Confidentiality.  For example, sometimes the Privacy Act 
allows release of information from your medical record without your permission, for example, if 
it is requested by Congress. Information may also be released for certain research purposes with 
due consideration and protection, to those engaged by the agency for research purposes, to certain 
IRB NUMBER: 17C0082
IRB APPROVAL DATE: 04/29/2020


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 03/19/2020
Page 16 of 17
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
federal and state agencies, for HIV partner notification, for infectious disease or abuse or neglect 
reporting, to tumor registries, for quality assessment and medical audits, or when the NIH is 
involved in a lawsuit.  However, NIH will only release information from your medical record if it 
is permitted by both the Certificate of Confidentiality and the Privacy Act.
POLICY REGARDING RESEARCH-RELATED INJURIES  
The NIH 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 NIH, the NIH Clinical Center, or the Federal 
Government. However, you have the right to pursue legal remedy if you believe that your injury 
justifies such action.
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., gretentf@mail.nih.gov, 240-760-6114. You may also call the NIH Clinical Center Patient 
Representative at 301-496-2626, or the NIH Office of IRB Operations at 301-402-3713, if you 
have a research-related complaint or concern.
CONSENT DOCUMENT 
Please keep a copy of this document in case you want to read it again.
IRB NUMBER: 17C0082
IRB APPROVAL DATE: 04/29/2020


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 03/19/2020
Page 17 of 17
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
Adult Research Participant: I have read the explanation about this study and have been given the opportunity 
to discuss it and to ask questions. I consent to participate in this study.
Signature of Research Participant
Print Name of Research Participant
Date
Legally Authorized Representative (LAR) for an Adult Unable to Consent: I have read the explanation 
about this study and have been given the opportunity to discuss it and to ask questions. I am legally authorized 
to make research decisions on behalf of the adult participant unable to consent and have the authority to provide 
consent to this study. As applicable, the information in the above consent was described to the adult participant 
unable to consent who agrees to participate in the study.
Signature of LAR
Print Name of LAR
Date
Investigator:
Signature of Investigator
Print Name of Investigator
Date
Witness to the oral short-form consent process only: This section is only required if you are doing the oral 
short-consent process and this English consent form has been approved by the IRB for use as the basis of 
translation.
Witness:
Signature of Witness*
Print Name of Witness
Date
*NIH ADMINISTRATIVE SECTION TO BE COMPLETED REGARDING THE USE OF AN 
INTERPRETER:
An interpreter, or other individual, who speaks English and the participant’s preferred language facilitated
the administration of informed consent and served as a witness. The investigator obtaining consent may not 
also serve as the witness.
An interpreter, or other individual, who speaks English and the participant’s preferred language facilitated
the administration of informed consent but did not serve as a witness. The name or ID code of the person 
providing interpretive support is:
.
IRB NUMBER: 17C0082
IRB APPROVAL DATE: 04/29/2020