Conditions: Biliary Cancer
Keywords: Advanced Locally-advanced Not eligible for resection Prior chemotherapy treatment
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 42
Healthy volunteers: no

Brief summary:
This is an open label phase II trial to examine efficacy and safety of a novel combination of pembrolizumab plus induction GM-CSF in patients with advanced biliary cancers treated at University of California, San Francisco (UCSF).

This phase II study will examine the efficacy and safety of the novel combination of pembrolizumab plus induction GM-CSF in advanced biliary cancer patients with the hypotheses that the combination may increase proportion of patients with overall response compared to contemporary historical controls, with acceptable safety.

Detailed description:

Arms:
arm 1: Patients receive pembrolizumab IV over 30 minutes on day 1. Patients also receive sargramostim subcutaneous injection (SC) on days 1-14 of courses 1-2 or 2-3. Treatment repeats every 21 days for up to 2 courses for sargramostim and for up to 35 courses (24 months) for pembrolizumab in the absence of disease or unaccepted toxicity.

Interventions: intervention 1: Pembrolizumab intervention 2: Sargramostim
Intervention descriptions: intervention 1: 200 mg given intravenously (IV) intervention 2: 250 µg given subcutaneously (SC)

Protocol document:
Prot_SAP_000.pdf: 
Proprietary and Confidential
The information in this document is considered privileged and confidential, and may not be disclosed to others except 
to the extent necessary to obtain Institutional Review Board approval and informed consent, or as required by federal 
and state laws.  Persons to whom this information is disclosed should be informed that this information is privileged 
and confidential and that it should not be further disclosed.
Phase II Trial of Pembrolizumab (MK-3475) with GM-CSF 
Induction in Advanced Biliary Cancers
Protocol number: CC# 154524
Investigational Product(s): pembrolizumab, GM-CSF (Sargramostim)
Version number: 7.0
Version date: 10/01/2019
IND NUMBER: 129373
NCT Number: NCT02703714
Sponsor/Principal Investigator/Study Chair:
Robin K. Kelley, MD
University of California San Francisco (UCSF)
  
Biostatistician:
Paige Bracci, PhD, MPH, MS
Revision History
Version Number
Version Date
7.0
10/01/2019
6.0
08/23/2018
5.0
11/30/2017
4.0
03/01/2017
3.0
11/23/2016
2.0
05/03/2016
1.0
01/27/2016


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Phase II – pembrolizumab, GM-CSF
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TABLE OF CONTENTS
1.0
TRIAL SUMMARY ....................................................................................................6
2.0
TRIAL DESIGN ..........................................................................................................6
2.1
Trial Design..............................................................................................................6
2.2
Trial Diagram ..........................................................................................................7
3.0
OBJECTIVE(S) & HYPOTHESIS(ES) ....................................................................7
3.1
Primary Objective & Hypothesis ...........................................................................7
3.2
Secondary Objective(s) & Hypothesis (es) ............................................................7
3.3
Exploratory Objective(s).........................................................................................8
3.4
Additional Exploratory Objectives in Expansion Biopsy Cohort Only: ............9
4.0
BACKGROUND & RATIONALE ............................................................................9
4.1
Background on Indication ......................................................................................9
4.2
Background on Compounds .................................................................................10
4.2.1
Pharmaceutical and Therapeutic Background on Pembrolizumab......................10
4.2.2
Pharmaceutical and Therapeutic Background on GM-CSF (Sargramostim) ......11
4.2.3
Preclinical and Clinical Trial Data for Pembrolizumab and GM-CSF................12
4.3
Rationale.................................................................................................................12
4.3.1
Rationale for the Trial and Selected Subject Population .....................................12
4.3.2
Rationale for Pembrolizumab Dose and Schedule ..............................................13
4.3.3
Rationale for GM-CSF in Combination with Pembrolizumab............................14
4.3.4
Rationale for GM-CSF Induction Dose and Schedule.........................................15
4.3.5
Rationale for Expansion Cohort ..........................................................................16
4.3.6
Rationale for Endpoints .......................................................................................17
5.0
METHODOLOGY ....................................................................................................21
5.1
Entry Criteria ........................................................................................................21
5.1.1
Diagnosis/Condition for Entry into the Trial for All Cohorts .............................21
5.1.2
Subject Inclusion Criteria for All Cohorts...........................................................22
5.1.3
Additional Expansion Cohort Subject Inclusion Criteria ....................................23
5.1.4
Subject Exclusion Criteria for All Cohorts..........................................................24
5.2
Trial Treatments....................................................................................................25
5.2.1
Dose Selection .....................................................................................................25
5.2.2
Dose Modifications or Interruptions for Toxicity................................................26
5.2.3
Dose Preparation and Timing ..............................................................................31


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5.2.4
Trial Blinding/Masking........................................................................................32
5.3
Randomization or Treatment Allocation ............................................................32
5.4
Stratification...........................................................................................................32
5.5
Concomitant Medications/Vaccinations (Allowed and Prohibited)..................32
5.5.1
Acceptable Concomitant Medications.................................................................32
5.5.2
Prohibited Concomitant Medications ..................................................................32
5.6
Rescue Medications & Supportive Care..............................................................33
5.6.1
Supportive Care Guidelines for Pembrolizumab.................................................33
5.6.2
Supportive Care for GM-CSF..............................................................................37
5.6.3
General Supportive Care for Biliary Tract Cancer ..............................................37
5.7
Diet/Activity/Other Considerations .....................................................................38
5.7.1
Diet.......................................................................................................................38
5.7.2
Contraception.......................................................................................................39
5.7.3
Use in Pregnancy .................................................................................................39
5.7.4
Use in Nursing Women........................................................................................39
5.8
Subject Withdrawal/Discontinuation Criteria....................................................40
5.8.1
Discontinuation of Study Therapy after CR ........................................................41
5.9
Subject Replacement Strategy..............................................................................41
5.10
Clinical Criteria for Early Trial Termination ....................................................41
6.0
STUDY FLOW CHARTS.........................................................................................42
6.1
Safety Cohort Flow Chart (Safety Population)...................................................42
6.2
Main Study Flow Chart (Efficacy Population) ...................................................46
6.3
Second Course* Pembrolizumab Flow Chart.....................................................49
6.4
Expansion Cohort Flow Chart .............................................................................52
7.0
TRIAL PROCEDURES ............................................................................................56
7.1
Trial Procedures ....................................................................................................56
7.1.1
Administrative Procedures...................................................................................56
7.1.2
Clinical Procedures/Assessments ........................................................................58
7.1.3
Laboratory Procedures/Assessments ...................................................................60
7.1.4
Tumor and Blood Sample Collection for Correlative Analyses..........................61
7.1.5
Other Procedures..................................................................................................62
7.1.6
Visit Requirements ..............................................................................................63


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7.2
Assessing and Recording Adverse Events ...........................................................64
7.2.1
Definition of an Overdose for This Protocol and Reporting of Overdose to the 
Study Chair and to Merck....................................................................................65
7.2.2
Reporting of Pregnancy and Lactation to the Study Chair and to Merck............65
7.2.3
Immediate Reporting of Adverse Events to the Study Chair, Merck, and the FDA
.............................................................................................................................66
7.2.4
Evaluating Adverse Events..................................................................................67
7.2.5
Study Chair Responsibility for Reporting Adverse Events .................................70
8.0
STATISTICAL ANALYSIS PLAN .........................................................................70
8.1
Study Statistical Design.........................................................................................70
8.2
Study Objectives and Hypotheses ........................................................................70
8.3
Definition of Study Endpoints ..............................................................................70
8.3.1
Primary Endpoint.................................................................................................70
8.3.2
Secondary Endpoints ...........................................................................................70
8.4
Sample Size and Accrual Rate..............................................................................71
8.4.1
Sample Size..........................................................................................................71
8.4.2
Accrual Rate ........................................................................................................72
8.4.3
Interim Analyses..................................................................................................72
8.4.4
Interim Safety Analysis and Stopping Rules.......................................................72
8.4.5
Interim Efficacy Analysis....................................................................................73
8.5
Analysis Populations..............................................................................................73
8.5.1
Safety Population.................................................................................................73
8.5.2
Efficacy Population..............................................................................................73
8.6
Planned Analyses ...................................................................................................73
8.6.1
Primary Endpoint Analysis..................................................................................73
8.6.2
Secondary and Exploratory Endpoints ................................................................74
8.6.3
Exploratory Correlative Analyses........................................................................75
9.0
LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL 
SUPPLIES ..................................................................................................................77
9.1
Investigational Products........................................................................................77
9.1.1
Pembrolizumab....................................................................................................77
9.1.2
GM-CSF (Sargramostim) ....................................................................................77
9.2
Packaging and Labeling Information..................................................................77
9.3
Clinical Supplies Disclosure..................................................................................77


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9.4
Storage and Handling Requirements...................................................................78
9.5
Returns and Reconciliation...................................................................................78
9.6
Disposal and Destruction of Unused Investigational Products .........................78
10.0
ADMINISTRATIVE AND REGULATORY DETAILS .......................................78
10.1
Pre-Study Documentation.....................................................................................78
10.2
Institutional Review Board Approval..................................................................78
10.3
Informed Consent..................................................................................................79
10.4
Changes in the Protocol ........................................................................................79
10.5
Handling and Documentation of Clinical Supplies ............................................79
10.6
Case Report Forms (CRFs) ..................................................................................79
10.7
Oversight and Monitoring Plan............................................................................80
10.8
Record Keeping and Record Retention...............................................................80
11.0
APPENDICES............................................................................................................82
11.1
Data and Safety Monitoring Plan for a Phase 2 or 3 Institutional Study.........82
11.2
Patient Diary/Injection Record for GM-CSF .....................................................85
11.3
Common Terminology Criteria for Adverse Events V4.0 (CTCAE) ...............86
11.4
ECOG Performance Status...................................................................................87
11.5
Child Pugh Score ...................................................................................................88
11.6
Specimen Collection and Shipping Instructions and Laboratory Contact 
Information ............................................................................................................89
11.6.1 Archival FFPE Tumor Blocks .............................................................................89
11.6.2 Whole Blood for PBMC Isolation .......................................................................89
11.6.3 Expansion Cohort Research Biopsies..................................................................90
11.6.4 Optional Specimen Banking in UCSF Hepatobiliary Tissue Bank CC#124512.91
11.7
Adverse Event Reporting to Merck and FDA.....................................................92
12.0
References...................................................................................................................94


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1.0 TRIAL SUMMARY
Abbreviated Title
Pembrolizumab plus GM-CSF Induction in Advanced Biliary 
Cancers
Trial Phase
II
Clinical Indication
Advanced biliary cancers including unresectable intrahepatic or 
extrahepatic cholangiocarcinoma and gall bladder carcinoma 
Trial Type
Open label, single arm phase II therapeutic clinical trial
Type of control
None
Route of 
administration
Intravenous (pembrolizumab) and subcutaneous (GM-CSF)
Trial Blinding
N/A
Treatment Groups 
N/A (not randomized)
Number of trial 
subjects
Total enrollment of 42 subjects for expected PFS6-evaluable n=40 
and overall response evaluable n=37, combined between the 
following three cohorts:
Stage 1: n=9 (completed)
Stage 2: n=18 (completed)
Expansion Cohort: n=15
Estimated 
enrollment period
Stages 1 and 2: 16 months (completed); Expansion Cohort: 12 
months
Estimated duration 
of trial
52 months for accrual plus up to 2 years on treatment from start of 
treatment of last enrolled patient in the Expansion Cohort, with 
potential for up to 2 additional years of survival follow up in event 
that last patient has prolonged stable disease and discontinues 
without progression after 24 months or 35 cycles
Duration of 
Participation
Expect median time on pembrolizumab treatment of 6 months
2.0 TRIAL DESIGN
2.1
Trial Design
This is an open-label phase II trial to examine efficacy and safety of a novel combination of 
pembrolizumab plus induction GM-CSF in patients with advanced biliary cancers treated at UCSF. 


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Phase II – pembrolizumab, GM-CSF
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2.2
Trial Diagram
3.0 OBJECTIVE(S) & HYPOTHESIS(ES)
3.1
Primary Objective & Hypothesis
(1) Objective:  Determine overall response rate (ORR) by RECIST 1.11 in the overall study 
population.
Hypothesis:  The ORR by RECIST 1.1 in overall study population will be 20% which is a 
meaningful proportion with response compared to a null hypothesis response rate of 
approximately 5% for no treatment in 2nd line advanced biliary cancers, noting that there is no 
current FDA-approved therapy after failure of 1st line gemcitabine-based regimens and 
uncontrolled and retrospective studies show that responses to standard cytotoxic therapies are 
modest and transient.2-4  ORR on treatment with single-agent pembrolizumab in unselected ≥ 
2nd line biliary cancer patients has not yet been reported from KEYNOTE-158 (unpublished 
data, Merck).
3.2
Secondary Objective(s) & Hypothesis (es)
(1) Objective:  Measure safety (NCI CTCAE v.4.0) for the novel combination overall and 
according to anatomic subtype.
Hypothesis:  The combination is safe and feasible with ≤ 50% related ≥ grade 3 toxicity rate 
(Common Terminology Criteria for Adverse Events (CTCAE) version 4.0) during first 3 cycles 
(completion of Induction Phase plus 1 additional cycle).


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(2) Objective:  Determine proportion PD-L1+ overall.
Hypothesis:  Approximately 40% of tumors will be PD-L1+ overall based upon PD-L1+ 
rates observed in KEYNOTE-028 biliary cohort.5
(3) Objective:  Determine overall response rate (ORR) by RECIST 1.11 according to PD-L1 
status.
Hypothesis:  The ORR by RECIST 1.1 will be higher in PD-L1+ biliary cancers compared to 
PD-L1- tumors. 
(4) Objective:  Determine proportion with progression-free survival at 6 months (%PFS6) overall 
and according to PD-L1 status.
Hypothesis:  In advanced biliary tract cancer patients after failure of 1st-line chemotherapy, 
pembrolizumab plus induction GM-CSF will achieve proportion with PFS at 6 months of 40% 
(H1), a meaningful proportion compared to 20% (H0) in historical controls treated with 
conventional 2nd line chemotherapy. 
(5) Objective:  Measure median duration of response (DOR), PFS, and OS in overall cohort and 
according to PD-L1 status.
Hypothesis:  The median OS in overall cohort will be improved compared to historical control 
OS of approximately 6.7 months from start of treatment with 2nd line chemotherapy for 
advanced biliary cancer.6
3.3
Exploratory Objective(s)
(1) Describe clinical outcomes according to anatomic subtype of biliary tract cancer.
(2) Explore proportion PD-L1+ on tumor cells and tumor infiltrating immune cells (TIIC) in 
archival tumor samples according to anatomic subtype of biliary tract cancer.
(3) Measure proportions with CA19-9 decline ≥ 25% and ≥ 50% at best response from baseline 
overall and according to PD-L1 status.
(4) Characterize serial peripheral blood mononuclear cells (PBMC) (at baseline, on treatment, 
and at progression) for immune cell profiles by methods which may include multiparameter 
flow cytometry and/or Cytof, gene expression profiling, and T cell repertoire by T cell 
receptor sequencing.
(5) Characterize TIIC quantity and profile and T cell repertoire in archival pre-treatment tumor 
tissue.
(6) Explore for associations between ORR by RECIST 1.1 and irRC, PFS, OS, and PD-L1 status 
with clinically-available tumor genotyping results including common mutations, MSI/MMR 
status, and TMB.  


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(7) Measure Re-induction (r) PFS (rPFS and rPFS6), safety, response rate (rRR), and CA 19-9 
response for any patients who undergo re-induction with GM-CSF for progression after 
response or stabilization post first induction. 
(8) Measure Second Course (s) PFS (sPFS and sPFS6), safety, response rate (sRR), and CA 19-9 
response for any patients who receive Second Course of treatment with pembrolizumab for 
progression post discontinuation.
3.4
Additional Exploratory Objectives in Expansion Biopsy Cohort Only:
(1) Measure proportions PD-L1+ in tumor cells and TIICs in pre-treatment archival samples 
and in research biopsy samples 1) on pembrolizumab monotherapy and 2) in combination 
with GM-CSF.
(2) Quantify total tumor infiltrating immune cells (TIICs) in pre-treatment archival samples 
and in research biopsy samples 1) on pembrolizumab monotherapy and 2) in combination 
with GM-CSF.
(3) Characterize immune cell profiles  in pre-treatment archival samples and in research biopsy 
samples 1) on pembrolizumab monotherapy and 2) in combination with GM-CSF
4.0 BACKGROUND & RATIONALE
4.1
Background on Indication
Cancers of the biliary tract are a family of epithelial cancers which include intra- and extrahepatic 
cholangiocarcinoma (CCA) and gall bladder carcinoma (GBC).  Biliary cancers represent the 
second most common primary cancer of the liver after hepatocellular carcinoma (HCC) and their 
incidence, particularly for intrahepatic CCA, has risen significantly over the past decade.7  Though 
the risk factors for biliary cancers are not well understood, conditions associated with chronic 
inflammation including hepatitis B virus (HBV) or hepatitis C virus (HCV), chronic cholangitis, 
or a history of liver fluke infection are associated with higher rates of CCA.7,8 
In patients with advanced biliary cancers including CCA and gall bladder adenocarcinoma not 
amenable to resection, the “Advanced Biliary Cancer-02” (ABC-02) trial established the 
combination of gemcitabine plus cisplatin as the global standard for 1st-line therapy, showing 
significantly improved survival compared to gemcitabine alone.9 Though the ABC-02 regimen 
achieved significant survival benefit, overall outcomes remain grim, with median overall survival 
of 11.7 months for patients treated with the combination of gemcitabine plus cisplatin compared 
to 8.1 months for patients treated with gemcitabine alone.9
There is no standard 2nd-line chemotherapy for advanced biliary cancers, though 5-fluorouracil-
based regimens are commonly used.2  A retrospective study of 2nd line therapy with the 
combination of 5-fluorouracil, leucovorin, and irinotecan (FOLFIRI) after 1st-line gemcitabine 
plus oxaliplatin among 34 patients with advanced cholangiocarcinoma treated at a single-center in 
France between 2005-2013 reported median 2nd-line PFS of 2.9 months.4  Another retrospective 
analysis of outcomes from 603 patients treated with 1st-line gemcitabine plus platinum across 17 
centers in France between 2002-2013 showed that 32% of patients received 2nd-line chemotherapy 


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after progression on 1st-line therapies.2  For those who received 2nd-line chemotherapy, the median 
PFS was 3.2 months and median OS was 6.7 months in the 2nd-line setting, without significant 
differences by regimen. The ORR was 12%.  A retrospective registry analysis of 198 advanced 
biliary tract cancer patients treated with 2nd line chemotherapy at UCSF, Memorial Sloan Kettering 
Cancer Center, and Vanderbilt University Cancer Center after failure of 1st-line gemcitabine plus 
platinum regimens showed median time on treatment of only 2.2 months, supporting %PFS6 as a 
meaningful endpoint.10
There is an urgent need for more effective treatments for this grim family of cancers, across lines 
of therapy but particularly post failure of standard 1st line therapy, after which there are no 
established treatments.
4.2
Background on Compounds
Pembrolizumab and GM-CSF are both approved by the United States Food and Drug 
Administration (FDA) for multiple indications.  Please refer to the Investigator’s Brochures (IB) 
and approved FDA labeling for additional detailed background information on MK-3475 and GM-
CSF.
4.2.1
Pharmaceutical and Therapeutic Background on Pembrolizumab
The importance of intact immune surveillance in controlling outgrowth of neoplastic 
transformation has been known for decades.  Accumulating evidence shows a correlation between 
tumor-infiltrating lymphocytes (TILs) in cancer tissue and favorable prognosis in various 
malignancies.  In particular, the presence of CD8+ T-cells and the ratio of CD8+ effector T-cells / 
FoxP3+ regulatory T-cells seems to correlate with improved prognosis and long-term survival in 
many solid tumors.
The PD-1 receptor-ligand interaction is a major pathway hijacked by tumors to suppress immune 
control, also known as an immune “checkpoint.”  The normal function of PD-1, expressed on the 
cell surface of activated T-cells under healthy conditions, is to down-modulate unwanted or 
excessive immune responses, including autoimmune reactions.  PD-1 (encoded by the gene Pdcd1) 
is an Ig superfamily member related to CD28 and CTLA-4 which has been shown to negatively 
regulate antigen receptor signaling upon engagement of its ligands (PD-L1 and/or PD-L2).  The 
structure of murine PD-1 has been resolved.  PD-1 and family members are type I transmembrane 
glycoproteins containing an Ig Variable-type (V-type) domain responsible for ligand binding and 
a cytoplasmic tail which is responsible for the binding of signaling molecules.  The cytoplasmic 
tail of PD-1 contains 2 tyrosine-based signaling motifs, an immunoreceptor tyrosine-based 
inhibition motif (ITIM) and an immunoreceptor tyrosine-based switch motif (ITSM).  Following 
T-cell stimulation, PD-1 recruits the tyrosine phosphatases SHP-1 and SHP-2 to the ITSM motif 
within its cytoplasmic tail, leading to the dephosphorylation of effector molecules such as CD3ζ, 
PKCθ and ZAP70 which are involved in the CD3 T-cell signaling cascade.  The mechanism by 
which PD-1 down modulates T-cell responses is similar to, but distinct from that of CTLA-4 as 
both molecules regulate an overlapping set of signaling proteins.  PD-1 was shown to be expressed 
on activated lymphocytes including peripheral CD4+ and CD8+ T-cells, B-cells, T regs and 
Natural Killer cells.  Expression has also been shown during thymic development on CD4-CD8- 
(double negative) T-cells as well as subsets of macrophages and dendritic cells.  The ligands for 


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PD-1 (PD-L1 and PD-L2) are constitutively expressed or can be induced in a variety of cell types, 
including non-hematopoietic tissues as well as in various tumors.  Both ligands are type I 
transmembrane receptors containing both IgV- and IgC-like domains in the extracellular region 
and contain short cytoplasmic regions with no known signaling motifs.  Binding of either PD-1 
ligand to PD-1 inhibits T-cell activation triggered through the T-cell receptor.  PD-L1 is expressed 
at low levels on various non-hematopoietic tissues, most notably on vascular endothelium, whereas 
PD-L2 protein is only detectably expressed on antigen-presenting cells found in lymphoid tissue 
or chronic inflammatory environments.  PD-L2 is thought to control immune T-cell activation in 
lymphoid organs, whereas PD-L1 serves to dampen unwarranted T-cell function in peripheral 
tissues.  Although healthy organs express little (if any) PD-L1, a variety of cancers were 
demonstrated to express abundant levels of this T-cell inhibitor.  PD-1 has been suggested to 
regulate tumor-specific T-cell expansion in subjects with melanoma.  This suggests that the PD-
1/PD-L1 pathway plays a critical role in tumor immune evasion and should be considered as an 
attractive target for therapeutic intervention.
Pembrolizumab is a potent and highly selective humanized monoclonal antibody (mAb) of the 
IgG4/kappa isotype designed to directly block the interaction between PD-1 and its ligands, PD-
L1 and PD-L2.  KeytrudaTM (pembrolizumab) has recently been approved in the United Stated for 
the treatment of patients with unresectable or metastatic melanoma and disease progression 
following ipilumumab and, if BRAF V600 mutation positive, a BRAF inhibitor.
Nivolumab is another humanized IgG4 mAb inhibitor of ligand activation of the PD-1 receptor 
which is being studied in multiple tumor types, including hepatocellular carcinoma (HCC) 
associated with underlying viral hepatitis,11 and has been approved in the United States for 
treatment of patients with metastatic melanoma or advanced squamous, non-small cell lung cancer. 
4.2.2
Pharmaceutical and Therapeutic Background on GM-CSF (Sargramostim)
GM-CSF is a cytokine that regulates the survival, proliferation, differentiation, and function of 
granulocytes and macrophages. GM-CSF has also been demonstrated to enhance the functional 
activities of effector cells including dendritic cells (DC), neutrophils, and monocytes. Increased 
class II MHC expression on DC as a result of exposure to GM-CSF leads to increased antigen 
presentation to T cells, stimulating T cell responses. Additionally, increased co-stimulatory 
molecule expression on DC with GM-CSF enhances T cell response. In vitro, GM-CSF is among 
the principal adjuvants used for production of DC from monocytes. In a phase 1 study of 
neoadjuvant granulocyte colony stimulating factor (GM-CSF) before prostatectomy for localized 
prostate cancer, GM-CSF subcutaneously for 2-4 weeks resulted in CD8+ T cell recruitment to 
tumors, in addition to increases in circulating dendritic cells, CD4+ T cells, and proliferative 
CD8+ T cells.12
GM-CSF at a dose of 250 µg/m2 daily is approved in the United States to promote neutrophil 
recovery following induction chemotherapy for acute myelogenous leukemia and for myeloid 
reconstitution post autologous or allogeneic peripheral blood progenitor cell or bone marrow 
transplantation (see FDA package insert). The pleiotropic immunological effects described above 
also have resulted in the investigation of GM-CSF using various schedules and doses in multiple 
immunotherapeutic anti-tumor strategies.  GM-CSF has shown single-agent anti-tumor activity 
in clinical trials in prostate and ovarian carcinomas.13-15


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4.2.3
Preclinical and Clinical Trial Data for Pembrolizumab and GM-CSF
Please refer to the Investigator’s Brochures for preclinical and clinical data on pembrolizumab and 
GM-CSF.
4.3
Rationale
This phase II study will examine the efficacy and safety of the novel combination of 
pembrolizumab plus induction GM-CSF in advanced biliary cancer patients with the hypotheses 
that the combination may increase proportion of patients with PFS6 compared to contemporary 
historical controls, with acceptable safety.
4.3.1
Rationale for the Trial and Selected Subject Population
Cancers associated with infectious etiologies16-18 and cancers with chromosomal instability19,20 
have shown higher response rates to immune checkpoint inhibitors such as anti-PD-1 or anti-
CTLA-4 monoclonal antibodies.  Chronic infections and inflammatory conditions are well-
established risk factors for biliary cancers.7,8,21  Gene expression profiling has identified an 
inflammatory subclass of CCA, including a transcriptome signature unique to prior fluke 
infection.22-25  Chromosomal instability and defects in DNA repair pathways, including a small 
subset of patients with microsatellite instability, also occur in CCA.22,25,26  These characteristics 
provide a theoretical rationale for the study of checkpoint inhibition in biliary cancers.  
Early clinical data also provide a strong signal for efficacy of checkpoint inhibition in biliary 
cancer patients.  As part of the KEYNOTE-028 (NCT02054806) phase Ib basket trial of 
pembrolizumab in 20 tumor types, a biliary cancer cohort of 23 patients with PD-L1+ tumors was 
enrolled (including 3 patients from UCSF). Approximately 40% of the biliary cancer patients 
screened for KEYNOTE-028 had tumors which were PD-L1+ as defined by at least 1% PD-L1 
expression on a proprietary immunohistochemistry (IHC) assay.5  The overall response rate for the 
biliary cancer cohort was approximately 17% in the KEYNOTE-028 trial and was notable for 
several patients with profound and prolonged responses, some of which remain ongoing.  One 
example is a UCSF patient with metastatic intrahepatic CCA and rapid progression on 1st-line 
gemcitabine plus cisplatin therapy who experienced a confirmed PR on KEYNOTE-028, with 
RECIST 1.1 decrease by approximately 14% after 2 months, 23% after 4 months, and eventually 
achieving complete response (CR) which remains ongoing now over 36 months since enrollment 
on KEYNOTE-028 and approximately 16 months since discontinuation of pembrolizumab after 2 
years of treatment per protocol (confidential, unpublished data from RKK).  Multiple dermal and 
muscle metastases including a cardiac intraventricular septum metastasis have decreased in size 
and/or become clinically and radiographically occult on treatment, without any significant toxicity.  
Further supporting that biliary cancers may be susceptible to immune-mediated anti-cancer effects, 
a case of near complete response to mutation-specific (ERBB2IP) tumor infiltrating lymphocyte 
adoptive transfer27 and spontaneous tumor regressions28 have also been described in CCA patients.
This study permits inclusion of patients with underlying viral hepatitis, a common risk factor in 
biliary cancers.  Though viral hepatitis was an exclusion factor for prior pembrolizumab studies, 
studies of other checkpoint inhibitors in HCC patients with viral hepatitis have not demonstrated 
an increased risk of hepatic decompensation or fulminant hepatitis.  In a large phase I/II study in 


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HCC patients, nivolumab demonstrated a promising overall response rate of 23% with prolonged 
duration of responses, very mild toxicity, and no evidence of reactivation of viral hepatitis nor 
fulminant inflammatory responses in HCC cohorts defined by HBV, HCV, and nonviral 
etiologies.11  The CTLA-4 inhibitor tremelimumab also showed a favorable PR rate of almost 18% 
without any events of hepatic decompensation in advanced HCC patients with underlying HCV 
cirrhosis (though transient and reversible grade 3 and 4 transaminitis was observed in 
approximately 45% of cases, without hepatic decompensation).29  
4.3.2
Rationale for Pembrolizumab Dose and Schedule
An open-label phase I trial (Protocol 001) was conducted to evaluate the safety and clinical 
activity of single agent MK-3475.  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 MK-3475 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 has been identified to date.  10.0 mg/kg Q2W was the highest dose 
tested in PN001.  Recent data from other clinical studies within the MK-3475 program has 
shown that a lower dose of MK-3475 and a less frequent schedule may be sufficient for target 
engagement and clinical activity.
PK data analysis of MK-3475 administered Q2W and Q3W showed slow systemic clearance, 
limited volume of distribution, and a long half-life (refer to IB).  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 has been performed using serum concentration time data 
from 476 patients. Within the resulting population PK model, clearance and volume parameters 
of MK-3475 were found to be dependent on body weight. The relationship between clearance 
and body weight, with an allometric exponent of 0.59, is within the range observed for other 
antibodies and would support both body weight normalized dosing or a fixed dose across all 
body weights.  MK-3475 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 MK-3475 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 


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assessed by the population PK model) and 4) the assumption that the dynamics of pembrolizumab 
target engagement will not vary meaningfully with tumor type.
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.
The optimal duration of therapy with PD-1 inhibition in patients with radiographic response or 
stable disease after prolonged therapy is not known.  Ongoing responses to pembrolizumab and 
nivolumab have been demonstrated, continuing in many cases for over a year post final dose of 
therapy.  For this study, treatment with pembrolizumab will be continued until documented disease 
progression or other reason for study discontinuation (such as unacceptable toxicity or withdrawal 
of consent) until completing approximately 24 months of treatment (up to 35 doses) or after 
attaining confirmed CR (see Section 5.8.1) at which time treatment will be discontinued.  In 
eligible cases of progression within 6 months after discontinuation of pembrolizumab after prior 
CR, PR, or SD with evidence for clinical benefit (see Section 7.1.5.2), retreatment with a “Second 
Course” of pembrolizumab may be considered on a case-by-case basis with approval from Study 
Chair and Merck (see Section 7.1.5.2).  Second Course (s) PFS (sPFS and sPFS6), response rate 
(sRR), and CA 19-9 response will be described in these cases.  
4.3.3
Rationale for GM-CSF in Combination with Pembrolizumab
In preclinical models, the addition of GM-CSF-secreting tumor vaccines to checkpoint blockade 
by a CTLA-4 inhibitor is synergistic.30  The GM-CSF-secreting whole cell pancreas cancer vaccine 
GVAX has been shown to induce PD-1 and PD-LI expression in pancreatic tumors and/or in 
tumor-associated lymphoid cells or monocytes,31 and the combination of anti-PD-1 therapy and 
GM-CSF-secreting tumor cell immunotherapy shows synergy in mouse models of colon cancer 
and melanoma.32
There are multiple clinical studies which demonstrate safety and preliminary efficacy of GM-CSF 
in combination with CTLA-4 inhibition.  In a phase I trial of patients (n=24) with advanced 
prostate cancer conducted at UCSF, addition of granulocyte macrophage colony stimulating factor 
(GM-CSF) to checkpoint inhibition by the anti-CTLA4 antibody, ipilimumab, resulted in prostate 
specific antigen (PSA) decline, along with expansion of tumor antigen-specific T cells, specific 
tumor antibody response (to NY-ESO-1 and TP53), and activation of effector T cells.33  The 
correlative analyses for this study were conducted in the laboratory of Dr. Larry Fong at UCSF.  
Building from this data, a recent phase II randomized clinical trial examined the efficacy of the 
combination of ipilimumab 10 mg/kg IV every 21 days with fixed doses of GM-CSF (250 μg) 
administered subcutaneously (SC) daily on days 1-14 every 21 days, compared to ipilimumab 
alone, in 245 patients with advanced melanoma.34  This study showed significantly improved OS 


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in patients treated with the combination (68.9% vs. 52.9% at 1 year, p=0.01), while rates of grade 
3-5 adverse events were lower in the combination arm (44.9% vs. 58.3% for ipilimumab alone, 
p=0.04).  In pancreatic cancer, a cancer closely related to biliary cancers both anatomically and 
biologically, a phase 1b study of the combination of ipilimumab and GM-CSF-secreting whole 
cell vaccine (GVAX) in 30 patients showed acceptable safety of the combination compared to 
ipilimumab alone, higher rates of CA 19-9 decline, and higher absolute 1-year OS rate of 27% in 
the combination arm, compared with 7% in the ipilimumab arm.35
To date, there are no published clinical data on the combination of PD-1 inhibition and GM-CSF 
or GVAX.  A multicenter phase 2 trial of GVAX, nivolumab, and CRS207 (an attenuated listeria 
vaccine expressing the tumor antigen, mesothelin) is underway in advanced pancreatic cancer 
patients (NCT02243371).
Interim and ongoing analyses of safety and efficacy of Stage 1 and 2 of this study showed 
acceptable safety without any unexpected adverse events along with promising response rate as 
described below in Section 4.3.5.1, Rationale for Expansion Cohort.
4.3.4
Rationale for GM-CSF Induction Dose and Schedule
GM-CSF may enhance antigen presentation, in which case a priming dose of GM-CSF prior to 
checkpoint inhibitor administration could be sufficient to enhance T cell activation. 
Alternatively, GM-CSF may increase the numbers of Fc receptor bearing antigen-presenting 
cells to enhance the activation of T cells by providing a cellular scaffold for a checkpoint 
inhibitor.  With this mechanism, GM-CSF may need to be administered simultaneously with a 
checkpoint inhibitor in order to potentiate T cells. 
We hypothesize that any potential contribution of GM-CSF will be most important during a 
priming or “induction” phase of treatment.  This study will examine the efficacy of a novel 
induction regimen of GM-CSF administered at a fixed dose of 250 µg SC once daily on days 1-
14 every 21 days for 2 cycles (6 weeks), in combination with pembrolizumab at fixed dose of 
200 mg IV every 21 days as above, based upon the observed efficacy of this GM-CSF dose and 
schedule in combination with ipilimumab in metastatic melanoma, and in similar combinations 
in prostate cancer and pancreatic cancer.33-35  
For the initial Safety Cohort (Stage 1) of 9 patients, pembrolizumab was initiated as a single 
agent on Cycle 1, Day 1, and GM-CSF was administered days 1-14 in Cycles 2 and 3.  A 
planned interim safety analysis showed that the incidence of ≥ Grade 3 adverse events 
adjudicated as at least possibly treatment-related to the combination of GM-CSF plus 
pembrolizumab met criteria to continue with study enrollment (see Section 8.5.1). Enrollment to 
Efficacy Cohort (Stage 2) was subsequently completed with 18 additional patients.  In the 
Efficacy Cohort, GM-CSF was initiated concurrently with pembrolizumab starting Cycle 1, Day 
1 for two induction cycles, based upon the rationale that priming by GM-CSF is optimized if 
administered in advance or concurrently with PD-1 inhibition. 
Acknowledging that the optimal duration and schedule of GM-CSF induction is unknown, re-
induction with GM-CSF for 2 additional cycles is allowed in patients who demonstrate CR, PR, 
or prolonged SD with evidence of clinical benefit after the Induction Phase and within 12 months 
from enrollment, but who subsequently progress on single-agent pembrolizumab between 


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approximately 6-12 months (corresponding to Cycle 8-16) after enrollment (after the primary 
endpoint of PFS6 has been ascertained for that patient) (see Section 7.1.5.1).  Repeat GM-CSF 
induction requires approval on a case-by-case basis from the Study Chair.  Re-induction (r) PFS 
(rPFS and rPFS6) and response rate (rRR) will be described in these cases.  
If ≥5 patients (approx. 20%) undergo GM-CSF re-induction and demonstrate restored CR or PR 
within 6 months after re-induction, the study team will consider whether to amend the protocol to 
allow for prolonged GM-CSF treatment or serial re-induction depending on the observed 
outcomes.
4.3.5
Rationale for Expansion Cohort
The Safety and Efficacy Cohorts (Stages 1 and 2) of this study completed enrollment as of 18-
SEP-2017. After completion of accrual and follow up to the Safety Cohort (n=9), the UCSF Data 
and Safety Monitoring Committee (DSMC) conducted planned safety and efficacy analyses and 
determined that the target safety and efficacy thresholds were reached, enabling continuation of 
study enrollment to the Efficacy Cohort (Stage 2) (n=18 additional patients). The Safety Cohort 
interim safety analysis did not identify any unexpected toxicity of the combination. Related grade 
3-4 toxicity occurred in 2/9 (22%): 1 event grade 4 hyperglycemia/ketoacidosis, 1 event grade 3 
alkaline phosphatase.  An additional grade 2 serious adverse event (SAE) of grade 2 
hyperthyroidism with ophthalmopathy resolved after a course of prednisone.  The interim efficacy 
analysis indicated PFS6 in 4/9 (44%), along with 2 partial responses (PR), 1 confirmed and 1 
preceded by prolonged minor regression and achievement of PFS6.  Minor regression and 
prolonged CA 19-9 decline >50% occurred in 2 additional Safety Cohort patients, both of whom 
achieved PFS6 and one who remains on treatment as of 18-SEP-2017 now with prolonged stable 
disease over 1.5 years, sustained CA 19-9 tumor marker decline >50% from baseline, and 
resolution of prior abdominal pain and anorexia since starting treatment. 
As of 18-SEP-2017, the Efficacy Cohort (Stage 2) has completed enrollment with an additional 18 
patients. Ongoing safety analyses are consistent with the known safety profile of pembrolizumab, 
without any unexpected events.  Preliminary ORR results show 3 additional cases with 
unconfirmed + confirmed PR out of 13 evaluable cases, as well as another case with prolonged 
minor regression, resolution of pain, and > 50% CA 19-9 decline ongoing over 12 months since 
start of treatment.  PFS6 results are not yet mature in this cohort. 
Based upon the promising preliminary ORR (5/21 evaluable cases, 23.8%) and additional durable 
clinical responses observed in a meaningful subset of patients enrolled to Stages 1 and 2 of the 
study coupled with acceptable safety, the protocol will be amended to enroll an additional 
Expansion Cohort (n=15) in order to improve confidence on ORR and PFS endpoints as well as to 
obtain additional biospecimens for correlative analyses.  
4.3.5.1
Rationale for Expansion Cohort Schedule and Biopsies
An important exploratory objective of the Expansion Cohort is to obtain paired biopsy samples 
from patients while on treatment with pembrolizumab monotherapy and in combination with GM-
CSF, in addition to archival pre-treatment samples. Correlative analyses of tumor and TIIC PD-
L1 expression, TIIC profiles, and PBMC profiles will explore for changes associated with 


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pembrolizumab alone and with addition of GM-CSF to better understand the differential 
contributions of each study drug to the observed clinical and radiographic responses in this study.
To enable comparisons of pembrolizumab monotherapy and in combination with GM-CSF, the 
schedule for the Expansion Cohort will be the same as the Safety Cohort, starting with 1 cycle of 
pembrolizumab monotherapy before adding induction GM-CSF during Cycles 2 and 3.  The 
observed safety and efficacy of the Safety Cohort and Efficacy Cohort are similar, though limited 
by small sample sizes, supporting the choice of the Safety Cohort schedule for the Expansion 
Cohort.  Biopsies will be planned during Week 3 of pembrolizumab monotherapy and Week 9 
after addition of GM-CSF and after first restaging imaging has been obtained.  PMBC profiles will 
be compared between the Safety and Expansion Cohorts (expected n=23) and the Efficacy Cohort 
(n=18), enabling further characterization of the impact of GM-CSF on immune cell profiles in a 
larger group of subjects.
4.3.6
Rationale for Endpoints
4.3.6.1
Primary Efficacy Endpoint: Overall Response Rate (ORR)
Based upon results from Stages 1 and 2 indicating a promising proportion of patients with durable 
radiographic and clinical responses, the primary endpoint for this study will be changed to overall 
response rate (ORR) by locally-assessed RECIST 1.1,1 previously a key secondary endpoint, 
and %PFS6 will be changed to a key secondary endpoint. In advanced biliary cancer patients 
treated with standard 2nd-line chemotherapies, the historical response rate is approximately 10% 
with short duration of response,2,4 and there is no standard therapy approved by the FDA in this 
context owing to limited efficacy.  In unselected advanced biliary cancer patients treated with 
pembrolizumab monotherapy in KEYNOTE-158, the response rate has not yet been reported.  A 
target ORR of 20% (H1) on treatment with pembrolizumab plus induction GM-CSF would 
represent a meaningful improvement in this population, with H0 5% as null hypothesis in the 
absence of any established effective standard 2nd line therapy in advanced biliary cancers.
4.3.6.2
Secondary Efficacy Endpoints
Proportion with PFS at 6 months (%PFS6) %PFS6 will be a key secondary endpoint for the overall 
study.  In advanced biliary cancers treated with standard ≥ 2nd line systemic chemotherapies, 
retrospective studies report median PFS of only approximately 2 to 3 months (corresponding 
to %PFS6 of approximately 20% (H0) assuming normal distribution).2,4,10 A target %PFS6 of 40% 
(H1) on treatment with pembrolizumab plus induction GM-CSF would represent a clinically 
meaningful improvement.  Locally-assessed RECIST 1.11 will be used to determine progression.
Overall survival will be measured as another key secondary endpoint with the hypothesis that the 
median overall survival will be increased compared to a historical control median OS of 6.7 months 
from start of standard second line chemotherapy for advanced biliary cancers.6
An additional secondary efficacy endpoint is DOR, defined as time from first RECIST 1.1 
response to disease progression in subjects who achieve a PR or better, as a clinically-relevant 
measure of efficacy.  The duration of response or disease stabilization with 2nd line conventional 
chemotherapy in biliary tract cancers is very short, with median PFS only approximately 2-3 


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months on standard 2nd line therapies, and the majority of objective responses transient, lasting 
less than 6 months.2,37 
Re-induction and Second Course efficacy endpoints will also be described.
4.3.6.3
Safety Endpoints
Safety is a key secondary endpoint for this novel combination.  The combination of GM-CSF plus 
ipilimumab showed an improved toxicity profile compared to ipilimumab alone with significantly 
lower rates of treatment-related grade 3-5 adverse events (44.9% versus 58.3%, p=0.04),34 but the 
safety of pembrolizumab in combination with induction GM-CSF has not been studied in humans.  
The interim safety analysis after 9 patients in the Safety Cohort completed 3 cycles of therapy (1 
cycle of pembrolizumab followed by 2 cycles with GM-CSF induction plus pembrolizumab, for 
total of 9 weeks in the Safety Cohort) or been removed for related toxicity events showed 
acceptable safety to continue enrollment to the Efficacy Cohort (see Section 4.3.5).  The interim 
safety analysis showed that related ≥ Grade 3 toxicity rate during the first 3 cycles did not exceed 
50%, a target set based upon the safety profile of standard chemotherapy in biliary tract cancers, 
and based upon the reported rate of related Grade 3-5 toxicity of approximately 45% for the 
combination of ipilimumab plus GM-CSF in advanced melanoma.9,34  The all-cause Grade 3 or 4 
toxicity rate was approximately 70% in advanced biliary cancer patients treated with combination 
of standard 1st line chemotherapy with gemcitabine plus cisplatin in the ABC-02 trial,9 while the 
rate of Grade 3 or 4 toxicity was reported as 32% for 2nd line chemotherapy (predominantly 5-
fluorouracil-based combinations) in a multicenter, retrospective AGEO analysis.6
Re-induction and Second Course safety will also be described at completion of study.
4.3.6.4
Biomarker Research
4.3.6.4.1 Tumor and TIIC PD-L1 Expression by Immunohistochemistry (IHC)
Tumor and/or TIIC PD-L1 expression by IHC are associated with an increased likelihood of 
response to immune checkpoint inhibition with PD-1 inhibitors in some cancer types.38  A pooled 
analysis of 20 trials including 1475 patients with melanoma, non-small cell lung cancer (NSCLC), 
and genitourinary cancer showed a significant interaction between PD-L1 expression and response 
overall, with overall RR 34.1% vs. 19.9% (p<0.0001).38  Response rates were significantly higher 
in PD-L1+ melanoma and NSCLC but no significant difference in response rate was observed 
according to PD-L1 status for genitourinary cancers, and a significant proportion of patients with 
PD-L1-negative tumors achieved tumor response to PD-1 inhibition across tumor types.  
It is not known whether tumor PD-L1 expression is a predictive biomarker for response in biliary 
cancers, as the KEYNOTE-028 biliary cohort required PD-L1 expression for eligibility5 and the 
unselected KEYNOTE-158 biliary cohort results have not been reported.  Intra-tumoral spatial and 
temporal heterogeneity in PD-L1 expression may also confound interpretation of tumor PD-L1 
expression in archival pre-treatment samples which, in some cases, may have been harvested long 
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Priming by an induction course of GM-CSF could also induce expression of PD-L1 in tumors or 
in TIIC such as tumor-associated lymphoid cells or monocytes, as has been demonstrated with 
administration of GVAX in pancreatic tumors.31
Based upon these findings which suggest that pre-treatment tumor PD-L1 expression may not be 
essential for response to treatment with the combination of pembrolizumab plus induction GM-
CSF, tumor PD-L1 expression by IHC is not required as an integral biomarker for eligibility but 
will be tested as an integrated biomarker and secondary objective.  Archival tumor biopsy or 
resection samples will be accessioned and tested centrally in batch at end of study for PD-L1 
expression using an approved IHC assay (QualTek Laboratories).  It is expected that the majority 
of samples will have been obtained pre-treatment.  Treatment history at time of tumor sampling 
for each case will be documented in case report forms (CRFs), and an exploratory analysis may be 
conducted to compare proportion with PD-L1 expression based upon whether sample was obtained 
pre-treatment or after treatment with prior chemotherapy.  An exploratory analysis will also be 
performed to compare tumor PD-L1 status in primary versus metastatic sites and according to 
anatomic location of the primary biliary cancer (e.g., intrahepatic CCA, extrahepatic CCA, GBC) 
or the metastatic site (e.g., liver vs. non-liver).  
Paired primary and metastatic site tumor samples from the same patient will be tested and 
described when available.  On-treatment or post-treatment tumor samples will also be analyzed if 
available in cases for which tumor resection or biopsy is required for clinical care (e.g. palliative 
metastatectomy, biopsy of an equivocal lesion to confirm progression, or if fiducial placement is 
required for palliative radiotherapy).  PD-L1 expression will also be measured in on-treatment 
tumor biopsy samples obtained on pembrolizumab therapy and on combination therapy in patients 
enrolled to the Expansion Cohort.
4.3.6.4.2 Peripheral Blood Mononuclear Cell (PBMC) Immune Cell Subsets, TCR 
Clonotype Frequency and Diversity, and Other Analyses
Research blood samples will be collected from all patients at baseline, at multiple time points 
during treatment, and at progression (see Section 6.0 – Study Flow Chart).  Whole blood will be 
processed into PBMC and cryopreserved at the UCSF Immune Monitoring Core for future 
analyses in batch at completion of study, pending funding and if warranted based upon clinical 
outcomes.
PBMC samples  may be used to characterize immune cell subsets and T cell receptor (TCR) 
sequencing. .  Other analyses including immune cell gene expression profiling may be performed 
depending on adequacy of samples available, funding, and evolving biomarker data from other 
immune checkpoint inhibitor studies.  Dr. Fong’s laboratory has demonstrated that treatment with 
the combination of CTLA-4 blockade plus GM-CSF results in expansion of activated effector 
CD8+ T cells as well as expansion of tumor antigen-specific T cells in patients with advanced 
prostate cancer.33,39  Dr. Fong’s laboratory and collaborators also have shown that checkpoint 
blockade by treatment with CTLA-4 inhibition in patients with metastatic prostate cancer and 
melanoma can increase T cell clonotype repertoire and diversity.33,40  Circulating immune cell 
subsets will be measured using flow cytometry and Cytof as has been previously described.33,39  
The frequency of individual clonotypes, and the diversity of overall clonotype repertoire, will be 
measured by next-generation sequencing.40  Baseline and changes on treatment in PBMC immune 


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cell subsets, TCR clonotype frequency and diversity, and gene expression profiles may be 
examined for relationship to clinical outcomes including PFS, RR, DOR, OS, and CA 19-9 
response.
In the initial Safety Cohort (n=9) and the Expansion Cohort (n=15), PBMC samples for TCR 
analyses are collected before and after pembrolizumab alone in Cycle 1, followed by after the 
combination of pembrolizumab plus GM-CSF in Cycles 2 and 3.  In the Efficacy Cohort (n=18), 
PBMC samples are collected before and after start of combination pembrolizumab plus induction 
GM-CSF, then on pembrolizumab monotherapy after completion of 2 cycles of GM-CSF.  The 
variation in schedules of GM-CSF administration will enable intra-patient and inter-patient 
comparisons of immune cell profiles, TCR clonotype frequency and diversity, and other analyses 
pre-treatment, after pembrolizumab alone, and after the combination of pembrolizumab plus 
GM-CSF, as well as inter-patient comparisons between pembrolizumab and the combination of 
pembrolizumab plus GM-CSF after the first cycle, to better understand the relative impact of 
pembrolizumab alone and in combination with GM-CSF in this non-randomized study.   
4.3.6.4.3 Tumor Infiltrating Immune Cell (TIIC) Numbers and Profiles Pre-Treatment 
and On-Treatment
Preexisting tumor immune infiltration is associated with increased likelihood of tumor response to 
checkpoint inhibition.41,42  This association between tumor immune infiltration and increased 
response to immunotherapy may be due to preexisting tumor-specific T cell clones within the 
tumor which have been primed by tumor antigens but attenuated by checkpoint signaling, which 
are then activated upon checkpoint inhibition.  
To explore the impact of tumor immune infiltration in biliary cancers treated with the combination 
of pembrolizumab plus induction GM-CSF, archival pre-treatment tumor core biopsy or resection 
samples (primary and/or non-nodal metastatic site depending on availability) will be obtained 
when available.  Pending funding and adequate sample size, the samples may be examined in batch 
for immune cell infiltrates (TIIC) and T cell subset composition in batch at study completion in 
the laboratory of Dr. Larry Fong at UCSF as has been previously described.33,39,43  The presence 
of TIIC  and immune cell subset composition will be explored for association with clinical 
outcomes including PFS, ORR, DOR, OS, and CA 19-9- response.  
If available from a standard of care tissue sampling event, , such as in cases for which an on-
treatment or post-treatment tumor resection or biopsy is required for clinical care (e.g. palliative 
metastatectomy/debulking, biopsy of an equivocal lesion, or if fiducial placement is required for 
palliative radiotherapy), paired archival on-treatment or post-treatment tumor samples will also be 
analyzed in comparison to the baseline/pre-treatment specimen.
In the Expansion Cohort, paired biopsies will be obtained on pembrolizumab and on 
pembrolizumab plus GM-CSF to ascertain the relative impact of pembrolizumab alone compared 
to pre-treatment archival sample, then the impact of addition of GM-CSF to pembrolizumab 
compared to pre-treatment and compared to pembrolizumab monotherapy.  It is expected that GM-
CSF effect will be apparent after 2 weeks of exposure based upon tumor tissue analyses showing 
increased tumor T cell infiltration in prostate cancer patients treated with GM-CSF prior to radical 
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In Expansion Cohort biopsy samples, TIIC studies will be performed in batch at conclusion of 
study, pending additional grant funding. TIIC in tumor tissue will be compared descriptively to 
paired PBMC from the same patient (Section 4.3.5.3.2).33  TIIC will be quantified and individual 
immune cell subsets profiled by IHC and other methods in paired FFPE biopsy specimens 
including but not limited to: cytotoxic CD8+, helper CD4+FOXP3-, and regulatory CD4+FOXP3+ 
T cells. The proportion of activated T cells (defined using markers such as PD1+ and Ki67+) will 
also be analyzed, as will myeloid-derived suppressor cells (using markers such as M2 CD68/Arg-1, 
M1 CD68/iNOS).  Other techniques such as laser capture microdissection may be used if needed 
to isolate tumor from microenvironment, pending funding and depending on standard IHC results. 
In Expansion Cohort biopsy samples, tumor infiltrating T cell TCR clonotypes, gene expression 
profiles, and/or other analytes may also be analyzed by next generation sequencing and other 
methods, pending funding and adequate sample availability.  If performed, these analyses will be 
performed on pre-treatment archival tumor samples if adequate material is available as well as 
from fresh frozen or FFPE core biopsy samples 1) on pembrolizumab monotherapy and 2) in 
combination with GM-CSF. 
4.3.6.4.4 Tumor Genotype and Association with Response Outcomes, PD-L1 status, T-cell 
Infiltration, and TCR Repertoire
Higher tumor mutation burden (TMB) and genomic instability are associated with increased 
likelihood of response to pembrolizumab in non-small cell lung cancers.19,20  It is thought that 
increased mutational burden overall, as well as certain specific mutations, may be immunogenic.  
Multiple clinical trials are now available for genotype-defined populations in cholangiocarcinoma, 
including FGFR2 fusions and IDH1 or IDH2 mutations.44  It is expected that the majority of 
patients enrolled on this study will have had targeted tumor next generation tumor sequencing such 
as FoundationOne (http://foundationone.com) performed as standard of care prior to enrollment, 
based upon emerging evidence for targeted therapies in advanced biliary cancers.
For patients with available tumor sequencing results performed as part of clinical care, specific 
mutations, pathways, TMB, and presence of genomic instability-related mutations will be explored 
for association with clinical outcomes including PFS, RR, DOR, and OS.  The tumor mutation 
profile and TMB will also be explored for association with PD-L1 status and presence of immune 
infiltrates, based upon emerging evidence that specific tumor mutations can impact T cell 
infiltration and activation.19,45
5.0 METHODOLOGY
5.1
Entry Criteria
5.1.1
Diagnosis/Condition for Entry into the Trial for All Cohorts
1. Histologically- or cytologically-diagnosed advanced or locally-advanced biliary cancer not 
eligible for resection or other curative therapies, including:
a.
Intrahepatic (peripheral) cholangiocarcinoma; 


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b. Extrahepatic cholangiocarcinoma including hilar/perihilar (Klatskin), middle, and 
distal locations; 
c.
Gallbladder carcinoma (GBC); 
d. Mixed/combined hepatocellular-cholangiocarcinoma;
e.
Ampullary carcinoma and pancreas ductal adenocarcinoma are NOT eligible.
2. Clinical and/or radiographic progression on ≥ 1 prior systemic treatment regimen with 
cytotoxic chemotherapy, targeted therapy, and/or investigational therapy for advanced 
biliary cancer.  Cumulative toxicity or intolerability (such as progressive cytopenias, 
neuropathy, or asthenia on a 1st line regimen of gemcitabine plus cisplatin) requiring 
treatment discontinuation of ≥ 1 prior systemic treatment regimen is also sufficient for 
eligibility.  There is no maximum eligible prior number of lines of therapy provided all 
eligibility criteria are met.  Adjuvant chemotherapy including gemcitabine and/or 
fluoropyrimidine after prior surgical resection of CCA or GBC will be considered as 1 line 
of prior therapy if relapse/recurrence with incurable disease occurred within ≤ 6 months of 
last dose.
5.1.2
Subject Inclusion Criteria for All Cohorts
In order to be eligible for participation in this trial, the subject must:
1. Be willing and able to provide written informed consent for the trial.
2. Be  18 years of age on day of signing informed consent.
3. Have a performance status of 0 or 1 on the ECOG Performance Scale.
4. Demonstrate adequate organ function as defined in Table 1; all screening labs should be 
performed within 28 days of treatment initiation.  
Table 1
Adequate Organ Function Laboratory Values
System
Laboratory Value
Hematological
Absolute neutrophil count (ANC)
≥1,000 /mcL
Platelets
≥60,000 / mcL (≥ 75,000/mcL in Expansion Cohort, see below)
Hemoglobin
≥9 g/dL or ≥5.6 mmol/L without transfusion or EPO dependency 
(within 7 days of assessment)
Renal
Serum creatinine OR
Measured or calculateda creatinine 
clearance
(GFR can also be used in place of 
creatinine or CrCl)
≤1.5 X upper limit of normal (ULN) OR
≥60 mL/min for subject with creatinine levels > 1.5 X 
institutional ULN
Hepatic
Serum total bilirubin
≤ 1.5 X ULN OR
Direct bilirubin ≤ ULN for subjects with total bilirubin levels > 
1.5 ULN


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AST (SGOT) and ALT (SGPT)
≤ 5 X ULN 
Albumin
>2.5 g/dL
Coagulation
International Normalized Ratio (INR) or 
Prothrombin Time (PT)
Activated Partial Thromboplastin Time 
(aPTT)
≤1.5 X ULN unless subject is receiving anticoagulant therapy
as long as PT or PTT is within therapeutic range of intended use 
of anticoagulants
≤1.5 X ULN unless subject is receiving anticoagulant therapy
as long as PT or PTT is within therapeutic range of intended use 
of anticoagulants
aCreatinine clearance should be calculated per institutional standard.
5. Patients with known hepatitis B or C virus (HBV or HCV) infection are eligible provided 
liver function parameters meet laboratory eligibility criteria in Table 1. 
a.
Patients with active HBV infection must have monitoring of viral load and 
demonstrate adequate treatment with appropriate antiviral therapy according to 
institutional practice.
b. Patients with active HCV infection must have monitoring of liver function tests 
and viral load if indicated according to institutional practice.
6. Female subject of childbearing potential should have a negative urine or serum pregnancy 
within 72 hours prior to receiving the first dose of study medication.  If the urine test is 
positive or cannot be confirmed as negative, a serum pregnancy test will be required.  
7. Female subjects of childbearing potential should be willing to use 2 methods of birth 
control or be surgically sterile, or abstain from heterosexual activity for the course of the 
study through 120 days after the last dose of study medication (Reference Section 5.7.2).  
Subjects of childbearing potential are those who have not been surgically sterilized or have 
not been free from menses for > 1 year. 
8. Male subjects should agree to use an adequate method of contraception starting with the 
first dose of study therapy through 120 days after the last dose of study therapy. 
5.1.3
Additional Expansion Cohort Subject Inclusion Criteria 
1. Presence of ≥ 1 target lesion measurable by RECIST 1.11 not planned for biopsy.
2. Presence of ≥ 1 tumor lesion accessible for paired on-treatment minimally-invasive 
percutaneous biopsies (CT, ultrasound or punch), as assessed by investigator and/or 
radiologist; this lesion may be included as a target or non-target lesion for RECIST 1.1. 
3. Platelet count ≥ 75,000/mcL
4. No contraindication to tumor biopsy at time of study enrollment.
5. Consent for on-treatment paired biopsies.


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5.1.4
Subject Exclusion Criteria for All Cohorts
The subject must be excluded from participating in the trial if the subject:
1) Is currently participating and receiving study therapy or has participated and received study 
therapy in a study of an investigational agent, or used an investigational device within 4 weeks 
of the first dose of treatment.
2) Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy for purposes of 
immunosuppression or any other form of immunosuppressive therapy within 7 days prior to 
the first dose of trial treatment.
3) Has a known history of active TB (Bacillus Tuberculosis).
4) Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).
5) Has untreated active Hepatitis B (e.g., HBsAg reactive).
6) Has an active infection requiring systemic antibiotic therapy at time of enrollment. 
a) Treatment with antibiotic prophylaxis for indwelling biliary stent(s) or peri-procedural 
antibiotics for uncomplicated biliary stent exchanges is allowed and not an exclusion.
7) Hypersensitivity to pembrolizumab or any of its excipients.
8) Has received treatment with an anti-cancer monoclonal antibody (mAb) within 4 weeks prior 
to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events 
due to agents administered more than 4 weeks earlier.
9) Has received treatment with chemotherapy, targeted small molecule therapy, or radiation 
therapy to non-liver sites within 2 weeks prior to study Day 1 or who has not recovered (i.e., 
≤ Grade 1 or at baseline) from adverse events due to a previously administered agent 
administered more than 2 weeks earlier.
a) Subjects with ≤ Grade 2 neuropathy or alopecia are an exception to this criterion and may 
qualify for the study.
b) If subject received major surgery, they must have recovered adequately from the toxicity 
and/or complications from the intervention prior to starting therapy.  
10) Has had prior chemoembolization, bland embolization, radioembolization, local ablative 
therapies, radiation to liver tumors, or major surgery such as liver resection within 4 weeks 
prior to study enrollment or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse 
events due to intervention more than 4 weeks earlier.
11) Has a known additional malignancy that is progressing or requires active treatment.  
Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the skin 
that has undergone potentially curative therapy or in situ cervical cancer.


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12) Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis.  
Subjects with previously treated brain metastases may participate provided they are stable 
(without evidence of progression by imaging for at least four weeks prior to the first dose of 
trial treatment and any neurologic symptoms have returned to baseline), have no evidence of 
new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial 
treatment.  This exception does not include carcinomatous meningitis which is excluded 
regardless of clinical stability.  
13) Has active autoimmune disease that has required systemic treatment in the past 2 years (i.e. 
with use of disease modifying agents, corticosteroids or immunosuppressive drugs). 
Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement 
therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic 
treatment. 
14) Has known history of or any evidence of active, non-infectious pneumonitis.
15) Has had prior organ or stem cell transplantation.
16) Has a history or current evidence of any condition, therapy, or laboratory abnormality that 
might confound the results of the trial, interfere with the subject’s participation for the full 
duration of the trial, or is not in the best interest of the subject to participate, in the opinion of 
the treating investigator.  
17) Has known psychiatric or substance abuse disorders that would interfere with cooperation with 
the requirements of the trial.
18) Is pregnant or breastfeeding, or expecting to conceive or father children within the projected 
duration of the trial, starting with the pre-screening or screening visit through 120 days after 
the last dose of trial treatment.
19) Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent.
a) This criterion does not apply to eligibility for Second Course treatment.
20) Has received a live vaccine within 30 days of planned start of study therapy.
a) Seasonal influenza vaccines for injection are generally inactivated flu vaccines and are 
allowed; however intranasal influenza vaccines (e.g., Flu-Mist®) are live attenuated 
vaccines, and are not allowed.
5.2
Trial Treatments
5.2.1
Dose Selection
The rationale for selection of doses and schedules to be used in this trial is provided in Section 4.0 
– Background and Rationale.  The treatment to be used in this trial is outlined below in Table 2.  
See Study Flow Chart (Section 6.0) for additional information on treatment schedule.


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Phase II – pembrolizumab, GM-CSF
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Table 2
Trial Treatment
Drug
Dose
Dose 
Frequency
Route of 
Administratio
n
Treatment Period1
Use
Pembrolizumab
200 mg
Once Q3 
weeks
IV infusion 
over 30 minutes
Every 3 week cycle 
for up to 24 months 
or 35 cycles (see 
Section 5.8)
Experimental
GM-CSF
250 µg
Daily on 
days 1-14 
Q3 weeks 
for 2 cycles
SC**
Two Induction 
Cycles:
Cycles 2 and 3 in 
Safety Cohort (n=9) 
and Expansion 
Cohort (n=15); 
Cycles 1 and 2 in 
Efficacy Cohort
Experimental
Key: IV=intravenous; SC=subcutaneous.  1A subset of patients may be eligible for Second Course 
pembrolizumab and/or re-induction with GM-CSF (see Section 7.1.5).  *Cycle length is 21 days (Q3 
weeks) with GM-CSF “induction” in Cycles 2-3 (Safety and Expansion Cohorts) or 1-2 (Efficacy 
Cohort). **Patients will be instructed on self-injection administration prior to first dose, with re-
training each cycle or more often as needed.
5.2.2
Dose Modifications or Interruptions for Toxicity
Toxicity will be assessed according to the NCI CTCAE v4.0.  Dose modifications, interruptions, 
and treatment discontinuation for one or both study drugs will be determined according to the 
system showing the greatest degree of toxicity and according to the treating investigator’s 
assessment of toxicity attribution.  Toxicity will be formally assessed at protocol-defined safety 
assessment time points well as by investigator review of weekly laboratory testing and, in the 
interim, by patient contact with the study team.  General principles of toxicity management are 
listed below:

Laboratory values should be rounded to one significant digit for grade determination 
according to standard rounding practice.

Optimal supportive care should be provided for all clinically relevant toxicity.
o
See section 5.6 for guidance on supportive care/rescue medications for specific 
toxicities.

Dose interruptions or delays in start of a cycle for any reason (toxicity or non-toxicity) 
during the Induction Phase (Cycles 1 and 2 in Efficacy Cohort, Cycles 2 and 3 in Safety 
and Expansion Cohorts) should be applied to both drugs together so that both drugs are 
restarted on Day 1 of each cycle.


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
Doses of GM-CSF which are held during a cycle due to toxicity will not be re-administered.

Doses of GM-CSF which are missed/skipped (e.g. due to logistical reasons, patient 
oversight, or other non-toxicity related factors) may be made up at end of cycle, daily for 
up to 3 doses.  Missed/skipped doses >3 will not be re-administered.

A patient will be removed from protocol therapy if pembrolizumab is permanently 
discontinued but may continue on pembrolizumab if GM-CSF is discontinued for toxicity 
before completing induction (2 cycles). 

For any toxicity (regardless of grade), despite optimal supportive care, that is felt by the 
treating investigator to represent a risk to the patient’s safety, additional dose reduction, 
treatment delay, or treatment discontinuation is permitted at the discretion of the treating 
investigator.
5.2.2.1
Dose Modifications for Pembrolizumab 
Adverse events (both non-serious and serious) associated with pembrolizumab exposure may 
represent an immunologic etiology.  These adverse events may occur shortly after the first dose or 
several months after the last dose of treatment. Pembrolizumab must be withheld for drug-related 
toxicities and severe or life-threatening AEs as per Table 3 below.  As toxicity on pembrolizumab 
has not been shown to be dose related, dose reductions are not thought to ameliorate specific 
toxicities.  See Section 5.6.1 and Events of Clinical Interest Guidance Document for supportive 
care guidelines, including use of corticosteroids.


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The information in this document is considered privileged and confidential, and may not be disclosed to others except to the extent necessary to obtain Institutional 
Review Board approval and informed consent, or as required by federal and state laws.  Persons to whom this information is disclosed should be informed that this 
information is privileged and confidential and that it should not be further disclosed.
Table 3
Dose Modification Guidelines for Pembrolizumab-Related Adverse Events
Toxicity
Hold Treatment For Grade
Timing for Restarting* Treatment
Discontinue Subject
2-3
Hold until toxicity resolves to Grade 0-1
If toxicity does not resolve within 12 weeks of last dose or inability to 
reduce corticosteroid to 10 mg or less of prednisone or equivalent per 
day within 12 weeks
Diarrhea/colitis
4
Permanently discontinue
Permanently discontinue
21-32
Hold until toxicity resolves to Grade 0-1 
or baseline grade (if Grade 2 at 
baseline)1
If toxicity does not resolve within 12 weeks of last dose
AST, ALT, or increased 
bilirubin (despite optimal 
supportive care including 
biliary drainage if 
obstruction is present)
32-4
Permanently discontinue
Permanently discontinue
Type 1 diabetes mellitus (if 
new onset) or 
hyperglycemia
T1DM or 
3-4
Hold for new onset Type 1 diabetes 
mellitus or Grade 3-4 hyperglycemia 
associated with evidence of beta cell 
failure; resume pembrolizumab when 
patients are clinically and metabolically 
stable
If toxicity does not resolve within 12 weeks of last dose or inability to 
reduce corticosteroid to 10 mg or less of prednisone or equivalent per 
day within 12 weeks
2-3
Hold until toxicity resolves to Grade 0-1
If toxicity does not resolve within 12 weeks of last dose or inability to 
reduce corticosteroid to 10 mg or less of prednisone or equivalent per 
day within 12 weeks
Hypophysitis
4
Permanently discontinue
Permanently discontinue
3
Hold until toxicity resolves to Grade 0-1
If toxicity does not resolve within 12 weeks of last dose or inability to 
reduce corticosteroid to 10 mg or less of prednisone or equivalent per 
day within 12 weeks
Hyperthyroidism 
4
Permanently discontinue
Permanently discontinue
Hypothyroidism
2-4
Therapy with pembrolizumab can be 
continued while treatment for the 
thyroid disorder is instituted
Therapy with pembrolizumab can be continued while treatment for the 
thyroid disorder is instituted
Grade 1 or 2
Withhold
Myocarditis
Grade 3 or 4
Permanently 
discontinue
Based on severity of AE administer 
corticosteroids
Ensure adequate evaluation to confirm etiology and/or exclude other 
causes
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
Infusion reaction
3-4
Permanently discontinue
Permanently discontinue
2
Hold until toxicity resolves to Grade 0-1
If toxicity does not resolve within 12 weeks of last dose or inability to 
reduce corticosteroid to 10 mg or less of prednisone or equivalent per 
day within 12 weeks
Pneumonitis
3-4
Permanently discontinue
Permanently discontinue
Renal failure or nephritis
2
Hold until toxicity resolves to Grade 0-1
If toxicity does not resolve within 12 weeks of last dose or inability to 
reduce corticosteroid to 10 mg or less of prednisone or equivalent per 
day within 12 weeks


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Toxicity
Hold Treatment For Grade
Timing for Restarting* Treatment
Discontinue Subject
3-4
Permanently discontinue
Permanently discontinue
3 or severe 2
Hold until toxicity resolves to Grade 0-1 
or baseline grade if abnormal at baseline
If toxicity does not resolve within 12 weeks of last dose or inability to 
reduce corticosteroid to 10 mg or less of prednisone or equivalent per 
day within 12 weeks
All other drug-related 
toxicity3 attributed to 
pembrolizumab 
4
Permanently discontinue
Permanently discontinue
Note: Permanently discontinue for any severe AE that recurs or any life-threatening event.
* Dose interruptions or delays in start of a cycle for any reason (toxicity or non-toxicity) during Induction Phase (Cycles 1 and 2 in Efficacy Cohort (Part 2), Cycles 2 and 3 in Safety and Expansion 
Cohorts (Parts 1 and 3)) should be applied to both GM-CSF and pembrolizumab together so that both drugs are restarted on Day 1 of each cycle.
1 For patients with liver metastasis who begin treatment with Grade 2 AST or ALT, treatment is not required to be held for Grade 2 AST or ALT.  
2 For patients with baseline Grade 2 AST or ALT, Grade 3 AST or ALT does not automatically require treatment discontinuation.  If AST or ALT increases by greater than or equal to 50% relative to 
baseline and is assessed as treatment-related (e.g. no evidence of interval tumor progression or biliary obstruction) and lasts for at least 1 week despite supportive care, then patients should be 
discontinued.
3 Patients with intolerable or persistent Grade <3 drug-related AE may hold study medication at physician discretion.  Permanently discontinue study drug for persistent Grade 2 adverse reactions for 
which treatment with study drug has been held, that do not recover to Grade 0-1 within 12 weeks of the last dose. Patients with mild grade 3 toxicity (e.g. mild or asymptomatic rashes or 
asymptomatic laboratory abnormalities) may be continue on treatment with augmented supportive care and close monitoring at discretion of treating physician.


Proprietary and Confidential
The information in this document is considered privileged and confidential, and may not be disclosed to others except 
to the extent necessary to obtain Institutional Review Board approval and informed consent, or as required by federal 
and state laws.  Persons to whom this information is disclosed should be informed that this information is privileged 
and confidential and that it should not be further disclosed.
5.2.2.2
Dose Modifications for GM-CSF
GM-CSF can induce hematologic effects including variable increases in WBC and/or platelet 
counts, possibly leading to potential complications of excessive leukocytosis such as 
hyperviscosity, allergic reactions including anaphylaxis, fluid retention, and respiratory symptoms 
due to sequestration of granulocytes in pulmonary circulation.  Monitoring of blood counts (CBC 
with differential) is recommended at least twice weekly during GM-CSF administration at standard 
doses. CBC with differential was checked twice weekly during GM-CSF induction cycles (Cycles 
2 and 3) in Safety Cohort.  As no increased leukocytosis was observed, weekly testing is performed 
in the Efficacy and Expansion Cohorts.  Liver function and renal function should be monitored at 
least every 2 weeks on GM-CSF in patients at risk for renal or hepatic dysfunction.  Body weight 
and hydration status should be carefully monitored during GM-CSF administration.
Table 4
Dose Modification Guidelines for GM-CSF-Related Adverse Events
Toxicity
Hold Treatment 
For Grade
Timing for Restarting*,** Treatment
Discontinue Subject
WBC 50,000-
100,000/mm3 
and/or ANC > 
20,000/mm3
Hold drug and recheck within 3-7 days; if ANC < 10,000 
mm3 and WBC < 50,000 mm3 and asymptomatic, re-start 
with 50% dose reduction (125 µg SQ daily) to complete 
14 days; maintain dose reduction for next cycle(s)
If WBC count does not decrease to < 
50,000/mm3 within 3 weeks or recurs  
>100,000/mm3 despite 50% dose reduction
Leukocytosis
≥ 3 (WBC 
>100,000/mm3) 
and/or 
hyperviscosity 
syndrome or 
complication
Permanently discontinue
Permanently discontinue
Platelet count 
>500,000/mm3
Hold drug and recheck within 3-7 days; if platelet count  < 
500,000/mm3 and asymptomatic, then  re-start with 50% 
dose reduction (125 µg SQ daily) to complete 14 days; 
maintain dose reduction for next cycle(s)
If platelet count does not decrease to < 
500,000/mm3 within 3 weeks or recurs  
>500,000/mm3 despite 50% dose reduction
Thrombocytosis
>1,000,000/mm3 
and/or 
hyperviscosity 
syndrome or 
complication
Permanently discontinue
Permanently discontinue
Allergic reactions
3-4
Permanently discontinue
Permanently discontinue
Edema/fluid 
retention despite 
optimal supportive 
care (e.g. 
elevation, 
diuretics)
Moderate or severe  
(e.g. Grade ≥ 2 if 
obscuring normal 
contours or 
interfering with 
self-care)
Hold until edema recovers to Grade 0-1 or baseline, then  
re-start with 50% dose reduction (125 µg SQ daily) to 
complete 14 days; maintain dose reduction for next 
cycle(s)
If moderate or severe edema does not recover 
to Grade 0-1 or baseline within 3 weeks or if 
recurs despite dose reduction
3 or severe 2
Hold until toxicity resolves to Grade 0-1 or baseline, then  
re-start with 50% dose reduction (125 µg SQ daily) to 
complete 14 days; maintain dose reduction for next 
cycle(s)
Toxicity does not recover to Grade 0-1 or 
baseline within 3 weeks of last dose
All other drug-
related toxicity3 
attributed to GM-
CSF 
4
Permanently discontinue
Permanently discontinue
Note: Permanently discontinue for any severe AE that recurs or any life-threatening event.
* Dose interruptions or delays in start of a cycle for any reason (toxicity or non-toxicity) during Induction Phase (Cycles 1 and 2 in Efficacy Cohort (Part 2), 
Cycles 2 and 3 in Safety and Expansion Cohorts (Parts 1 and 3)) should be applied to both GM-CSF and pembrolizumab together so that both drugs are restarted 
on Day 1 of each cycle.
 
**Skipped or missed doses of GM-CSF during a cycle (e.g. due to logistical reasons, patient oversight, or other non-toxicity-related factors) may be made up at end 
of cycle daily up to 3 doses.  
3 Patients with intolerable or persistent Grade <3 drug-related AE may hold study medication at physician discretion.  Permanently discontinue study drug for 
persistent Grade 2 adverse reactions for which treatment with study drug has been held, that do not recover to Grade 0-1 within 3 weeks of the last dose.


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5.2.2.3
Dose Interruptions or Delays for Reasons Other than Toxicity
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, administrative reasons, 
patient vacation, and/or holidays). Subjects should be placed back on study therapy within 
approximately 3 weeks of the scheduled interruption, unless otherwise discussed with the Study 
Chair. The reason for interruption should be documented in the patient's study record.
5.2.3
Dose Preparation and Timing
GM-CSF and pembrolizumab doses will be prepared by Investigational Pharmacist according to 
FDA package insert instructions for each drug.
All trial treatments will be administered on an outpatient basis.
5.2.3.1
Timing of Pembrolizumab Administration
Pembrolizumab will be administered on Day 1 of each 21-day cycle after all 
procedures/assessments have been completed as detailed on the Trial Flow Chart (Section 6.0).  
Trial treatment may be adjusted up to 3 days before or after the scheduled Day 1 of each cycle due 
to administrative or other logistical reasons such as holidays/schedule conflicts.
Pembrolizumab 200 mg will be administered as a 30 minute IV infusion on Day 1 of each cycle, 
every 3 weeks.  Sites should make every effort to target infusion timing to be as close to 30 minutes 
as possible.  However, given the variability of infusion pumps from site to site, a window of 
approximately -5 minutes and +10 minutes is permitted (i.e., approximate infusion time is 30 
minutes: -5 min/+10 min).
5.2.3.2
Timing of GM-CSF Administration
GM-CSF will be administered starting Day 1 of each induction cycle after all 
procedures/assessments have been completed as detailed on the Trial Flow Chart (Section 6.0), 
then continued daily through Day 14 (Days 1-14 Q21 days, in Cycles 2 and 3 for the Safety Cohort 
(n=9) and Expansion Cohort (n=15).  GM-CSF induction is administered in Cycles 1 and 2 in the 
Efficacy Cohort based upon acceptable safety in the Safety Cohort.  Trial treatment may be 
adjusted up to 3 days before or after the scheduled Day 1 of each cycle due to administrative or 
other logistical reasons such as holidays/schedule conflicts.
GM-CSF 250 µg will be administered as a SC injection days 1-14 every 3 weeks during the 
Induction Phase (Cycles 1 and 2).  Day 1 injection each cycle will be self-administered (after self-
injection teaching by an infusion center RN or another qualified medical provider), after 
pembrolizumab infusion with additional self-injection training/re-training as needed at each GM-
CSF time point.  Subsequent injections will be self-administered by patient or family 
member/friend.  Effort should be made to administer GM-CSF at approximately the same time 
each day (±3 hours from Day 1 dosing time).  
Missed/skipped GM-CSF doses (e.g. due to logistical reasons, patient oversight, or other non-
toxicity-related factors) may be made up at end of cycle daily up to 3 doses.  


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5.2.3.3
GM-CSF Patient Diary/Injection Record
Patient diaries will be used to record GM-CSF SC injection compliance, site, and any injection-
related symptomatic toxicity (see Appendix 11.2) during induction cycles.  The Clinical Research 
Coordinator (CRC) at each site will collect the completed diary at start of subsequent cycle.
5.2.4
Trial Blinding/Masking
This is an open-label trial; therefore, the investigator and subject will know the treatment 
administered.
5.3
Randomization or Treatment Allocation
This is not a randomized trial.
5.4
Stratification
No stratification is planned.
5.5
Concomitant Medications/Vaccinations (Allowed and Prohibited)
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed during 
the ongoing trial.  If there is a clinical indication for one of these or other medications or 
vaccinations specifically prohibited during the trial, discontinuation from trial therapy or 
vaccination may be required.  The investigator should discuss any questions regarding this with 
the Study Chair and the Merck Clinical team.  The final decision on any supportive therapy or 
vaccination rests with the investigator and/or the subject's primary physician. 
5.5.1
Acceptable Concomitant Medications
All treatments that the investigator considers necessary for a subject’s welfare may be administered 
at the discretion of the investigator in keeping with the community standards of medical care.  All 
concomitant medication will be recorded on the case report form (CRF) including all prescription, 
over-the-counter (OTC), herbal supplements, and IV medications and fluids.  If changes occur 
during the trial period, documentation of drug dosage, frequency, route, and date may also be 
included on the CRF.
All concomitant medications received within 28 days before the first dose of trial treatment and 
30 days after the last dose of trial treatment should be recorded.  Concomitant medications 
administered after 30 days after the last dose of trial treatment should be recorded for SAEs as 
defined in Section 7.2.
5.5.2
Prohibited Concomitant Medications
Subjects are prohibited from receiving the following therapies during the Screening and Treatment 
Phase (including retreatment for post-complete response relapse) of this trial:

Antineoplastic systemic chemotherapy or biological therapy 


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
Immunotherapy not specified in this protocol

Chemotherapy not specified in this protocol

Investigational agents other than pembrolizumab and GM-CSF

Radiation therapy 

Live vaccines within 30 days prior to the first dose of trial treatment and while participating 
in the trial. 
o
Examples of live vaccines include, but are not limited to, the following: measles, 
mumps, rubella, varicella/zoster, yellow fever, rabies, BCG, and typhoid vaccine. 

Systemic glucocorticoids for any purpose other than to modulate symptoms from a 
suspected immune-related AE (irAE) or as premedication for iodinated contrast if not 
amenable to MRI imaging instead of contrast CT.  The use of physiologic/replacement 
doses of corticosteroids may be approved after consultation with the Study Chair.

Antiviral therapy for active HCV is not allowed during protocol therapy unless approved 
by the Study Chair due to unknown potential for toxicity in combination.
Subjects who, in the assessment by the investigator, require the use of any of the aforementioned 
treatments for clinical management should be removed from the trial.  Subjects may receive other 
medications that the investigator deems to be medically necessary.
The Exclusion Criteria section 5.1.3 describes other medications which are prohibited in this trial.
There are no prohibited therapies during the Post-Treatment Follow-up Phase.
5.6
Rescue Medications & Supportive Care
5.6.1
Supportive Care Guidelines for Pembrolizumab
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 and in greater detail in the ECI guidance 
document. 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. 
If after the evaluation the event is determined not to be related, the investigator is instructed to 
follow the ECI reporting guidance but does not need to follow the treatment guidance (as outlined 
in the ECI guidance document). Refer to Section 5.2.2.1 for guidance on pembrolizumab dose 
modifications. 


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Suggested steroid regimens include:
o
Systemic steroids equivalent to prednisone 1-2 mg/kg/day for severe immune-
related toxicity requiring immunosuppressive therapy.
o
Oral prednisone 0.5 mg/kg/day or other equivalent steroid regimen for mild-
moderate immune-related toxicity requiring immunosuppressive therapy.
o
Topical corticosteroids for mild-moderate dermatitis.
o
Corticosteroid eye drops for ocular immune-related toxicity.
o
Once symptoms resolve or return to Grade 1/baseline, initiate slow steroid taper 
over at least 4 weeks, with close monitoring.
It may be necessary to perform conditional procedures such as bronchoscopy, endoscopy, or skin 
photography as part of evaluation of the event. Suggested conditional procedures, as appropriate, 
can be found in the ECI guidance document.

Pneumonitis: 
o
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.
o
For Grade 3-4 events, immediately treat with intravenous steroids.  Administer 
additional anti-inflammatory measures, as needed.
o
Add prophylactic antibiotics for opportunistic infections in the case of prolonged 
steroid administration.

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).
o
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 be substituted via IV infusion.  For Grade 2 or higher diarrhea, 
consider GI consultation and endoscopy to confirm or rule out colitis.
o
For Grade 2 diarrhea/colitis that persists greater than 3 days, administer oral 
corticosteroids. 
o
For Grade 3 or 4 diarrhea/colitis that persists > 1 week, treat with intravenous 
steroids followed by high dose oral steroids.  
o
When symptoms improve to Grade 1 or less, steroid taper should be started and 
continued over no less than 4 weeks.

Type 1 diabetes mellitus (if new onset, including diabetic ketoacidosis [DKA]) or ≥ 
Grade 3 hyperglycemia, if associated with ketosis (ketonuria) or metabolic acidosis 
(DKA):


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o
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. 

Hypophysitis:
o
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.
o
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.
o
Grade 2 hyperthyroidism events (and Grade 2-4 hypothyroidism):

In hyperthyroidism, non-selective beta-blockers (e.g. propranolol) are 
suggested as initial therapy.

In hypothyroidism, thyroid hormone replacement therapy, with 
levothyroxine or liothyroinine, is indicated per standard of care.
o
Grade 3-4 hyperthyroidism events: 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.

Hepatitis attributed to immune toxicity: Assessment should be based upon greatest 
increase in AST, ALT, or total bilirubin.  Elevations in alkaline phosphatase alone should 
not be used to determine treatment-related toxicity grade or supportive care interventions 
since this marker is commonly elevated in biliary tract cancers and may be an index of 
biliary obstruction independent of treatment-related toxicity.  Evaluation for viral 
reactivation and antiviral therapy for HBV or HCV should be considered if any evidence 
hepatotoxicity according to standard institutional practice in HBV/HCV patients receiving 
anti-cancer therapies
o
For Grade 2 events (if normal or Grade 1 at baseline), monitor liver function tests 
more frequently until returned to baseline values (consider weekly) to ensure not 
progressive.


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o
For Grade 4 events and Grade 3 if increased by greater than or equal to 50% 
relative to baseline and is assessed as treatment-related (e.g. no evidence of interval 
tumor progression or biliary obstruction), treat with intravenous corticosteroids for 
24 to 48 hours. 
o
When symptoms improve to Grade 0-1 or baseline, a steroid taper should be started 
and continued over no less than 4 weeks.

Renal failure or Nephritis:
o
For Grade 2 events assessed as treatment-related and despite best supportive care 
(e.g. oral or IV hydration), treat with oral or systemic corticosteroids.
o
For Grade 3-4 events, treat with systemic corticosteroids.
o
When creatinine value improves to Grade 1 or less, steroid taper should be started 
and continued over no less than 4 weeks. 

Other immune-mediated adverse reactions, including ocular manifestations
o
Permanently discontinue pembrolizumab if clinically significant or severe 
immune-mediated adverse reactions (see 5.2.2.1).
o
Initiate systemic corticosteroids at a dose of 1 to 2 mg/kg/day prednisone or 
equivalent for severe immune-mediated adverse reactions.
o
Administer corticosteroid eye drops to patients who develop uveitis, iritis, or 
episcleritis. Permanently discontinue ipilimumab for immune-mediated ocular 
disease that is unresponsive to local immunosuppressive therapy.

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 4 below shows treatment guidelines for subjects who experience an infusion reaction 
associated with administration of pembrolizumab (MK-3475).
Table 4
Infusion Reaction Treatment Guidelines
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
Subject may be premedicated 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
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 (e.g., from 100 
mL/hr to 50 mL/hr).  Otherwise dosing will be 
held until symptoms resolve and the subject 
should be premedicated 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.
5.6.2
Supportive Care for GM-CSF

Edema:  Diuretics, dietary sodium restriction, limb elevation, compression stockings, and 
other standard supportive care interventions may be implemented according to standard of 
care at investigator discretion.

Injection site reactions:  Patients and/or caregivers will receive subcutaneous injection 
teaching each induction cycle, including instructions to avoid administering near waist or 
navel and to rotate injection sites.

See Section 5.2.2.2 for guidance on dose modifications for toxicity attributed to GM-CSF.
5.6.3
General Supportive Care for Biliary Tract Cancer

Antibiotics for cholangitis or stent/biliary drain prophylaxis: Antibiotics with biliary tract 
coverage may be administered at discretion of treating investigator for symptoms of 
cholangitis or prophylactically (such as before/after elective biliary drain or stent exchange or 
replacement).

Antiviral therapy: Subjects with active HBV infection should receive appropriate antiviral 
therapy and close monitoring for reactivation according to institutional practice in patients 


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receiving potentially immunosuppressive anti-cancer therapies.  Evaluation for viral 
reactivation and antiviral therapy for HBV or HCV should be considered if any evidence 
hepatotoxicity according to standard institutional practice in HBV/HCV patients receiving 
anti-cancer therapies.  Antiviral therapy for HCV is not permitted during protocol therapy 
unless approved by Study Chair.

Diuretics:  Diuretics such as furosemide and spironolactone may be used for the management 
of edema or ascites at the discretion of the treating physician.  Severe episodes of edema, 
such as congestive heart failure, pleural effusion, ascites, pericardial effusion, or pulmonary 
edema may require additional measures such as percutaneous drainage, hospitalization, 
and/or discontinuation of protocol therapy. 

Electrolyte supplementation:  Electrolytes should be repleted according to standard 
institutional protocols.   

Esophageal varices management: All patients with history of esophageal varices should be 
treated with optimal supportive care for this condition such as proton pump inhibitor and 
propranolol or other non-selective beta-blocker.

Palliative radiation: Patients who require palliative radiation for worsening symptoms related 
to underlying malignancy must be removed from study.  This may be considered a clinical 
progression event depending on judgment of treating investigator and clinical context.

Supplements and alternative therapy: Treatment with non-conventional therapies (e.g., herbs 
or acupuncture), and vitamin/mineral supplements is acceptable provided that they do not 
interfere with treatment and the study endpoints and there is no known potential for drug 
interactions, according to assessment by the treating investigator and/or Investigational 
Pharmacist or designee.

Topical agents: Topical steroid creams may be used to manage pruritic skin toxicity at the 
discretion of the treating physician.  Non-alcohol-based topical emollients and non-alcohol-
based moisturizers may be used for dry skin.  

Treatment of hypersensitivity or allergic reactions: Subjects who experience study drug-
associated temperature elevations ≥ 38.5°C or other hypersensitivity symptoms may be 
treated symptomatically with acetaminophen, steroids, diphenhydramine, meperidine, or 
other medications at the discretion of the treating investigator.  
In addition, optimal standard of care therapies and best supportive care should be provided for 
other toxicity, comorbidity, or complications of biliary obstruction or liver disease which occur 
during protocol therapy, according to institutional standards.
5.7
Diet/Activity/Other Considerations
5.7.1
Diet
Subjects should maintain a normal diet unless modifications are required to manage an AE such 
as diarrhea, nausea or vomiting.


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5.7.2
Contraception
Pembrolizumab may have adverse effects on a fetus in utero.  Furthermore, it is not known if 
pembrolizumab has transient adverse effects on the composition of sperm.  Non-pregnant, non-
breast-feeding women may be enrolled if they are willing to use 2 methods of birth control or are 
considered highly unlikely to conceive.  Highly unlikely to conceive is defined as 1) surgically 
sterilized, or 2) postmenopausal (a woman who is ≥45 years of age and has not had menses for 
greater than 1 year will be considered postmenopausal), or 3) not heterosexually active for the 
duration of the study.  The two birth control methods can be either two barrier methods, or a barrier 
method plus a hormonal method to prevent pregnancy. Subjects should start using birth control 
from date of consent throughout the study period up to 120 days after the last dose of study therapy. 
The following are considered adequate barrier methods of contraception: diaphragm, condom (by 
the partner), copper intrauterine device, sponge, or spermicide.  Appropriate hormonal 
contraceptives will include any registered and marketed contraceptive agent that contains an 
estrogen and/or a progestational agent (including oral, subcutaneous, intrauterine, or intramuscular 
agents).
Subjects should be informed that taking the study medication may involve unknown risks to the 
fetus (unborn baby) if pregnancy were to occur during the study.  In order to participate in the 
study they must adhere to the contraception requirement (described above) for the duration of the 
study and during the Follow-Up Phase defined in section 7.2.2-Reporting of Pregnancy and 
Lactation to the Study Chair and to Merck.  If there is any question that a subject will not reliably 
comply with the requirements for contraception, that subject should not be entered into the study.
5.7.3
Use in Pregnancy
If a subject inadvertently becomes pregnant while on treatment with pembrolizumab, the subject 
will immediately be removed from the study.  The site will contact the subject at least monthly 
and document the subject’s status until the pregnancy has been completed or terminated.  The 
outcome of the pregnancy will be reported to the Study Chair and to Merck without delay and 
within 24 business hours to the Study Chair and within 2 business days from investigator 
awareness, to Merck if the outcome is a serious adverse experience (e.g., death, abortion, 
congenital anomaly, or other disabling or life-threatening complication to the mother or newborn).  
The study investigator will make every effort to obtain permission to follow the outcome of the 
pregnancy and report the condition of the fetus or newborn to the Study Chair.  If a male subject 
impregnates his female partner the study personnel at the site must be informed immediately and 
the pregnancy reported to the Study Chair and to Merck and followed as described above and in 
Section 7.2.2.
5.7.4
Use in Nursing Women
It is unknown whether pembrolizumab is excreted in human milk.  Since many drugs are excreted 
in human milk, and because of the potential for serious adverse reactions in the nursing infant, 
subjects who are breast-feeding are not eligible for enrollment.


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5.8
Subject Withdrawal/Discontinuation Criteria
Subjects may withdraw consent at any time for any reason or be dropped from the trial at the 
discretion of the investigator should any untoward effect occur.  In addition, a subject may be 
withdrawn by the investigator or the Study Chair if enrollment into the trial is inappropriate, the 
trial plan is violated, or for administrative and/or other safety reasons.  Specific details regarding 
discontinuation or withdrawal are provided in Section 7.1.5 – Other Procedures.
A subject must be discontinued from the trial for any of the following reasons:

The subject or legal representative (such as a parent or legal guardian) withdraws consent.

Radiographic disease progression by RECIST 1.1.
Note:  A subject may be granted an exception by Study Chair to continue on treatment 
until another scan time point (approximately 8 more weeks) if scans within first 6 
months demonstrate radiographic progression to account for possible delayed 
responses on immunotherapy,46 provided the patient is clinically stable or clinically 
improved (see Section 8.3.1).
Note:  A subject with progression occurring between approximately 6-12 months 
(Cycles 8-16) on protocol therapy may be eligible for re-induction with GM-CSF if 
progression occurs after a documented response to prior induction (see Section 7.1.5.1).

Unacceptable adverse experiences as described in Section 5.2.1.2.

Intercurrent illness that prevents further administration of treatment.

Investigator’s decision to withdraw the subject.

The subject has a confirmed positive serum pregnancy test.

Noncompliance with trial treatment or procedure requirements.

The subject is lost to follow-up.

Completed 24 months of uninterrupted treatment with pembrolizumab or 35 
administrations of study medication, whichever is later.
Note: 24 months of study medication is calculated from the date of first dose. Subjects who 
stop pembrolizumab at 24 months may be eligible for up to one year of additional study 
treatment as Second Course treatment if they progress within 6 months after stopping study 
treatment provided they meet the requirements detailed in Section 7.1.5.2.

Administrative reasons
The End of Treatment and Follow-Up Phase procedures are listed in Section 6 (Protocol Flow 
Chart) and Section 7.1.5 (Visit Requirements).  After the end of treatment, each subject will be 


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followed for 30 days for adverse event monitoring (serious adverse events will be collected for 90 
days after the end of treatment as described in Section 7.2.3.1).  Subjects who discontinue for 
reasons other than progressive disease will have scheduled post-treatment follow-up monitoring 
for disease status until disease progression, initiating a non-study cancer treatment, withdrawing 
consent or becoming lost to follow-up.  After documented disease progression each subject will 
be followed by chart review, clinic visits, or telephone contact for overall survival until death, 
withdrawal of consent, or the end of the study, whichever occurs first.
5.8.1
Discontinuation of Study Therapy after CR 
Discontinuation of treatment may be considered for subjects who have attained a confirmed CR 
that have been treated for at least 24 weeks with pembrolizumab and had at least two treatments 
with pembrolizumab beyond the date when the initial CR was declared.  Subjects who then 
experience radiographic disease progression may be eligible for up to one year of additional 
treatment with Second Course pembrolizumab at the discretion of the investigator if no cancer 
treatment was administered since the last dose of pembrolizumab, the subject meets the safety 
parameters listed in the original entry criteria in Section 5.1 (except for exclusion 19 which is not 
applicable to Second Course eligibility) and the trial remains open to enrollment.  Subjects will 
resume therapy at the same dose and schedule at the time of initial discontinuation.  Additional 
details on Second Course are provided in Section 7.1.5.2.
5.9
Subject Replacement Strategy
See Section 8.6 for definition of analysis populations for safety and efficacy.  Approximately 10% 
over-enrollment is planned to account for possible non-evaluability.  
5.10 Clinical Criteria for Early Trial Termination
Early trial termination will be the result of the criteria specified below:
1. Quality or quantity of data recording is inaccurate or incomplete.
2. Poor adherence to protocol and regulatory requirements.
3. Incidence or severity of adverse drug reaction in this or other studies indicates a potential health 
hazard to subjects (see Section 8.2.1 – Interim Safety Analysis and Stopping Rules).
4. Plans to modify or discontinue the development of the study drug. In the event of Merck 
decision to no longer supply study drug, ample notification will be provided so that appropriate 
adjustments to subject treatment can be made.


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6.0 STUDY FLOW CHARTS
6.1
Safety Cohort Flow Chart (Safety Population)
Trial Period:
Screening 
Phasep
Treatment Cyclesa
End of 
Treatment
Post-Treatment
Cycle (C) 1
C2, C3
To be repeated on D1 each cycle 
beyond 8 cycles
Treatment Cycle/Title:
Main Study 
Screening 
Day 
(D) 1
D8
D15
D1
D8
D15
C4
D1
C5
D1
C6
D1
C7
D1
C8
D1
Safety 
Follow-Up 
Visitb
Follow-Up Visitsb
Survival 
Follow-
Up
Scheduling Window (Days):
-28 to 1
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
Approx. 30 
days (±14 
days) post 
last 
treatment
Every 8 weeks ±28 
days for 1 year post 
last treatment. then 
every 12 weeks ±28 
days
Every 12 
weeks 
±28 days
Administrative Procedures
Informed Consent
X
Inclusion/Exclusion Criteria 
X
Demographics and Medical History
X
Prior and Concomitant Medication Review
X
X
X
X
X
X
X
X
X
X
X
X
X
Pembrolizumab Administrationa
X
X
X
X
X
X
X
GM-CSF Administration Days 1-14a,m
D1-
14m 
GM-CSF Patient Diary/Injection Recordc,m 
(Appendix 11.2)
Xm
Xm
Post-Study Anticancer Therapy Status
X
X
X
Survival Status
X
X
X
Clinical Procedures/Assessments
Review Adverse Events
X
X
X
X
X
X
X
X
X
X
X
X
Xd
Full Physical Examination
X
X
X
Xo
X
X
Xo
X
X
X
X
X
X
Vital Signs and Weight
X
X
X
Xo
X
X
Xo
X
X
X
X
X
X
ECOG Performance Status (Appendix 11.4)
X
X
X
X
X
X
X
X
X
Child Pugh Score (Appendix 11.5)
X


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Trial Period:
Screening 
Phasep
Treatment Cyclesa
End of 
Treatment
Post-Treatment
Cycle (C) 1
C2, C3
To be repeated on D1 each cycle 
beyond 8 cycles
Treatment Cycle/Title:
Main Study 
Screening 
Day 
(D) 1
D8
D15
D1
D8
D15
C4
D1
C5
D1
C6
D1
C7
D1
C8
D1
Safety 
Follow-Up 
Visitb
Follow-Up Visitsb
Survival 
Follow-
Up
Scheduling Window (Days):
-28 to 1
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
Approx. 30 
days (±14 
days) post 
last 
treatment
Every 8 weeks ±28 
days for 1 year post 
last treatment. then 
every 12 weeks ±28 
days
Every 12 
weeks 
±28 days
Laboratory Procedures/Assessments: analysis performed by LOCAL laboratory
Pregnancy Test – Urine or Serum β-HCGe
X
X
X
X
X
X
X
X
PT/INR
X
X
X
X
X
X
X
X
X
X
X
X
X
aPTT
X
X
X
X
X
X
X
X
X
X
CBC with Differentialn
X
X
X
X
Xn
Xn
X
X
X
X
X
X
X
Comprehensive Serum Chemistry Panelf
X
X
X
X
X
X
X
X
X
X
X
X
X
Urinalysisg
X
Every 8 weeks from C1D1 ± 14 days
X
T3, FT4 and TSHg
X
Every 8 weeks from C1D1 ± 14 days
X
Efficacy Measurements
Tumor Imagingh
X
Every 8 weeks from C1D1 (± 7 days for first 6 months of treatment, ±14 days 
after 6 months until end of treatment)h
Xh
CA 19-9 Tumor Markeri
X
Every 8 weeks from C1D1 ± 14 days
Xi
Archival Tissue Collection/Correlative Studies Blood (Appendix 11.6)
Archival Tumor Tissue Collectionj
Xj
Xj
Xj
PBMC Blood Collectionk
X
X
X
Xo
X
Every 8 weeks ± 14 days through 
C9D1
X
Xk
a
Cycle length is 21 days, ±3 days. Pembrolizumab is administered IV Q21 days ±3 up to 24 months or 35 cycles (Sections 5.2, 5.8, 7.1.5.2).  GM-CSF is administered days 1-14 Q21 days, ±3 days for induction 
Cycles 2 and 3 only with option for re-induction in cases meeting criteria in Section 7.1.5.1; Day 1 and subsequent doses are self-administered after self-injection teaching by infusion center RN or another 
qualified medical provider.
b
A mandatory Safety Follow-Up Visit should be conducted approximately 30 days after the last dose of trial treatment or before the initiation of a new anti-cancer treatment, whichever comes first.  All AEs that 
occur prior to the Safety Follow-Up Visit should be recorded. Though the Safety Follow-Up Visit and assessments should be performed at UCSF when possible, safety follow up assessments (including 
administrative, clinical, laboratory, and efficacy assessments) may be extracted from clinical data obtained from a subject’s local physician’s office visit, during a hospitalization, and/or during any other standard 


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Trial Period:
Screening 
Phasep
Treatment Cyclesa
End of 
Treatment
Post-Treatment
Cycle (C) 1
C2, C3
To be repeated on D1 each cycle 
beyond 8 cycles
Treatment Cycle/Title:
Main Study 
Screening 
Day 
(D) 1
D8
D15
D1
D8
D15
C4
D1
C5
D1
C6
D1
C7
D1
C8
D1
Safety 
Follow-Up 
Visitb
Follow-Up Visitsb
Survival 
Follow-
Up
Scheduling Window (Days):
-28 to 1
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
Approx. 30 
days (±14 
days) post 
last 
treatment
Every 8 weeks ±28 
days for 1 year post 
last treatment. then 
every 12 weeks ±28 
days
Every 12 
weeks 
±28 days
medical encounter, if travel to UCSF would confer hardship due to distance and/or due to initiation of new therapy.   Subjects with at least possibly treatment-related AE of Grade > 1 will be followed until the 
resolution of the AE to Grade 0-1, assessment as chronic or irreversible by investigator, or until the beginning of a new anti-neoplastic therapy, whichever occurs first.  Subjects who discontinue trial treatment for 
a reason other than disease progression will move into the Follow-Up Phase and should be assessed approximately every 8 weeks (56 ± 28 days) by radiographic imaging to monitor disease status.  After 1 year, 
the Follow Up visits and imaging timepoints will occur approximately every 12 weeks (± 28 days). After 2 years, patients will be followed according to Survival Follow-Up phase.
c
GM-CSF Patient Diary/Injection Record and instructions will be provided to each patient on Day 1 of Cycles 2 and 3 and any subsequent re-induction cycles.  The completed diaries will be collected on Day 1 of 
Cycles 3 and 4 and after any re-induction cycles. See Appendix 11.2.
d
Subjects with at least possibly treatment-related AE of Grade > 1 will be followed until the resolution of the AE to baseline or Grade 0-1, assessment as chronic or irreversible by investigator, or until the 
beginning of a new anti-neoplastic therapy, whichever occurs first.  SAEs that occur within 90 days of the end of treatment or before initiation of a new anti-cancer treatment, whichever occurs first, will also be 
followed and recorded.
e
Perform on women of childbearing potential only at screening and prior to each pembrolizumab infusion. If urine pregnancy results cannot be confirmed as negative, a serum pregnancy test will be required.  
f
See Section 7.1.3 and Table 5 for specific laboratory tests required as part of comprehensive metabolic panel.
g
Or more often if clinically indicated.
h
Cross-sectional imaging with CT or MRI abdomen plus pelvis (including triphasic/multiphase liver preferred) and CT chest with/ or without contrast is required at screening, every 8 weeks (±7 days) during 
treatment for first 6 months then every 8 weeks (±14 days days) after 6 months on treatment until end of treatment. In subjects without evidence progression at treatment discontinuation, scans should be every 8 
weeks ±28 days for up to 1 year during Follow-Up Phase, then every 12 weeks ± 28 days (or more often if clinically indicated).  Imaging may be performed more often if clinically indicated to evaluate for 
progression or toxicity.  Imaging should be performed as close to time of Safety Follow-Up visit as possible in cases of discontinuation after confirmed response or completion of 24 months of treatment.
i
CA 19-9 should be checked at same time points as imaging.  Note that CA 19-9 may be elevated due to biliary obstruction/stent occlusion independent of progression.  CA 19-9 testing may be performed more 
often if clinically indicated to evaluate for progression.
j
Archival tumor samples (FFPE block when available and/or at least 10 unstained slides of approximately 10 µm thickness plus a paired H&E slide) should be obtained from prior tumor sampling/diagnostic 
procedure(s) such as prior resection, core biopsy, or cytology/cell button when available.  FFPE block or slides should also be obtained from any subsequent tumor sampling which occurs during or after protocol 
therapy (such as repeat biopsy to confirm progression or palliative metastatectomy surgery). See Appendix 11.6.
k
Blood samples will be obtained in all patients for PBMC immune profiling at Screening, on Day 1, 8, and 15 of Cycle 1, on Cycle 2 Day 1, Cycle 3 Day 1, then Q8 weeks ± 14 days during subsequent cycles 
through C9D1. Screening sample may be used for Cycle 1, Day 1 if obtained within 3 days. Samples will be obtained at time of Safety Follow-Up visit (PBMC collection at this time-point may be omitted or 
delayed until next UCSF clinic visit if patient has Safety Follow-Up Visit assessments performed outside of UCSF), and at time of progression if patient discontinued treatment without progression and is 
identified with progression during Follow-Up. See Appendix 11.6.


UCSF Helen Diller Family Comprehensive Cancer Center
Version date: 10/01/2019
Protocol CC#: 154524
Phase II – pembrolizumab, GM-CSF
Page 45 of 96
Trial Period:
Screening 
Phasep
Treatment Cyclesa
End of 
Treatment
Post-Treatment
Cycle (C) 1
C2, C3
To be repeated on D1 each cycle 
beyond 8 cycles
Treatment Cycle/Title:
Main Study 
Screening 
Day 
(D) 1
D8
D15
D1
D8
D15
C4
D1
C5
D1
C6
D1
C7
D1
C8
D1
Safety 
Follow-Up 
Visitb
Follow-Up Visitsb
Survival 
Follow-
Up
Scheduling Window (Days):
-28 to 1
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
Approx. 30 
days (±14 
days) post 
last 
treatment
Every 8 weeks ±28 
days for 1 year post 
last treatment. then 
every 12 weeks ±28 
days
Every 12 
weeks 
±28 days
m
Re-induction GM-CSF will be allowed case-by-case according to Section 7.1.5.1, between approximately months 6-12 or Cycles 8-16 on protocol therapy.  In these cases, GM-CSF will be re-administered D1-14 
for 2 cycles (which will be named “R” along with original cycle number, e.g. RC8 and RC9) along with GM-CSF Patient Diary/Injection Record (Appendix 11.2) which will be provided along with instructions 
before re-induction and collected on D1 of each cycle following the 2 re-induction cycles.
n
CBCD must be checked day 1, day 5, day 8, and day 12 (±3 days) during Cycles 2 and 3 (induction GM-CSF) of Safety Cohort.
o
On Day 15 of Cycles 1, 2, and 3, the clinic visit for physical examination, vitals, and weight check may be omitted provided there are no clinically-significant AE requiring follow up at Day 8 visit at discretion of 
treating investigator. If clinic visit is omitted, telephone encounters must be performed to review AE and concomitant medications at these time points and documented in electronic medical record by treating 
investigator. Appropriate follow up for any new symptomatic or laboratory AE must be coordinated as needed based upon this encounter. Research PBMC sample may be omitted in cases which do not require 
clinic visit on Cycle 1, Day 15.
p
Screening tests and procedures do not need to be repeated on Cycle 1, Day 1 if performed within 3 days.


UCSF Helen Diller Family Comprehensive Cancer Center
Version date: 10/01/2019
Protocol CC#: 154524
Phase II – pembrolizumab, GM-CSF
Page 46 of 96
6.2
Main Study Flow Chart (Efficacy Population)
Trial Period:
Screening 
Phasep
Treatment Cyclesa
End of 
Treatment
Post-Treatment
Cycle (C) 1
C2, C3
To be repeated on D1 each cycle 
beyond 8 cycles
Treatment Cycle/Title:
Main 
Study 
Screening 
Day 
(D) 1
D8
D15
D1
D8
C4
D1
C5
D1
C6
D1
C7
D1
C8
D1
Safety 
Follow-Up 
Visitb
Follow-Up Visitsb
Survival 
Follow-
Up
Scheduling Window (Days):
-28 to 1
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
Approx. 30 
days (±14 
days) post 
last 
treatment
Every 8 weeks ±28 days 
for 1 year post last 
treatment then every 12 
weeks ±28 days
Every 12 
weeks 
±28 days 
Administrative Procedures
Informed Consent
X
Inclusion/Exclusion Criteria 
X
Demographics and Medical History
X
Prior and Concomitant Medication Review
X
X
X
X
X
X
X
X
X
X
X
X
Pembrolizumab Administrationa
X
X
X
X
X
X
X
GM-CSF Administration Days 1-14a,m
D1-14m
D1-
14m 
GM-CSF Patient Diary/Injection Recordc,m 
(Appendix 11.2)
Xm
Xm
Post-Study Anticancer Therapy Status
X
X
X
Survival Status
X
X
X
Clinical Procedures/Assessments
Review Adverse Events
X
X
X
X
X
X
X
X
X
X
X
Xd
Full Physical Examination
X
X
X
Xo
X
Xo
X
X
X
X
X
X
Vital Signs and Weight
X
X
X
Xo
X
Xo
X
X
X
X
X
X
ECOG Performance Status (Appendix 11.4)
X
X
X
X
X
X
X
X
X
Child Pugh Score (Appendix 11.5)
X
Laboratory Procedures/Assessments: analysis performed by LOCAL laboratory
Pregnancy Test – Urine or Serum β-HCGe
X
X
X
X
X
X
X
X


UCSF Helen Diller Family Comprehensive Cancer Center
Version date: 10/01/2019
Protocol CC#: 154524
Phase II – pembrolizumab, GM-CSF
Page 47 of 96
Trial Period:
Screening 
Phasep
Treatment Cyclesa
End of 
Treatment
Post-Treatment
Cycle (C) 1
C2, C3
To be repeated on D1 each cycle 
beyond 8 cycles
Treatment Cycle/Title:
Main 
Study 
Screening 
Day 
(D) 1
D8
D15
D1
D8
C4
D1
C5
D1
C6
D1
C7
D1
C8
D1
Safety 
Follow-Up 
Visitb
Follow-Up Visitsb
Survival 
Follow-
Up
Scheduling Window (Days):
-28 to 1
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
Approx. 30 
days (±14 
days) post 
last 
treatment
Every 8 weeks ±28 days 
for 1 year post last 
treatment then every 12 
weeks ±28 days
Every 12 
weeks 
±28 days 
PT/INR 
X
X
X
X
X
X
X
X
X
aPTT
X
X
X
CBC with Differential
X
X
X
X
X
X
X
X
X
X
X
X
Comprehensive Serum Chemistry Panelf
X
X
X
X
X
X
X
X
X
X
X
X
Urinalysisg
X
Every 8 weeks from C1D1 ± 14 days
T3, FT4 and TSHg
X
Every 8 weeks from C1D1 ± 14 days
Efficacy Measurements
Tumor Imagingh
X
Every 8 weeks from C1D1 (±7 days for first 6 months of treatment, ±14 
days after 6 months until end of treatment)h
Xh
CA 19-9 Tumor Markeri
X
Every 8 weeks from C1D1 ± 14 days
Xi
Archival Tissue Collection/Correlative Studies Blood (Appendix 11.6)
Archival Tumor Tissue Collectionj
Xj
Xj
Xj
PBMC Blood Collectionk
X
X
X
Xo
X
Every 8 weeks ± 14 days through 
C9D1
X
Xk
a
Cycle length is 21 days, ±3 days. Pembrolizumab is administered IV Q21 days ±3 up to 24 months or 35 cycles (Sections 5.2, 5.8, 7.1.5.2).  GM-CSF is administered days 1-14 Q21 days, ±3 days for induction 
cycles 1 and 2 only with option for re-induction in cases meeting criteria in Section 7.1.5.1; Day 1 and subsequent doses are self-administered after self-injection teaching by infusion center RN or another 
qualified medical provider.
b
A mandatory Safety Follow-Up Visit should be conducted approximately 30 days after the last dose of trial treatment or before the initiation of a new anti-cancer treatment, whichever comes first.  All AEs 
that occur prior to the Safety Follow-Up Visit should be recorded. Though the Safety Follow-Up Visit and assessments should be performed at UCSF when possible, safety follow up assessments (including 
administrative, clinical, laboratory, and efficacy assessments) may be extracted from clinical data obtained from a subject’s local physician’s office visit, during a hospitalization, and/or during any other 
standard medical encounter, if travel to UCSF would confer hardship due to distance and/or due to initiation of new therapy.   Subjects with at least possibly treatment-related AE of Grade > 1 will be followed 
until the resolution of the AE to Grade 0-1, assessment as chronic or irreversible by investigator, or until the beginning of a new anti-neoplastic therapy, whichever occurs first.  Subjects who discontinue trial 
treatment for a reason other than disease progression will move into the Follow-Up Phase and should be assessed approximately every 8 weeks (56 ± 28 days) by radiographic imaging to monitor disease status.  
After 1 year, the Follow Up visits and imaging timepoints will occur approximately every 12 weeks (± 28 days). After 2 years, patients will be followed according to Survival Follow-Up phase.
c
GM-CSF Patient Diary/Injection Record and instructions will be provided to each patient on Day 1 of Cycles 1 and 2 and any subsequent re-induction cycles.  The completed diaries will be collected on Day 


UCSF Helen Diller Family Comprehensive Cancer Center
Version date: 10/01/2019
Protocol CC#: 154524
Phase II – pembrolizumab, GM-CSF
Page 48 of 96
Trial Period:
Screening 
Phasep
Treatment Cyclesa
End of 
Treatment
Post-Treatment
Cycle (C) 1
C2, C3
To be repeated on D1 each cycle 
beyond 8 cycles
Treatment Cycle/Title:
Main 
Study 
Screening 
Day 
(D) 1
D8
D15
D1
D8
C4
D1
C5
D1
C6
D1
C7
D1
C8
D1
Safety 
Follow-Up 
Visitb
Follow-Up Visitsb
Survival 
Follow-
Up
Scheduling Window (Days):
-28 to 1
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
Approx. 30 
days (±14 
days) post 
last 
treatment
Every 8 weeks ±28 days 
for 1 year post last 
treatment then every 12 
weeks ±28 days
Every 12 
weeks 
±28 days 
1 of Cycles 2 and 3 and after any re-induction cycles. See Appendix 11.2.
d
Subjects with at least possibly treatment-related AE of Grade > 1 will be followed until the resolution of the AE to baseline or Grade 0-1, assessment as chronic or irreversible by investigator, or until the 
beginning of a new anti-neoplastic therapy, whichever occurs first.  SAEs that occur within 90 days of the end of treatment or before initiation of a new anti-cancer treatment, whichever occurs first, will also 
be followed and recorded.
e
Perform on women of childbearing potential only at screening and prior to each pembrolizumab infusion. If urine pregnancy results cannot be confirmed as negative, a serum pregnancy test will be required.  
f
See Section 7.1.3 and Table 5 for specific laboratory tests required as part of comprehensive metabolic panel.
g
Or more often if clinically indicated.
h
Cross-sectional imaging with CT or MRI abdomen plus pelvis (including triphasic/multiphase liver preferred) and CT chest with or without contrast is required at screening, every 8 weeks (±7 days) during 
treatment for first 6 months then every 8 weeks (±14 days days) after 6 months on treatment until end of treatment. In subjects without evidence progression at treatment discontinuation, scans should be every 
8 weeks ±28 days for up to 1 year during Follow-Up Phase, then every 12 weeks ± 28 days (or more often if clinically indicated).  Imaging may be performed more often if clinically indicated to evaluate for 
progression or toxicity.  Imaging should be performed as close to time of Safety Follow-Up visit as possible in cases of discontinuation after confirmed response or completion of 24 months of treatment. 
i
CA 19-9 should be checked at same timepoints as imaging.  Note that CA 19-9 may be elevated due to biliary obstruction/stent occlusion independent of progression.  CA 19-9 testing may be performed more 
often if clinically indicated to evaluate for progression.
j
Archival tumor samples (FFPE block when available and/or at least 10 unstained slides of approximately 10 µm thickness plus a paired H&E slide) should be obtained from prior tumor sampling/diagnostic 
procedure(s) such as prior resection, core biopsy, or cytology/cell button when available.  FFPE block or slides should also be obtained from any subsequent tumor sampling which occurs during or after 
protocol therapy (such as repeat biopsy to confirm progression or palliative metastatectomy surgery). See Appendix 11.6.
k
Blood samples will be obtained in all patients for PBMC immune profiling at Screening, on Day 1, 8, and 15 of Cycle 1, on Cycle 2 Day 1, Cycle 3 Day 1, then Q8 weeks ± 14 days during subsequent cycles 
through C9D1.  Screening sample may be used for Cycle 1, Day 1 if obtained within 3 days. Samples will be obtained at time of Safety Follow-Up visit (PBMC collection at this time-point may be omitted or 
delayed until next UCSF clinic visit if patient has Safety Follow-Up Visit assessments performed outside of UCSF),, and at time of progression if patient discontinued treatment without progression and is 
identified with progression during Follow-Up. See Appendix 11.6.
m
Re-induction GM-CSF will be allowed case-by-case according to Section 7.1.5.1, between approximately months 6-12 or Cycles 8-16 on protocol therapy.  In these cases, GM-CSF will be re-administered 
D1-14 for 2 cycles (which will be named “R” along with original cycle number, e.g. RC8 and RC9) along with GM-CSF Patient Diary/Injection Record (Appendix 11.2) which will be provided along with 
instructions before re-induction and collected on D1 of each cycle following the 2 re-induction cycles.  PTT will be repeated on Day 1 of each re-induction cycle and one cycle following re-induction to monitor 
for coagulopathy, as for Cycles 1-3.
o
On Day 15 of Cycle 1 and Day 8 of Cycles 2 and 3, the clinic visit for physical examination, vitals, and weight check may be omitted provided there are no clinically-significant AE requiring follow up at the 
discretion of treating investigator. If clinic visit is omitted, telephone encounters must be performed to review AE and concomitant medications at these time points and documented in electronic medical 
record by treating investigator. Appropriate follow up for any new symptomatic or laboratory AE must be coordinated as needed based upon this encounter. Research PBMC sample may be omitted in cases 
which do not require clinic visit on Cycle 1, Day 15.
p
Screening tests and procedures do not need to be repeated on Cycle 1, Day 1 if performed within 3 days.


UCSF Helen Diller Family Comprehensive Cancer Center
Version date: 10/01/2019
Protocol CC#: 154524
Phase II – pembrolizumab, GM-CSF
Page 49 of 96
6.3
Second Course* Pembrolizumab Flow Chart
Trial Period:
Screening 
Phasep
Treatment Cyclesa
End of 
Treatment
Post-Treatment
Cycle (C) S1
CS2, CS3
To be repeated on D1 each cycle 
beyond 8 cycles
Treatment Cycle/Title:
Second 
Course 
Screening
Day 
(D) 1
D8
D15
D1
D8
C
S4
D1
C
S5
D1
C
S6
D1
C
S7
D1
C
S8
D1
Safety Follow-
Up Visitb
Follow-Up Visitsb
Survival 
Follow-
Up
Scheduling Window (Days):
-28 to 1
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
Approx. 30 
days (±14 
days) post last 
treatment
Every 8 weeks ±28 days 
for 1 year post last 
treatment then every 12 
weeks ±28 days
Every 12 
weeks 
±28 days 
Administrative Procedures
Inclusion/Exclusion Criteria for Second 
Course (Section 7.1.5.2)
X
Prior and Concomitant Medication Review
X
X
X
X
X
X
X
X
X
X
X
X
Pembrolizumab Administrationa
X
X
X
X
X
X
X
Post-Study Anticancer Therapy Status
X
X
X
Survival Status
X
X
X
Clinical Procedures/Assessments
Review Adverse Events
X
X
X
X
X
X
X
X
X
X
X
Xd
Full Physical Examination
X
X
X
Xo
X
Xo
X
X
X
X
X
X
Vital Signs and Weight
X
X
X
Xo
X
Xo
X
X
X
X
X
X
ECOG Performance Status (Appendix 11.4)
X
X
X
X
X
X
X
X
X
X
Child Pugh Score (Appendix 11.5)
X
Laboratory Procedures/Assessments: analysis performed by LOCAL laboratory
Pregnancy Test – Urine or Serum β-HCGe
X
X
X
X
X
X
X
X
PT/INR
X
X
X
X
X
X
X
X
X
aPTT
X
CBC with Differential
X
X
X
X
X
X
X
X
X
X
X
X
Comprehensive Serum Chemistry Panelf
X
X
X
X
X
X
X
X
X
X
X
X
Urinalysisg
X
Every 8 weeks from C1D1 ± 14 days
X


UCSF Helen Diller Family Comprehensive Cancer Center
Version date: 10/01/2019
Protocol CC#: 154524
Phase II – pembrolizumab, GM-CSF
Page 50 of 96
Trial Period:
Screening 
Phasep
Treatment Cyclesa
End of 
Treatment
Post-Treatment
Cycle (C) S1
CS2, CS3
To be repeated on D1 each cycle 
beyond 8 cycles
Treatment Cycle/Title:
Second 
Course 
Screening
Day 
(D) 1
D8
D15
D1
D8
C
S4
D1
C
S5
D1
C
S6
D1
C
S7
D1
C
S8
D1
Safety Follow-
Up Visitb
Follow-Up Visitsb
Survival 
Follow-
Up
Scheduling Window (Days):
-28 to 1
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
Approx. 30 
days (±14 
days) post last 
treatment
Every 8 weeks ±28 days 
for 1 year post last 
treatment then every 12 
weeks ±28 days
Every 12 
weeks 
±28 days 
T3, FT4 and TSHg
X
Every 8 weeks from C1D1 ± 14 days
X
Efficacy Measurements
Tumor Imagingh
X
Every 8 weeks from C1D1 (±7 days for first 6 months of treatment, ± 14 
days after 6 months until end of treatment)h
Xh
CA 19-9 Tumor Markeri
X
Every 8 weeks from C1D1 ± 14 days
Xi
Archival Tissue Collection/Correlative Studies Blood (Appendix 11.6)
Archival Tumor Tissue Collectionjj
Xjj
Xjj
Xjj
PBMC Blood Collectionk
X
X
X
Xo
X
Every 8 weeks ± 14 days through 
C9D1
X
Xk
*
Requires approval on case-by-case basis from Study Chair and Merck.
a
Cycle length is 21 days, ±3 days. Pembrolizumab Second Course is administered IV Q21 days ±3 days for up to 12 additional months or 17 cycles (Section 7.1.5.2).  
b
A mandatory Safety Follow-Up Visit should be conducted approximately 30 days after the last dose of trial treatment or before the initiation of a new anti-cancer treatment, whichever comes first.  All AEs that 
occur prior to the Safety Follow-Up Visit should be recorded. Though the Safety Follow-Up Visit and assessments should be performed at UCSF when possible, safety follow up assessments (including administrative, 
clinical, laboratory, and efficacy assessments) may be extracted from clinical data obtained from a subject’s local physician’s office visit, during a hospitalization, and/or during any other standard medical encounter, 
if travel to UCSF would confer hardship due to distance and/or due to initiation of new therapy.  Subjects with at least possibly treatment-related AE of Grade > 1 will be followed until the resolution of the AE to 
Grade 0-1, assessment as chronic or irreversible by investigator, or until the beginning of a new anti-neoplastic therapy, whichever occurs first.  Subjects who discontinue trial treatment for a reason other than 
disease progression will move into the Follow-Up Phase and should be assessed approximately every 8 weeks (56 ± 28 days) by radiographic imaging to monitor disease status.  After 1 year, the Follow Up visits 
and imaging time points will occur approximately every 12 weeks (± 28 days). After 2 years, patients will be followed according to Survival Follow-Up phase.
d
Subjects with at least possibly treatment-related AE of Grade > 1 will be followed until the resolution of the AE to baseline or Grade 0-1, assessment as chronic or irreversible by investigator, or until the beginning 
of a new anti-neoplastic therapy, whichever occurs first.  SAEs that occur within 90 days of the end of treatment or before initiation of a new anti-cancer treatment, whichever occurs first, will also be followed and 
recorded.
e
Perform on women of childbearing potential only at screening and prior to each pembrolizumab infusion. If urine pregnancy results cannot be confirmed as negative, a serum pregnancy test will be required.  
f
See Section 7.1.3 and Table 5 for specific laboratory tests required as part of comprehensive metabolic panel.
g
Or more often if clinically indicated.
h
Cross-sectional imaging with CT or MRI abdomen plus pelvis (including triphasic/multiphase liver preferred) and CT chest with or without contrast is required at screening, every 8 weeks (±7 days) during treatment 
for first 6 months then every 8 weeks (±14 days days) after 6 months on treatment until end of treatment. In subjects without evidence progression at treatment discontinuation, scans should be every 8 weeks ±28 


UCSF Helen Diller Family Comprehensive Cancer Center
Version date: 10/01/2019
Protocol CC#: 154524
Phase II – pembrolizumab, GM-CSF
Page 51 of 96
Trial Period:
Screening 
Phasep
Treatment Cyclesa
End of 
Treatment
Post-Treatment
Cycle (C) S1
CS2, CS3
To be repeated on D1 each cycle 
beyond 8 cycles
Treatment Cycle/Title:
Second 
Course 
Screening
Day 
(D) 1
D8
D15
D1
D8
C
S4
D1
C
S5
D1
C
S6
D1
C
S7
D1
C
S8
D1
Safety Follow-
Up Visitb
Follow-Up Visitsb
Survival 
Follow-
Up
Scheduling Window (Days):
-28 to 1
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
Approx. 30 
days (±14 
days) post last 
treatment
Every 8 weeks ±28 days 
for 1 year post last 
treatment then every 12 
weeks ±28 days
Every 12 
weeks 
±28 days 
days for up to 1 year during Follow-Up Phase, then every 12 weeks ± 28 days (or more often if clinically indicated).  Imaging may be performed more often if clinically indicated to evaluate for progression or 
toxicity.  Imaging should be performed as close to time of Safety Follow-Up visit as possible in cases of discontinuation after confirmed response or completion of 24 months of treatment.
i
CA 19-9 should be checked at same timepoints as imaging. Note that CA 19-9 may be elevated due to biliary obstruction/stent occlusion independent of progression.  CA 19-9 testing may be performed more often 
if clinically indicated to evaluate for progression.  
jj
Archival tumor samples (FFPE block when available and/or at least 10 unstained slides of approximately 10 µm thickness plus a paired H&E slide) should be obtained from any new  tumor sampling/diagnostic 
procedure(s) before or during Second Course pembrolizumab, such as core or needle biopsy to confirm progression. See Appendix 11.6.
k
Blood samples in all patients will be obtained for PBMC immune profiling at Screening, on Day 1, 8, and 15 of Cycle 1, on Cycle 2 Day 1, Cycle 3 Day 1, then Q8 weeks ± 14 days during subsequent cycles through 
C9D1. Screening sample may be used for Cycle 1, Day 1 if obtained within 3 days . Samples will be obtained at time of Safety Follow-Up visit (PBMC collection at this time-point may be omitted or delayed until 
next UCSF clinic visit if patient has Safety Follow-Up Visit assessments performed outside of UCSF), and at time of progression if patient discontinued treatment without progression and is identified with 
progression during Follow-Up. See Appendix 11.6.
o
On Day 15 of Cycle 1 and Day 8 of Cycles 2 and 3, the clinic visit for physical examination, vitals, and weight check may be omitted provided there are no clinically-significant AE requiring follow up at the 
discretion of treating investigator. If clinic visit is omitted, telephone encounters must be performed to review AE and concomitant medications at these time points and documented in electronic medical record by 
treating investigator. Appropriate follow up for any new symptomatic or laboratory AE must be coordinated as needed based upon this encounter. Research PBMC sample may be omitted in cases which do not 
require clinic visit on Cycle 1, Day 15.
p
Screening tests and procedures do not need to be repeated on Cycle 1, Day 1 if performed within 3 days.


UCSF Helen Diller Family Comprehensive Cancer Center
Version date: 10/01/2019
Protocol CC#: 154524
Phase II – pembrolizumab, GM-CSF
Page 52 of 96
6.4
Expansion Cohort Flow Chart
Trial Period:
Screening 
Phasep
Treatment Cyclesa
End of 
Treatment
Post-Treatment
Cycle (C) 1
C2, C3
To be repeated on D1 each cycle 
beyond 8 cycles
Treatment Cycle/Title:
Main 
Study 
Screening 
Day 
(D) 1
D8
D15
D1
D8
D15
C4
D1
C5
D1
C6
D1
C7
D1
C8
D1
Safety 
Follow-Up 
Visitb
Follow-Up Visitsb
Survival 
Follow-Up
Scheduling Window (Days):
-28 to 1
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
Approx. 30 
days (±14 
days) post 
last 
treatment
Every 8 weeks ±28 days 
for 1 year post last 
treatment then every 12 
weeks ±28 days
Every 12 
weeks ±28 
days
Administrative Procedures
Informed Consent
X
Inclusion/Exclusion Criteria 
X
Demographics and Medical History
X
Prior and Concomitant Medication Review
X
X
X
X
X
X
X
X
X
X
X
X
X
Pembrolizumab Administrationa
X
X
X
X
X
X
X
GM-CSF Administration Days 1-14a,m
D1-14m 
GM-CSF Patient Diary/Injection Recordc,m 
(Appendix 11.2)
Xm
Xm
Post-Study Anticancer Therapy Status
X
X
X
Survival Status
X
X
X
Clinical Procedures/Assessments
Review Adverse Events 
X
X
X
X
X
X
X
X
X
X
X
X
Xd
Full Physical Examination
X
X
X
X
X
X
X
X
X
X
X
Vital Signs and Weight
X
X
X
X
X
X
X
X
X
X
X
ECOG Performance Status (Appendix 11.4)
X
X
X
X
X
X
X
X
X
X
X
Child Pugh Score (Appendix 11.5)
X
Laboratory Procedures/Assessments: analysis performed by LOCAL laboratory
Pregnancy Test – Urine or Serum -HCGe
X
X
X
X
X
X
X
X
PT/INR
X
X
X
X
X
X
X
X
X
X


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Version date: 10/01/2019
Protocol CC#: 154524
Phase II – pembrolizumab, GM-CSF
Page 53 of 96
Trial Period:
Screening 
Phasep
Treatment Cyclesa
End of 
Treatment
Post-Treatment
Cycle (C) 1
C2, C3
To be repeated on D1 each cycle 
beyond 8 cycles
Treatment Cycle/Title:
Main 
Study 
Screening 
Day 
(D) 1
D8
D15
D1
D8
D15
C4
D1
C5
D1
C6
D1
C7
D1
C8
D1
Safety 
Follow-Up 
Visitb
Follow-Up Visitsb
Survival 
Follow-Up
Scheduling Window (Days):
-28 to 1
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
Approx. 30 
days (±14 
days) post 
last 
treatment
Every 8 weeks ±28 days 
for 1 year post last 
treatment then every 12 
weeks ±28 days
Every 12 
weeks ±28 
days
aPTT
X
CBC with Differential
X
X
X
X
X
X
X
X
X
X
X
Comprehensive Serum Chemistry Panelf
X
X
X
X
X
X
X
X
X
X
X
Urinalysisg
X
Every 8 weeks from C1D1 ± 14 days
X
T3, FT4 and TSHg
X
Every 8 weeks from C1D1 ± 14 days
X
Efficacy Measurements
Tumor Imagingh
X
Every 8 weeks from C1D1 (±7 days for first 6 months of treatment, ± 14 
days after 6 months until end of treatment)h
Xh
Confirmation of RECIST 1.1-Measurableq
X
Confirmation of Biopsy-Accessibleq
X
CA 19-9 Tumor Markeri
X
Every 8 weeks from C1D1 ± 14 days
Xi
Archival Tissue Collection/Correlative Studies Blood (Appendix 11.6)
Archival Tumor Tissue Collectionj
Xj
Xj
Xj
On-Treatment Tumor Research Biopsyr
C1D
15
C3D
15 
after 
scans
PBMC Blood Collectionk
X
X
X
X
X
Every 8 weeks ± 14 days through C9D1
X
Xk
a
Cycle length is 21 days, ±3 days. Pembrolizumab is administered IV Q21 days ±3 up to 24 months or 35 cycles (Sections 5.2, 5.8, 7.1.5.2).  GM-CSF is administered days 1-14 Q21 days, ±3 days for induction Cycles 2 
and 3 only with option for re-induction in cases meeting criteria in Section 7.1.5.1; Dayday 1 and subsequent doses are self-is administered after self-injection teaching by infusion center RN or another qualified medical 
provider each cycle.
b
A mandatory Safety Follow-Up Visit should be conducted approximately 30 days after the last dose of trial treatment or before the initiation of a new anti-cancer treatment, whichever comes first.  All AEs that occur prior 
to the Safety Follow-Up Visit should be recorded. Though the Safety Follow-Up Visit and assessments should be performed at UCSF when possible, safety follow up assessments (including administrative, clinical, 


UCSF Helen Diller Family Comprehensive Cancer Center
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Protocol CC#: 154524
Phase II – pembrolizumab, GM-CSF
Page 54 of 96
Trial Period:
Screening 
Phasep
Treatment Cyclesa
End of 
Treatment
Post-Treatment
Cycle (C) 1
C2, C3
To be repeated on D1 each cycle 
beyond 8 cycles
Treatment Cycle/Title:
Main 
Study 
Screening 
Day 
(D) 1
D8
D15
D1
D8
D15
C4
D1
C5
D1
C6
D1
C7
D1
C8
D1
Safety 
Follow-Up 
Visitb
Follow-Up Visitsb
Survival 
Follow-Up
Scheduling Window (Days):
-28 to 1
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
Approx. 30 
days (±14 
days) post 
last 
treatment
Every 8 weeks ±28 days 
for 1 year post last 
treatment then every 12 
weeks ±28 days
Every 12 
weeks ±28 
days
laboratory, and efficacy assessments) may be extracted from clinical data obtained from a subject’s local physician’s office visit, during a hospitalization, and/or during any other standard medical encounter, if travel to 
UCSF would confer hardship due to distance and/or due to initiation of new therapy.   Subjects with at least possibly treatment-related AE of Grade > 1 will be followed until the resolution of the AE to Grade 0-1, 
assessment as chronic or irreversible by investigator, or until the beginning of a new anti-neoplastic therapy, whichever occurs first.  Subjects who discontinue trial treatment for a reason other than disease progression will 
move into the Follow-Up Phase and should be assessed approximately every 8 weeks (56 ± 28 days) by radiographic imaging to monitor disease status.  After 1 year, the Follow Up visits and imaging timepoints will occur 
approximately every 12 weeks (± 28 days). After 2 years, patients will be followed according to Survival Follow-Up phase.
c
GM-CSF Patient Diary/Injection Record and instructions will be provided to each patient on Day 1 of Cycles 2 and 3 and any subsequent re-induction cycles.  The completed diaries will be collected on Day 1 of Cycles 3 
and 4 and after any re-induction cycles. See Appendix 11.2.
d
Subjects with at least possibly treatment-related AE of Grade > 1 will be followed until the resolution of the AE to baseline or Grade 0-1, assessment as chronic or irreversible by investigator, or until the beginning of a 
new anti-neoplastic therapy, whichever occurs first.  SAEs that occur within 90 days of the end of treatment or before initiation of a new anti-cancer treatment, whichever occurs first, will also be followed and recorded.
e
Perform on women of childbearing potential only at screening and prior to each pembrolizumab infusion. If urine pregnancy results cannot be confirmed as negative, a serum pregnancy test will be required.  
f
See Section 7.1.3 and Table 5 for specific laboratory tests required as part of comprehensive metabolic panel.
g
Or more often if clinically indicated.
h
Cross-sectional imaging with CT or MRI abdomen plus pelvis (including triphasic/multiphase liver preferred) and CT chest with or without contrast is required at screening, every 8 weeks (±7 days) during treatment for 
first 6 months then every 8 weeks (±14 days days) after 6 months on treatment until end of treatment. In subjects without evidence progression at treatment discontinuation, scans should be every 8 weeks ±28 days for up 
to 1 year during Follow-Up Phase, then every 12 weeks ± 28 days (or more often if clinically indicated).  Imaging may be performed more often if clinically indicated to evaluate for progression or toxicity.  Imaging 
should be performed as close to time of Safety Follow-Up visit as possible in cases of discontinuation after confirmed response or completion of 24 months of treatment. 
i
CA 19-9 should be checked at same time points as imaging.  Note that CA 19-9 may be elevated due to biliary obstruction/stent occlusion independent of progression.  CA 19-9 testing may be performed more often if 
clinically indicated to evaluate for progression.
j
Archival tumor samples (FFPE block when available and/or at least 10 unstained slides of approximately 10 µm thickness plus a paired H&E slide) should be obtained from prior tumor sampling/diagnostic procedure(s) 
such as prior resection, core biopsy, or cytology/cell button when available.  FFPE block or slides should also be obtained from any subsequent tumor sampling which occurs during or after protocol therapy (such as repeat 
biopsy to confirm progression or palliative metastatectomy surgery). See Appendix 11.6.
k
Blood samples will be obtained in all patients for PBMC immune profiling at Screening, on Days 1 and 8 of Cycles 1, 2, and 3, then Q8 weeks ± 14 days during subsequent cycles through C9D1. Screening sample may be 
used for Cycle 1, Day 1 if obtained within 3 days. Samples will be obtained at time of Safety Follow-Up visit (PBMC collection at this time-point may be omitted or delayed until next UCSF clinic visit if patient has 
Safety Follow-Up Visit assessments performed outside of UCSF), and at time of progression if patient discontinued treatment without progression and is identified with progression during Follow-Up. See Appendix 11.6.
m
Re-induction GM-CSF will be allowed case-by-case according to Section 7.1.5.1, between approximately months 6-12 or Cycles 8-16 on protocol therapy.  In these cases, GM-CSF will be re-administered D1-14 for 2 
cycles (which will be named “R” along with original cycle number, e.g. RC8 and RC9) along with GM-CSF Patient Diary/Injection Record (Appendix 11.2) which will be provided along with instructions before re-
induction and collected on D1 of each cycle following the 2 re-induction cycles.
o
On Day 15 of Cycles 1, 2, and 3, the clinic visit for physical examination, vitals, and weight check may be omitted provided there are no clinically-significant AE requiring follow up at Day 8 visit at discretion of treating 
investigator. If clinic visit is omitted, telephone encounters must be performed to review AE and concomitant medications at these time points and documented in electronic medical record by treating investigator. 
Appropriate follow up for any new symptomatic or laboratory AE must be coordinated as needed based upon this encounter. 
p
Screening tests and procedures do not need to be repeated on Cycle 1, Day 1 if performed within 3 days.
q
Screening for Expansion Cohort requires confirmation of RECIST 1.1-measurable disease with ≥ 1 target lesion not planned for research biopsy, as well as assessment of ≥ 1 lesion amenable percutaneous biopsy per 
Sections 5.1.3 and 7.1.4.3,


UCSF Helen Diller Family Comprehensive Cancer Center
Version date: 10/01/2019
Protocol CC#: 154524
Phase II – pembrolizumab, GM-CSF
Page 55 of 96
Trial Period:
Screening 
Phasep
Treatment Cyclesa
End of 
Treatment
Post-Treatment
Cycle (C) 1
C2, C3
To be repeated on D1 each cycle 
beyond 8 cycles
Treatment Cycle/Title:
Main 
Study 
Screening 
Day 
(D) 1
D8
D15
D1
D8
D15
C4
D1
C5
D1
C6
D1
C7
D1
C8
D1
Safety 
Follow-Up 
Visitb
Follow-Up Visitsb
Survival 
Follow-Up
Scheduling Window (Days):
-28 to 1
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
Approx. 30 
days (±14 
days) post 
last 
treatment
Every 8 weeks ±28 days 
for 1 year post last 
treatment then every 12 
weeks ±28 days
Every 12 
weeks ±28 
days
r
Core needle biopsies (CNB) will be obtained in Expansion Cohort subjects with lesions safely amenable to percutaneous biopsy (by assessment of proceduralist, Section 5.1.3) during Cycle 1 on approximately C1D15 (±3 
days) and during Cycle 3 approximately C3D15 ±3 days, preferably after completion of restaging imaging for 8 week time point.  See Appendix 11.6.3 for processing instructions.


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Phase II – pembrolizumab, GM-CSF
Page 56 of 96
7.0 TRIAL PROCEDURES
7.1
Trial Procedures
The Study Flow Charts in Section 6.0 summarize the trial procedures to be performed at each visit.  
Individual trial procedures are described in detail below.  It may be necessary to perform these 
procedures at additional or unscheduled time points if deemed clinically necessary by the 
investigator.
In some cases, the evaluations or testing may be potentially sensitive in nature (e.g., HIV, HBV, 
or HCV results), and thus local regulations may require that additional informed consent be 
obtained from the subject.  In these cases, such evaluations/testing will be performed in accordance 
with those regulations.
7.1.1
Administrative Procedures
7.1.1.1
Informed Consent
The treating investigator must obtain documented consent from each potential subject prior to 
participating in a clinical trial.
7.1.1.1.1  General Informed Consent
Consent must be documented by the subject’s dated signature or by the subject’s legally acceptable 
representative’s dated signature on a consent form along with the dated signature of the person 
conducting the consent discussion. 
A copy of the signed and dated consent form should be given to the subject before participation in 
the trial.
The initial informed consent form, any subsequent revised written informed consent form and any 
written information provided to the subject must receive the IRB/ERC’s approval/favorable 
opinion in advance of use.  The subject or his/her legally acceptable representative should be 
informed in a timely manner if new information becomes available that may be relevant to the 
subject’s willingness to continue participation in the trial.  The communication of this information 
will be provided and documented via a revised consent form or addendum to the original consent 
form that captures the subject’s dated signature or by the subject’s legally acceptable 
representative’s dated signature.
Specifics about a trial and the trial population will be added to the consent form template at the 
protocol level.  
The informed consent will adhere to IRB/ERC requirements, applicable laws and regulations and 
Study Chair requirements.


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Phase II – pembrolizumab, GM-CSF
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7.1.1.2
Inclusion/Exclusion Criteria
All inclusion and exclusion criteria will be reviewed by the investigator or qualified designee to 
ensure that the subject qualifies for the trial. 
7.1.1.3
Medical History
A medical history will be obtained by the investigator or qualified designee.  Medical history will 
include all active conditions, and any historical condition diagnosed within the prior approximately 
5 years that are considered to be clinically significant by the Investigator.  Details regarding the 
disease for which the subject has enrolled in this study will be recorded separately and not listed 
as medical history.  
7.1.1.4
Prior and Concomitant Medications Review
7.1.1.4.1 Prior Medications
The investigator or qualified designee will review prior medication use, including any protocol-
specified washout requirement, and record prior medication taken by the subject within 28 days 
before starting the trial.  Treatment for the disease for which the subject has enrolled in this study 
will be recorded separately and not listed as a prior medication. 
7.1.1.4.2 Concomitant Medications
The investigator or qualified designee will record medication, if any, taken by the subject during 
the trial treatment and during the Follow-Up Phase.  All medications related to reportable SAEs 
should be recorded as defined in Section 7.2.
7.1.1.5
Disease Details and Treatments
7.1.1.5.1 Disease Details
The investigator or qualified designee will obtain prior and current details regarding disease status, 
including current stage, stage at diagnosis, diagnostic test(s). 
7.1.1.5.2 Prior Treatment Details
The investigator or qualified designee will review all prior cancer treatments including surgery, 
ablative treatments, arterial therapies (such as radioembolization), radiation, and systemic 
treatments.
7.1.1.5.3 Liver Disease Details
The investigator or qualified designee will review liver disease history including risk factors for 
biliary cancer (such as prior or intercurrent liver infections including viral hepatitis, alcohol use, 
non-alcoholic steatohepatitis or fatty liver disease diagnosis or risk factors, cirrhosis/fibrosis, 
autoimmune disease, any other prior injury to biliary tract).  Biliary obstruction history and 
drainage procedures (e.g., percutaneous drain or indwelling stent placement) at baseline, during 


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Phase II – pembrolizumab, GM-CSF
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treatment, and during the Follow-Up Phase will be documented.  History of and any new episodes 
of cholangitis will be documented at baseline, during treatment, and during the Follow-Up Phase.
7.1.1.5.4 Subsequent Anti-Cancer Therapy Status
The investigator or qualified designee will review all new anti-neoplastic therapy initiated after 
the last dose of trial treatment.  If a subject initiates a new anti-cancer therapy within 30 days after 
the last dose of trial treatment, the 30 day Safety Follow-Up visit must occur before the first dose 
of the new therapy.  Once new anti-cancer therapy has been initiated or if transition to 
palliative/end of life care such as Hospice enrollment occurs, the subject will move into Survival 
Follow-Up Phase. 
7.1.1.6
Registration
All patients who consent will be registered in OnCore®, the UCSF Helen Diller Family 
Comprehensive Cancer Center Clinical Trial Management System (CTMS).  
7.1.1.7
Enrollment
Once screening is completed, eligibility documents and checklist for all patients will be submitted 
via HIPAA-compliant method (e.g., secure e-mail or fax) for central review at UCSF by the Study 
Chair or designee.  Once eligibility is confirmed by the Study Chair or designee, a study ID number 
will be assigned by the study coordinator and provided to treating investigator as confirmation of 
enrollment to proceed with protocol therapy.  
7.1.1.8
Trial Compliance (Medication/Diet/Activity/Other)
See Section 5.2.3.3 and Appendix 11.2 for information on GM-CSF Patient Diary/Injection Record.
7.1.2
Clinical Procedures/Assessments
7.1.2.1
Adverse Event (AE) Monitoring
The investigator or qualified designee will assess each subject to evaluate for potential new or 
worsening AEs as specified in the Trial Flow Chart and more frequently if clinically indicated.  
Adverse experiences will be graded and recorded throughout the study and during the Follow-Up 
Phase according to NCI CTCAE Version 4.0 (see Appendix 11.3).  Toxicities will be characterized 
in terms regarding seriousness, causality, toxicity grading, and action taken with regard to trial 
treatment. 
All AEs of unknown etiology associated with pembrolizumab exposure should be evaluated to 
determine if it is possibly an immune-related adverse event (irAE).  Please refer to section 7.2 for 
detailed information regarding the assessment and recording of AEs and irAEs.  
7.1.2.2
Complete Physical Examination
The investigator or qualified designee will perform a complete physical examination according to 
institutional practice for the management and monitoring of patients with biliary cancers during 


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Phase II – pembrolizumab, GM-CSF
Page 59 of 96
the screening period, at all follow up visits, and at end of treatment visit according to standard of 
care.  Clinically significant abnormal findings during Screening should be recorded as medical 
history.  
7.1.2.3
Vital Signs
The investigator or qualified designee will obtain vital signs at the timepoints specified in the 
Study Flow Chart (Section 6.0).  Vital signs should include temperature, pulse, respiratory rate, 
oxygen saturation (pulse oximetry), weight and blood pressure.  Height will be measured at 
screening only.
7.1.2.4
Eastern Cooperative Oncology Group (ECOG) Performance Scale
The investigator or qualified designee will assess ECOG status (see Appendix 11.4) at the 
timepoints specified in the Trial Flow Chart (Section 6.0).  
7.1.2.5
Liver Function Assessment
The investigator or qualified designee will assess liver function by Child Pugh score (see Appendix 
11.5) at the timepoints specified in the Study Flow Chart (Section 6.0). 
7.1.2.6
Tumor Imaging and Assessment of Disease
Cross-sectional imaging with CT (preferred) or MRI abdomen plus pelvis and CT chest 
with/without or without contrast is required at screening, every 8 weeks (±7 days) during first 6 
months of treatment until ascertainment of PFS6, then every 8 weeks (±14 days for patient 
convenience in scheduling on same day as infusions) until end of treatment. In subjects without 
evidence progression at treatment discontinuation, scans should be every 8 weeks ±28 days for up 
to 1 year during Follow-Up Phase, then every 12 weeks ± 28 days (or more often if clinically 
indicated). for RECIST 1.1 response assessment1 (see Section 6.0 – Study Flow Charts for 
timepoints).  Multiphase/triphasic liver imaging should be included as appropriate.  Additional 
baseline imaging such as PET scan, bone scan, or MRI brain are only required if clinically 
indicated by symptoms and/or to assess known bone metastases or other sites of known metastatic 
disease.  All baseline evaluations will be performed as close as possible to the beginning of 
treatment and ≤ approximately 28 days before C1D1.  The same imaging modality/modalities 
should be used if possible throughout study unless there is a clinical indication to use a different 
modality (i.e. based upon Radiology recommendation to better assess a target lesion, an event of 
new contrast allergy, etc.).  RECIST 1.1 measurements will be performed by a radiologist or 
qualified investigator.
7.1.2.7
Assessment of Tumor Amenable to Percutaneous Biopsy in Expansion Cohort
Assessment of tumor likely to be safely accessible to acceptable mode of percutaneous core 
needle biopsy (punch, ultrasound-guided, or CT-guided) will be performed during Screening by 
Radiologist or qualified investigator.  


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Phase II – pembrolizumab, GM-CSF
Page 60 of 96
7.1.3
Laboratory Procedures/Assessments
Details regarding specific laboratory procedures/assessments to be performed in this trial are 
provided below in Table 5.  
Table 5
Laboratory Tests
Hematology
Chemistry
Urinalysis
Other
Hematocrit
Albumin
Blood
Serum β-human chorionic 
gonadotropin†
Hemoglobin
Alkaline phosphatase
Glucose
(β-hCG)†
Platelet count
Alanine aminotransferase (ALT)
Protein
PT (INR)
WBC (total and 
differential)
Aspartate aminotransferase 
(AST)
Specific gravity 
Thyroid-stimulating hormone 
(TSH)
Red Blood Cell Count
Creatinine
Microscopic exam (If 
abnormal) 
Total triiodothyronine (T3)
Absolute Neutrophil 
Count
Carbon Dioxide (C02 or 
bicarbonate) 
Urine pregnancy test †
Free thyroxine (T4)
Absolute Lymphocyte 
Count
Calcium
CA 19-9 
Chloride
Blood for correlative studies*
Glucose
Phosphorus
Archival tumor sample 
accessioning*
Potassium  
 
Sodium
 
Magnesium
 
Total Bilirubin
 
Direct Bilirubin
 
Blood Urea Nitrogen
† Perform urine pregnancy test on women of childbearing potential only. If urine pregnancy results cannot be confirmed as 
negative, a serum pregnancy test is required. *See Section 7.1.4 and Appendix 11.6 for further information on research sample 
collection. 
Laboratory tests for screening or entry on Second Course (S) should be performed within 10 days 
prior to the first dose of Second Course treatment (see Section 6.3 – Second Course 
Pembrolizumab Flow Chart).  After Second Course Cycle 1 (SC1), pre-dose laboratory procedures 
must be obtained within 3 days prior to dosing.  Results must be reviewed by the investigator or 
qualified designee and found to be acceptable prior to each dose of trial treatment. 
7.1.4
Tumor and Blood Sample Collection for Correlative Analyses
Tumor and blood samples will be obtained and stored from all patients for planned future 
correlative analyses (see Section 8.7.3), which will be performed in batch after completion of study 
and pending funding.  In addition, for patients who consent to optional specimen banking,  any 
left-over blood and archival tumor samples will be banked in the UCSF Tissue Core for future 


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Version date: 10/01/2019
Protocol CC#: 154524
Phase II – pembrolizumab, GM-CSF
Page 61 of 96
research as part of the UCSF Hepatobiliary Tissue Bank, CC#124512 as a companion to this 
protocol.  See Appendix 11.67 for correlative specimen procurement and handling instructions.
7.1.4.1
Archival Tumor Tissue Collection
In all patients, left-over diagnostic tumor block and/or slides from any tumor sampling 
procedure(s) (e.g. biopsy, fine needle aspiration, cytology brushings, and/or resection specimens) 
performed prior to enrollment, during study treatment, and/or during the Follow-Up Phase will be 
obtained to determine tumor PD-L1 expression status, to characterize tumor immune infiltrates/T 
cell subsets, and (optional)to bank for future correlative analyses as part of the UCSF Hepatobiliary 
Tissue Bank and Registry (CC#124512) as a companion protocol to this study.  Formalin-fixed, 
paraffin-embedded (FFPE) tumor tissue blocks will be accessioned whenever available.  In 
addition to blocks or if a block is not available, at least 10 unstained slides (prefer 10 µm) plus 1 
H&E slide from a tumor tissue block may be accessioned.  Corresponding pathology reports from 
initial diagnosis and/or subsequent tumor sampling will be obtained.  Specimens will be obtained 
from the Pathology Department for banking as soon as possible after consent and/or occurrence of 
post-enrollment tumor sampling and stored the Helen Diller Family Comprehensive Cancer Center 
(HDFCCC) Tissue Core (UCSF patients).  Correlative analyses using archival tissue samples will 
be performed in batch at completion of study and pending funding.  See Appendix 11.6 for 
correlative specimen procurement and handling instructions.
7.1.4.2
Peripheral Blood Mononuclear Cell (PBMC) Collection
In all patients, approximately 60 mL of whole blood will be collected into green top tubes (e.g. 
six 10 cc tubes filled approximately to 10 mL) at the time points listed in the Study Flow Chart 
in Section 6.0.  The tubes will be delivered directly to the UCSF Immune Monitoring Core for 
PBMC isolation then freezing for future analysis in batch at end of study and pending funding.  
See Appendix 11.6 for correlative specimen procurement and handling instructions.
7.1.4.3
Expansion Cohort Research Biopsies
Expansion Cohort enrollment requires radiographic assessment of measurable disease by RECIST 
1.1 with ≥ 1 target lesion not planned for biopsy, as well as tumor accessible to minimally-invasive 
percutaneous biopsy (by CT, ultrasound, or punch) based upon assessment of qualified radiologist.  
More invasive methods of biopsy such as surgery, laparoscopy, or endoscopy are not allowed for 
purposes of research biopsy on this study due to patient risk.  Consent for paired research biopsies 
during Cycle 1 and Cycle 3 is required for enrollment to Expansion Cohort.  Two to 4 core needle 
biopsies (CNB), preferred 18-gauge and 1 cm depth (or equivalent) if safely accessible based upon 
evaluation by proceduralist, should be obtained at each time point (Section 6.4) with prioritization 
and handling instructions per Appendix 11.6.3.  Biopsy samples will be analyzed for exploratory 
biomarker endpoints as described in 4.3.6.4
7.1.4.4
Specimen Banking
For patients enrolled at UCSF who consent to optional specimen banking, all left-over blood and/or 
tumor samples will be banked in the UCSF Hepatobiliary Tissue Bank, CC#124512.  


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Phase II – pembrolizumab, GM-CSF
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See Appendix 11.6 for correlative specimen procurement and handling instructions.
7.1.5
Other Procedures
7.1.5.1
Re-Induction with GM-CSF
In patients who demonstrate CR, PR, or prolonged stable disease ≥ 6 months with evidence of 
clinical benefit (such as minor response radiographically, decline in CA 19-9, and/or improved 
symptoms) after the Induction Phase but within 12 months from enrollment, but who subsequently 
progress on single-agent pembrolizumab between 6-12 months after enrollment (after the primary 
endpoint of PFS6 has been ascertained for that patient), re-induction with GM-CSF may be 
administered in case-by-case situations with approval from Study Chair provided patient remains 
eligible for ongoing treatment on protocol (section 7.1.5.3).
7.1.5.2
Second Course Pembrolizumab 
Subjects who stop pembrolizumab with SD or better may be eligible for up to one year of 
additional pembrolizumab therapy if they progress within 6 months after stopping study treatment, 
without any evidence of progression prior to discontinuation, with case-by-case approval from 
Study Chair and Merck.  This retreatment is termed the Second Course of this study and is only 
available if the study remains open to enrollment and the subject meets the following conditions:

Either 
o
Stopped initial treatment with pembrolizumab after attaining an investigator-
determined confirmed CR according to RECIST 1.1, and:

Was treated for at least 24 weeks with pembrolizumab before discontinuing 
therapy.

Received at least two treatments with pembrolizumab beyond the date when the 
initial CR was declared.
OR
o
Had CR, PR, or SD with evidence of clinical benefit (such as minor response 
radiographically, decline in CA 19-9, and/or improved symptoms) and stopped 
pembrolizumab treatment after 24 months of study therapy due to protocol-defined 
treatment duration, without any evidence of disease progression or intolerability.
AND

Experienced an investigator-determined confirmed radiographic disease progression 
within 6 months after stopping their initial treatment with pembrolizumab.

Did not receive any other anti-cancer treatment since the last dose of pembrolizumab.


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
Meets original entry criteria in Section 5.1 (with exception of exclusion 19 which is not 
applicable to re-induction or Second Course).
Subjects who restart treatment will be retreated at the same dose and dose interval as when they 
last received pembrolizumab.  Treatment will be administered for up to one additional year.
7.1.5.3
Withdrawal/Discontinuation
When a subject discontinues/withdraws prior to trial completion, all applicable activities scheduled 
for the final trial visit should be performed at the time of Safety Follow-Up Visit (Section 6).  Any 
adverse events which are present at the time of discontinuation/withdrawal should be followed in 
accordance with the safety requirements outlined in Section 7.2 - Assessing and Recording 
Adverse Events.  Subjects who a) attain a CR or b) complete 24 months of treatment with 
pembrolizumab may discontinue treatment with the option of restarting treatment if they meet the 
criteria specified in Section 7.1.5.2.  After discontinuing treatment following assessment of CR, 
these subjects should return to the clinic for a Safety Follow-Up Visit (described in Section 
7.1.5.3.1) and then proceed to the Follow-Up Phase of the study (described in Section 7.1.5.4).
7.1.5.4
Blinding/Unblinding
Not applicable to this study.
7.1.6
Visit Requirements
7.1.6.1
Screening, On-Treatment, and Discontinuation/End of Treatment Visits
Visit requirements for the main study are outlined in Section 6.2 –Main Study Flow Chart.  Specific 
procedure-related details are provided above in Section 7.1 - Trial Procedures.
7.1.6.2
Re-Induction with GM-CSF
Visit requirements for patients eligible for re-induction with GM-CSF are outlined in Section 6.0 
– Main Study Flow Chart.  Specific procedure-related details are provided above in Section 7.1 - 
Trial Procedures and 7.1.5.1 – Re-Induction with GM-CSF.
7.1.6.3
Post-Treatment Visits
7.1.6.3.1
Safety Follow-Up Visit
The mandatory Safety Follow-Up Visit should be conducted approximately 30 days after the last 
dose of trial treatment or before the initiation of a new anti-cancer treatment, whichever comes 
first. Though the Safety Follow-Up Visit and assessments should be performed at UCSF when 
possible, safety follow up assessments (including administrative, clinical, laboratory, and efficacy 
assessments, see Sections 6.1-6.3) may extracted from clinical data obtained from a subject’s local 
physician’s office visit, during a hospitalization, and/or during any other standard medical 
encounter, if travel to UCSF would confer hardship due to distance and/or due to initiation of new 
therapy. All AEs that occur prior to the Safety Follow-Up Visit should be recorded.  Subjects with 


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an at least possibly treatment-related AE of Grade > 1 will be followed until the resolution of the 
AE to Grade 0-1, assessment as chronic or irreversible by investigator, or until the beginning of a 
new anti-neoplastic therapy, whichever occurs first.  SAEs that occur within 90 days of the end of 
treatment or before initiation of a new anti-cancer treatment should also be followed and recorded.  
Subjects who are eligible for Second Course of pembrolizumab (as described in Section 7.1.5.4.1) 
may have up to two Safety Follow-Up visits, one after the Treatment Period and one after the 
Second Course.
7.1.6.4
Follow-Up Phase
Subjects who discontinue trial treatment for a reason other than disease progression will move into 
the Follow-Up Phase and should be assessed every 8 weeks (±28 days) by radiography to monitor 
disease status.  After 1 year, the imaging time point will occur every 12 weeks (±28 days) or more 
often if clinically indicated. After 2 years in Follow-Up Phase, patients will discontinue active 
follow up and be followed only for survival according to Survival Follow-Up Phase (Section 
7.1.6.4.2).  Every effort should be made to collect information regarding disease status until the 
start of new anti-neoplastic therapy, disease progression, death, end of the study or if the subject 
begins retreatment with Second Course pembrolizumab as detailed in Section 7.1.5.2.  Information 
regarding post-study anti-neoplastic treatment will be collected if new treatment is initiated.
7.1.6.4.1 Second Course Pembrolizumab 
Subjects who are eligible to receive retreatment with pembrolizumab according to the criteria in 
Section 7.1.5.2 will move from the Follow-Up Phase to the Second Course when they experience 
disease progression.  Visit requirements are provided in Section 6.3 – Second Course 
Pembrolizumab Flow Chart.  Specific procedure-related details are provided above in Section 7.1 
– Trial Procedures and 6.3 – Second Course Pembrolizumab Flow Chart.
7.1.6.4.2 Survival Follow-Up Phase
Once a subject experiences confirmed disease progression, starts a new anti-cancer therapy, has 
no evidence of progression after 2 years in Follow-Up Phase (Section 7.1.6.4), or transitions to 
palliative/end of life care, the subject moves into the Survival Follow-Up Phase.  Survival status 
should be ascertained by clinic visit (if appropriate for patient’s medical care, chart review, or by 
telephone contact approximately every 12 weeks ±28 days to assess for survival status until death, 
withdrawal of consent, or the end of the study, whichever occurs first.
7.2
Assessing and Recording Adverse Events
An adverse event is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product and which does not necessarily have 
to have a causal relationship with this treatment. An adverse event can therefore be any unfavorable 
and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease 
temporally associated with the use of a medicinal product or protocol-specified procedure, whether 
or not considered related to the medicinal product or protocol-specified procedure.  Any worsening 
(i.e., any clinically significant adverse change in frequency and/or intensity) of a preexisting 


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condition that is temporally associated with the use of the investigational product(s), is also an 
adverse event. Adverse events may occur during the course of the use of the investigational 
products during the Treatment Period or within the Follow-Up Phase of this study.  Progression of 
the cancer under study is not considered an adverse event unless it is considered to be drug related 
by the investigator.
The investigational products in this study are pembrolizumab and GM-CSF.
All adverse events will be recorded from the time the consent form is signed through 30 days 
following cessation of treatment and at each examination on the Adverse Event case report 
forms/worksheets. The reporting timeframe for adverse events meeting any serious criteria is 
described in section 7.2.3.
7.2.1
Definition of an Overdose for This Protocol and Reporting of Overdose to the Study 
Chair and to Merck
For purposes of this trial, an overdose of pembrolizumab will be defined as any dose of 1,000 mg 
or greater or GM-CSF 1250 µg or greater in a single dose (≥5 times the indicated dose).  No 
specific information is available on the treatment of overdose of pembrolizumab. Appropriate 
supportive treatment should be provided if clinically indicated. In the event of overdose, the 
subject should be observed closely for signs of toxicity.  Appropriate supportive treatment should 
be provided if clinically indicated.
If an adverse event(s) is associated with (“results from”) the overdose of a Merck product, the 
adverse event(s) is reported as a serious adverse event, even if no other seriousness criteria are 
met.
If a dose of Merck’s product meeting the protocol definition of overdose is taken without any 
associated clinical symptoms or abnormal laboratory results, the overdose is reported as a non-
serious ECI, using the terminology “accidental or intentional overdose without adverse effect.”
All reports of overdose with and without an adverse event must be reported within 24 business 
hours to the Study Chair and within 2 business days to Merck Global Safety, from the time of 
investigator awareness. See Appendix 11.7.
7.2.2
Reporting of Pregnancy and Lactation to the Study Chair and to Merck
Although pregnancy and lactation are not considered adverse events, it is the responsibility of 
investigators or their designees to report any pregnancy or lactation in a subject (spontaneously 
reported to them), including the pregnancy of a male subject's female partner that occurs during 
the trial or within 120 days of completing the trial completing the trial, or 30 days following 
cessation of treatment if the subject initiates new anticancer therapy, whichever is earlier.  All 
subjects and female partners of male subjects who become pregnant must be followed to the 
completion/termination of the pregnancy.  Pregnancy outcomes of spontaneous abortion, missed 
abortion, benign hydatidiform mole, blighted ovum, fetal death, intrauterine death, miscarriage 
and stillbirth must be reported as serious events (Important Medical Events).  If the pregnancy 
continues to term, the outcome (health of infant) must also be reported.


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Such events must be reported within 24 business hours to the Study Chair and within 2 business 
days to Merck Global Safety, from the time of investigator awareness.  See Appendix 11.7.
7.2.3
Immediate Reporting of Adverse Events to the Study Chair, Merck, and the FDA
7.2.3.1
Serious Adverse Events 
A serious adverse event is any adverse event occurring at any dose or during any use of either 
investigational product (GM-CSF and/or pembrolizumab) that:

Results in death;

Is life threatening;

Results in persistent or significant disability/incapacity;

Results in or prolongs an existing inpatient hospitalization;

Is a congenital anomaly/birth defect;

Is a new cancer (that is not a condition of the study);

Is associated with an overdose.
Refer to Table 6 for additional details regarding each of the above criteria.
Any serious adverse event, or follow up to a serious adverse event, including death due to any 
cause other than progression of the cancer under study that occurs to any subject from the time the 
consent is signed through 90 days following cessation of treatment, or the initiation of new anti-
cancer therapy, whichever is earlier, whether or not related to either or both investigational 
products, must be reported within 24 business hours to the Study Chair and within 2 business days 
to Merck Global Safety, from the time of investigator awareness.  See Appendix 11.7.
Additionally, any serious adverse event, considered by an investigator who is a qualified physician 
or health care professional to be related to either or both investigational products that is brought to 
the attention of the investigator at any time outside of the time period specified in the previous 
paragraph also must be reported immediately to the Study Chair and to Merck in the same manner 
as SAEs.  
All subjects with serious adverse events must be followed up for outcome.
7.2.3.2
Protocol-Specific Exceptions to Serious Adverse Event Reporting 
Efficacy endpoints as outlined in this section will not be reported to Merck as described in Section 
7.2.3.- Immediate Reporting of Adverse Events to Study Chair, Merck, and FDA, unless there is 
evidence suggesting a causal relationship between the drug and the event. 
Specifically, the suspected/actual events covered in this exception include any event that is related 
to or caused by disease progression of the cancer under study.
Hospitalization related to convenience (e.g., transportation issues, etc.) also will not be considered 
a SAE.
The Study Chair will monitor unblinded aggregated efficacy endpoint events and safety data to 
ensure the safety of the subjects in the trial. Any suspected endpoint which upon review is not 


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progression of the cancer under study will be forwarded to Merck Global Safety as a SAE within 
2 working days of determination that the event is not progression of the cancer under study.
7.2.3.3
IND Safety Reporting to FDA
UCSF will report to the FDA all IND reportable events occurring in patients enrolled on this study 
using FDA Form 3500A (MedWatch, Appendix 11.7).  Reportable events must meet the definition 
in Federal Regulations (21 CFR §312.32): 

Suspected adverse reaction (defined as a reasonable possibility that the investigational 
agent caused the adverse event)  

Unexpected (not listed in the investigator brochure or package insert(s), or is not listed at 
the specificity or severity that has been observed)

Serious (as defined in 7.2.3.1)
If the adverse event does not meet all three of the definitions, it should not be submitted as an 
expedited IND safety report.  The timeline for submitting an IND safety report to FDA is no later 
than 15 calendar days after the Investigator determines that the suspected adverse reaction qualifies 
for reporting (21 CFR 312.32(c)(1)).  Any unexpected fatal or life-threatening suspected adverse 
reaction will be reported to FDA no later than 7 calendar days after the Investigator’s initial receipt 
of the information (21 CFR 312.32(c)(2)). 
Any relevant additional information that pertains to a previously submitted IND safety report will 
be submitted to FDA as a Follow-up IND Safety Report without delay, as soon as the information 
is available (21 CFR 312.32(d)(2)). 
A copy of all 15 Day Reports and Annual Progress Reports will be submitted as required by FDA.  
Investigators will cross-reference this submission according to local regulations to the Merck 
Investigational Compound Number (IND) at the time of submission.  Additionally, investigators 
will submit a copy of these reports to Merck & Co., Inc. (Attn: Worldwide Product Safety; FAX 
215 993-1220) at the time of submission to FDA.
7.2.4
Evaluating Adverse Events
An investigator who is a qualified physician or health professional (e.g., Nurse Practitioner) will 
evaluate all adverse events according to the NCI Common Terminology for Adverse Events 
(CTCAE), version 4.0. Any adverse event which changes CTCAE grade over the course of a given 
episode will have each change of grade recorded on the adverse event case report 
forms/worksheets.
All adverse events, regardless of CTCAE grade must also be evaluated for seriousness.


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Table 6
Evaluating Adverse Events
An investigator, who is a qualified physician or health care professional, will evaluate all adverse events as to:
V4.0 
CTCAE 
Grading
Grade 1
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated.
Grade 2
Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental ADL.
Grade 3
Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; 
disabling; limiting self-care ADL.
Grade 4
Life-threatening consequences; urgent intervention indicated.
Grade 5
Death related to AE
Seriousness
A serious adverse event is any adverse event occurring at any dose or during any use of Merck product that:
†Results in death; or
†Is life-threatening; or places the subject, in the view of the investigator, at immediate risk of death from the event as it occurred (Note: This does not include an 
adverse event that, had it occurred in a more severe form, might have caused death.); or
†Results in a persistent or significant disability/incapacity (substantial disruption of one’s ability to conduct normal life functions); or
†Results in or prolongs an existing inpatient hospitalization (hospitalization is defined as an inpatient admission, regardless of length of stay, even if the 
hospitalization is a precautionary measure for continued observation. (Note: Hospitalization [including hospitalization for an elective procedure] for a preexisting 
condition which has not worsened does not constitute a serious adverse event.); or
†Is a congenital anomaly/birth defect (in offspring of subject taking the product regardless of time to diagnosis);or
Is a new cancer; (that is not a condition of the study) or
Is an overdose (whether accidental or intentional).  Any adverse event associated with an overdose is considered a serious adverse event. An overdose that is not 
associated with an adverse event is considered a non-serious important medical event and must be reported within 24 hours.
Other important medical events that may not result in death, not be life-threatening, or not require hospitalization may be considered a serious adverse event when 
based upon appropriate medical judgment, the event may jeopardize the subject and may require medical or surgical intervention to prevent one of the outcomes 
listed previously (designated above by a †).
Duration
Record the start and stop dates of the adverse event. If less than 1 day, indicate the appropriate length of time and units
Action taken 
Did the adverse event cause the Merck product to be discontinued?
Relationship to 
test drug 
Did the Merck product cause the adverse event? The determination of the likelihood that the Merck product caused the adverse event will be provided by an 
investigator who is a qualified physician or health care professional. The investigator’s signed/dated initials on the source document or worksheet that supports the 
causality noted on the AE form ensures that a medically qualified assessment of causality was done. This initialed document must be retained for the required 
regulatory time frame. The criteria below are intended as reference guidelines to assist the investigator in assessing the likelihood of a relationship between the test 
drug and the adverse event based upon the available information. 
The following components are to be used to assess the relationship between the Merck product and the AE; the greater the correlation with the components and 
their respective elements (in number and/or intensity), the more likely the Merck product caused the adverse event (AE):
Exposure
Is there evidence that the subject was actually exposed to the Merck product such as reliable history, acceptable compliance assessment (pill 
count, diary, etc.), expected pharmacologic effect, or measurement of drug/metabolite in bodily specimen?
Time Course
Did the AE follow in a reasonable temporal sequence from administration of the Merck product? 
Is the time of onset of the AE compatible with a drug-induced effect (applies to trials with investigational medicinal product)?
Likely Cause
Is the AE not reasonably explained by another etiology such as underlying disease, other drug(s)/vaccine(s), or other host or environmental 
factors


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Relationship
The following components are to be used to assess the relationship between the test drug and the AE: (continued)
to Merck 
product
(continued) 
Dechallenge
Was the Merck product discontinued or dose/exposure/frequency reduced?
If yes, did the AE resolve or improve?
If yes, this is a positive dechallenge. If no, this is a negative dechallenge.
(Note: This criterion is not applicable if: (1) the AE resulted in death or permanent disability; (2) the AE resolved/improved despite continuation 
of the Merck product; or (3) the trial is a single-dose drug trial); or (4) Merck product(s) is/are only used one time.)
Rechallenge
Was the subject re-exposed to the Merck product in this study?
If yes, did the AE recur or worsen?
If yes, this is a positive rechallenge. If no, this is a negative rechallenge.
(Note: This criterion is not applicable if: (1) the initial AE resulted in death or permanent disability, or (2) the trial is a single-dose drug trial); or 
(3) Merck product(s) is/are used only one time).
NOTE: IF A RECHALLENGE IS PLANNED FOR AN ADVERSE EVENT WHICH WAS SERIOUS AND WHICH MAY HAVE BEEN 
CAUSED BY THE MERCK PRODUCT, OR IF REEXPOSURE TO THE MERCK PRODUCT POSES ADDITIONAL POTENTIAL 
SIGNIFICANT RISK TO THE SUBJECT, THEN THE RECHALLENGE MUST BE APPROVED IN ADVANCE BY THE U.S. CLINICAL 
MONITOR AS PER DOSE MODIFICATION GUIDELINES IN THE PROTOCOL.
Consistency 
with Trial 
Treatment 
Profile
Is the clinical/pathological presentation of the AE consistent with previous knowledge regarding the Merck product or drug class pharmacology 
or toxicology?
The assessment of relationship will be reported on the case report forms /worksheets by an investigator who is a qualified physician or health care professional according to his/her best 
clinical judgment, including consideration of the above elements.
Record one of the following
Use the following scale of criteria as guidance (not all criteria must be present to be indicative of a Merck product relationship).
Yes, there is a reasonable 
possibility of Merck product 
relationship.
There is evidence of exposure to the Merck product.  The temporal sequence of the AE onset relative to the administration of the Merck product 
is reasonable.  The AE is more likely explained by the Merck product than by another cause.
No, there is not a reasonable 
possibility Merck product 
relationship
Subject did not receive the Merck product OR temporal sequence of the AE onset relative to administration of the Merck product is not reasonable 
OR there is another obvious cause of the AE.  (Also entered for a subject with overdose without an associated AE.)


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7.2.5
Study Chair Responsibility for Reporting Adverse Events
All Adverse Events will be reported to regulatory authorities, IRB/IECs and other investigators by 
the Study Chair in accordance with all applicable local laws and regulations. 
8.0 STATISTICAL ANALYSIS PLAN
8.1
Study Statistical Design
This is an open-label, two-stage, single-arm phase 2 study of pembrolizumab plus GM-CSF as 
≥2nd line therapy for advanced biliary tract cancer. The sample size for Stages 1 and 2 was based 
on a two-stage Simon’s Optimal Design using proportion with PFS at 6 months (%PFS6) as the 
primary efficacy endpoint. Based upon results of Stages 1 and 2, the study was amended to change 
primary endpoint to overall response rate (ORR) for overall study with addition of the Expansion 
Cohort.47  
8.2
Study Objectives and Hypotheses
See Section 3.
8.3
Definition of Study Endpoints
8.3.1
Primary Endpoint
The primary endpoint was amended to be overall response rate (ORR) with addition of Expansion 
Cohort, based upon the promising responses observed during Stages 1 and 2 (Safety and Efficacy 
Cohorts).  ORR is defined as the proportion of subjects with RECIST 1.1-measurable disease at 
study entry who have a complete response (CR) or partial response (PR) (confirmed + 
unconfirmed) using RECIST 1.11 at any time during the main study.  Measurable disease has been 
added as a required inclusion criterion for Expansion Cohort eligibility. Re-induction and Second 
Course ORR (rORR, sORR) will be determined based upon response after first dose of re-
induction or first dose of Second Course.  Subjects with measurable disease at study entry who 
have unknown or missing response information will be treated as non-responders.  Subjects with 
non-measurable disease at study entry will be excluded from ORR and DOR analyses.
8.3.2
Secondary Endpoints
1) Safety endpoint assessment is described in Section 7.2.  The safety endpoints are AEs graded 
using CTCAE (Version 4.0) criteria. Safety will be assessed by quantifying the toxicities and 
grades experienced by subjects who have received pembrolizumab plus GM-CSF induction, 
including SAEs and ECIs.  Other safety endpoints include laboratory safety assessments, 
ECOG performance status, Child Pugh score, vital signs, and physical examinations.  The 
incidence and frequency of dose reduction, treatment delays, and discontinuation for lack of 
tolerability will be quantified.  Re-induction and Second Course safety events will be addressed 
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2) Tumor PD-L1 status will be measured by IHC and classified as positive or negative by central 
laboratory testing (QualTek Laboratories) using pre-specified cut-points.
3) A key secondary endpoint is %PFS6 (formerly primary endpoint, changed by amendment 
with addition of Expansion Cohort).  For each patient, PFS will be calculated in days and 
months from date of first dose of protocol therapy to date of first documented radiographic 
and/or clinical disease progression or death from any cause.  For patients removed from 
study for other reasons than progression or death, PFS will be censored at the date last known 
to be progression-free.  See Section 5.9 for Replacement policy for non-evaluable patients.  
The %PFS6 will be calculated as the proportion of evaluable patients progression-free at 6 
months. Censored patients without progression will be treated as non-progression statistically 
and counted in denominator toward %PFS6.  
For patients who continue on treatment despite radiographic progression based upon 
impression of clinical benefit an/or assessment with possible pseudo-progression or a delayed 
response46 (see Section 5.8), PFS will be calculated at time of first documented progression 
after subsequent imaging confirms progression.  If subsequent imaging does not demonstrate 
progression, then a PFS event will not have occurred and the patient will continue with 
scheduled imaging assessments per protocol to determine PFS.
Re-induction and Second Course PFS (rPFS, sPFS) will be calculated in months from date of 
first dose of re-induction or Second Course to date of first documented radiographic and/or 
clinical disease progression during or after re-induction or Second Course, or death from any 
cause.  RPFS and sPFS will be reported descriptively.
4) DOR is defined in the subset of subjects with RECIST 1.1-measurable disease at study entry 
with a CR or PR as the time from first documented evidence of CR or PR until the first 
documented sign of disease progression or death.  Re-induction and Second Course DOR 
(rDOR, sDOR) will be measured as the time from first documented CR or PR during or after 
re-induction or Second Course.  
5) OS is defined as the time from the date of first dose of protocol therapy to the date of death 
due to any cause. Censoring will be performed using the date of last known contact for those 
who are alive at the time of analysis. 
8.4
Sample Size and Accrual Rate
8.4.1
Sample Size
For the primary endpoint of ORR, a sample size of 37 response-evaluable subjects will provide 
power of 77% with 2-sided 5% alpha and 88% with 1-sided 5% alpha to show ORR improvement 
from H0 of 5% to H1 of 20%, under protocol treatment. Based upon a subset with non-measurable 
disease enrolled to Stages 1 and 2 before amendment requiring RECIST 1.1-measurable tumors 
for enrollment to Expansion Cohort, along with potential for dropout in this population with 
comorbidity of biliary obstruction and liver disease, it is estimated that total enrollment of 42 
subjects will include at least 37 response-evaluable subjects.  


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The key secondary endpoint of %PFS6 was previously the primary endpoint for Stages 1 and 2, 
prior to amendment adding Expansion Cohort, which also changed to primary endpoint of ORR 
based upon the promising response rate observed in Stages 1 and 2.  For the key secondary 
endpoint of PFS, an expected overall study PFS-evaluable sample size of at least 40 patients will 
have power 78% with 2-sided alpha 5% and power 87% with 1-sided alpha to show PFS 
improvement from H0 of 20% to H1 of 40% on protocol therapy. 
Pre-amendment, a Simon’s 2 stage design was employed to determine if adequate efficacy was 
observed in Stage 1 to warrant proceeding to Stage 2.  The pembrolizumab/GM-CSF combination 
was considered worthy of additional investigation if the true %PFS6 is 50%, and hence the 
alternative hypothesis, %PFS1=0.50. Therefore assuming an α error probability of 5%, and a β 
error of 20%, the first stage had 9 patients. If ≤2 of 9 had been observed progression-free, the study 
would not proceed to second stage.  Since  ≥3 of 9 patients are observed progression-free at 6 
months (4/9 achieved PFS6 in Stage 1), enrollment continued to the second stage with 18 
additional patients, with a goal of at least 24 evaluable patients (with planned over-enrollment of 
3 additional patients to account for expected 10% dropout rate).  If ≤9 patients are observed 
progression-free at 6 months out of 24 evaluable patients by the end of second stage, then no 
further investigation of the drug is warranted under this PFS6 hypothesis.  Conversely, if ≥10 
patients are progression-free at 6 months among Stages 1 and 2 subjects, the study would be 
considered positive for the hypothesis: H0: %PFS0<25% versus Ha: %PFS1 >50%.    
8.4.2
Accrual Rate
Accrual of approximately 2 patients per month was achieved for Stages 1 and 2, with completion 
of enrollment to Stages 1 and 2 within 16 months.  Owing to additional eligibility requirements 
for paired biopsies and measurable disease, accrual rate for Expansion Cohort is expected to be 
slower, approximately 1-1.5 per month with enrollment completion within 12 months.
8.4.3
Interim Analyses
8.4.4
Interim Safety Analysis and Stopping Rules
An interim safety analysis was performed after completion of 1st stage enrollment corresponding 
to approximately 33% enrollment (9 patients in Safety Cohort).  The interim safety analysis 
examined safety during first 3 cycles of treatment (1 cycle single-agent pembrolizumab followed 
by 2 induction cycles with GM-CSF for total of 9 weeks).  If >20% or more SAE and/or ECI, 
and/or >50% Grade ≥ 3 adverse events by NCI CTCAE v.4.0, have occurred during first 3 cycles 
of treatment and are assessed as both clinically relevant and at least possibly treatment-related, a 
decision would have been required whether to amend or close the study after the 1st stage.  The 
interim safety analysis showed overall rate of Grade ≥3 at least possibly related AE rate of 11%, 
with 1 related SAE event (11%), meeting criteria to proceed with enrollment to Stage 2 Efficacy 
Cohort.  
The target rate of ≤ 50% at least possibly treatment-related ≥ Grade 3 events during the first 3 
cycles was conservative based upon rate of 70% for all-cause Grade 3 or 4 toxicity observed with 
standard first-line chemotherapy in this population,9 and treatment-related Grade 3-5 rate of 
approximately 45% for the combination of ipilimumab plus GM-CSF in advanced melanoma 


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patients.34 Accrual was placed on hold after the 9th patient was enrolled during 1st stage safety 
analysis, until at least 8 of the 9 patients had potential to complete 3 cycles (9 weeks) of treatment 
or had a qualifying safety event.  Accrual resumed after completion of safety interim analysis 
without unexpected safety signals identified.
8.4.5
Interim Efficacy Analysis
An interim efficacy analysis examined %PFS6 after the first stage (n=9) are evaluable for PFS6.  
See Section 8.2.  Three or more patients (r1 ≥3) were required to be progression-free at 6 months 
to continue 2nd stage enrollment.  If ≤2 patients were progression-free at 6 months in first stage, 
the study would have been placed on hold and evaluated for closure for lack of efficacy.  If the 
true %PFS is 0.25, the probability of terminating the study during the first stage is 0.60.  If the true 
%PFS is 0.50, the probability that the study will be stopped during the first stage is 0.09.  Accrual 
was continued during interim efficacy analysis.  Four of 9 patients enrolled to Stage 1 were 
determined to be progression-free at 6 months, thus Stage 2 enrollment was continued and 
completed in September 2017.  
8.5
Analysis Populations
8.5.1
Safety Population  
The safety population will include all enrolled patients who receive at least one dose each of 
pembrolizumab plus GM-CSF and have the potential to complete 3 cycles (9 weeks) of safety 
assessments.  All patients will be evaluable for toxicity and safety assessment from the time of 
their first treatment with the investigational combination.  Patients who are determined ineligible 
after enrollment or who are not evaluable for safety analysis (e.g., due to withdrawal of consent or 
complications of biliary obstruction or drainage procedures assessed as not related to tumor 
progression and not treatment-related toxicity) prior to completing 3 cycles (9 weeks) will be 
replaced (see Section 5.9).
8.5.2
Efficacy Population
The evaluable population for the primary endpoint of ORR will include all enrolled patients who 
have measurable disease present at baseline, have received at least one complete cycle of therapy, 
and have had at least 1 radiographic response assessment or been removed from study due to event 
of clinical progression.  Over-enrollment by approximately 10% is planned to ensure at least 37 
patients are evaluable for primary endpoint of ORR.  
8.6
Planned Analyses
8.6.1
Primary Endpoint Analysis
With expectation of at least 37 subjects with RECIST 1.1-measurable disease evaluable for 
response, ORR calculated as the proportion with CR + PR (confirmed + unconfirmed) by RECIST 
1.1 at any time during the main study.  Subjects with measurable disease at study entry who have 
unknown or missing response information will be treated as non-responders.  Subjects with non-
measurable disease at study entry will be excluded from ORR and DOR analyses.


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For the primary endpoint of ORR, a sample size of 37 response-evaluable subjects will provide 
power of 77% with 2-sided 5% alpha and 88% with 1-sided 5% alpha to show ORR improvement 
from H0 of 5% to H1 of 20% on protocol treatment, using Fisher’s Exact tests. Based upon a subset 
with non-measurable disease enrolled to Stages 1 and 2 before amendment requiring RECIST 1.1-
measurable tumors for study enrollment to Expansion Cohort, along with potential for dropout in 
this population with comorbidity of biliary obstruction and liver disease, it is estimated that total 
enrollment of 42 subjects will yield approximately 37 response-evaluable subjects.
8.6.2
Secondary and Exploratory Endpoints
For secondary endpoints, due to the limited sample size in the study, descriptive statistics with 
mean and 95% confidence intervals will be used.  For continuous variables, descriptive statistics 
will include the number of non-missing values, mean, standard deviation, median, min and 
maximum. For categorical variables, descriptive statistics will include counts and percentages per 
category. For comparison between subgroups, ANOVA and t-tests will be used when appropriate 
to determine the association of the efficacy endpoints and specific biomarkers.
8.6.2.1
Safety 
Safety events will be summarized based on frequency and proportion of total subjects, by system 
organ class and preferred term. Separate summaries with descriptive statistics will be presented 
according to anatomic subtype of biliary cancer (e.g. intrahepatic, hilar/perihilar, extrahepatic, 
GBC).  
8.6.2.2
Tumor PD-L1 Expression Rate
The proportion of subjects overall and according to anatomic subtype with archival tumor samples 
positive for PD-L1 expression using the protocol-defined central IHC assay (QualTek 
Laboratories) (see Section 4.3.5.3.1) will be reported along with 95% CI.  For subjects with more 
than one tumor sample available for testing, designation as positive for PD-L1 expression will be 
based upon ≥1 positive sample.  With an expected evaluable sample size of approximately 36 
tumor samples adequate for PD-L1 testing expected out of planned 42 total enrollment in the study, 
assuming 40% of tumors will be PD-L1+ expression, we will be able to estimate the 95%CI of the 
PD-L1+ expression as 27.7% - 53.9%].  Concordance and rates of positivity between primary and 
metastatic site, tumor location (e.g. liver vs. non-liver), and pre- and post-treatment samples will 
be described individually due to expectation of small subset/paired sample sizes.
8.6.2.3
PFS6
Proportion with PFS at 6 months (%PFS6) %PFS6 will be a key secondary endpoint for the overall 
study.  With H0 %PFS6 of approximately 20% (Section 4.3.6.2) and H1 %PFS6 of 40% if n=40 
are evaluable for PFS6, the power is 78% for 2-sided 5% alpha, or 87% with 1-sided 5% alpha 
using Fisher’s Exact tests.  


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8.6.2.4
 Median DOR, PFS, and OS 
Median DOR will be summarized overall and according to anatomic subtype.  Kaplan-Meier 
medians and quartiles may be provided if data warrant.  Median PFS and OS will be summarized 
overall and according to anatomic subtype. If data warrant, Kaplan-Meier quartile estimates along 
with the 95% CI will be calculated.  Descriptive summaries, including swim lane plots, may also 
be generated depending on results.
8.6.2.5
Re-Induction and Second Course Endpoints
Re-induction and Second Course outcomes for PFS, ORR, DOR, and OS will be measured as 
defined in Section 8.3.  
8.6.3
Exploratory Correlative Analyses
For exploratory endpoints, due to the limited sample size in the study, descriptive statistics with 
mean and 95% confidence intervals will be used.  We will explore immunologic and genomic 
biomarkers (including PBMC immune cell subsets, TCR clonotypes frequency and diversity, 
tumor immune subset composition and immune infiltrates, and tumor genotype) for relationships 
to anatomic subtype of biliary cancer, treatment received, and to the primary and secondary 
efficacy endpoints. No type I error will be adjusted for multiple endpoints. For continuous 
variables, descriptive statistics will include the number of non-missing values, mean, standard 
deviation, median, min and maximum. For categorical variables, descriptive statistics will include 
counts and percentages per category. For comparison between subgroups, ANOVA and t-tests will 
be used when appropriate to determine the association of the efficacy endpoints and the specific 
biomarkers. For association between biomarkers, Spearman correlations will be calculated to 
determine the significance of the association between the biomarkers of interest.  Planned analyses 
are described further below.
8.6.3.1
PBMC Immune Cell Subsets, TCR Clonotype Frequency and Diversity, and Other 
Molecular and Genetic Analyses on PBMC
Serial blood samples will be collected at timepoints in Section 6.0 – Study Flow Chart.  Circulating 
immune cell subsets will be measured using flow cytometry as has been previously described.33,39  
Pending funding and to be guided by clinical results of the overall study, frequency of individual 
TCR clonotypes and the diversity of overall TCR clonotype repertoire may be measured by next-
generation sequencing as has been previously described.40  
Baseline levels of individual PBMC immune cell subset components as well as change in levels 
after GM-CSF induction will be explored for relationship with ORR, PFS at 6 months, and other 
safety and efficacy endpoints (including DOR, OS, and CA 19-9 response) to determine if there is 
an association using Fisher’s Exact tests.  
If TCR sequencing is performed on PBMC derived T cells, the frequency of TCR clonotypes with 
identical sequences40 would be calculated by dividing the number of identical sequence reads by 
the total number of sequencing reads for that sample.  TCR repertoire diversity will be calculated 
as the number of unique clonotypes comprising the top 25% of cumulative reads sorted by 


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abundance.40  Baseline frequency and diversity as well as changes in these parameters after GM-
CSF induction would be explored for relationship with PFS at 6 months as well as secondary 
efficacy endpoints using Fisher’s Exact tests.  
 Exploratory analyses will be conducted to compare clonotype diversity/frequency in the safety 
population and Expansion Cohort after single agent pembrolizumab on Cycle 2, Day 1 before 
initiation of GM-CSF, with clonotype diversity/frequency after initiation of GM-CSF (intra-
patient comparison), as well as to compare clonotype diversity/frequency between the safety 
population and Expansion Cohort (after single-agent pembrolizumab) and the efficacy population 
(after combination therapy) on Cycle 2, Day 1 to better understand the relative impacts and 
timecourse of each study drug.  TCR clonotypes frequency and diversity in PBMC samples may 
also be compared to tumor TCR analyses if adequate sample and funding for these analyses.
Additional analyses such as immune cell gene expression profiles may also be performed 
depending on sample adequacy for additional testing, procurement of funding, and the main study 
clinical outcomes.
8.6.3.2
Tumor Immune Infiltrating Cells (TIIC) and Immune Cell Subsets in Pre-
Treatment and On-Treatment Tumor Samples
The presence of tumor immune infiltrating cells (TIIC) and tumor immune cell profiles will be 
explored for relationship with ORR, PFS at 6 months, and other  secondary efficacy endpoints 
(including DOR, OS, CA 19-9 response) and with tumor PD-L1 status by IHC to determine if there 
is a relationship using Fisher’s Exact tests.  
Descriptive comparisons between baseline and on-treatment or post-treatment tumor samples, or 
between primary and metastatic site samples and according to tumor location (e.g. liver vs. non-
liver), will be performed in cases with paired samples available and between subsets in the overall 
study.
8.6.3.3
Tumor Mutation Profile
For patients with available tumor sequencing results, specific mutations, TMB, pathways, and 
presence of genomic instability-related mutations will be described and explored for relationship 
to clinical outcomes including PFS, RR, DOR, OS, and CA 19-9 response.  The tumor mutation 
profile will also be explored for association with PD-L1 status and presence of TIIC, based upon 
emerging evidence that specific tumor mutations can impact immune cell infiltration and 
activation.19,45  Based upon current practice patterns at UCSF, it is expected that over 75% of the 
study population will have commercial tumor next-generation sequencing results available for 
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9.0 LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL SUPPLIES
9.1
Investigational Products
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.
9.1.1
Pembrolizumab 
Clinical Supplies will be provided by Merck as summarized in Table 7.
Table 7
Product Descriptions
Product Name & Potency
Dosage Form
Pembrolizumab 100 mg/ 4mL
Solution for Injection
9.1.2
GM-CSF (Sargramostim)
GM-CSF vials will be ordered by the Investigational Pharmacist from commercial supply. Vials 
will be provided along with syringes for injection and alcohol wipes for injection site sterilization 
at the start of each cycle.  Day 1 dose for each Induction Cycle will be administered after 
pembrolizumab infusion by an infusion center RN or another qualified provider, along with self-
injection training/re-training.  Treatment adherence will be monitored by GM-CSF Patient 
Diary/Injection Record (see Section 5.2.3). 
Table 8
Product Descriptions
Product Name & Potency
Dosage Form
GM-CSF solution
Liquid formulation containing benzyl 
alcohol in vials containing 500 µg
9.2
Packaging and Labeling Information
Clinical supplies will be affixed with a clinical label in accordance with regulatory requirements.
9.3
Clinical Supplies Disclosure
This trial is open-label; therefore, the subject, the study personnel, the Study Chair 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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9.4
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.  Clinical supplies may not be used for any purpose other than that stated in the 
protocol.
9.5
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. 
9.6
Disposal and Destruction of Unused Investigational Products
Upon completion or termination of the study, all unused and/or partially used investigational 
product will be destroyed 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.
10.0 ADMINISTRATIVE AND REGULATORY DETAILS
10.1 Pre-Study Documentation
This study will be conducted in accordance with the ethical principles that have their origin in the 
Declaration of Helsinki as stated in 21 CFR §312.120(c)(4); consistent with GCP and all applicable 
regulatory requirements.
Before initiating this trial, the Study Chair will have written and dated approval from the UCSF 
IRB for the protocol, written informed consent form, subject recruitment materials, and any other 
written information to be provided to subjects before any protocol related procedures are 
performed on any subjects.  
The clinical investigation will not begin until either FDA has determined that the study under the 
Investigational Drug Application (IND) is allowed to proceed or the Investigator has received a 
letter from FDA stating that the study is exempt from IND requirements. 
All investigators must comply with the applicable regulations in Title 21 of the Code of Federal 
Regulations (21 CFR §50, §54, and §312), GCP/ICH guidelines, and all applicable regulatory 
requirements.  The IRB must comply with the regulations in 21 CFR §56 and applicable regulatory 
requirements.
10.2 Institutional Review Board Approval
The protocol, the proposed informed consent form, and all forms of participant information related 
to the study (e.g. advertisements used to recruit participants) will be reviewed and approved by the 
UCSF IRB (Institutional Review Board).  Prior to obtaining IRB approval, the protocol must be 


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approved by the Helen Diller Family Comprehensive Cancer Center GI Oncology Site Committee 
and by the Protocol Review Committee (PRC).  The initial protocol and all protocol amendments 
must be approved by the IRB prior to implementation.
10.3 Informed Consent
All participants must be provided a consent form describing the study with sufficient information 
for each participant to make an informed decision regarding their participation.  Participants must 
sign the IRB-approved informed consent form prior to participation in any study specific 
procedure.  The participant must receive a copy of the signed and dated consent document.  The 
original signed copy of the consent document must be retained in the medical record or research 
file. 
10.4 Changes in the Protocol
Once the protocol has been approved by the UCSF IRB, any changes to the protocol must be 
documented in the form of an amendment.  The amendment must be signed by the Investigator 
and approved by PRC and the IRB prior to implementation.  
If it becomes necessary to alter the protocol to eliminate an immediate hazard to patients, an 
amendment may be implemented prior to IRB approval.  In this circumstance, however, the 
Investigator must then notify the IRB in writing within five (5) working days after implementation.  
10.5 Handling and Documentation of Clinical Supplies
The UCSF Study Chair will maintain complete records showing the receipt, dispensation, return, 
or other disposition of all investigational drugs.  The date, quantity and batch or code number of 
the drug, and the identification of patients to whom study drug has been dispensed by patient 
number and initials will be included.  The UCSF Study Chair or Pharmacy designee will maintain 
written records of any disposition of the study drug.
The Study Chair shall not make the investigational drug available to any individuals other than to 
qualified study patients.  Furthermore, the Study Chair will not allow the investigational drug to 
be used in any manner other than that specified in this protocol.
10.6 Case Report Forms (CRFs)
The Study Chair and/or qualified designees will prepare and maintain adequate and accurate 
participant case histories with observations and data pertinent to the study.  Study specific Case 
Report Forms (CRFs) will document safety and treatment outcomes for safety monitoring and data 
analysis.  All study data will be entered into OnCore® via standardized CRFs in accordance with 
the CTMS study calendar (see Section 6.0), using single data entry with a secure access account.  
The Clinical Research Coordinator (CRC) will complete the CRFs as soon as possible upon 
completion of the study visit; the Investigator will review and approve the completed CRFs. 
The information collected on CRFs shall be identical to that appearing in original source 
documents.  Source documents will be found in the patient’s medical records maintained by UCSF 
personnel.  All source documentation should be kept in separate research folders for each patient.


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In accordance with federal regulations, the Investigator is responsible for the accuracy and 
authenticity of all clinical and laboratory data entered onto CRFs.  The Study Chair or another 
qualified investigator will approve all completed CRFs to attest that the information contained on 
the CRFs is true and accurate. 
All source documentation and CTMS data will be available for review/monitoring by the UCSF 
DSMC and regulatory agencies.
The Study Chair will be responsible for ensuring the accurate capture of study data.  At study 
completion, when the CRFs have been declared to be complete and accurate, the database will be 
locked.  Any changes to the data entered into the CRFs after that time can only be made by joint 
written agreement among the Study Chair, the Trial Statistician, and the Protocol Project Manager.
10.7 Oversight and Monitoring Plan
The UCSF Helen Diller Family Comprehensive Cancer Center DSMC will be the monitoring 
entity for this study.  The UCSF DSMC will monitor the study in accordance with the NCI-
approved Data and Safety Monitoring Plan (DSMP).  The DSMC will routinely review all adverse 
events and suspected adverse reactions considered “serious”.  The DSMC will audit study-related 
activities to ensure that the study is conducted in accordance with the protocol, local standard 
operating procedures, FDA regulations, and Good Clinical Practice (GCP).  Significant results of 
the DSMC audit will be communicated to the IRB and the appropriate regulatory authorities at the 
time of continuing review, or in an expedited fashion, as applicable.  See Appendix 11.1 Data and 
Safety Monitoring Plan for a Phase 2 or 3 Institutional Study, for additional information.
10.8 Record Keeping and Record Retention
The Principal Investigator is required to maintain adequate records of the disposition of the study 
drugs, including dates, quantity, and use by subjects, as well as written records of the disposition 
of the drug when the study ends.  
The Principal Investigator is required to prepare and maintain adequate and accurate case histories 
that record all observations and other data pertinent to the investigation on each individual 
administered the investigational drug or employed as a control in the investigation. Case histories 
include the case report forms and supporting data including, for example, signed and dated consent 
forms and medical records including, for example, progress notes of the physician, the individual's 
hospital chart(s), and the nurses' notes. The case history for each individual shall document that 
informed consent was obtained prior to participation in the study.
Study documentation includes all CRFs, data correction forms or queries, source documents, Study 
Chair-Investigator correspondence, monitoring logs/letters, and regulatory documents (e.g., 
protocol and amendments, IRB correspondence and approval, signed patient consent forms).
Source documents include all recordings of observations or notations of clinical activities and all 
reports and records necessary for the evaluation and reconstruction of the clinical research study.
In accordance with FDA regulations, the study shall retain records for a period of 2 years following 
the date a marketing application is approved for the drug for the indication for which it is being 


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investigated; or, if no application is to be filed or if the application is not approved for such 
indication, until 2 years after the investigation is discontinued and FDA is notified.


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11.0 APPENDICES
11.1 Data and Safety Monitoring Plan for a Phase 2 or 3 Institutional Study
1. Oversight and Monitoring Plan 
The UCSF Helen Diller Family Comprehensive Cancer Center (HDFCCC) Data and Safety 
Monitoring Committee (DSMC) is responsible for monitoring data quality and subject safety for 
all HDFCCC institutional clinical studies. A summary of DSMC activities for this study 
includes: 
 Review of patient data. 
 Review of serious adverse events. 
 Auditing every six months (depending on study accrual). 
 Minimum of a yearly regulatory audit. 
2. Monitoring and Reporting Guidelines 
Investigators will conduct continuous review of data and patient safety and discuss each patient’s 
treatment at monthly site committee meetings. These discussions are documented in the site 
committee meeting minutes. The discussion will include the number of patients, significant 
toxicities in accordance with the protocol, and observed responses. 
All institutional Phase II and III studies are designated with a moderate risk assessment (see 
Appendix H). The data is audited twice per year with twenty percent of the patients monitored 
(or at least three patients if the calculated value is less than three).
3. Review and Oversight Requirements
3.1 Adverse Event Monitoring
All Grade 3-5 Adverse Events (AEs), whether or not considered to be expected or 
unexpected and whether or not considered to be associated with the use of the study drug, 
will be entered into OnCore®, UCSF’s Clinical Trial Management System. 
Adverse Events are graded according to the Common Terminology Criteria for Adverse 
Events (CTCAE) (version 4.03) as developed and revised by the Common Therapy 
Evaluation Program (CTEP) of the National Cancer Institute. Adverse events are further 
given an assignment of attribution or relationship to treatment or medical procedure. 
Attribution categories are:
• Definite – The adverse event is clearly related to the investigational agent(s) or medical 
procedure. 
• Probable – The adverse event is likely related to the investigational agent(s) or medical 
procedure. 
• Possible – The adverse event may be related to the investigational agent(s) or medical 
procedure. 


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• Unlikely – The adverse event is doubtfully related to the investigational agent(s) or 
medical procedure. 
• Unrelated – the adverse event is clearly not related to the investigational agent(s) or 
medical procedure
All Grade 3-5 adverse events entered into OnCore® will be reviewed on a monthly basis 
at the Site Committee meetings. The Site Committee will review and discuss the selected 
toxicity, the toxicity grade, and the attribution of relationship of the adverse event to the 
administration of the study drug(s).
3.2 Serious Adverse Event Reporting 
By definition, an adverse event is defined as a serious adverse event (SAE) according to 
the following criteria: 
• Death. 
• Life-threatening (i.e., results in an immediate risk of death). 
• Requires inpatient hospitalization or prolongation of existing hospitalization. 
• Permanent or significant disability/incapacity. 
• Gives rise to a congenital anomaly/birth defect, or cancer, or any experience that 
suggests a significant hazard, contraindication, side effect, or precaution that may require 
medical or surgical intervention to prevent one of the outcomes listed above. 
• Event occurring in a gene therapy study. 
• Event that changes the risk/benefit ratio of a study. 
• Any other event the Principal Investigator judges to be serious or which would suggest 
a significant hazard, contraindication, side effect, or precaution. 
Serious Adverse Event reporting will be in accordance with the UCSF IRB Regulations 
and Code of Federal Regulation Title 21 Part 312.32. The SAE will be reported on a Med 
Watch form. 
UCSF IRB website for guidance in reporting serious adverse events: 
https://irb.ucsf.edu/adverse-event 
FDA website for guidance in reporting serious adverse events:
www.fda.gov/Safety/MedWatch/HowToReport/default.htm
Med Watch forms and information: 
www.fda.gov/medwatch/getforms.htm
All serious adverse events are entered into OnCore®, as well as submitted to the IRB (per 
IRB guidelines) via iRIS®. The SAEs are reviewed and monitored by the Data and 
Safety Monitoring Committee on an ongoing basis and discussed at DSMC meetings, 
which take place every six weeks. The date the SAE is sent to all required reporting 
agencies will be documented in OnCore®. 


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If the SAE involves a subject death, and is determined to be possibly, probably or 
definitely related to the investigational drug or any research related procedure, the event 
must be reported to the DSMC Chair or Vice Chair within 1 business day. 
The reporting procedure is by communication via phone or in person with written 
documentation of the one-on-one communication via e-mail, with a copy of the e-mail to 
the DSMC Manager.
3.3 Review of Adverse Event Rates 
If an increase in the frequency of Grade 3 or 4 adverse events (above the rate reported in 
the Investigator Brochure or package insert) is noted in the study, the Principal 
Investigator will notify the DSMC at the time the increased rate is identified. The report 
will indicate if the incidence of adverse events observed in the study is above the range 
stated in the Investigator Brochure or package insert. 
If at any time the Investigator stops enrollment or stops the study due to safety issues, the 
DSMC Chair and DSMC Director must be notified within 1 business day via e-mail. and 
the IRB must be notified within 10 business days via an iRIS Reporting Form. 
Data and Safety Monitoring Committee Contacts: 
 
 
Box 1705 
UCSF HDFCCC 
San Francisco, CA 94158
DSMC Monitors 
Box 0128 
UCSF HDFCCC 
San Francisco, CA 94143
(HDFCCC DSMP version 08Dec2017)


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11.2 Patient Diary/Injection Record for GM-CSF
KEY-G GM-CSF Injection Record
Patient Name
Dates of Treatment
Physician
Cycle Number (1, 2, 3 or R(number))
Use a different injection site each day. Record the date, time, and 
injection site below.
Instructions: Inject once daily for 14 days in a row.
Date
Time
Site
Date
Time
Site
Patient Signature
Date


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11.3 Common Terminology Criteria for Adverse Events V4.0 (CTCAE)
The descriptions and grading scales found in the revised NCI Common Terminology Criteria for 
Adverse Events (CTCAE) version 4.0 will be utilized for adverse event reporting. 
(http://ctep.cancer.gov/reporting/ctc.html).


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11.4 ECOG Performance Status
Grade
Description
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.
* As published in Am. J. Clin. Oncol.:  Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E., 
McFadden, E.T., Carbone, P.P.: Toxicity And Response Criteria Of The Eastern Cooperative Oncology 
Group. Am J Clin Oncol 5:649-655, 1982. The Eastern Cooperative Oncology Group, Robert Comis 
M.D., Group Chair.


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11.5 Child Pugh Score
The Child Pugh score will be calculated at timepoints specified in Section 6.0, Study Flow Chart.  
Ascites should be assessed by clinical examination (rather than radiographic findings).  
Encephalopathy and ascites are considered as present (i.e. at least 2 points) in any patient taking 
medications for these conditions (e.g., lactulose, diuretics) even if well-controlled at the time of 
Child Pugh score assessment.


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11.6 Specimen Collection and Shipping Instructions and Laboratory Contact Information
11.6.1 Archival FFPE Tumor Blocks
Samples of all available archival specimens (preferentially at least 1 representative FFPE block(s) 
plus H&E slide(s) from prior diagnostic core biopsy or biopsies and/or resection specimen(s), or 
if block not available, at least 10*10µm unstained slides plus H&E slide will be requested, or 
maximum available in cases of limited sample) will be accessioned from UCSF and/or outside 
institution clinical laboratories as soon as possible after consent is obtained for study 
participation.  Archival block will be logged and stored according to UCSF Tissue Core SOP or 
returned at end of study (after all planned tissue extraction for study correlative analyses in 
Section 8.7 has been completed) to outside institutions’ Pathology departments depending on 
whether subject consented for any leftover material to be banked in companion banking and 
registry study, CC#124512 (see below).   If multiple tumors and/or satellite nodules are present, 
at least 1 block and/or at least 10 unstained slides plus matching H&E slide should be requested 
for each discrete lesion whenever available.
Block/slides should be delivered or shipped to: 
Attn: CC#154524
UCSF-Biospecimen Repository and Tissue Biomarker Technology Lab
UCSF Helen Diller Family Comprehensive Cancer Center 
11.6.2 Whole Blood for PBMC Isolation
In all patients, approximately 60 mL of whole blood will be collected into green top (sodium 
heparin) tubes (e.g. six 10 cc tubes filled approximately to 10 mL) at the timepoints listed in the 
Study Flow Chart in Section 6.0 and according to instructions below.  The tubes will be 
delivered by study coordinator or approved courier directly to the UCSF Immune Monitoring 
Core for PBMC isolation then freezing for future analysis in batch at end of study and pending 
funding.
Whole blood for PBMC Sample Collection and Delivery Instructions:

Draw 60 mL into the appropriate number of green top tubes (e.g. six 10cc tubes) by 
phlebotomist or other trained health care provider.

Invert the tube gently several times to avoid clotting.

Label samples with study ID (CC#154524), subject ID, cycle/day, date, time of blood 
draw.

For each delivery, an inventory of the samples should accompany the delivery. This 
inventory should include the study ID (CC#154524), subject ID, cycle/day, date, and 
time of blood draw.


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
All samples should be delivered on a Monday through Thursday between 
approximately 9am-5pm PST or on a Friday between approximately 9am-1pm PST 
by a coordinator or approved courier service:

Samples should not be sent after approximately 1pm Friday through Sunday or on 
University holidays, to prevent arrival over the weekend or on holidays, unless by 
special arrangement with the Fong lab staff.

Samples have to be packed according to the ICAO/IATA-Packing-Instructions in a 
room temperature shipper or specimen bag.
Deliver samples at room temperature within approximately 12 hours or less after time of blood 
collection to:
Attn: CC#154524
Dr. Lawrence Fong’s laboratory/UCSF HDFCCC Immune Monitoring Core
11.6.3 Expansion Cohort Research Biopsies
Among n=15 subjects enrolled to Expansion Cohort, it is expected that at least 12 will undergo 
paired tumor biopsy during Week 3 and Week 9 (Sections 6.4, 7.1.4.3).  Two to 4 core needle 
biopsies (CNB), preferred 18-gauge (or smaller if needed to optimize safety) and 1 cm depth (or 
equivalent) if safely accessible based upon evaluation by proceduralist, should be obtained at each 
time point (Section 6.4) with the prioritization below. A fine needle aspirate is not acceptable 
unless CNB determined not feasible during procedure.

Core biopsies (at least 2, up to 4) in order of priority depending on tissue accessibility:

FFPE (1 core)

Fresh (2 cores) with mirror matched FFPE slide

Snap frozen (1 core) with mirror matched FFPE slide
FFPE and frozen research biopsy samples will be procured and stored by UCSF Biorepository: 
Attn: CC#154524
UCSF-Biospecimen Repository and Tissue Biomarker Technology Lab
UCSF Helen Diller Family Comprehensive Cancer Center 


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Fresh research biopsy samples will be stored in the Fong Laboratory:
 Attn: CC#154524
Dr. Lawrence Fong’s laboratory/UCSF HDFCCC Immune Monitoring Core
11.6.4 Optional Specimen Banking in UCSF Hepatobiliary Tissue Bank CC#124512
For patients who consent to the companion study CC#124512, left-over specimens will be 
collected, processed, and banked according to CC#124512 protocol.


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11.7 Adverse Event Reporting to Merck and FDA
Merck: Attn: Worldwide Product Safety; 
FDA
MedWatch 3500A Reporting Guidelines
In addition to completing appropriate patient demographic and suspect medication information, 
the report should include the following information within the Event Description (section 5) of the 
MedWatch 3500A form:

Protocol description (and number, if assigned)

Description of event, severity, treatment, and outcome if known

Supportive laboratory results and diagnostics

Investigator’s assessment of the relationship of the adverse event to each investigational 
product and suspect medication
Follow-Up Information
Additional information may be added to a previously submitted report by any of the following 
methods:

Adding to the original MedWatch 3500A report and submitting it as follow-up

Adding supplemental summary information and submitting it as follow-up with the 
original MedWatch 3500A form

Summarizing new information and faxing it with a cover letter including patient identifiers 
(i.e. D.O.B., initials, patient number), protocol description and number, if assigned, brief 
adverse event description, and notation that additional or follow-up information is being 
submitted (the patient identifiers are important so that the new information is added to the 
correct initial report).
MedWatch 3500A (Mandatory Reporting) form is available at:
http://www.fda.gov/Safety/MedWatch/HowToReport/DownloadForms/default.htm
Additional Reporting Requirements for IND Holders
For Investigator-Sponsored IND studies, some additional reporting requirements for the FDA 
apply in accordance with the guidance set forth in 21 CFR § 600.80.
Events meeting the following criteria need to be submitted to the Food and Drug Administration 
(FDA) as expedited IND Safety Reports, according to the following guidance and timelines. 
Seven (7) Calendar Day Telephone or Fax Report:


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The Investigator is required to notify the FDA of any fatal or life-threatening adverse event that is 
unexpected and assessed by the investigator to be possibly related to the use of pembrolizumab 
and GM-CSF. An unexpected adverse event is one that is not already described in the Investigator 
Brochure. Such reports are to be telephoned or faxed to the FDA within 7 calendar days of first 
learning of the event.
Fifteen (15) Calendar Day Written Report:
The investigator is also required to notify the FDA and all participating investigators, in a written 
IND Safety Report, of any serious, unexpected AE that is considered reasonably or possibly related 
to the use of pembrolizumab and GM-CSF. An unexpected adverse event is one that is not already 
described in the Investigator Brochure.
Written IND Safety Reports should include an Analysis of Similar Events in accordance with 
regulation 21 CFR § 312.32. All safety reports previously filled by the investigatory with the IND 
concerning similar events should be analyzed and the significance of the new report in light of the 
previous, similar reports commented on.
Written IND Safety Reports with Analysis of Similar Events are to be submitted to the FDA within 
15 calendar days of first learning of the event. The FDA prefers these reports on a MedWatch 
3500A form, but alternative formats are acceptable (e.g. summary letter).


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