Testing the Ability of Immunotherapy to Alter the Tumor Immune MicroEnvionment (TIME) and Reduce or Eradicate High Risk DCIS
Phase: EARLY_PHASE1
Conditions: Carcinoma, Intraductal, Noninfiltrating
Sponsor: Laura Esserman

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.
TITLE: Testing the ability of Pembrolizumab to alter the Tumor 
Immune MicroEnvironment (TIME) of high risk DCIS
CC# 16704
IND NUMBER: 130487
Version Number:
6.1  
Version Date:  
October 23, 2018
Study Drug:  
Pembrolizumab
Study Site:  
University of California, San Francisco
Principal Investigator:         Laura Esserman, MD, MBA
Director, UCSF Carol Franc Buck Breast Care Center
Professor of Surgery and Radiology, UCSF
Co-Investigators:
Jasmine Wong, MD
Michael Campbell, PhD
Cheryl Ewing, MD 
Michael Alvarado, MD
Amy Jo Chien, MD
Rita Mukhtar, MD
Statistician:
Study Coordinator:
Merck Supplied Agent:
Pembrolizumab
NCT# 02872025

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PROTOCOL SIGNATURE PAGE
Protocol No.: 16704
Version Date: 23OCT2016
UCSF Principal Investigator / Study Chair
Laura Esserman, MD, MBA
Printed Name
Signature
Date
1.
I agree to follow this protocol version as approved by the UCSF Protocol Review
Committee (PRC), Institutional Review Board (IRB), and Data Safety Monitoring
Committee (DSMC).
2.
I will conduct the study in accordance with applicable IRB requirements, Federal
regulations, and state and local laws to maintain the protection of the rights and welfare of
study participants.
3.
I certify that I, and the study staff, have received the requisite training to conduct this
research protocol.
4.
I have read and understand the information in the Investigators’ Brochure (or
Manufacturer’s Brochure) regarding the risks and potential benefits. I agree to conduct the
protocol in accordance with Good Clinical Practices (ICH-GCP), the applicable ethical
principles, the Statement of Investigator (Form FDA 1572), and with local regulatory
requirements. In accordance with the FDA Modernization Act, I will ensure the registration
of the trial on the www.clinicaltrials.gov website.
5.
I agree to maintain adequate and accurate records in accordance with IRB policies,
Federal, state and local laws and regulations.

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TABLE OF CONTENTS
Protocol Signature Page..........................................................................................................2
1.0
TRIAL SUMMARY ....................................................................................................7
2.0
TRIAL DESIGN ..........................................................................................................7
2.1
Trial Design Summary ............................................................................................7
2.2
Trial Diagram ..........................................................................................................8
3.0
OBJECTIVES..............................................................................................................9
3.1  Primary objectives (dose escalation phase) ................................................................9
3.2  Primary objective (dose expansion phase) .................................................................9
3.3  Exploratory objectives .................................................................................................9
4.0
BACKGROUND & RATIONALE ..........................................................................10
4.1
Background ............................................................................................................10
4.1.1
Pharmaceutical and Therapeutic Background .....................................................10
4.1.2
Preclinical and Clinical Trial Data.......................................................................11
4.2
Rationale.................................................................................................................11
4.2.1
Rationale for the Trial and Selected Subject Population .....................................11
4.2.2
Rationale for Dose Selection/Regimen/Modification..........................................13
4.3
Correlative Studies ................................................................................................14
5.0
Methodology...............................................................................................................15
5.1 Entry Criteria ..............................................................................................................15
5.1.1
Diagnosis/Condition for Entry into the Trial.......................................................15
5.1.2
Subject Inclusion Criteria ....................................................................................15

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5.1.3
Subject Exclusion Criteria ...................................................................................17
5.2
Study design and investigational treatment ........................................................18
5.2.1
Definition of Dose-Limiting Toxicities...............................................................19
5.2.2
Dose Selection/Modification ...............................................................................20
5.2.3
Timing of Dose Administration...........................................................................24
5.2.4
Trial Blinding/Masking........................................................................................25
5.3
Treatment Allocation ............................................................................................25
5.4
Stratification...........................................................................................................25
5.5
Concomitant Medications/Vaccinations (allowed & prohibited)......................25
5.5.1
Acceptable Concomitant Medications.................................................................25
5.5.2
Prohibited Concomitant Medications ..................................................................26
5.6
Rescue Medications & Supportive Care..............................................................26
5.6.1
Supportive Care Guidelines.................................................................................26
5.7
Diet/Activity/Other Considerations .....................................................................30
5.7.1
Diet.......................................................................................................................30
5.7.2
Contraception.......................................................................................................30
5.7.3
Use in Pregnancy .................................................................................................30
5.7.4
Use in Nursing Women........................................................................................31
5.8
Subject Withdrawal/Discontinuation Criteria....................................................31
5.9
Subject Replacement Strategy..............................................................................32
5.10   Clinical Criteria for Early Trial Termination ......................................................32
6.0
TRIAL FLOW CHART............................................................................................33
6.1
Study Flow Chart...................................................................................................33
7.0
TRIAL PROCEDURES ............................................................................................34

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7.1
Trial Procedures ....................................................................................................34
7.1.1
Administrative Procedures...................................................................................35
7.1.2
General Informed Consent...................................................................................35
7.1.3
Clinical Procedures/Assessments ........................................................................37
7.1.4
Laboratory Procedures/Assessments ...................................................................38
7.1.5
Other Procedures..................................................................................................40
7.1.6
Visit Requirements ..............................................................................................40
7.2
Assessing and Recording Adverse Events ...........................................................41
7.2.1
Definitions of Adverse Events.............................................................................41
7.2.2
Recording of an Adverse Event...........................................................................43
7.2.3
Follow-up of Adverse Events ..............................................................................44
7.2.4
Adverse Events Monitoring.................................................................................44
7.2.5
Expedited Reporting ............................................................................................45
7.2.6
Evaluating Adverse Events..................................................................................50
7.2.7
Sponsor Responsibility for Reporting Adverse Events .......................................53
8.0
STATISTICAL ANALYSIS PLAN .........................................................................53
8.1  Analysis of primary endpoints (dose escalation cohort) .........................................53
9.0
LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL 
SUPPLIES ..................................................................................................................54
9.1
Investigational Product .........................................................................................54
9.2
Packaging and Labeling Information..................................................................54
9.3
Clinical Supplies Disclosure..................................................................................54
9.4
Storage and Handling Requirements...................................................................54
9.5
Returns and Reconciliation...................................................................................55
10.0
ADMINISTRATIVE AND REGULATORY DETAILS .......................................55

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10.1
Pre-study Documentation .....................................................................................55
10.2
Institutional Review Board Approval..................................................................55
10.3
Informed Consent..................................................................................................56
10.4
Changes in the Protocol ........................................................................................56
10.5
Handling and Documentation of Clinical Supplies ............................................56
10.6
Case Report Forms (CRFs) ..................................................................................56
10.7
Oversight and Monitoring Plan............................................................................57
10.8
Regulatory Documentation...................................................................................57
10.9
Protection of Human Subjects..............................................................................58
10.9.1 Protection from Unnecessary Harm.....................................................................58
10.9.2 Protection of Privacy ...........................................................................................58
11.0
References...................................................................................................................59
12.0
APPENDICES............................................................................................................61
12.1
ECOG Performance Status and Contraceptive Guidance ................................61
12.2
Common Terminology Criteria for Adverse Events V4.0 (CTCAE) ...............65
12.3
UCSF Policy/Procedure for required regulatory documents for single site and 
multicenter investigator-initiated oncology clinical trials .................................66
12.4
Data and Safety Monitoring Plan for a Phase 1/2 Institutional Study .............71
12.5
EVENT OF CLINICAL INTEREST GUIDANCE DOCUMENT (V3.0)........73

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1.0 TRIAL SUMMARY
1.0
Trial Summary
Abbreviated Title
Testing the ability of Pembrolizumab to alter the tumor 
immune microenvironment of high risk DCIS
Trial Phase
Single agent pilot study
Clinical Indication
High risk DCIS 
Trial Type
Pilot 
Type of control
Untreated, proceed to surgical treatment at least 2 weeks after 
diagnosis
Route of administration
Intralesional 
Trial Blinding
None
Treatment Groups 
Controls; Intralesional injection of agent 
Number of trial subjects
3 dose cohorts using a 3+3 cohort dose escalation design (9 
patients) 30 in dose expansion group (10 controls, 20 
treatment) total of 39 patients
Estimated enrollment period
42 months – June 2016 – December 2020
Estimated duration of trial
48 months – June 2020 target date for submission of 
publication 
Duration of Participation
9 weeks (dose escalation), 5-9 weeks or 8-15 weeks (dose 
expansion)
2.0 TRIAL DESIGN
2.1
Trial Design Summary
2.1 Trial Design Summary 
We propose a pilot study to investigate the change in the immune microenvironment of high risk 
ductal carcinoma in situ (DCIS) after short term exposure to pembrolizumab. This study will 
include 3 dose cohorts using a 3+3 cohort dose escalation design (see figure 1) followed by a 4th 
cohort at the maximum tolerated dose. Unless a dose limiting toxicity (DLT), defined any grade 3 
or 4 toxicity, is observed requiring expansion of a cohort or a subject withdraws, 3 subjects will 
be enrolled into each cohort in the dose escalation phase. Subjects, upon diagnosis with high risk 
DCIS, will be offered 2 doses of pembrolizumab injected intralesionally (IL) 3 weeks apart (+/- 1 
week) with surgery 3 weeks (+/- 2 weeks) after the 2nd dose. The subject will then undergo the 
surgical treatment as determined by the surgeon and the subject (partial mastectomy or 

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mastectomy). The primary objective of this phase of the study will be safety and feasibility of 
intralesional injection of pembrolizumab. The maximum tolerated dose will be used in the 
expansion phase. The expansion cohort will have a target enrollment of 30 subjects enrolled to 
either the control group or the treatment group. The treatment group will consist of 20 subjects 
who agree to receive the treatment. The control group will consist of 10 eligible subjects who 
decline treatment and agree to tissue collection and to the use of tissue for research purposes. The 
control group will proceed to surgery alone within a 4 month timeframe following the diagnosis 
of high risk DCIS. The treatment group will receive 4 doses of intralesional pembrolizumab 3 
weeks apart (+/- 1 week) prior to surgery. All subjects in the expansion cohort will also undergo a 
baseline MRI at diagnosis and undergo a 2nd MRI prior to surgery. Baseline and pre-surgical MRI 
images will be evaluated for changes in tumor volume. 
Cohort
Pembrolizumab Dose
Number of Subjects
1
2 mg
3-6
2
4 mg
3-6
3
8 mg
3-6
4
8 mg
30*
* 10 patient control group, 20 patient treatment group
2.2
Trial Diagram
Dose Escalation Cohort 
Core Biopsy: 
DCIS
High Risk
Pembrolizumab IL x 2 doses
Surgical Resection
MD/Pt choice
Tissue sections prepared for immunologic assays

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Dose Expansion Cohort
3.0 OBJECTIVES
3.1  Primary objectives (dose escalation phase)
3.1a)  To determine the maximum tolerated dose (MTD), and recommended dose for 
subsequent expansion cohort, of intralesionally administered pembrolizumab in patients 
with ductal carcinoma in situ (DCIS) of the breast.
3.1b)  To define the dose-limiting toxicities (DLTs), tolerability, and feasibility of 
intralesional administration of pembrolizumab in patients with DCIS. 
3.2  Primary objective (dose expansion phase)
3.2a)  To determine the response rate to intralesional pembrolizumab in patients with 
DCIS, as measured by an increase (baseline vs. post treatment) in intralesional CD8+ T 
cells, compared to untreated controls.
3.3  Exploratory objectives
3.3a) To determine whether intralesional pembrolizumab decreases tumor volume on 
MRI imaging.
3.3b) To determine the extent of cell death within the DCIS lesions (pre- vs. post-therapy) 
using a cleaved caspase 3 IHC assay.
3.3c) To characterize changes in the immune landscape of DCIS following intralesional 
administration of pembrolizumab.
3.3d). To characterize changes in peripheral blood-based immune biomarkers.
Cohort Selection
Core Biopsy: 
DCIS
Pre-tx
MRI
No active treatment
Pembrolizumab IL x4 
doses, 3 weeks apart 
(+/- 1 week)
Pre-op
MRI
Surgical Resection
MD/Pt choice
Tissue sections prepared for immunologic assays
 

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4.0 BACKGROUND & RATIONALE
4.1
Background
Pembrolizumab is a potent humanized immunoglobulin G4 (IgG4) monoclonal antibody (mAb) 
with high specificity of binding to the programmed cell death 1 (PD-1) receptor, thus inhibiting 
its interaction with programmed cell death ligand 1 (PD-L1) and programmed cell death ligand 2 
(PD-L2).  Based on preclinical in vitro data, pembrolizumab has high affinity and potent receptor 
blocking activity for PD-1.  Pembrolizumab has an acceptable preclinical safety profile and is in 
clinical development as an intravenous (IV) immunotherapy for advanced malignancies.  
Keytruda® (pembrolizumab) is indicated for the treatment of patients across a number of 
indications because of its mechanism of action to bind the PD-1 receptor on the T cell.  For more 
details on specific indications refer to the Investigator brochure.
4.1.1
Pharmaceutical and Therapeutic Background
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.  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 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 

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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 
(MEL).  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.
4.1.2
Preclinical and Clinical Trial Data
Refer to the Investigator’s Brochure for Preclinical and Clinical data.
4.2
Rationale
4.2.1
Rationale for the Trial and Selected Subject Population
Ductal carcinoma in situ (DCIS) of the breast is a premalignant condition. Although DCIS is 
treated as an obligate precursor of invasive ductal carcinoma, the rate and latency of progression 
from DCIS to invasive breast cancer (IBC) in the absence of treatment are unknown.  DCIS itself 
is not a lethal condition, but women with DCIS are at higher risk of developing subsequent local 
or metastatic IBC over a time period of 1-20 years depending on DCIS subtype.  
DCIS is not one condition, but rather a spectrum of disease ranging from indolent lesions more 
akin to markers of increased risk for ER positive disease over 20 years and true precursors of triple 
negative or Her2 positive cancers that are likely to arise in a one to two year timeframe.  The latter 
likely only comprises about 20% of the DCIS diagnosed.   
Features of DCIS that are associated with high risk of recurrence include large size (> 5cm), high 
grade, comedo necrosis, palpable mass, hormone receptor (HR) negativity, and HER2 positivity.  
We selected such cases to investigate the immune microenvironment.1-3 
Our studies, as well as those of others, have shown that high grade, HR-negative invasive breast 
cancers have a greater inflammatory component (significant macrophage and T cell infiltration) 
compared with low grade, HR-positive tumors.4-8 Importantly, tumor associated macrophages are 
associated with early recurrence in HR-negative invasive breast cancer.  High grade DCIS are also 

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characterized by a high proportion of macrophages as measured by CD68 positive cells by 
immunohistochemistry.9-11 
To further characterize the immune microenvironment of DCIS, we recently completed an IHC 
study of 53 cases of high grade DCIS, enriched for large lesions and history of recurrence, age 
matched with 65 cases of non-high grade DCIS. Immunohistochemical analyses were performed 
as single color stains for the following antigens: CD115, FoxP3, Ki-67, and HER2. Two color IHC 
was performed for the following antigen pairs: CD68/PCNA; CD68/Mac 387; CD8/HLA-DR; 
CD68/MRC1, and CD4/CD20.  Stromal TILs were visually estimated from H&E stained sections 
as a percentage of total stroma per section.  HR status was determined from ER and PR staining 
results in pathology reports. For each case, 3 hot spots were identified and marked on 10 
consecutive sections. Nuance multispectral imaging software was used to image each hot spot. 
Protocols for automated image analysis were developed using CellProfiler software. Clinical 
parameters of interest included tumor palpability, recurrence, and Van Nuys Prognostic Index, 
(VNPI, 12 point scale-margins, age, size, grade). Associations were identified with non-parametric 
Spearman correlation test.
In general, immune infiltrates were correlated with high risk DCIS features (high VNPI, 
palpability, high grade, comedo necrosis, high proliferation, HER2-positivity, and HR-negativity).  
Comparing the mean percentages of immune cell populations in cases with a recurrence versus 
those without, we found no cell types that, by themselves, were associated with outcomes.  We 
then constructed a prognostic model using the RPART function in R.  A classification tree was 
generated using as input 16 immune cell populations along with 8 clinical parameters (grade, 
VNPI, tumor size, palpable, comedonecrosis, HR status, HER2 status, and DCIS density).  Of the 
24 input parameters, the best RPART model was built using only 3 immune cell populations:  
CD8+HLADR+ cells, CD8+HLADR- cells and CD115+ cells. This model had an accuracy of 87% 
(sensitivity=76%; specificity=89%).  Importantly, all four cases with metastatic recurrences were 
correctly predicted.  
The highest risk of recurrence was in cases with low numbers of activated CD8+HLADR+ cells.  
Cases with high CD8+HLADR+ cells, but also high numbers of non-activated CD8+HLADR- cells 
and high numbers of CD115+ cells were also at a high risk for recurrence.  In contrast, cases with 
high CD8+HLADR+ cells and low CD8+HLADR- cells or high CD8+HLADR+ cells, high 
CD8+HLADR- cells, and low CD115+ cells were at a low risk for recurrence.  
Using HLA-DR as a marker of T cell activation, we observed that activated CD8+HLA-DR+ T 
cells were associated with good outcomes whereas non-activated or suppressed CD8+HLA-DR- T 
cells were associated with increased risk of recurrence.  This suggests that activating the 
CD8+HLA-DR- T cells, perhaps via checkpoint blockade, could potentially alter disease 
progression.
These high-risk DCIS lesions truly represent an opportunity to prevent cancer. Tools to measure 
the complexity of the tumor immune microenvironment may provide an early measure of 
preventative potential.  The focus of this proposal is to see if the immune microenvironment can 
be changed with short term exposure to an immunomodulating agent, pembrolizumab. This setting 

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will provide an ideal opportunity to evaluate short term single agent exposure, using diagnostic 
core biopsies (pre) and surgical resection specimens (post).
4.2.2
Rationale for Dose Selection/Regimen/Modification 
An open-label Phase I trial (Protocol 001) is being conducted to evaluate the safety and clinical 
activity of single agent pembrolizumab.  The dose escalation portion of this trial evaluated three 
dose levels, 1 mg/kg, 3 mg/kg, and 10 mg/kg, administered every 2 weeks (Q2W) in subjects 
with advanced solid tumors.  All three dose levels were well tolerated and no dose-limiting 
toxicities were observed.  This first in human study of pembrolizumab showed evidence of target 
engagement and objective evidence of tumor size reduction at all dose levels (1 mg/kg, 3 mg/kg 
and 10 mg/kg Q2W).  No MTD has been identified to date.  Recent data from other clinical 
studies within the pembrolizumab program has shown that a lower dose of pembrolizumab and a 
less frequent schedule may be sufficient for target engagement and clinical activity.
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 pembrolizumab 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.  Pembrolizumab has been found to have a wide therapeutic range based on the 
melanoma indication.  The differences in exposure for a 200 mg fixed dose regimen relative to a 
2 mg/kg Q3W body weight based regimen are anticipated to remain well within the established 
exposure margins of 0.5 – 5.0 for pembrolizumab in the melanoma indication. The exposure 
margins are based on the notion of similar efficacy and safety in melanoma at 10 mg/kg Q3W vs. 
the proposed dose regimen of 2 mg/kg Q3W (i.e. 5-fold higher dose and exposure). The 
population PK evaluation revealed that there was no significant impact of tumor burden on 
exposure. In addition, exposure was similar between the NSCLC and melanoma indications. 
Therefore, there are no anticipated changes in exposure between different indication settings.
The rationale for further exploration of 2 mg/kg and comparable doses of pembrolizumab in solid 
tumors is based on: 1) similar efficacy and safety of pembrolizumab when dosed at either 2 mg/kg 
or 10 mg/kg Q3W in melanoma patients, 2) the flat exposure-response relationships of 
pembrolizumab for both efficacy and safety in the dose ranges of 2 mg/kg Q3W to 10 mg/kg Q3W, 
3) the lack of effect of tumor burden or indication on distribution behavior of pembrolizumab (as 
assessed by the population PK model) and 4) the assumption that the dynamics of pembrolizumab 
target engagement will not vary meaningfully with tumor type.
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. 

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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.
Preclinical studies in mice have demonstrated the efficacy of immunomodulatory antibodies 
administered intratumorally at 1/100th the standard systemic dose.12 The intratumoral injection 
reduces systemic toxicities by giving it locally and at a lower dose.  In a mouse lymphoma model, 
intratumoral administration of 1 ug/dose anti-CTLA4 is as effective as systemic administration of 
100 ug/dose.  There are additional mouse studies that demonstrate the efficacy of low-dose 
intratumoral injection of other inmunomodulatory antibodies as well (anti-CD40 and anti-
CD137).12-16 
In the dose escalation phase of this study, no systemic adverse events were observed at the highest 
dose of 8 mg.  Therefore, we propose to use this dose in the expansion cohort.  Although we 
observed dramatic increases in CD8+ T cell infiltrates in the majority of patients post therapy, this 
was not accompanied by a reduction in the extent of DCIS in these patients.  This was likely due 
to the short time interval between the initiation of treatment and surgical excision.   We therefore 
propose to extend the time between initiation of therapy and surgery, and add additional injections 
of pembrolizumab during this time.  We hypothesize that this will give the immune response more 
time to act and result in the reduction or elimination of the DCIS lesions.
4.3
 Correlative Studies
4.3.1  Characterization of the immune landscape in DCIS
H&E stained sections will be obtained from core biopsies (pre-treatment) and surgical specimens 
(post-treatment).  Tumor infiltrating lymphocyte (TIL) counts will be performed using an automated 
counting algorithm in QuPath.  Stromal TIL, intra-lesional TIL, and total TIL counts will be compared 
in pre and post samples. 
Formalin-fixed paraffin embedded (FFPE) tissues from core biopsies (pre-treatment) and surgical 
specimens (post-treatment) will be obtained from all enrolled patients.  Multiplex immunofluorescence 
staining for panels of immune markers will be performed using Opal staining kits (Perkin Elmer).  A 
multispectral imaging platform (Vectra, Perkin Elmer) will be used to analyze stained sections for 
various populations of infiltrating immune cells.  Analysis of samples from control patients (initial core 
biopsy vs. surgical specimen) will be used to determine what effects (if any) the biopsy procedure has 
on the local immune microenvironment.  Analysis of samples from pembrolizumab treated patients 
(initial core biopsy vs. surgical specimen) will be used to determine what effects (if any) 
pembrolizumab treatment has on the local immune microenvironment.  In addition, we will use an IHC 
assay for apoptosis (cleaved caspase 3 staining) to determine if the increase in CD8+ cytotoxic T cells 
is associated with increased cell death within the DCIS lesions.   
4.3.2  Analysis of peripheral blood immune biomarkers.
From complete blood count data we will calculate the following leukocyte ratios as potential 
biomarkers of systemic immune activity:

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a.
neutrophil-to-lymphocyte ratio; NLR
b. platelet-to-lymphocyte ratio; PLR
c.
monocyte-to-lymphocyte ratio; MLR
d. neutrophil-to-monocyte ratio; NMR
e.
eosinophil-to-lymphocyte ratio; ELR
f.
basophil-to-lymphocyte ratio; BLR
These ratios, as well as absolute cell counts, LDH levels, and CRP levels, will be obtained from 
pre-treatment, on-treatment, and post-treatment samples.  This will yield a dynamic picture of 
peripheral immunity across the course of therapy.  We will run correlation analyses between these 
peripheral blood immune biomarkers and immune cell populations identified by multiplex 
immunofluorescence in pre- and post-treatment tissue samples to determine if changes in 
peripheral blood biomarkers predict changes in the tissue immune microenvironment, and 
ultimately with changes in the extent of DCIS.
5.0 METHODOLOGY
5.1 Entry Criteria
5.1.1
Diagnosis/Condition for Entry into the Trial
The patient must have high risk, biopsy proven DCIS. Patients who were previously enrolled on 
the dose escalation arm are eligible to enroll on the dose expansion arm. 
5.1.2
Subject Inclusion Criteria
In order to be eligible for participation in this trial, the subject must:
1. Plan on having surgical treatment for her DCIS.
2. Have at least 2 of the following high risk features associated with her DCIS – high-grade 
(grade II-III), palpable mass, hormone receptor negative (less than 1%), Her2 positive, 
young age (less than 45 years old), and large size (greater than 5 cm).
3. Patients with a history of tamoxifen and/or aromatase inhibitor use for treatment or 
prevention are eligible but should discontinue these medications at least 2 weeks prior to 
starting this trial.
4. Be willing and able to provide written informed consent/assent for the trial.
5. Be   18 years of age on day of signing informed consent.
6. Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1 
(defined in Appendix 1). 

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7. Demonstrate adequate organ function as defined in Table 1 Adequate Organ Function 
Laboratory Values. All screening labs should be performed within 10 days of treatment 
initiation. 
Table 1.  Adequate Organ Function Laboratory Values
System
Laboratory Value
Hematological
Absolute neutrophil count (ANC)
≥1,500 /mcL
Platelets
≥100,000 / mcL
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
AST (SGOT) and ALT (SGPT)
≤ 2.5 X ULN  
Albumin
>2.5 mg/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.
8. A female participant is eligible to participate if she is not pregnant (see Appendix 1.1), not 
breastfeeding, and at least one of the following conditions applies: 
a.
Not a woman of childbearing potential (WOCBP) as defined in Appendix 1.1 
OR 
b. A WOCBP who agrees to follow the contraceptive guidance in Appendix 1.1 during 
the treatment period and for at least 90 days corresponding to time needed to 
eliminate any study treatment plus 30 days (a menstruation cycle) after the last dose 
of study treatment.
9. A male participant must agree to use a contraception as detailed in Appendix 1.1 of this 
protocol during the treatment period and for at least 90 days corresponding to time needed 
to eliminate any study treatment plus an additional 120 days (a spermatogenesis cycle) 
after the last dose of study treatment and refrain from donating sperm during this period.

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5.1.3
Subject Exclusion Criteria
The subject must be excluded from participating in the trial if the subject:
1. Is currently participating and receiving study therapy or has participated in a study of an 
investigational agent and received study therapy 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 or any other 
form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment.
3. Is not interested in surgical treatment for her DCIS.
4. Has invasive breast cancer. This does not include microinvasion.
5. Has a known history of active TB (Bacillus Tuberculosis).
6. Hypersensitivity to pembrolizumab or any of its excipients.
7. 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.
8. 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. 
9. Has a history of (non-infectious) pneumonitis that required steroids or has current 
pneumonitis.
10. 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.  
11. Has known psychiatric or substance abuse disorders that would interfere with cooperation 
with the requirements of the trial.
12. 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.
13. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).

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14. Has a known history of Hepatitis B (defined as Hepatitis B surface antigen [HBsAg] 
reactive) or known active Hepatitis C virus (defined as HCV RNA [qualitative] is detected) 
infection. Note: no testing for Hepatitis B and Hepatitis C is required unless mandated by 
local health authority. 
15. Has received a live vaccine within 30 days prior to the first dose of study drug.  Examples 
of live vaccines include, but are not limited to, the following:  measles, mumps, rubella, 
varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette–Guérin (BCG), 
and typhoid vaccine.  Seasonal influenza vaccines for injection are generally killed virus 
vaccines and are allowed; however, intranasal influenza vaccines (eg, FluMist®) are live 
attenuated vaccines and are not allowed.
5.2
Study design and investigational treatment
This is a pilot study in patients with DCIS.  The primary objective of this trial is to define the MTD 
and recommended dose of intralesional pembrolizumab.  The dose escalation phase of this study 
followed a standard 3+3 trial design (Table 2).   
The initial dose of intralesional pembrolizumab (2 mg) were chosen to be 1:100 the standard IV 
dose (200 mg) based on preclinical studies with immunomodulatory mAbs.  Doses were escalated 
2-fold as shown in Table 3.  
Patients enrolled in the expansion cohort will receive intralesional pembrolizumab at the MTD as 
determined from the escalation phase.  If a MTD is not reached, patients in the expansion cohort 
will receive the highest dose evaluated (8 mg). 
Table 2.  Dose escalation 3+3 trial design.
Number of Patients with DLT 
at a Given Dose Level
Escalation Decision Rule
0 out of 3
Escalate dose to next higher dose level
1 out of 3
Enter at least 3 more patients at this dose level
If 0 of these 3 additional patients experience DLT (1 of 6), proceed to the next 
dose level
If 1 or more of the 3 additional patients suffer DLT (2 of 6), then dose 
escalation is stopped and this dose is declared the maximal administered dose 
(highest dose administered)
Determination of the MTD will continue at the next lowest dose cohort, at 
which an additional 3 patients will be added, for a total of 6 (unless that cohort 
already has 6 patients)
≥ 2 out of 3
Dose escalation will be stopped

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This dose level is declared the maximal administered dose
The next lower cohort will be expanded to 6 patients
If < 1 experience DLT, this dose is the maximal tolerated dose (MTD)
≤ 1 out of 6 at highest dose level 
below the maximal administered 
dose
This is generally the recommended Phase 2 dose
At least 6 patients must be entered at the recommended Phase 2 dose
5.2.1
Definition of Dose-Limiting Toxicities
All toxicities will be graded using National Cancer Institute (NCI) CTCAE Version 4.0 
(Appendix 12.2). The occurrence of any of the following toxicities during Cycle 1 will be 
considered a DLT:
 
Grade 4 non-hematologic toxicity

Grade 3 non-hematologic toxicity lasting >3 days despite optimal supportive care

Any Grade 3 or 4 non-hematologic laboratory value if: 
o
Medical intervention is required to treat the patient, or 
o
The abnormality leads to hospitalization, or 
o
The abnormality persists for >1 week

Neutropenia that is: 
o
Grade 3 or 4 (i.e., ANC <1000 per mm3) and associated with fever (oral 
temperature ≥39ºC) requiring antibiotic therapy
o
Grade 4 which lasts >7 days or leads to use of therapeutic G-CSF

Grade 4 thrombocytopenia (i.e., platelets <25,000 per mm3) or Grade 3 
thrombocytopenia (i.e., platelets <50,000 per mm3) with bleeding
Table 3.  Trial Treatment
Dose Escalation 
Drug
Dose/
Potency
Dose 
Frequency
Route of 
Administration
Regimen/
Treatment 
Period
Use
Pembrolizumab
2 mg 
(1:100 IV  
dose)
2 doses 3 
weeks 
apart (+/- 
1 week)
Intralesional 
injection
Day 1 of each 
3 week cycle
Experimental

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Pembrolizumab
4 mg 
(1:50 IV 
dose) 
2 doses 3 
weeks 
apart (+/- 
1 week)
Intralesional 
injection
Day 1 of each 
3 week cycle
Experimental
Pembrolizumab
8 mg 
(1:25 IV 
dose)
2 doses 3 
weeks 
apart (+/- 
1 week)
Intralesional 
injection
Day 1 of each 
3 week cycle
Experimental
Dose Expansion
Drug
Dose/
Potency
Dose 
Frequenc
y
Route 
of 
Administratio
n
Regimen/
Treatment 
Period
Use
Pembrolizumab
8 mg (1:25 
IV dose)
4 doses 3 
weeks 
apart (+/- 
1 week)
Intralesional 
Injection
Day 1 of each 3 
week cycle 
Experimental
The patient will proceed to the operating room for the operation as determined by the subject and 
the surgeon (partial mastectomy versus mastectomy) 3 weeks (+/- 2 weeks) after the 4th dose of 
intralesional pembrolizumab. 
Trial treatment should begin on the day of treatment selection or as close as possible to the date 
on which treatment is allocated/assigned.
5.2.2
Dose Selection/Modification
5.2.2.1
Dose Selection
The rationale for selection of doses to be used in this trial is provided in Section 4.0 – Background 
and Rationale.  Briefly, based on preclinical studies in mice that have demonstrated the efficacy 
of immunomodulatory antibodies administered intratumorally at 1/100th the standard systemic 
dose, we chose a starting dose of 2 mg (1:100 the standard i.v. dose of pembrolizumab).  Doses 
will be escalated 2-fold in each subsequent escalation cohort.
Details on preparation and administration of pembrolizumab (MK-3475) are provided in the 
Pharmacy Manual.  

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5.2.2.2
Dose Modification and toxicity management for immune-related AEs associated 
with pembrolizumab
AEs associated with pembrolizumab exposure may represent an immunologic etiology. These 
immune-related AEs (irAEs) may occur shortly after the first dose or several months after the last 
dose of pembrolizumab treatment and may affect more than on body system simultaneously. 
Therefore, early recognition and initiation of treatment is critical to reduce complications.  Based 
on existing clinical study data, most irAEs were reversible and could be managed with 
interruptions of pembrolizumab, administration of corticosteroids and/or other supportive care. 
For suspected irAEs, ensure adequate evaluation to confirm etiology or exclude other causes. 
Additional procedures or tests such as bronchoscopy, endoscopy, skin biopsy may be included as 
part of the evaluation. Based on the severity of irAEs, withhold or permanently discontinue 
pembrolizumab and administer corticosteroids. Dose modification and toxicity management 
guidelines for irAEs associated with pembrolizumab are provided in Table 4.
Table 4. Dose modification and toxicity management guidelines for immune-related AEs 
associated with pembrolizumab
General instructions:
1.
Corticosteroid taper should be initiated upon AE improving to Grade 1 or less and continue to taper over at 
least 4 weeks.
2.
For situations where pembrolizumab has been withheld, pembrolizumab can be resumed after AE has been 
reduced to Grade 1 or 0 and corticosteroid has been tapered. Pembrolizumab should be permanently 
discontinued if AE does not resolve within 12 weeks of last dose or corticosteroids cannot be reduced to ≤10 
mg prednisone or equivalent per day within 12 weeks. 
3.
For severe and life-threatening irAEs, IV corticosteroid should be initiated first followed by oral steroid. 
Other immunosuppressive treatment should be initiated if irAEs cannot be controlled by corticosteroids.
Immune-related 
AEs
Toxicity grade 
or conditions 
(CTCAEv4.0)
Action taken to 
pembrolizumab
irAE management with 
corticosteroid and/or other 
therapies 
Monitor and follow-up 
Grade 2
Withhold 
Pneumonitis 
Grade 3 or 4, or 
recurrent Grade 
2
Permanently 
discontinue

Administer 
corticosteroids (initial 
dose of 1-2 mg/kg 
prednisone or equivalent) 
followed by taper

Monitor participants 
for signs and symptoms 
of pneumonitis

Evaluate participants 
with suspected 
pneumonitis with 
radiographic imaging 
and initiate 
corticosteroid treatment

Add prophylactic 
antibiotics for 
opportunistic infections

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Grade 2 or 3
Withhold
Diarrhea / Colitis 
Grade 4
Permanently 
discontinue

Administer 
corticosteroids (initial 
dose of 1-2 mg/kg 
prednisone or equivalent) 
followed by taper

Monitor participants for 
signs and symptoms of 
enterocolitis (ie, 
diarrhea, abdominal 
pain, blood or mucus in 
stool with or without 
fever) and of bowel 
perforation 
(ie, peritoneal signs and 
ileus).

Participants with ≥ 
Grade 2 diarrhea 
suspecting colitis 
should consider GI 
consultation and 
performing endoscopy 
to rule out colitis. 

Participants with 
diarrhea/colitis should 
be advised to drink 
liberal quantities of 
clear fluids.  If 
sufficient oral fluid 
intake is not feasible, 
fluid and electrolytes 
should be substituted 
via IV infusion.
Grade 2
Withhold

Administer 
corticosteroids (initial 
dose of 0.5- 1 mg/kg 
prednisone or equivalent) 
followed by taper
AST / ALT 
elevation or 
Increased 
bilirubin
Grade 3 or 4 
Permanently 
discontinue

Administer 
corticosteroids (initial 
dose of 1-2 mg/kg 
prednisone or equivalent) 
followed by taper

Monitor with liver 
function tests (consider 
weekly or more 
frequently until liver 
enzyme value returned 
to baseline or is stable
Type 1 diabetes 
mellitus (T1DM) 
or 
Hyperglycemia
Newly onset 
T1DM or 
Grade 3 or 4 
hyperglycemia 
associated with 
evidence of  -
cell failure
Withhold

Initiate insulin 
replacement therapy for 
participants with T1DM 

Administer anti-
hyperglycemic in 
participants with 
hyperglycemia 

Monitor participants 
for hyperglycemia or 
other signs and 
symptoms of diabetes.
Grade 2
Withhold
Hypophysitis
Grade 3 or 4 
Withhold or 
permanently 
discontinue1 

Administer 
corticosteroids and 
initiate hormonal 
replacements as 
clinically indicated.  

Monitor for signs and 
symptoms of 
hypophysitis (including 
hypopituitarism and 
adrenal insufficiency) 

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Grade 2
Continue 
Hyperthyroidism 
Grade 3 or 4 
Withhold or 
permanently 
discontinue1

Treat with non-selective 
beta-blockers (eg, 
propranolol) or 
thionamides as 
appropriate 

Monitor for signs and 
symptoms of thyroid 
disorders. 
Hypothyroidism
Grade 2-4
Continue 

Initiate thyroid 
replacement hormones 
(eg, levothyroxine or 
liothyroinine) per 
standard of care

Monitor for signs and 
symptoms of thyroid 
disorders. 
Grade 2
Withhold 
Nephritis and 
Renal 
dysfunction
Grade 3 or 4 
Permanently 
discontinue

Administer 
corticosteroids 
(prednisone 1-2 mg/kg 
or equivalent) followed 
by taper.

Monitor changes of 
renal function
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
Intolerable/ 
persistent 
Grade 2
Withhold
Grade 3
Withhold or 
discontinue 
based on the 
type of event.  
Events that 
require 
discontinuation 
include and not 
limited to:  
Gullain-Barre 
Syndrome, 
encephalitis
All other 
immune-related 
AEs
Grade 4 or 
recurrent Grade 
3 
Permanently 
discontinue

Based on type and 
severity of AE 
administer 
corticosteroids 

Ensure adequate 
evaluation to confirm 
etiology and/or exclude 
other causes
1.
Withhold or permanently discontinue pembrolizumab is at the discretion of the investigator or treating physician.  
NOTE: 
For participants with Grade 3 or 4 immune-related endocrinopathy where withhold of pembrolizumab is required, 
pembrolizumab may be resumed when AE resolves to ≤ Grade 2 and is controlled with hormonal replacement 
therapy or achieved metabolic control (in case of T1DM).  
Dosing interruptions are permitted in the case of medical / surgical events or logistical reasons not 
related to study therapy (e.g., elective surgery, unrelated medical events, patient vacation, and/or 
holidays). Subjects should be placed back on study therapy within 3 weeks of the scheduled 
interruption, unless otherwise discussed with the Sponsor. The reason for interruption should be 
documented in the patient's study record.

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5.2.3
Timing of Dose Administration
Trial treatment should be administered on Day 1 of each cycle after all procedures/assessments 
have been completed as detailed on the Trial Flow Chart (Section 6.0).  Trial treatment may be 
administered up to 7 days before or after the scheduled Day 1 of each cycle due to administrative 
reasons.
All trial treatments will be administered on an outpatient basis.
Dose Escalation Cohort
For intralesional injection, concentrated pembrolizumab will be injected into the palpable DCIS 
or in the vicinity of the non-palpable lesion. Injections will be given on 2 occasions 3 weeks apart 
(+/- 1 week).  The surgeon, in clinic, will use ultrasound imaging (an ultrasound visible clip placed 
at the time of initial biopsy) to guide the placement of the single injection. If a hydromark clip was 
not used, we will work with the radiologists to localize the clip and perform the injection.
Dose Expansion Cohort
Given satisfactory safety data an additional 20 patients will be treated with intralesional injections 
and 10 patients will act as the control group.  The control group will proceed directly to surgery. 
In the intralesional treated cohort, concentrated pembrolizumab will be injected into the palpable 
DCIS or in the vicinity of the non-palpable lesion. Injections will be given on four occasions, 3 
weeks apart (+/- 1 week). The surgeon, in clinic, will use ultrasound imaging (an ultrasound visible 
clip placed at the time of initial biopsy) to guide the placement of the single injection. If a 
hydromark clip was not used, we will work with the radiologists to localize the clip and perform 
the injection. 
The patient will proceed to the operating room for the operation as determined by the subject and 
the surgeon (partial mastectomy versus mastectomy) 3 weeks (+/- 2 weeks) after the 4th dose of 
intralesional pembrolizumab. 
The Pharmacy Manual contains specific instructions for the preparation of the Pembrolizumab for 
injection.  A 50 mg lyophilized powder single use vial will be reconstituted with sterile water and 
then diluted to the correct dose for injection using normal saline. The total injection volume will 
be 2 milliliters.  
Dose
Volume of NS to 1 mL of 25 
mg/mL pembrolizumab
Volume of injection
2 mg/2 mL
24 mL
2.05 mL
4 mg/2 mL
11.5 mL
2.05 mL

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8 mg/2mL
5.25 mL
2.05 mL
  
5.2.4
Trial Blinding/Masking
This is an open-label trial; therefore, the Sponsor, investigator and subject will know the treatment 
administered.  The immune markers will be performed and evaluated by a team that does not know 
treatment status (blinded to study arm).
5.3
Treatment Allocation
In the dose escalation cohort, target enrollment was 3-6 patients at each dose.
In the expansion cohort, target enrollment in the expansion study will be 10 patients in the control 
arm and 20 patients in the treatment arm. Patients who agree to receive treatment will be enrolled 
to the treatment arm. Patients who are eligible to participate but decline treatment will be enrolled 
to the control arm. The core biopsies and surgical specimen of control patients will be banked for 
research.
5.4
Stratification
Based on the limited number of patients in the study, we will not stratify. 
5.5
Concomitant Medications/Vaccinations (allowed & 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 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 and 
ECIs as defined in Section 7.2.

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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 

Immunotherapy not specified in this protocol

Chemotherapy not specified in this protocol

Investigational agents other than pembrolizumab

Radiation therapy 

Live vaccines within 30 days prior to the first dose of trial treatment and while participating 
in the trial.  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 an event 
of clinical interest of suspected immunologic etiology.  The use of physiologic doses of 
corticosteroids may be approved after consultation with the Sponsor.
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 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
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. 
Note: 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 5.2.1 for dose modification. 

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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)
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. 

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.

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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 

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.

Hepatic:
o
For Grade 2 events, monitor liver function tests more frequently until returned to 
baseline values (consider weekly).

Treat with IV or oral corticosteroids
o
For Grade 3-4 events, treat with intravenous corticosteroids for 24 to 48 hours. 
o
When symptoms improve to Grade 1 or less, a steroid taper should be started and 
continued over no less than 4 weeks.

Renal Failure or Nephritis:
o
For Grade 2 events, treat with corticosteroids.
o
For Grade 3-4 events, treat with systemic corticosteroids.
o
When symptoms improve to Grade 1 or less, steroid taper should be started and continued 
over no less than 4 weeks. 

Management of Local Reactions: Signs and symptoms may develop during or shortly 
after drug injection and generally resolve completely within 24 hours of completion of 
injection. .
5 below shows treatment guidelines for subjects who experience a local reaction associated 
with administration of pembrolizumab.

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Table 5. Injection 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 participant is deemed medically 
stable in the opinion of the investigator.
None
Grade 2
Requires therapy or 
infusion interruption but 
responds promptly to 
symptomatic treatment 
(e.g., antihistamines, 
NSAIDs, narcotics, IV 
fluids); prophylactic 
medications indicated 
for ≤24 hrs
Stop Infusion.
Additional appropriate medical therapy may 
include but is not limited to:
IV fluids
Antihistamines
NSAIDs
Acetaminophen
Narcotics
Increase monitoring of vital signs as medically 
indicated until the participant is deemed medically 
stable in the opinion of the investigator.
If symptoms resolve within 1 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 participant should be 
premedicated for the next scheduled dose.
Participants who develop Grade 2 toxicity 
despite adequate premedication should be 
permanently discontinued from further study 
drug treatment
Participant may be 
premedicated 1.5h (± 30 
minutes) prior to infusion of 
_____ with:
Diphenhydramine 50 mg po 
(or equivalent dose of 
antihistamine).
Acetaminophen 500-1000 mg 
po (or equivalent dose of 
analgesic).
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:
Epinephrine**
IV fluids
Antihistamines
NSAIDs
Acetaminophen
Narcotics
Oxygen
Pressors
Corticosteroids
Increase monitoring of vital signs as medically 
indicated until the participant is deemed medically 
stable in the opinion of the investigator.
Hospitalization may be indicated.
**In cases of anaphylaxis, epinephrine should be 
used immediately.
Participant is permanently discontinued from 
further study drug treatment.
No subsequent dosing
Appropriate resuscitation equipment should be available at the bedside and a physician readily available during the period of 
drug administration.
For further information, please refer to the Common Terminology Criteria for Adverse Events v4.0 (CTCAE) at 
http://ctep.cancer.gov

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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.
5.7.2
Contraception
Pembrolizumab may have adverse effects on a fetus in utero.  Refer to Appendix 12.1.1 for 
approved methods of 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 study Visit 1 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 period defined in section 7.2.5.2-Reporting of Pregnancy and 
Lactation to the Sponsor 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 Sponsor and to Merck without delay and within 
24 hours to the Sponsor and within 2 working days 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).  

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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 Sponsor.   If a male subject 
impregnates his female partner the study personnel at the site must be informed immediately and 
the pregnancy reported to the Sponsor and to Merck and followed as described above and in 
Section 7.2.5.2.
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.
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 Sponsor 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.

Unacceptable adverse experiences as described in Section 7.2

Intercurrent illness that prevents further administration of treatment

The participant has a medical condition or personal circumstance which, in the opinion of 
the investigator and/or sponsor, placed the participant at unnecessary risk from continued 
administration of study treatment.

The subject has a confirmed positive serum pregnancy test

Noncompliance with trial treatment or procedure requirements

The subject is lost to follow-up

Administrative reasons

Recurrent Grade 2 pneumonitis

Completion of 35 treatments (approximately 2 years) with pembrolizumab
The End of Treatment and Follow-up visit procedures are listed in Section 6 (Protocol Flow Chart) 
and Section 7.1.6 (Visit Requirements).  After the end of treatment, each subject will be followed 

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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). 
5.9
Subject Replacement Strategy
This is an intent to treat study with a short course of therapy. Our goal is to have 20 evaluable 
patients (as long as there is no safety contraindication after the dose escalation phase). Patients 
who withdraw consent or opt to go elsewhere for surgical treatment without enabling us to obtain 
blocks will be replaced. Enrollment will re-open, and an additional eligible patient will be enrolled 
until we reach a cohort of 20 evaluable patients.
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
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 TRIAL FLOW CHART
6.1
Study Flow Chart
Trial Period
Treatment Cycles
End of 
Treatment
Post-Treatment
Treatment Cycle/Title
Screenin
g
1st 
dose
2nd 
dose 
3rd 
dose 
4th 
dose 
Surgical 
treatment
Safety Follow-
up/Post-op 
Visito
Follow Up 
Visits
Scheduling Window
-28 to 0 
days
± 1 wk
± 1 wk
± 1 wk
± 1 wk
1-5 wks post 
second dose
1- 3 wks post-
surgery 
8 wks +/- 
2 weeks 
post-
surgery 
Informed Consenta
x
Review of eligibility criteriab
x
Demographics and Medical 
Historyc
x
Prior and Concomitant Medication 
Reviewd
x
x
x
x
x
x
x
Intralesional injection 
pembrolizumabe
x
x
x
x
Review Adverse Eventsf
x
x
x
x
x
x
x
Full Physical Examinationg
x
Directed Physical Examinationh
x
x
x
x
x
x
Vital Signs and Weighti
x
x
x
x
x
x
x
ECOG Performance Statusj
x
x
x
x
x
x
x
x
Tissue Collectionk
Core 
biopsy 
(archival)
Surgical 
specimen
Laboratory Proceduresl
Pregnancy Test – Urine or Serumm
x
x
Coagulation
x
x
x
CBC with Differential
x
x
x
Comprehensive Serum Chemistry 
Panel(BMP and LFTs)
x
x
x
Urinalysis
x
x
x
Thyroid Function
x
x
x
Imaging Proceduren

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Trial Period
Treatment Cycles
End of 
Treatment
Post-Treatment
Treatment Cycle/Title
Screenin
g
1st 
dose
2nd 
dose 
3rd 
dose 
4th 
dose 
Surgical 
treatment
Safety Follow-
up/Post-op 
Visito
Follow Up 
Visits
Scheduling Window
-28 to 0 
days
± 1 wk
± 1 wk
± 1 wk
± 1 wk
1-5 wks post 
second dose
1- 3 wks post-
surgery 
8 wks +/- 
2 weeks 
post-
surgery 
MRI scan (dose expansion group 
only)
x
x
aDuring dose expansion cohort: At the time of enrollment patients will be assigned an enrollment number. Patients and their 
corresponding enrollment numbers will be logged and organized in OnCore.
bPatients with a diagnosis of high risk DCIS will come in to the clinic for a screening visit and identified as a potential candidate 
for the study during their clinic visit (i.e., eligibility). Eligible subjects, identified in clinic by the treating surgeon, will be assigned 
a screening number by the study coordinator at the time of identification. Screening numbers will be stored in an encrypted, secure 
Microsoft Excel file. 
cMedical history includes all active conditions, and any condition diagnosed within the prior 10 years that are considered to be 
clinically significant by the Investigator.
dThe investigator or qualified designee will record medication, if any, taken by the subject during the trial.  All medications related 
to reportable SAEs and ECIs should be recorded as defined in Section 7.2.
eDuring dose escalation and patients on the treatment arm during dose expansion: On Day 1 of each 3 week (+/- 1 week) 
cycle. Treatment window is +/- 7 days of scheduled Day 1 administration of each cycle due to administrative reasons.
fSignificant baseline AEs prior to treatment and surgery will be collected.
gThe investigator or qualified designee will perform a complete physical exam during the screening period.  Clinically significant 
abnormal findings should be recorded as medical history.  A full physical exam should be performed during screening, 
hThe investigator or qualified designee will perform a directed physical exam as clinically indicated prior to trial treatment 
administration.  
iVital signs include temperature, pulse, respiratory rate, weight and blood pressure.  Height will be measured at screening only.
jAt screening, prior to the administration of each dose of trial treatment, and at discontinuation of trial treatment.
kPatients will receive a core biopsy upon diagnosis as part of standard clinical procedure. At surgery, tissue will be banked and 
sectioned for immunohistological analysis. 
lRepeat labs not necessary provided baseline lab results within normal range. See Table 6 Laboratory Tests for specific tests
mPregnancy test must be negative within 3 days prior to Day 1 except in dose expansion cohort who are enrolled to control arm 
(surgical treatment only).
nDuring dose expansion cohort: Patients will undergo MRI imaging of the breast to evaluate the extent and volume of DCIS. 
Patients will be offered an additional breast MRI pre-surgery. Breast MRI images will be evaluated for changes in tumor volume 
and tumor immune microenvironment.
oSafety follow-up visit and post-op visit will typically occur during the 2 week mark. 
p Screening procedures can occur on the same day as C1D1. Vital signs, ECOG performance status, adverse event review, and 
concomitant medication review from that day will be recorded for both visits.
7.0 TRIAL PROCEDURES
7.1
Trial Procedures
The Trial Flow Chart - Section 6.0 summarizes 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 unscheduled time points if deemed clinically necessary by the investigator.

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Furthermore, additional evaluations/testing may be deemed necessary by the Sponsor and/or 
Merck for reasons related to subject safety. In some cases, such evaluation/testing may be 
potentially sensitive in nature (e.g., HIV, Hepatitis C, etc.), 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 Investigator must obtain documented consent from each potential subject prior to participating 
in a clinical trial.
7.1.2
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 UCSF IRB’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 UCSF IRB requirements, applicable laws and regulations and 
Sponsor requirements.
7.1.2.1
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. 
7.1.2.2
Medical History
A medical history will be obtained by the investigator or qualified designee.  Medical history will 
include all active conditions, and any condition diagnosed within the prior 10 years that are 

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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.  
7.1.2.3
Prior and Concomitant Medications Review
7.1.2.3.1 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. 
7.1.2.3.2 Concomitant Medications
The investigator or qualified designee will record medication, if any, taken by the subject during 
the trial.  All medications related to reportable SAEs and ECIs should be recorded as defined in 
Section 7.2.
7.1.2.4
Disease Details and Treatments
7.1.2.4.1 Disease Details
The investigator or qualified designee will obtain prior and current details regarding disease status. 
7.1.2.5
Assignment of Screening Number
Eligible subjects, identified in clinic by the treating surgeon, will be assigned a screening number 
by the study coordinator at the time of identification. Any identifying information associated with 
this number will be destroyed if the patient does not consent to participate in the study. Screening 
numbers will be stored in an encrypted, secure Microsoft Excel file. 
7.1.2.6
Assignment of Enrollment Number
At the time of treatment selection, patients on study in the expansion cohort will be assigned an 
enrollment number. Patients and their corresponding enrollment numbers will be logged and 
organized in OnCore – The Online Collaborative Research Environment. This secure system will 
keep all patient personal health information secure and standardized. 
7.1.2.7
Trial Compliance (Medication/Diet/Activity/Other)
Pembrolizumab will be administered in clinic. Subjects on the treatment arm will be required to 
be present for treatment. Patients will be advised not to change diet or activity and to remain 
compliant with home medications. 

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7.1.3
Clinical Procedures/Assessments
7.1.3.1
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 
period according to NCI CTCAE Version 4.0 (see Section 11.2).  Toxicities will be characterized 
in terms regarding seriousness, causality, toxicity grading, and action taken with regard to trial 
treatment. 
For subjects receiving treatment with pembrolizumab all AEs of unknown etiology associated with 
pembrolizumab exposure should be evaluated to determine if it is possibly an event of clinical 
interest (ECI) of a potentially immunologic etiology (termed immune-related adverse events, or 
irAEs); see the separate ECI guidance document in Appendix 4 regarding the identification, 
evaluation and management of potential irAEs.  
Please refer to section 7.2 for detailed information regarding the assessment and recording of AEs.  
7.1.3.2
Full Physical Exam
The investigator or qualified designee will perform a complete physical exam during the screening 
period.  Clinically significant abnormal findings should be recorded as medical history.  A full 
physical exam should be performed during screening, 
7.1.3.3
Directed Physical Exam
For cycles that do not require a full physical exam per the Trial Flow Chart, the investigator or 
qualified designee will perform a directed physical exam as clinically indicated prior to trial 
treatment administration.  
7.1.3.4
Vital Signs
The investigator or qualified designee will take vital signs at screening, prior to the administration 
of each dose of trial treatment and at treatment discontinuation as specified in the Trial Flow Chart 
(Section 6.0).  Vital signs should include temperature, pulse, respiratory rate, weight and blood 
pressure.  Height will be measured at screening only.
7.1.3.5
Eastern Cooperative Oncology Group (ECOG) Performance Scale
The investigator or qualified designee will assess ECOG status (see Section 11.1) at screening, 
prior to the administration of each dose of trial treatment and discontinuation of trial treatment as 
specified in the Trial Flow Chart.  

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7.1.3.6
Tumor Imaging and Assessment of Disease
Patients will undergo MRI imaging of the breast to evaluate the extent and volume of DCIS pre-
treatment and pre-surgery. Breast MRI images will be evaluated for changes in tumor volume and 
tumor immune microenvironment.
7.1.3.7
Tumor Tissue Collection and Correlative Studies Blood Sampling
Patients will receive a core biopsy upon diagnosis as part of standard clinical procedure. At 
surgery, tissue will be banked and sectioned for immunohistological analysis. 
Peripheral blood will be collected from patients prior to each injection of pembrolizumab for standard 
blood counts and chemistries.  An additional EDTA tube will be collected at baseline and prior to 
surgery from which plasma will be frozen for subsequent assays of cytokines and chemokines and 
white blood cells will be processed and frozen for subsequent flow cytometry or CyTOF analyses.
7.1.4
Laboratory Procedures/Assessments
Details regarding specific laboratory procedures/assessments to be performed in this trial are 
provided below Laboratory Safety Evaluations (Hematology, Chemistry and Urinalysis)
Laboratory tests for hematology, chemistry, urinalysis, and others are specified in Table 6.  

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Table 6. 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 
aPTT
Red Blood Cell Count
Lactate dehydrogenase (LDH)
Microscopic exam (If abnormal) 
Total 
thriiodothyronin
e (T3)
Absolute Neutrophil 
Count
Carbon Dioxide ‡
results are noted
Free thyroxine 
(T4)
Absolute Lymphocyte 
Count
  (CO2 or biocarbonate)
Urine pregnancy test †
Thyroid 
stimulating 
hormone (TSH)
Monocyte count
Uric Acid
Platelet count
Calcium
Eosinophil count
Chloride
Basophil count
Glucose
 
Phosphorus
 
Potassium  
 
Sodium
 
Magnesium
 
Total Bilirubin
 
Direct Bilirubin (If total bilirubin 
is elevated above the upper limit of 
normal)
Total protein
Blood Urea Nitrogen
Creatinine
CRP
† Perform on women of childbearing potential only. If urine pregnancy results cannot be confirmed as negative, a 
serum pregnancy test will be required.  
‡ If considered standard of care in your region.

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7.1.5
Other Procedures
7.1.5.1
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 discontinuation.  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.  
7.1.5.2
Blinding/Unblinding
This trial is open-label; therefore, the subject, the trial site personnel, the Sponsor and/or designee 
are not blinded to treatment. Drug identity (name, strength) is included in the label text; random 
code/disclosure envelopes or lists are not provided.
7.1.6
Visit Requirements
Visit requirements are outlined in Section 6.0 - Trial Flow Chart.   Specific procedure-related 
details are provided above in Section 7.1 - Trial Procedures.
7.1.6.1
Screening
7.1.6.1.1 Screening Period
We will determine eligibility at initial patient consult based on pathology and imaging results. 
Patients who choose to participate in the study will be enrolled on the day that they sign consent. 
Core biopsy specimens will be archived during screening.
The screening visit can occur on the same day as the first injection (C1D1). The patient will be 
seen in clinic and complete all screening procedures and labs. Once the patient is deemed eligible 
for enrollment and has provided informed consent, the patient will be able to receive the first 
injection that same day. We will record the vital signs, ECOG performance status, adverse event 
review, and concomitant medication review from that day for both the screening visit and the 
C1D1 visit.   
7.1.6.2
Treatment Period
Patients will be seen in clinic on the day of each treatment administration. For the dose escalation 
cohort, there will two drug administrations, 3 weeks (+/- 1 week) apart. In the expansion cohort, 
for patients on the treatment arm, there will be four drug administrations, 3 weeks (+/- 1 week) 
apart. In both cohorts, surgery will occur 3 weeks (+/- 2 weeks) after the 2nd or 4th dose of 
intralesional pembrolizumab  

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7.1.6.3
Post-Treatment Visits
Patients will be seen on a standard post-operative visit (2-3 weeks after surgery). 
7.1.5.3.1 Safety Follow-Up Visit
The mandatory Safety Follow-Up Visit should be conducted approximately 8 weeks post-surgery 
(+/- 2 weeks). All non-surgically-related AEs that occur prior to the Safety Follow-Up Visit should 
be recorded.  Subjects with an AE of Grade > 1 will be followed until the resolution of the AE to 
Grade 0-1 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. 
7.1.6.4
Follow-up Visits
7.1.6.4.1 Survival Follow-up
This is a short term study using surgical endpoints. We will follow patients for toxicity (8 weeks 
post-surgery (+/- 2 weeks)).
7.2
Assessing and Recording Adverse Events
7.2.1
Definitions of Adverse Events
7.2.1.1
Adverse Event
An adverse event (also known as an adverse experience) is defined as any untoward medical 
occurrence associated with the use of a drug in humans, whether or not considered drug related.  
More specifically, an adverse event (can be any unfavorable and unintended sign (e.g., an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a drug, without any 
judgment about causality.  An adverse event can arise from any use of the drug (e.g., off-label use, 
use in combination with another drug) and from any route of administration, formulation, or dose, 
including an overdose.
7.2.1.2
Adverse reaction
An adverse reaction is defined as any adverse event caused by the use of a drug.  Adverse reactions 
are a subset of all suspected adverse reactions for which there is reason to conclude that the drug 
caused the event.
7.2.1.3
Suspected
A suspected adverse reaction is defined as any adverse event for which there is a reasonable 
possibility that the drug caused the adverse event. For the purposes of IND safety reporting, 
“reasonable possibility” indicates that there is evidence to suggest a causal relationship between 

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the drug and the adverse event.  A suspected adverse reaction implies a lesser degree of certainty 
about causality than an adverse reaction.
7.2.1.4
Unexpected
An adverse event or suspected adverse reaction is considered unexpected if it is not listed in the 
investigator brochure or package insert(s), or is not listed at the specificity or severity that has been 
observed, or, if an investigator brochure is not required or available, is not consistent with the risk 
information described in the general investigational plan or elsewhere in the current application. 
“Unexpected,” as used in this definition, also refers to adverse events or suspected adverse 
reactions that are mentioned in the investigator brochure as occurring with a class of drugs or as 
anticipated from the pharmacological properties of the drug, but are not specifically mentioned as 
occurring with the particular drug under investigation.
Adverse events that would be anticipated to occur as part of the disease process are considered 
unexpected for the purposes of reporting because they would not be listed in the investigator 
brochure.  For example, a certain number of non-acute deaths in a cancer trial would be anticipated 
as an outcome of the underlying disease, but such deaths would generally not be listed as a 
suspected adverse reaction in the investigator brochure.
Some adverse events are listed in the Investigator Brochure  as occurring with the same class of 
drugs, or as anticipated from the pharmacological properties of the drug, even though they have 
not been observed with the drug under investigation.  Such events would be considered unexpected 
until they have been observed with the drug under investigation. For example, although 
angioedema is anticipated to occur in some patients exposed to drugs in the ACE inhibitor class 
and angioedema would be described in the investigator brochure as a class effect, the first case of 
angioedema observed with the drug under investigation should be considered unexpected for 
reporting purposes.
7.2.1.5
Serious
An adverse event or suspected adverse reaction is considered serious if, in the view of either the 
investigator or sponsor, it results in any of the following outcomes: 

Death

Life-threatening adverse event

Inpatient hospitalization or prolongation of existing hospitalization

A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life function

Congenital anomaly/birth defect
Important medical events that may not result in death, are life-threatening, or require 
hospitalization may be considered serious when, based upon appropriate medical judgment, they 
may jeopardize the patient or subject and may require medical or surgical intervention to prevent 

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one of the outcomes listed in this definition.  Examples of such medical events include allergic 
bronchospasm requiring intensive treatment in an emergency room or at home, blood dyscrasias 
or convulsions that do not result in inpatient hospitalization, or the development of drug 
dependency or drug abuse.
7.2.1.6
Life-threatening
An adverse event or suspected adverse reaction is considered life-threatening if, in the view of 
either the investigator or sponsor, its occurrence places the patient or subject at immediate risk of 
death. It does not include an adverse event or suspected adverse reaction that, had it occurred in a 
more severe form, might have caused death. 
7.2.2
Recording of an Adverse Event
All Grade 3 and above adverse events will be entered into OnCore®, whether or not the event is 
believed to be associated with use of the study drug.  Data about these events and their severity 
will be recorded using the NCI CTCAE v4.0.  
If there are specific data plans to this study, such as Grade 1 & 2 AEs are also being entered into 
OnCore, describe that process here.
The Investigator will assign attribution of the possible association of the event with use of the 
investigational drug, and this information will be entered into OnCore® using the classification 
system listed below: 
Relationship 
Attribution 
Description 
Unrelated
The AE is clearly NOT related to the 
intervention 
Unrelated to investigational 
drug/intervention
Unlikely
The AE is doubtfully related to the 
intervention 
Possible
The AE may be related to the intervention 
Probable
The AE is likely related to the intervention 
Related to investigational 
drug/intervention
Definite
The AE is clearly related to the intervention 
Signs or symptoms reported as adverse events will be graded and recorded by the Investigator 
according to the CTCAE.  When specific adverse events are not listed in the CTCAE they will be 
graded by the Investigator as none, mild, moderate or severe according to the following grades and 
definitions:

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Grade 0
No AE (or within normal limits)
Grade 1
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated
Grade 2
Moderate; minimal, local, or noninvasive intervention (e.g., packing, cautery) 
indicated; limiting age-appropriate instrumental activities of daily living (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
7.2.3
Follow-up of Adverse Events
All adverse events will be followed with appropriate medical management until resolved.  Patients 
removed from study for unacceptable adverse events will be followed until resolution or 
stabilization of the adverse event.  For selected adverse events for which administration of the 
investigational drug was stopped, a re-challenge of the subject with the investigational drug may 
be conducted if considered both safe and ethical by the Investigator.
7.2.4
Adverse Events Monitoring
All adverse events, whether or not unexpected, and whether or not considered to be associated 
with the use of the study drug, will be entered into OnCore®, as noted above.
The Investigator will assess all adverse events and determine reportability requirements to the 
UCSF Data and Safety Monitoring Committee (DSMC) and UCSF’s Institutional Review Board, 
the Institutional Review Board (IRB); and, when the study is conducted under an Investigational 
New Drug Application (IND), to the Food and Drug Administration (FDA) if it meets the FDA 
reporting criteria.
[The manufacturer and/or grant sponsor may also need to be notified, as applicable.]
All adverse events entered into OnCore® will be reviewed by the Helen Diller Family 
Comprehensive Cancer Center Site Committee on a weekly basis.  The Site Committee will review 
and discuss at each weekly meeting the selected toxicity, the toxicity grade, and the attribution of 
relationship of the adverse event to the administration of the study drug(s).
All grade(s) 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 
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In addition, all suspected adverse reactions considered “serious” entered into OnCore®, will be 
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.
For a detailed description of the Data and Safety Monitoring Plan for a Multicenter Phase 2 or 3 
Institutional Study at the Helen Diller Comprehensive Cancer Center please refer Appendix 4 
Multicenter Institutional Studies.
7.2.5
Expedited Reporting
Reporting to the Data and Safety Monitoring Committee
If a death occurs during the treatment phase of the study or within 30 days after the last 
administration of the study drug(s) and it is determined to be related either to the study drug(s) or 
to a study procedure, the Investigator or his/her designee must notify the DSMC Chair (or qualified 
alternate) within 1 business day of knowledge of the event.  The contact may be by phone or e-
mail.
Reporting to UCSF Institutional Review Board (IRB)
The Principal Investigator must report events meeting the UCSF IRB definition of “Unanticipated 
Problem” (UP) within 10 business days of his/her awareness of the event. 
Expedited Reporting to the Food and Drug Administration
If the study is being conducted under an IND, the Sponsor-Investigator is responsible for 
determining whether or not the suspected adverse reaction meets the criteria for expedited 
reporting in accordance with Federal Regulations (21 CFR §312.32). 
The Investigator must report in an IND safety report any suspected adverse reaction that is both 
serious and unexpected.  The Sponsor-Investigator needs to ensure that the event meets all three 
definitions: 

Suspected adverse reaction - A suspected adverse reaction is defined as any adverse event 
for which there is a reasonable possibility that the treatment or procedure caused the 
adverse event. For the purposes of IND safety reporting, “reasonable possibility” 
indicates that there is evidence to suggest a causal relationship between the treatment or 
procedure and the adverse event.  A suspected adverse reaction implies a lesser degree of 
certainty about causality than an adverse reaction.

Unexpected - An adverse event or suspected adverse reaction is considered unexpected if 
it is not listed in the investigator brochure or package insert(s), or is not listed at the 
specificity or severity that has been observed, or, if an investigator brochure is not 
required or available, is not consistent with the risk information described in the general 
investigational plan or elsewhere in the current application. 
“Unexpected,” as used in this definition, also refers to adverse events or suspected 
adverse reactions that are mentioned in the investigator brochure as occurring with a class 
of treatment or procedure or as anticipated from the pharmacological properties of the 
treatment or procedure, but are not specifically mentioned as occurring with the particular 
treatment or procedure under investigation.

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Adverse events that would be anticipated to occur as part of the disease process are 
considered unexpected for the purposes of reporting because they would not be listed in 
the investigator brochure.  For example, a certain number of non-acute deaths in a cancer 
trial would be anticipated as an outcome of the underlying disease, but such deaths would 
generally not be listed as a suspected adverse reaction in the investigator brochure.
Some adverse events are listed in the Investigator’s Brochure as occurring with the same 
class of treatment, or as anticipated from the pharmacological properties of the drug, even 
though they have not been observed with the drug under investigation.  Such events 
would be considered unexpected until they have been observed with the drug under 
investigation. For example, although angioedema is anticipated to occur in some patients 
exposed to drugs in the ACE inhibitor class and angioedema would be described in the 
investigator brochure as a class effect, the first case of angioedema observed with the 
drug under investigation should be considered unexpected for reporting purposes.

Serious - An adverse event or suspected adverse reaction is considered serious if, in the 
view of either the investigator or sponsor, it results in any of the following outcomes: 
Death
Life-threatening adverse event
Inpatient hospitalization or prolongation of existing hospitalization
A persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life function
Congenital anomaly/birth defect
Important medical events that may not result in death, are life-threatening, or require 
hospitalization may be considered serious when, based upon appropriate medical judgment, they 
may jeopardize the patient or subject and may require medical or surgical intervention to prevent 
one of the outcomes listed in this definition.  Examples of such medical events include allergic 
bronchospasm requiring intensive treatment in an emergency room or at home, blood dyscrasias 
or convulsions that do not result in inpatient hospitalization, or the development of drug 
dependency or drug abuse.
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)). 

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Expedited Reporting to Merck.
Investigators must report all SAEs to Merck within 24 hours of becoming aware of the event.
7.2.5.1
Pembrolizumab overdose
For purposes of this trial, an overdose of pembrolizumab will be defined as any dose of 1,000 mg 
or greater (≥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 Event of Clinical Interest (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 hours to the 
Sponsor and within 2 working days hours to Merck Global Safety. 
 
7.2.5.2
Reporting of Pregnancy and Lactation to the Sponsor and to Merck
Although pregnancy and infant exposure during breast feeding are not considered adverse events, 
it is the responsibility of investigators or their designees to report any pregnancy or lactation in a 
participant (spontaneously reported to them) that occurs during the study.
Pregnancies and infant exposures during breastfeeding that occur after the consent form is signed 
but before treatment must be reported by the investigator if they cause the participant to be 
excluded from the trial, or are the result of a protocol-specified intervention, including but not 
limited to washout or discontinuation of usual therapy, diet, placebo treatment or a procedure. 
Pregnancies and infant exposures during breastfeeding that occur from the time of treatment 
through 120 days following cessation of Sponsor’s product, or 30 days following cessation of 
treatment if the participant initiates new anticancer therapy, whichever is earlier, must be reported 
by the investigator.  All reported pregnancies 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 hours to the Sponsor and within 2 working days 
 
7.2.5.3
Immediate Reporting of Adverse Events to the Sponsor and to Merck
7.2.5.4
Serious Adverse Events
A serious adverse event is any adverse event occurring at any dose or during any use of Merck’s 
product 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 any other important medical event 

Note: In addition to the above criteria, adverse events meeting either of the below criteria, 
although not serious per ICH definition, are reportable to the Merck in the same timeframe 
as SAEs to meet certain local requirements. Therefore, these events are considered serious 
by Merck for collection purposes.

Is a new cancer (that is not a condition of the study);

Is associated with an overdose;
Refer to Table 7 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 Merck product, must be reported 
within 24 hours to the Sponsor and within 2 working days to Merck Global Safety. 
Non-serious Events of Clinical Interest will be forwarded to Merck Global Safety and will be handled 
in the same manner as SAEs. 
Additionally, any serious adverse event, considered by an investigator who is a qualified physician 
to be related to Merck product 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 
Sponsor and to Merck.
SAE reports and any other relevant safety information are to be forwarded to the Merck Global 
Safety facsimile number:  +1-215-661-6229
A copy of all 15 Day Reports and Annual Progress Reports is submitted as required by FDA, 
European Union (EU), Pharmaceutical and Medical Devices agency (PMDA) or other local 

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regulators. Investigators will cross reference this submission according to local regulations to the 
Merck Investigational Compound Number (IND, CSA, etc.) at the time of submission.  
Additionally investigators will submit a copy of these reports to Merck & Co., Inc. 
 
 at the time of submission to FDA.
All subjects with serious adverse events must be followed up for outcome.
7.2.5.5
Events of Clinical Interest
Selected non-serious and serious adverse events are also known as Events of Clinical Interest (ECI) 
and must be recorded as such on the Adverse Event case report forms/worksheets and reported 
within 24 hours to the Sponsor and within 2 working days to Merck Global Safety. 
 
 
For the time period beginning when the consent form is signed until treatment, any ECI, or follow 
up to an ECI, that occurs to any participant must be reported within 2 working days to Merck 
Global Safety if it causes the participant to be excluded from the trial, or is the result of a protocol-
specified intervention, including but not limited to washout or discontinuation of usual therapy, 
diet, placebo treatment or a procedure.
For the time period beginning at treatment through 90 days following cessation of treatment, or 30 
days following cessation of treatment if the participant initiates new anticancer therapy, whichever 
is earlier, any ECI, or follow up to an ECI, whether or not related to Merck product, must be 
reported within 2 working days to Merck Global Safety.
Events of clinical interest for this trial include:
1.  an overdose of Merck product, as defined in Section 7.2.5.1 - Definition of an Overdose for 
This Protocol and Reporting of Overdose to the Sponsor, that is not associated with clinical 
symptoms or abnormal laboratory results. 
2.  an elevated AST or ALT lab value that is greater than or equal to 3X the upper limit of normal 
and an elevated total bilirubin lab value that is greater than or equal to 2X the upper limit of normal 
and, at the same time, an alkaline phosphatase lab value that is less than 2X the upper limit of 
normal, as determined by way of protocol-specified laboratory testing or unscheduled laboratory 
testing.*
*Note:  These criteria are based upon available regulatory guidance documents. The purpose 
of the criteria is to specify a threshold of abnormal hepatic tests that may require an additional 
evaluation for an underlying etiology.  The trial site guidance for assessment and follow up of 
these criteria can be found in the Investigator Trial File Binder (or equivalent).

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7.2.6
Evaluating Adverse Events
An investigator who is a qualified physician 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 7. Evaluating Adverse Events
An investigator who is a qualified physician, will evaluate all adverse events as to:
V4.0 
CTCAE 
Grading
Grade 1
Mild; asymptomatic or mid 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 or 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 event of 
clinical interest 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. 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 
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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7.2.7
Sponsor Responsibility for Reporting Adverse Events
All Adverse Events will be reported to regulatory authorities, IRB/IECs and investigators in 
accordance with all applicable global laws and regulations. 
8.0 STATISTICAL ANALYSIS PLAN
8.1  Analysis of primary endpoints (dose escalation cohort)
The primary endpoint of this study is the MTD of two intralesional injections of pembrolizumab in 
patients with DCIS.  The primary safety endpoint is DLT.  The MTD is defined as the dose at which no 
more than 1/6 patients experience a DLT.  Safety and tolerability will also be assessed by clinical 
review of all relevant parameters including adverse events (AEs), laboratory tests, and physical exam. 
Adverse events will be summarized as counts and frequencies for each dose level.  Other safety 
endpoints will be summarized as appropriate. These data are descriptive in nature and statistical 
analysis tools will not be required.  The recommended expansion dose will be explored in an 
additional cohort of 30 patients with DCIS (20 to receive pembrolizumab and 10 untreated control 
subjects). 
8.1.2 Analysis of primary endpoint (dose expansion cohort)
The secondary endpoint (dose expansion cohort) is the response rate to intralesional pembrolizumab 
as measured by an increase in intralesional CD8+ T cells.  For this study, we will define a responder 
to pembrolizumab as demonstrating a >= 50% increase (baseline to surgical sample) of intralesional 
CD8+ T cells.  In a recent study in melanoma, 44% of patients treated with pembrolizumab 
demonstrated a >=50% increase in intratumoral CD8+ T cells (Tumeh et al., 2014). Point estimate 
of the response rate and its 95% confidence interval will be obtained by arm, and two-sample 
proportion test will be used to test if the response rate is different between the two arms.  For the 
expansion cohort, a sample size of 30 patients (2:1 – treatment:control) will have 80% power, with 
an alpha of 0.05, to detect a 44% or greater response rate in the treatment arm compared to the control 
arm. 
8.2  Accrual objectives
A 3x3 dose escalation design will be followed, so sample size will be between 12 and 18 for this 
phase.  The expansion cohort will consist of 30 additional patients with DCIS.  We anticipate accruing 
2-3 patients per month and estimate that it will require approximately 16-20 months to complete the 
study.
8.3  Stratification factors

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There are no planned patient stratification factors.
9.0 LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL SUPPLIES
9.1
Investigational Product 
The investigator shall take responsibility for and shall take all steps to maintain appropriate records 
and ensure appropriate supply, storage, handling, distribution and usage of investigational product in 
accordance with the protocol and any applicable laws and regulations.
Clinical Supplies will be provided by Merck as summarized in Table 8.
Table 8.  Product Descriptions
Product Name & Potency
Dosage Form
Pembrolizumab 50 mg
Lyophilized Powder for Injection
Pembrolizumab 100 mg/ 4mL
Solution for Injection
9.2
Packaging and Labeling Information
9.3
Clinical Supplies Disclosure
This trial is open-label; therefore, the subject, the trial site personnel, the Sponsor and/or designee 
are not blinded to treatment. Drug identity (name, strength) is included in the label text; random 
code/disclosure envelopes or lists are not provided.
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 at the trial site.
Clinical supplies may not be used for any purpose other than that stated in the protocol.

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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. 
Upon completion or termination of the study, all unused and/or partially used investigational 
product will be destroyed at the site per institutional policy. It is the Investigator’s responsibility to 
arrange for disposal of all empty containers, provided that procedures for proper disposal have 
been established according to applicable federal, state, local and institutional guidelines and 
procedures, and provided that appropriate records of disposal are kept.
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 Investigator will have written and dated approval from the Institutional 
Review Board 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. 
The Investigator 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 Institutional Review Board (IRB).  Prior to obtaining IRB approval, the protocol must be 
approved by the Helen Diller Family Comprehensive Cancer Center 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.  

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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.  
The Study Chair and the UCSF study team will be responsible for updating any participating sites.
10.5 Handling and Documentation of Clinical Supplies
The UCSF Principal Investigator and each participating site 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 sponsor-investigator will maintain 
written records of any disposition of the study drug.
The Principal Investigator shall not make the investigational drug available to any individuals other 
than to qualified study patients.  Furthermore, the Principal Investigator 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 Principal Investigator and/or his/her designee 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, 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. 

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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.
In accordance with federal regulations, the Investigator is responsible for the accuracy and 
authenticity of all clinical and laboratory data entered onto CRFs.  The PI 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 Principal Investigator 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 12.4 Data and Safety 
Monitoring Plan for a Phase 1/2 Institutional Study, for additional information.
10.8 Regulatory Documentation
Prior to implementing this protocol at UCSF HDFCCC, the protocol, informed consent form, HIPAA 
authorization and any other information pertaining to participants must be approved by the UCSF 
Institutional Review Board (IRB). Prior to implementing this protocol at the participating sites, 
approval for the UCSF IRB approved protocol must be obtained from the participating site’s IRB. 
The following documents must be provided to UCSF HDFCCC before the participating site can be 
initiated and begin enrolling participants: 

Participating Site IRB approval(s) for the protocol, appendices, informed consent form and 
HIPAA authorization 

Participating Site IRB approved consent form 

Participating Site IRB membership list 

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
Participating Site IRB membership list  form ce number and OHRP Registration number 

Curriculum vitae and medical license for each investigator and consenting professional 

Documentation of Human Subject Research Certification training for investigators and key 
staff members at the Participating Site 

Participating site laboratory certifications and normals 
Upon receipt of the required documents, UCSF HDFCCC will formally contact the site and grant 
permission to proceed with enrollment.
10.9 Protection of Human Subjects
10.9.1  Protection from Unnecessary Harm
Each clinical site is responsible for protecting all subjects involved in human experimentation. This 
is accomplished through the IRB mechanism and the process of informed consent. The IRB reviews 
all proposed studies involving human experimentation and ensures that the subject’s rights and 
welfare are protected and that the potential benefits and/or the importance of the knowledge to be 
gained outweigh the risks to the individual. The IRB also reviews the informed consent document 
associated with each study in order to ensure that the consent document accurately and clearly 
communicates the nature of the research to be done and its associated risks and benefits.
10.9.2  Protection of Privacy
Patients will be informed of the extent to which their confidential health information generated from 
this study may be used for research purposes. Following this discussion, they will be asked to sign 
the HIPAA form and informed consent documents. The original signed document will become part 
of the patient’s medical records, and each patient will receive a copy of the signed document. The 
use and disclosure of protected health information will be limited to the individuals described in the 
informed consent document.

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11.0 REFERENCES
1. Silverstein, M. J. The University of Southern California/Van Nuys prognostic index for ductal carcinoma in situ of 
the breast. Am J Surg. 2003; 186(4): 337-343. 
2.  Wai, E. S., Lesperance, M. L., Alexander, C. S., Truong, P. T., Moccia, P., Culp, M., . . . Olivotto, I. A. Predictors 
of local recurrence in a population-based cohort of women with ductal carcinoma in situ treated with breast 
conserving surgery alone. Ann Surg Oncol. 2011; 18(1): 119-124. doi: 10.1245/s10434-010-1214-x
3.  Wang, S. Y., Shamliyan, T., Virnig, B. A., & Kane, R. Tumor characteristics as predictors of local recurrence after 
treatment of ductal carcinoma in situ: a meta-analysis. Breast Cancer Res Treat. 2011; 127(1): 1-14. doi: 
10.1007/s10549-011-1387-4
4.  Campbell MJ, Tonlaar NY, Garwood ER, Huo D, Moore DH, Khramtsov AI, Au A, Baehner F, Chen Y, Malaka 
DO, Lin A, Adeyanju OO, Li S, Gong C, McGrath M, Olopade OI, Esserman LJ.  Proliferating macrophages 
associated with high grade, hormone receptor negative breast cancer and poor clinical outcome.  Breast Cancer 
Res Treat. 2011 Aug;128(3):703-11.
5.  Mukhtar RA, Moore AP, Tandon VJ, Nseyo O, Twomey P, Adisa CA, Eleweke N, Au A, Baehner FL, Moore DH, 
McGrath MS, Olopade OI, Gray JW, Campbell MJ, Esserman LJ.  Elevated levels of proliferating and 
recently migrated tumor-associated macrophages confer increased aggressiveness and worse outcomes in 
breast cancer.  Ann Surg Oncol. 2012 Nov;19(12):3979-86. 
6.  Obeid E, Nanda R, Fu YX, Olopade OI.  The role of tumor-associated macrophages in breast cancer progression 
(review).  Int J Oncol. 2013 Jul;43(1):5-12. 
7.  de la Cruz-Merino L, Barco-Sánchez A, Henao Carrasco F, Nogales Fernández E, Vallejo Benítez A, Brugal Molina 
J, Martínez Peinado A, Grueso López A, Ruiz Borrego M, Codes Manuel de Villena M, Sánchez-Margalet V, 
Nieto-García A, Alba Conejo E, Casares Lagar N, Ibáñez Martínez J.  New insights into the role of the 
immune microenvironment in breast carcinoma.  Clin Dev Immunol. 2013;  Epub 2013 Jun 3.
8.  Campbell MJ, Wolf D, Mukhtar RA, Tandon V, Yau C, Au A, Baehner F, van't Veer L, Berry D, Esserman LJ.  The 
prognostic implications of macrophages expressing proliferating cell nuclear antigen in breast cancer depend 
on immune context.  PLoS One. 2013 Oct 29;8(10):e79114.
9.   Hussein MR, Hassan HI. Analysis of the mononuclear inflammatory cell infiltrate in the normal breast, benign 
proliferative breast disease, in situ and infiltrating ductal breast carcinomas: preliminary observations.  J Clin 
Pathol. 2006 Sep;59(9):972-7.
10.  Esserman LJ, Kumar AS, Herrera AF, Leung J, Au A, Chen YY, Moore DH, Chen DF, Hellawell J, Wolverton D, 
Hwang ES, Hylton NM.  Magnetic resonance imaging captures the biology of ductal carcinoma in situ.  J Clin 
Oncol. 2006 Oct 1;24(28):4603
11.  Sharma M, Beck AH, Webster JA, Espinosa I, Montgomery K, Varma S, van de Rijn M, Jensen KC, West RB.  
Analysis of stromal signatures in the tumor microenvironment of ductal carcinoma in situ.  Breast Cancer Res 
Treat. 2010 Sep;123(2):397-404.
12.  Marabelle A, Kohrt H, Sagiv-Barfi I, Ajami B, Axtell RC, Zhou G, Rajapaksa R, Green MR, Torchia J, Brody J, 
Luong R, Rosenblum MD, Steinman L, Levitsky HI, Tse V, Levy R.  Depleting tumor-specific Tregs at a 
single site eradicates disseminated tumors.  J Clin Invest. 2013 Jun;123(6):2447-63.
13. Asís Palazón, Iván Martínez-Forero, Alvaro Teijeira, et al.   The HIF-1α Hypoxia Response in Tumor-Infiltrating T 
Lymphocytes Induces Functional CD137 (4-1BB) for Immunotherapy.  Cancer Discovery 2012;2:608-623.
14. Van De Voort TJ, Felder MA, Yang RK, Sondel PM, Rakhmilevich AL.  Intratumoral delivery of low doses of 
anti-CD40 mAb combined with monophosphoryl lipid a induces local and systemic antitumor effects in 
immunocompetent and T cell-deficient mice.  J Immunother. 2013; 36(1):29-40.
15. Sandin LC, Eriksson F, Ellmark P, Loskog AS, Tötterman TH, Mangsbo SM.  Local CTLA4 blockade effectively 
restrains experimental pancreatic adenocarcinoma growth in vivo.  Oncoimmunology. 2014;3(1):e27614.
16.  Dai M, Yip YY, Hellstrom I, Hellstrom KE.  Curing mice with large tumors by locally delivering combinations of 
immunomodulatory antibodies.  Clin Cancer Res. 2015;21(5):1127-38.
17.  Tumeh PC, Harview CL, Yearley JH, Shintaku IP, Taylor EJ, Robert L, Chmielowski B, Spasic M, Henry G, 
Ciobanu V, West AN, Carmona M, Kivork C, Seja E, Cherry G, Gutierrez AJ, Grogan TR, Mateus C, 

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Tomasic G, Glaspy JA, Emerson RO, Robins H, Pierce RH, Elashoff DA, Robert C, Ribas A.  PD-1 blockade 
induces responses by inhibiting adaptive immune resistance.  Nature. 2014;515(7528):568-71.

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12.0 APPENDICES
12.1
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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12.1.1 Contraceptive Guidance and Pregnancy Testing
Woman of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming post-menopausal unless 
permanently sterile (see below) 
Women in the following categories are not considered WOCBP:
●
Premenarchal
●
Premenopausal female with 1 of the following:
○
Documented hysterectomy
○
Documented bilateral salpingectomy
○
Documented bilateral oophorectomy
Note:  Documentation can come from the site personnel’s review of the participant’s medical 
records, medical examination, or medical history interview.
●
Postmenopausal female
○
A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. 
▪
A high follicle stimulating hormone (FSH) level in the postmenopausal range may be 
used to confirm a postmenopausal state in women not using hormonal contraception or 
hormonal replacement therapy (HRT). However, in the absence of 12 months of 
amenorrhea, confirmation with two FSH measurements in the postmenopausal range is 
required. 
○
Females on HRT and whose menopausal status is in doubt will be required to use one of the 
non-hormonal highly effective contraception methods if they wish to continue their HRT 
during the study. Otherwise, they must discontinue HRT to allow confirmation of 
postmenopausal status before study enrollment.

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Contraception Requirements
Female Participants:
Female participants of childbearing potential are eligible to participate if they agree to use a highly 
effective method of contraception consistently and correctly as described in Table 9 during the 
protocol-defined time frame in Section 5.1.2.
Male Participants:
Male participants with female partners of childbearing potential are eligible to participate if they 
agree to one of the following during the protocol defined time frame in section 5.1.2: 
●
Be abstinent from penile-vaginal intercourse as their usual and preferred lifestyle (abstinent on 
a long term and persistent basis) and agree to remain abstinent
●
Use a male condom plus partner use of a contraceptive method with a failure rate of <1% per 
year as described in Table 9 when having penile-vaginal intercourse with a woman of 
childbearing potential who is not currently pregnant.
○
Note: Men with a pregnant or breastfeeding partner must agree to remain abstinent from 
penile-vaginal intercourse or use a male condom during each episode of penile penetration.
Pregnancy Testing
WOCBP should only be included after a negative highly sensitive urine or serum pregnancy test 
and in accordance with local requirements.  This test should be repeated a maximum of 72-hours 
before each dose.

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Table 9. Highly Effective Contraception Methods
Highly Effective Contraceptive Methods That Are User Dependent a 
Failure rate of <1% per year when used consistently and correctly.
●
Combined (estrogen- and progestogen- containing ) hormonal contraception b, c
○
Oral 
○
Intravaginal 
○
Transdermal 
○
Injectable
●
Progestogen-only hormonal contraception b, c
○
Oral 
○
Injectable 
Highly Effective Methods That Have Low User Dependency 
Failure rate of <1% per year when used consistently and correctly.
●
Progestogen- only contraceptive implant b, c 
●
Intrauterine hormone-releasing system (IUS) b 
●
Intrauterine device (IUD)
●
Bilateral tubal occlusion
●
Vasectomized partner 
A vasectomized partner is a highly effective contraception method provided that the partner is the sole 
male sexual partner of the WOCBP and the absence of sperm has been confirmed. If not, an additional 
highly effective method of contraception should be used. 
●
Sexual abstinence 
Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study treatment. The 
reliability of sexual abstinence needs to be evaluated in relation to the duration of the study and the 
preferred and usual lifestyle of the participant.) 
Notes: 
Use should be consistent with local regulations regarding the use of contraceptive methods for 
participants of clinical studies. 
a) Typical use failure rates are lower than perfect-use failure rates (i.e. when used consistently and 
correctly). 
b) If locally required, in accordance with Clinical Trial Facilitation Group (CTFG) guidelines, 
acceptable hormonal contraceptives are limited to those which inhibit ovulation. 

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12.2
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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12.3
 UCSF Policy/Procedure for required regulatory documents for single site and 
multicenter investigator-initiated oncology clinical trials
Purpose
This policy defines the required Regulatory Documents for Single Site and Multicenter Investigator 
Initiated Oncology Clinical Trials at the Helen Diller Family Comprehensive Cancer Center 
(HDFCCC) for both IND and IND-exempt trials.
Background
The International Conference on Harmonization (ICH) Good Clinical Practices (GCP) Guidelines 
define Essential Regulatory Documents as those documents which individually and collectively 
permit evaluation of the conduct of a trial and the quality of data produced. These documents serve 
to demonstrate compliance with standards of GCP and with all applicable regulatory requirements. 
Filing essential documents in a timely manner can greatly assist in the successful management of a 
clinical trial.
The Regulatory Documents will consist of electronic files in both iRIS and OnCore®, as well as paper 
files in the Regulatory Binders for both the Coordinating Site and the Participating Site(s) in the 
HDFCCC Investigator Initiated Oncology Clinical Trials.
Procedures
1.   Single Site (HDFCCC) Therapeutic Essential Regulatory Documents:
Documents Filed in iRIS:

Current and prior versions of the Informed Consent Form(s) (ICFs).

 IRB approvals for initial submission of application, all modifications, and continuing 
annual renewals.

Current and prior approved protocol versions.

IRB roster

Current and prior versions of the Investigator Brochure (IB).

Serious Adverse Event (SAE) Reports.

Subject diary and handouts (if applicable).

Single Patient Exception (SPE) Report(s) to  IRB with Approval Letter(s) from IRB.

Protocol Violation (PV) Reports with acknowledgement from the  IRB.
Documents Filed in OnCore®:

Package Insert (if the study drug is commercial).

Protocol signature page(s) with Pl signature(s) for all protocol versions.

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
Protocol Review Committee (PRC) approved protocols, protocol amendments and 
Summary of Changes (SOC) document.

Screening/enrollment log.

Data and Safety Monitoring Committee (DSMC) monitoring reports.

DSMC dose escalation approvals with study status summary forms.

Case Report Form (CRF) completion manual.

Drug Destruction Standard Operating Procedure (SOP).

Completed Food and Drug Administration (FDA) 1572 document with Principal 
Investigator's signature.

For all Principal Investigators and Sub-Investigators listed on the FDA 1572, will need 
Financial Disclosure Forms, CVs, MD Licenses, and Staff Training Documents (i.e., 
Collaborative Institute Training Initiative (CITI), etc.).

As applicable, approvals for Biosafety Committee, Radiation Committee, and Infusion 
Center.

Serious Adverse Event (SAE) reports to IRB and sponsor.

MedWatch reporting to FDA and sponsor.

Drug Destruction Standard Operating Procedure (SOP).

For all laboratories listed on the FDA 1572, will need CUA certifications, CAP 
certifications, lab licenses, CV(s) and Medical License(s) of Lab Director(s), and laboratory 
reference ranges.
Documents Filed in Regulatory Binder:

Delegation of Authority Log with signatures (to be scanned in OnCore once the trial is 
complete).
2. Additional Essential Documents for Therapeutic Multicenter Trials for the
Coordinating Center (filed in OnCore or Zip Drive):
•
Institutional Review Board (IRB) approval letters, IRB roster, Informed Consent Form 
(ICF), and Health Insurance Portability and Accountability Act {HIPAA) Consent Form for 
the Participating Site(s).
•
For all Principal Investigators and Sub-Investigators listed on the 1572 at the Participating 
Site(s), will need Financial Disclosure Forms, CVs, MD Licenses, and Staff Training 
documents (i.e. Collaborative Institute Training Initiative (CITI), etc.) (for investigational 
New Drug Application).
•
Site Initiation Visit (SIV) minutes and correspondence with the Participating Site(s).
•
As applicable, approvals for Biosafety Committee, Radiation Committee, and Infusion 
Center for the Participating Site(s).

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•
Protocol Violations (PV) Reports to IRB with acknowledgement from IRB for Participating 
Site(s).
•
Single Patient Exception (SPE) Reports to IRB with IRB Approval Letters for Participating 
Site(s).
•
Drug Destruction Standard Operating Procedure (SOP) for the Participating Site(s). 
•
Data and Safety Monitoring Committee (DSMC) monitoring reports for the Participating 
Site(s).
•
For all laboratories listed on FDA 1572, will need CUA certifications, CAP certifications, 
lab licenses, CVs and Medical License(s) of Lab Director(s), and laboratory reference 
ranges for the Participating Site(s).
•
Copy of the Data and Safety Monitoring Plan (DSMP) Monitoring Plan for all participating 
site(s) in Multicenter studies or Contract Research Organization (CRO) Monitoring Plan (if 
an outside CRO is used for the study).
•
Serious Adverse Event (SAE) forms submitted to the IRB for the Participating Site(s).
3. Required Multicenter Essential Regulatory Document Checklist for Therapeutic
and Non-Therapeutic Trials (For Start-Up Only):
•
See attached checklist(s).
4. Required Essential Regulatory Documents for Single Site and Multicenter
Therapeutic IND-Exempt Studies (filed in OnCore):
•
For IND Exempt studies, the Essential Regulatory Documents for UCSF would include all 
documents in Section #1 of this policy. The Essential Regulatory Documents from the 
participating site(s) for Multicenter Trials when UCSF is the Coordinating Center would 
only include the signed protocol signature page, CV of the Pl, and the IRB approval letters. 
All other documents in Section #2 of this policy would be the responsibility of the 
Participating Site(s).
5. Required Essential Regulatory Documents for Single Site Non-Therapeutic
Studies (filed in OnCore):
•
For Single Site non-therapeutic trials, all Regulatory Documents in Section #1 of this policy 
are required except for: current and prior versions of the Investigator Brochure (IB), 
package insert (if the study drug is commercial), DSMC dose escalation approvals with 
study status summary forms, approvals for Biosafety Committee, Radiation Committee, and 
Infusion Center, and drug destruction SOPs.
6. Required Essential Regulatory Documents for Multicenter Non-Therapeutic
Studies (filed in OnCore):

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•
For Multicenter non-therapeutic trials with UCSF as the Coordinating Site, all required 
Regulatory Documents listed above in Section #5 for Single Site non-therapeutic trials are 
required for the Coordinating Site. The only required Regulatory Documents from the 
Participating Site(s) will be: IRB approval letters, IRB roster, and ICF and HIPAA consent 
forms, the Delegation of Authority Log (with NIH or CITI human subject protection 
training certificates or GCP training certification), Protocol Violations and Single Patient 
Exception (SPE) reports to the IRB with supporting fax documentation (if applicable), 
Serious Adverse Event (SAE) forms submitted to both the IRB and the sponsor, and the 
Data and Safety Monitoring Committee (DSMC) monitoring reports for the Participating 
Site(s). If applicable, a copy of the Data and Safety Monitoring Plan (DSMP) Monitoring 
Plan for all participating site(s) in Multicenter studies or Contract Research Organization 
(CRO) Monitoring Plan (if an outside CRO is used for the study) will be required.
Alternate Procedures
There are no alternate procedures to the HDFCCC policy for requirements for Essential Regulatory 
Documents for Multicenter Investigator-Initiated Oncology Clinical Trials.
References
•
ICH Guidance for Industry: E6 Good Clinical Practice: Consolidated Guidance (current 
version).
•
International Conference on Harmonization: Good Clinical Practice: Consolidated 
Guideline (current version).
•
International Conference on Harmonization: Essential Documents for the Conduct of a 
Clinical Trial (current version).
•
21CFR50
•
21 CFR56.11
•
45CFR46
•
21 CFR312
Required Regulatory Documents for Sub-sites Participating in Therapeutic UCSF Investigator 
Initiated Multicenter trial 
Directions: Scan the documents in a zip drive and upload to OnCore.
1572
  PI and Sub investigators:

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
CV and Medical license 

Financial disclosure form

NIH or CITI human subject protection training certification
  Laboratories:  

CLIA &CAP and Lab Licenses

CV and Medical License of Lab Director

Laboratory reference ranges
Local Institutional Review Board 
  IRB Approval letter
  Reviewed/Approved documents

Protocol version date:  
___________

Informed consent version date:  ___________

Investigator Brochure version date:  ___________

HIPAA
  Current IRB Roster
Other 
  Delegation of Authority Log 

Include NIH or CITI human subject protection training certificates or GCP training 
certification
  Pharmacy

Drug destruction SOP and Policy
  Protocol signature page 
  Executed sub contract

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12.4
 Data and Safety Monitoring Plan for a Phase 1/2 Institutional Study
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 subject data in each cohort for the Phase 1 portion of trial
•
Review of suspected adverse reactions considered “serious”
•
During the Phase 1 portion of trial, approval of dose escalation by DSMC Chair (or 
qualified alternate)
•
Monthly monitoring (depending on study accrual) for the Phase 1 portion of trial and 
biannual monitoring for the Phase 2 portion of trial.
•
Minimum of a yearly regulatory audit
Monitoring and Reporting Guidelines
Investigators will conduct continuous review of data and subject safety and discuss each subject’s 
treatment at weekly Site Committee meetings. The discussions are documented in the Site 
Committee meeting minutes. For each dose level, the discussion will include the number of 
subjects, significant toxicities in accordance with the protocol, doses adjustments, and observed 
responses.

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All institutional Phase 1/2 therapeutic studies are designated with moderate to high-risk 
assessment; therefore, during the Phase 1 portion of trial, the data is monitored once per month, 
as subjects are enrolled, through the DLT period and, during the Phase 2 portion of the trial, the 
data is monitored twice per year, with twenty percent of the subjects monitored (or at least three 
subjects if the calculated value is less than three).
Adverse Event Review and Monitoring
During Phase 1:
All clinically significant adverse events, whether or not 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.
All clinically significant adverse events entered into OnCore® will be reviewed on a weekly 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).
In addition, all suspected adverse reactions considered “serious” are entered into OnCore® and 
will be reviewed and monitored by the Data and Safety Monitoring Committee on an ongoing 
basis and discussed at the DSMC meetings, which take place every six (6) weeks.
If a death occurs during the treatment phase of the study or within 30 days after the last 
administration of the study drug(s) and is determined to be related either to the study drug(s) or to 
a study procedure, the Investigator or his/her designee must notify the DSMC Chair or his 
qualified alternate within 1 business day of knowledge of this event. The contact may be by 
phone or e-mail.
Dose Escalations (During Phase 1)
At the time of dose escalation, a written report will be submitted to the DSMC Chair (or qualified 
alternate) describing the cohorts, dose levels, adverse events, safety reports, and any Dose 
Limiting Toxicities observed, in accordance with the protocol. The report will be reviewed by the 
DSMC Chair (or qualified alternate) and written authorization to proceed or a request for more 
information will be issued within 2 business days of the request.  Approval for dose escalation by 
the DSMC (or qualified alternate) must be obtained prior to implementation.
Increase in 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, a report should be submitted to 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.

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If at any time the Investigator stops enrollment or stops the study due to safety issues, the DSMC 
Chair and DSMC Manager must be notified within 1 business day via e-mail.
The DSMC must receive a formal letter within 10 business days and the CHR must be notified.
 
 
 
*  DSMP approved by NCI 09/February2012
12.5 EVENT OF CLINICAL INTEREST GUIDANCE DOCUMENT (V3.0)
REVISION HISTORY LOG
Version
Effective
Date*
Revision
Author
Action
1
08-Aug-2012
Kevin Gergich
Initial Release of guidance document for MK-3475

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2
07-June-2013
Marty Huber,
Kevin Gergich, 
Holly Brown
Revised title, formerly was “MK-3475 Immune-Related
Adverse Event Identification, Evaluation and Management
Guidance Document for Investigators”
Revised the format of irAE Guidance document, including 
layout, font, sectioning, etc. for consistency with Sponsor 
Events of Clinical Interest guidance documents.
Modified Categories for irAEs:
–
Replaced GI with Colitis category.
–
Removed Neurologic category.
–
Added Renal category.
Removed detail in the irAE Guidance document that can 
be located in the Investigator’s Brochure for MK-3475.
Removed details regarding non-MK-3475 compounds. 
Added ECI reporting guidelines.
Included a Table Events of Clinical Interest: Immune- 
Related Adverse Events that includes the key terms.
–
Also placed a pull-out quick-review sheet in the
Appendix.
Updated background, diagnosis and course of treatment 
details for irAEs.
3
Marty Huber, 
Kevin Gergich,
Holly Brown
Renamed the document: “Pembrolizumab Program (MK-
3475) - Events of Clinical Interest Guidance Document”.
Introduced generic name: pembrolizumab (MK-3475) and 
inserted throughout the document.
Updated Overview – Section 1
- Clarified the scope of the document and the reporting 
window for ECIs
- Updated Table 1 with medDRA Preferred Terms for 
adverse events to correspond with reporting of terms to 
clinical database, rearranged the order, and updated the 
reporting criteria.
-  Updated the dose modification/discontinuation section to 
clarify discontinuation and hold terminology.
Updated Section 2 – ECI Reporting Guidelines

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– Clarified that ECIs must be reported to Merck within 24
hours regardless of attribution to study treatment or 
etiology.
Updated Section 3
–   For All Sections, removed the Course of Action for
Grade 1 events.
-   Section 3.1 Pneumonitis
–
Moved Pneumonitis to beginning of ECI Section
–
Updated management guidelines for Grade 2 and
Grade 3-4 events
-
Section 3.2 Colitis:
-
Updated AE terms and ECI criteria, updated 
course of action language for clarity
- Section 3.3 Endocrine:
-
Updated ECI criteria and updated course of action 
language for clarity.
-
Added 
subsections 
for 
hypophysitis, 
hyperthyroidism and hypothyroidism to clarify 
management guidelines.
- Section 3.4 Hematologic:
-
New section added.
- Section 3.5: Hepatic:
-
Updated terms and added additional guidance for 
reporting of DILI ECI; updated course of action 
for clarity
- Section 3.6 Neurologic:
-
New section added.
- Section 3.7 Ocular:
-
Changed the name of this section from Eye to
Ocular
-
Added the term “iritis”, updated ECI guidance, 
and updated course of action language for clarity
- Section 3.8 Renal:
-
Updated section for clarity.
- Section 3.9 Skin:
-
Updated list of terms and added terms for 
reporting of other skin ECIs; added section 3.9.1: 
Immediate Evaluation for Potential Skin ECIs
- Section 3.10 Other:
-
Updated list of terms for clarity; revised course of 
action for clarity.

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- Section 3.11 Infusion Reactions:
-
New section added.
- Section 3.12: Follow-up to Resolution:
-
New section added.
- Section 4:
-
References updated.
- Section 5:
-
ECI table updated for consistency with Table 1.
- Section 6: Appendix 2 – Past Medical History Related to
Dermatologic Event:  New section added.
- Section 7: Appendix 3 – Presentation of the
Dermatologic Event:  New section added.
- Section 8: Appendix 4 – Focused Skin Examination: 
New section added.
*Ensure that you are using the most current version of this document.

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TABLE OF CONTENTS
1. OVERVIEW ............................................................................................................................... 6
2. ECI REPORTING GUIDELINES .............................................................................................. 8
3. ECI CATEGORIES AND TERMS ............................................................................................ 8
3.1 Pneumonitis .......................................................................................................................... 9
3.2 Colitis .................................................................................................................................. 11
3.3 Endocrine ............................................................................................................................ 13
3.4 Hematologic ........................................................................................................................ 15
3.5 Hepatic ................................................................................................................................ 16
3.6 Neurologic........................................................................................................................... 18
3.7 Ocular.................................................................................................................................. 19
3.8 Renal ................................................................................................................................... 20
3.9 Skin ..................................................................................................................................... 21
3.9.1. Immediate Evaluation for Potential Skin ECIs ........................................................... 22
3.10 Other ................................................................................................................................. 24
3.11 Infusion Reactions ............................................................................................................ 25
3.12 Follow-up to Resolution ................................................................................................... 27
4. REFERENCES ......................................................................................................................... 28
5. APPENDIX 1 –Events of Clinical Interest (ECI) – Reference Table ...................................... 29
6. APPENDIX 2 – Past Medical History Related to Dermatologic Event ................................... 30
7. APPENDIX 3 – Presentation of the Dermatologic Event ........................................................ 31
8. APPENDIX 4 – Focused Skin Examination............................................................................. 33

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1. OVERVIEW
The purpose of this document is to provide study sites with guidance on the identification and 
management of
Events of Clinical Interest for the MK-3475 (also known as pembrolizumab) 
program.
Based on the literature review [1-11], and consideration of mechanism of action of pembrolizumab, 
potential immune-related adverse events (irAEs) are the primary Event of Clinical Interest (ECI). 
Immune-related AEs are adverse events associated with the treatment of patients with immunotherapy 
treatments that appear to be associated with the immune therapy’s mechanism of action. Based on these 
potential irAEs, the sponsor has defined a list of specific adverse event terms (ECIs) that are selected 
adverse experiences that must be reported to Merck within 24 hours from the time the 
Investigator/physician is aware of such an occurrence, regardless of whether or not the 
investigator/physician considers the event to be related to study drug(s). In addition, these ECIs require 
additional detailed information to be collected and entered in the study database. ECIs may be 
identified through spontaneous patient report and / or upon review of subject data. Table 1 provides 
the list of terms and reporting requirements for AEs that must be reported as ECIs for MK-3475 
protocols.  Of note, the requirement for reporting of ECIs applies to all arms, including comparators, 
of MK-3475 clinical trials.
Given that our current list of events of clinical interest is not comprehensive for all potential immune-
related events, it is possible that AEs other than those listed in this document may be observed in 
patients receiving pembrolizumab. Therefore  any  Grade  3  or  higher  event  that  the  
investigator/physician considers  to  be immune-related should be reported as an ECI regardless of 
whether the specific event term is in Table 1 and reported to Merck within 24 hours from the time 
the Investigator/physician is aware of such an occurrence. Adverse events that are both an SAE and an 
ECI should be reported one time as an SAE only, however the event must be appropriately identified 
as an ECI as well in in the database.

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Table 1: Events of Clinical Interest
Pneumonitis (reported as ECI if  ≥ Grade 2)
Acute interstitial pneumonitis
Interstitial lung disease
Pneumonitis
Colitis (reported as ECI if ≥ Grade 2 or any grade resulting in dose modification or use of systemic steroids to treat the
AE)
Intestinal Obstruction
Colitis
Colitis microscopic
Enterocolitis
Enterocolitis hemorrhagic
Gastrointestinal perforation
Necrotizing colitis
Diarrhea
Endocrine (reported as ECI if  ≥ Grade 3 or ≥ Grade 2 and resulting in dose modification or use of systemic steroids to
treat the AE)
Adrenal Insufficiency
Hyperthyroidism
Hypophysitis
Hypopituitarism
Hypothyroidism
Thyroid disorder
Thyroiditis
Hematologic (reported as ECI if  ≥ Grade 3 or any grade resulting in dose modification or use of systemic steroids to treat
the AE)
Autoimmune hemolytic anemia
Aplastic anemia
Thrombotic Thrombocytopenic Purpura
(TTP)
Idiopathic (or immune) Thrombocytopenia
Purpura  (ITP)
Disseminated Intravascular Coagulation
(DIC)
Haemolytic Uraemic Syndrome (HUS)
Any Grade 4 anemia regardless of underlying mechanism
Hepatic (reported as ECI if  ≥ Grade 2, or any grade resulting in dose modification or use of systemic steroids to treat the AE)
Hepatitis
Autoimmune hepatitis
Transaminase elevations
Infusion Reactions (reported as ECI for any grade)
Allergic reaction
Anaphylaxis
Cytokine release syndrome
Serum sickness
Infusion reactions
Infusion-like reactions
Neurologic (reported as ECI for any grade)
Autoimmune neuropathy
Guillain-Barre syndrome
Demyelinating polyneuropathy
Myasthenic syndrome
Ocular (report as ECI if  ≥ Grade 2 or any grade resulting in dose modification or use of systemic steroids to treat the AE)
Uveitis
Iritis
Renal (reported as ECI if  ≥ Grade 2)
Nephritis
Nephritis autoimmune
Renal Failure
Renal failure acute
Creatinine elevations (report as ECI if ≥Grade 3 or any grade resulting in dose
modification or use of systemic steroids to treat the AE)
Skin (reported as ECI for any grade)
Dermatitis exfoliative
Erythema multiforme
Stevens-Johnson syndrome
Toxic epidermal necrolysis
Skin (reported as ECI if ≥ Grade 3)
Pruritus
Rash
Rash generalized
Rash maculo-papular
Any rash considered clinically significant in the physician’s judgment

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Other (reported as ECI for any grade)
Myocarditis
Pancreatitis
Pericarditis
Any other Grade 3 event which is considered immune-related by the physician

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Each of the events above is described within this guidance document, along with site requirements 
for reporting these events to the Sponsor.  The information collected should be entered into the 
narrative field(s) of the Adverse Event module in the database (please note, if narrative entry into the 
database is not available, please use the narrative text box on the 1727/AER Form).   If additional 
Medical History or Concomitant Medications are reported, the Medical History and Concomitant 
Medication modules in the database must be updated.
In addition, the guidelines include recommendations on the management of these ECIs. These 
guidelines are intended to be applied when the physician determines the events to be related to 
pembrolizumab. Note: if after the evaluation the event is determined not to be related, the physician is 
instructed to follow the ECI reporting guidance but does not need to follow the treatment guidance 
(below). Therefore, these recommendations should be seen as guidelines and the treating physician 
should exercise individual clinical judgment based on the patient.  For any question of dose 
modification or other treatment options, the specific language in the protocol should be followed.  
Any questions pertaining to the collection of this information or management of ECIs should be directed 
to your local Sponsor contact.
Dose Modification/Discontinuation
The treatment guidance provides specific direction when to hold and/or discontinue pembrolizumab 
for each immune related adverse event.  Of note, when the guidance states to “discontinue” 
pembrolizumab this is the permanent discontinuation of treatment with pembrolizumab. “Hold” means 
to stop treating with pembrolizumab but resumption of treatment may be considered assuming the 
patient meets the criteria for resumption of treatment.
2. ECI REPORTING GUIDELINES
ECIs are selected non-serious and serious adverse experiences that must be reported to Merck  within 
24 hours regardless of attribution to study treatment.  The AEs listed in this document and any event 
that meets the ECI criteria (as noted) in Table 1 or in the respective protocol (event term and Grade) 
must be reported regardless of physician-determined causality with study medication and whether or 
not considered immune-related by the physician (unless otherwise specified).   Physicians/study 
coordinators/designated site personnel are required to record these experiences as ECIs on the Adverse 
Experience electronic Case Report Forms (eCRFs) (or on paper) and to provide supplemental 
information (such as medical history, concomitant medications, investigations, etc.) about the event.
–
Please refer to the Data Entry Guidelines (DEGs) for your protocol.
–
Please refer to protocol for details on reporting timelines and reporting of Overdose and Drug Induced 
Liver Injury (DILI).
3. ECI CATEGORIES AND TERMS
This  section describes the  ECI  categories and  outlines subject management guidelines when an  ECI  is 
reported

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3.1 Pneumonitis
The following AE terms, if considered ≥ Grade 2, are considered ECIs and should be reported to the 
Sponsor within 24 hours of the event:
–
Pneumonitis
–
Interstitial lung disease
–
Acute interstitial pneumonitis
If symptoms indicate possible new or worsening cardiac abnormalities additional testing and/or a 
cardiology consultation should be considered.
All attempts should be made to rule out other causes such as metastatic disease, bacterial or viral 
infection.  It is important that patients with a suspected diagnosis of pneumonitis be managed as 
per the guidance below until treatment-related pneumonitis is excluded. Treatment of both a 
potential infectious etiology and pneumonitis in parallel may be warranted. Management of the 
treatment of suspected pneumonitis with steroid treatment should not be delayed for a 
therapeutic trial of antibiotics.  If an alternative diagnosis is established, the patient does not 
require management as below; however the AE should be reported regardless of etiology.
Course of Action
Grade 2 events:
–
Report as ECI
–
Hold pembrolizumab.
–
Consider pulmonary consultation with bronchoscopy and biopsy/BAL.
–
Consider ID consult
–
Conduct an in person evaluation approximately twice per week
–
Consider frequent Chest X-ray as part of monitoring
–
Treat with systemic corticosteroids at a dose of 1 to 2 mg/kg/day prednisone or equivalent.  
When symptoms improve to Grade 1 or less, steroid taper should be started and continued over 
no less than 4 weeks.
–
Permanently discontinue for inability to reduce corticosteroid dose to 10 mg or less of 
prednisone or equivalent per day within 12 weeks.
–
Second episode of pneumonitis – discontinue pembrolizumab if upon re-challenge the patient 
develops a second episode of Grade 2 or higher pneumonitis.
Grade 3 and 4 events:
–
Report as ECI
–
Discontinue pembrolizumab.
–
Hospitalize patient
–
Bronchoscopy with biopsy and/or BAL is recommended.
–
Immediately  treat  with  intravenous  steroids  (methylprednisolone 125  mg  IV).  When  
symptoms improve to Grade 1 or less, a high dose oral steroid (prednisone 1 to 2 mg/kg once 

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per day or dexamethasone 4 mg every 4 hours) taper should be started and continued over no 
less than 4 weeks.
–
If IV steroids followed by high dose oral steroids does not reduce initial symptoms within 48 
to 72 hours, treat with additional anti-inflammatory measures. Discontinue additional anti-
inflammatory measures upon symptom relief and initiate a prolonged steroid taper over 45 to 
60 days. If symptoms worsen during steroid reduction, initiate a retapering of steroids starting 
at a higher dose of 80 or 100 mg followed by a more prolonged taper and administer additional 
anti-inflammatory measures, as needed
–
Add prophylactic antibiotics for opportunistic infections.
3.2 Colitis
The following AE terms, if considered ≥ Grade 2 or resulting in dose modification or use of systemic 
steroids to treat the AE, are considered ECIs and should be reported to the Sponsor within 24 hours of 
the event:
–
Colitis
–
Colitis microscopic
–
Enterocolitis
–
Enterocolitis hemorrhagic
–
Gastrointestinal perforation
–
Intestinal obstruction
–
Necrotizing colitis
–
Diarrhea
All attempts should be made to rule out other causes such as metastatic disease, bacterial or parasitic 
infection, viral gastroenteritis, or the first manifestation of an inflammatory bowel disease by 
examination for stool leukocytes, stool cultures, a Clostridium difficile titer and endoscopy.   However 
the AE should be reported regardless of etiology.
Course of Action
Grade 2 Diarrhea/Colitis (4-6 stools/day over baseline, dehydration requiring IV fluids < 24 hours, 
abdominal pain, mucus or blood in stool):
–
Report as ECI
–
Hold pembrolizumab.
–
Symptomatic Treatment
–
For Grade 2 diarrhea that persists >1 week, and for diarrhea with blood and/or mucus,
o
Consider GI consultation and endoscopy to confirm or rule out colitis
o
Administer oral corticosteroids (prednisone 1-2 mg/kg QD or equivalent)
–
When symptoms improve to Grade 1 or less, steroid taper should be started and continued over 
no less
than 4 
weeks.

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–
Permanently discontinue for inability to reduce corticosteroid dose to 10 mg or less of 
prednisone or equivalent per day within 12 weeks.
–
If symptoms worsen or persist > 3 days treat as Grade 3
Grade 3 Diarrhea/Colitis (or Grade 2 diarrhea that persist for greater than 3 
days):
–
Report as ECI
–
Hold pembrolizumab.
–
Rule out bowel perforation. Imaging with plain films or CT can be useful.
–
Recommend consultation with Gastroenterologist and confirmation biopsy with endoscopy.
–
Treat with intravenous steroids (methylprednisolone 125 mg) followed by high dose oral 
steroids (prednisone 1 to 2 mg/kg once per day or dexamethasone 4 mg every 4 hours)   
When symptoms improve to Grade 1 or less, steroid taper should be started and continued over 
no less than 4 weeks. Taper over 6 to 8 weeks in patients with diffuse and severe ulceration 
and/or bleeding.
–
Permanently discontinue for inability to reduce corticosteroid dose to 10 mg or less of 
prednisone or equivalent per day within 12 weeks.
– If IV steroids followed by high dose oral steroids does not reduce initial symptoms within 48 
to 72 hours, consider treatment with additional anti-inflammatory measures as described in the 
literature [5]. Discontinue additional anti-inflammatory measures upon symptom relief and 
initiate a prolonged steroid taper over 45 to 60 days. If symptoms worsen during steroid 
reduction, initiate a retapering of steroids starting at a higher dose of 80 or 100 mg followed by a 
more prolonged taper and administer additional anti-inflammatory measures as needed.
Grade 4 events:
– Report as ECI
– Permanently discontinue pembrolizumab.
– Manage as per Grade 3.
3.3 Endocrine
The following AE terms, if considered ≥Grade 3 or if ≥Grade 2 and require holding/discontinuation/ 
modification of pembrolizumab dosing, are considered ECIs and should be reported to the Sponsor 
within 24 hours of the event:
–
Adrenal insufficiency
–
Hyperthyroidism
–
Hypophysitis
–
Hypopituitarism
–
Hypothyroidism
–
Thyroid disorder
–
Thyroiditis

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All attempts should be made to rule out other causes such as brain metastases, sepsis and/or 
infection. However the AE should be reported regardless of etiology.
Hypophysitis or other symptomatic endocrinopathy other than hypo- or 
hyperthyroidism
Grade 2 events:
–
Report as ECI if appropriate
–
Hold pembrolizumab
–
Monitor thyroid function or other hormonal level tests and serum chemistries more frequently 
until returned to baseline values.
–
Pituitary gland  imaging should be  considered (MRIs with  gadolinium and  selective cuts  
of  the pituitary can show enlargement or heterogeneity and confirm the diagnosis).
–
Treat with prednisone 40 mg p.o. or equivalent per day.  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.
–
Permanently discontinue for inability to reduce corticosteroid dose to 10 mg or less of 
prednisone or equivalent per day within 12 weeks.
–
Consultation with an endocrinologist may be considered.
Grade 3 events:
–
Report as ECI
–
Hold pembrolizumab.
–
Endocrine consultation is recommended.
–
Rule out infection and sepsis with appropriate cultures and imaging.
–
Treat  with  an  initial  dose  of  methylprednisolone 1  to  2  mg/kg  intravenously followed  
by  oral prednisone 1 to 2 mg/kg per day.  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.
–
Permanently discontinue for inability to reduce corticosteroid dose to 10 mg or less of 
prednisone or equivalent per day within 12 weeks.
–
Hypophysitis  with  clinically  significant  adrenal  insufficiency  and  hypotension, dehydration, 
and
electrolyte abnormalities (such as hyponatremia and hyperkalemia) constitutes adrenal crisis.
–
Hospitalization and endocrine consultation should be considered.
Grade 4 events:
–
Report as ECI
–
Discontinue pembrolizumab.
–
Manage as per Grade 3
Hyperthyroidism and Hypothyroidism

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Thyroid disorders can occur at any time during treatment. Monitor patients for changes in 
thyroid function (at the start of treatment, periodically during treatment, and as indicated 
based on clinical evaluation) and for clinical signs and symptoms of thyroid disorders.
Grade 
2 
events 
(and 
Grade 
3-4 
hypothyroidism):
–
Report as ECI if appropriate (see Table 1)
–
Monitor thyroid function or other hormonal level tests and serum chemistries more frequently 
until returned to baseline values.
–
Thyroid hormone and/or steroid replacement therapy to manage adrenal insufficiency.
–
Therapy with pembrolizumab can be continued while treatment for the thyroid disorder is 
instituted.
–
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.
–
Consultation with an endocrinologist may be considered.
Grade 3 hyperthyroidism events:
–
Report as ECI
–
Hold pembrolizumab.
–
Rule out infection and sepsis with appropriate cultures and imaging.
–
Treat with an initial dose of methylprednisolone 1 to 2 mg/kg intravenously followed by oral 
prednisone 1 to 2 mg/kg per day. 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.
–
Permanently discontinue for inability to reduce corticosteroid dose to 10 mg or less of 
prednisone or equivalent per day within 12 weeks.
Grade 4 events:
–
Report as ECI
–
Discontinue pembrolizumab
–
Manage as per Grade 3

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3.4 Hematologic
The following AE term, if considered Grade ≥3 or requiring dose modification or use of systemic 
steroids to treat the AE, are considered an ECI and should be reported to the Sponsor within 24 hours of 
the event:
–
Autoimmune hemolytic anemia
–
Aplastic anemia
–
Disseminated Intravascular Coagulation (DIC)
–
Haemolytic Uraemic Syndrome (HUS)
–
Idiopathic (or immune) Thrombocytopenia Purpura (ITP)
–
Thrombotic Thrombocytopenic Purpura (TTP)
–
Any Grade 4 anemia regardless of underlying mechanism
All attempts should be made to rule out other causes such as metastases, sepsis and/or infection.    
Relevant diagnostic studies such as peripheral blood smear, reticulocyte count, LDH, haptoglobin, bone 
marrow biopsy or Coomb’s test, etc., should be considered to confirm the diagnosis. However the 
AE should be reported regardless of etiology.
Course of Action
Grade 2 events:
–
Report as ECI
–
Hold pembrolizumab
–
Prednisone 1-2 mg/kg daily may be indicated
–
Consider Hematology consultation.
Permanently discontinue for inability to reduce corticosteroid dose to 10 mg or less of 
prednisone or equivalent per day within 12 weeks.
Grade 3 events:
–
Report as ECI
–
Hematology consultation.
–
Hold pembrolizumab  Discontinuation should be considered as per specific protocol guidance.
–
Treat with methylprednisolone 125 mg iv or prednisone 1-2 mg/kg p.o. (or equivalent) as 
appropriate
–
Permanently discontinue for inability to reduce corticosteroid dose to 10 mg or less of 
prednisone or equivalent per day within 12 weeks.
Grade 4 events:
–
Report as ECI
–
Hematology consultation

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–
Discontinue pembrolizumab for all solid tumor indications; refer to protocol for 
hematologic malignancies.
–
Treat with methylprednisolone 125 mg iv or prednisone 1-2 mg/kg p.o. (or equivalent) as 
appropriate

Versi o n date: 2 3 O C T 2 0 1 8
C C # 1 6 7 0 4
Pil ot: I ntr alesi o n al I njecti o n Pe m br oliz u m a b
Pa ge 9 0 of 1 0 2
3. 5 He p atic
T he f oll o wi n g A E ter ms, if c o nsi dere d ≥ Gra de 2 or greater ( or a n y gra de wit h d ose m o dificati o n or 
use of s yste mic ster oi ds t o treat t he A E), are c o nsi dere d E CIs a n d s h o ul d be re p orte d t o t he S p o ns or 
wit hi n 2 4 h o urs of t he e ve nt:
–
A ut oi m m u ne he patitis
–
He patitis
–
Tra nsa mi nase ele vati o ns
All atte m pts s h o ul d be ma de t o r ule o ut ot her ca uses s uc h as metastati c disease, i nfecti o n or ot her 
he patic diseases. H o we ver t he A E s h o ul d be re p orte d re gar dless of eti ol o g y.
Dr u g I n d uce d 
Li ver I nj ur y 
( DI LI)
I n a d diti o n, t he e ve nt m ust be re p orte d as a Dr u g I n d uce d Li ver I nj ur y ( DI LI) E CI, if t he patie nt 
meets t he la b orat or y criteria f or p ote ntial DI LI defi ne d as:
 
A n ele vate d ala ni ne tra nsa mi nase ( A L T) or as partate tra nsa mi nase ( A S T) la b val ue t hat is 
greater t ha n or e q ual t o t hree ti mes ( 3 X) t he u p per li mit of n or mal ( U L N) a n d
.
A n ele vate d t otal bilir u bi n la b val ue t hat is greater t ha n or e q ual t o t w o ti mes ( 2 X) U L N a n d
At t he sa me ti me, a n al kali ne p h os p hatase ( A L P) la b val ue t hat is less t ha n 2 X U L N,
As a res ult of wit hi n- pr ot oc ol-s pecific testi n g or u nsc he d ule d testi n g.
N ote t hat a n y he patic i m m u ne E CI meeti n g DI LI criteria s h o ul d o nl y be re p orte d o nce as a DI LI 
e ve nt.
C o urse of Acti o n
Gra de 2 e ve nts:
–
Re p ort as E CI
–
H ol d pe m br oliz u ma b w he n A S T or A L T > 3. 0 t o 5. 0 ti mes U L N a n d/ or t otal bilir u bi n > 1. 5 t o 3. 0 
ti mes
U L N.
–
M o nit or li ver f u ncti o n tests m ore fre q ue ntl y u ntil ret ur ne d t o baseli ne val ues (c o nsi der wee kl y).
o
Treat wit h 0. 5- 1 m g/ k g/ da y met h yl pre d nis ol o ne or oral e q ui vale nt a n d w he n L F T 
ret ur ns t o gra de 1 or baseli ne, ta per ster oi ds o ver at least 1 m o nt h, c o nsi der pr o p h ylactic 
a nti bi otics f or o p p ort u nistic i nfecti o ns, a n d res u me pe m br oliz u ma b per pr ot oc ol
–
Per ma ne ntl y disc o nti n ue f or i na bilit y t o re d uce c ortic oster oi d d ose t o 1 0 m g or less of 
pre d nis o ne or e q ui vale nt per da y wit hi n 1 2 wee ks.
–
Per ma ne ntl y disc o nti n ue pe m br oliz u ma b f or patie nts wit h li ver metastasis w h o be gi n treat me nt 
wit h Gra de 2 ele v ati o n of A S T or A L T, a n d A S T or A L T i ncreases ≥5 0 % relati ve t o baseli ne 
a n d lasts ≥1 wee k.

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Grade 3 events:
– Report as ECI
– Discontinue pembrolizumab when AST or ALT >5.0 times ULN and/or total bilirubin >3.0 
times ULN.
– Consider appropriate consultation and liver biopsy to establish etiology of hepatic injury, if 
necessary
– Treat with high-dose intravenous glucocorticosteroids for 24 to 48 hours. When symptoms 
improve to Grade 1 or less, a steroid taper with dexamethasone 4 mg every 4 hours or prednisone 
at 1 to 2 mg/kg should be started and continued over no less than 4 weeks.
–
If serum transaminase levels do not decrease 48 hours after initiation of systemic steroids, 
oral mycophenolate mofetil 500 mg every 12 hours may be given. Infliximab is not 
recommended due to its potential for hepatotoxicity.
–
Several courses of steroid tapering may be necessary as symptoms may worsen when the steroid 
dose is decreased.
–
Permanently discontinue for inability to reduce corticosteroid dose to 10 mg or less of 
prednisone or equivalent per day within 12 weeks.
Grade 4 events:
–
Report as ECI
–
Permanently discontinue pembrolizumab
–
Manage patient as per Grade 3 above
3.6 Neurologic
The following AE terms, regardless of grade, are considered ECIs and should be reported to the 
Sponsor within 24 hours of the event:
–
Autoimmune neuropathy
–
Demyelinating polyneuropathy
–
Guillain-Barre syndrome
–
Myasthenic syndrome
All attempts should be made to rule out other causes such as metastatic disease, other medications or 
infectious causes. However the AE should be reported regardless of etiology.
Course of Action
Grade 2 events:
–
Report as ECI
–
Moderate (Grade 2) – consider withholding pembrolizumab.
–
Consider treatment with prednisone 1-2 mg/kg p.o. daily as appropriate

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–
Consider Neurology consultation. Consider biopsy for confirmation of diagnosis.
–
Permanently discontinue for inability to reduce corticosteroid dose to 10 mg or less of 
prednisone or equivalent per day within 12 weeks.
Grade 3 and 4 events:
–
Report as ECI
–
Discontinue pembrolizumab
–
Obtain neurology consultation. Consider biopsy for confirmation of diagnosis
–
Treat with systemic corticosteroids at a dose of 1 to 2 mg/kg prednisone or equivalent once per 
day. If condition worsens consider IVIG or other immunosuppressive therapies as per local 
guidelines
When symptoms improve to Grade 1 or less, steroid taper should be started and continued over no less 
than 4 weeks.

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3.7 Ocular
The following AE terms, if considered Grade ≥2 or requiring dose modification or use of systemic 
steroids to treat the AE, is considered an ECI and should be reported to the Sponsor within 24 hours 
of the event:
–
Uveitis
–
Iritis
All attempts should be made to rule out other causes such as metastatic disease, infection or other 
ocular disease (e.g. glaucoma or cataracts). However the AE should be reported regardless of etiology.
Course of Action
Grade 2 events:
–
Evaluation by an ophthalmologist is strongly recommended.
–
Treat with topical steroids such as 1% prednisolone acetate suspension and iridocyclitics.
–
Discontinue  pembrolizumab  as  per  protocol  if  symptoms  persist  despite  treatment  with  
topical immunosuppressive therapy.
Grade 3 events:
–
Evaluation by an ophthalmologist is strongly recommended
–
Hold pembrolizumab and consider permanent discontinuation as per specific protocol guidance.
–
Treat with systemic corticosteroids such as prednisone at a dose of 1 to 2 mg/kg per day.   
When symptoms improve to Grade 1 or less, steroid taper should be started and continued over 
no less than 4 weeks.
–
Permanently discontinue for inability to reduce corticosteroid dose to 10 mg or less of 
prednisone or equivalent per day within 12 weeks.
Grade 4 events:
–
Evaluation by an ophthalmologist is strongly recommended
–
Permanently discontinue pembrolizumab.
–
Treat with corticosteroids as per Grade 3 above

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3.8 Renal
The following AEs if ≥ Grade 2 are considered ECIs and should be reported to the Sponsor within 24 
hours of the event:
–
Nephritis
–
Nephritis autoimmune
–
Renal failure
–
Renal failure acute
Creatinine elevations ≥ Grade 3 or any grade with dose modification or use of systemic steroids to 
treat the AE.
All attempts should be made to rule out other causes such as obstructive uropathy, progression of 
disease, or injury due to other chemotherapy agents.  A renal consultation is recommended. However 
the AE should be reported regardless of etiology.
Course of Action
Grade 2 events:
–
Hold pembrolizumab
–
Treatment with prednisone 1-2 mg/kg p.o. daily.
–
Permanently discontinue for inability to reduce corticosteroid dose to 10 mg or less of 
prednisone or equivalent per day within 12 weeks.
Grade 3-4 events:
–
Discontinue pembrolizumab
–
Renal consultation with consideration of ultrasound and/or biopsy as appropriate
–
Treat with systemic corticosteroids at a dose of 1 to 2 mg/kg prednisone IV or equivalent 
once per day.
When symptoms improve to Grade 1 or less, steroid taper should be started and continued over no less 
than 4 weeks.

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3.9 Skin
Rash and Pruritus
The following AEs should be considered as ECIs, if ≥ Grade 3 and should be reported to the Sponsor 
within 24 hours of the event:
–
Pruritus
–
Rash
–
Rash generalized
–
Rash maculo-papular
–
In addition to CTCAE Grade 3 rash, any rash that is considered clinically significant, in the 
physician's judgment, should be treated as an ECI. Clinical significance is left to the physician 
to determine, and could possibly include rashes such as the following:
o
rash with a duration >2 weeks; OR
o
rash that is >10% body surface area; OR
o
rash that causes significant discomfort not relieved by topical medication or temporary 
cessation of study drug.
Other Skin ECIs
The following AEs should always be reported as ECIs, regardless of grade, and should be reported 
to the
Sponsor within 24 hours of the event:
–
Dermatitis exfoliative
–
Erythema multiforme
–
Steven’s Johnson syndrome
–
Toxic epidermal necrolysis
Please note, the AE should be reported regardless of etiology.
Course of Action
Grade 2 events:
– Symptomatic treatment should be given such as topical glucocorticosteroids (e.g., 
betamethasone 0.1% cream or hydrocortisone 1%) or urea-containing creams in combination 
with oral anti-pruritics (e.g., diphenhydramine HCl or hydroxyzine HCl).
– Treatment with oral steroids is at physician’s discretion for Grade 2 events.
Grade 3 events:
–
Hold pembrolizumab.
–
Consider Dermatology Consultation and biopsy for confirmation of diagnosis.

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–
Treatment with oral steroids is recommended, starting with 1 mg/kg prednisone or equivalent 
once per day or dexamethasone 4 mg four times orally daily.  When symptoms improve to 
Grade 1 or less, steroid taper should be started and continued over no less than 4 weeks.
–
Permanently discontinue for inability to reduce corticosteroid dose to 10 mg or less of 
prednisone or equivalent per day within 12 weeks.
Grade 4 events:
–
Permanently discontinue pembrolizumab.
–
Dermatology consultation and consideration of biopsy and clinical dermatology photograph.
–
Initiate steroids at 1 to 2 mg/kg prednisone or equivalent.  When symptoms improve to Grade 
1 or less, steroid taper should be started and continued over no less than 4 weeks.
3.9.1. Immediate Evaluation for Potential Skin ECIs
A. 
Photographs:
Every attempt should be made to get a photograph of the actual ECI skin lesion or rash as soon as 
possible. Obtain appropriate consent for subject photographs if a consent form addendum is 
required by your IRB/ERC.
–
Take digital photographs of:
o
the head (to assess mucosal or eye involvement),
o
the trunk and extremities, and
o
a close-up of the skin lesion/rash.
–
If possible, a ruler should be placed alongside the site of a skin occurrence as a fixed 
marker of distance.
–
The time/date stamp should be set in the 'ON' position for documentation purposes.
–
Photographs should be stored with the subject’s study records.
–
The Sponsor may request copies of photographs. The local study contact (e.g., CRA) will 
provide guidance to the site, if needed.
B. Past Medical History:
Collect past medical history relevant to the event, using the questions in Appendix 2 (Past Medical 
History Related to Dermatologic Event) as a guide. Any preexisting conditions not previously 
reported (e.g., drug allergy) should be entered into the Medical History eCRF.
C. Presentation of the Event:
Collect information on clinical presentation and potential contributing factors using the questions in 
Appendix 3 (Presentation of the Dermatologic Event) as a guide. This information should be 
summarized and entered in narrative format in the AE eCRF. Please use the available free-text fields, 
such as Signs and Symptoms. Note pertinent negatives where applicable to reflect that the information 
was collected. Any treatments administered should be entered on the Concomitant Medication eCRF.

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D. Vitals Signs and Standard Laboratory Tests:
Measure vital signs (pulse, sitting BP, oral temperature, and respiratory rate) and record on the Vital 
Signs eCRF.  Perform standard laboratory tests (CBC with manual differential and serum chemistry 
panel, including LFTs).
E. Focused Skin Examination:
Perform a focused skin examination using the questions in Appendix 4 (Focused Skin Examination) 
as a guide. Information should be summarized and entered on the Adverse Experience eCRF as 
part of the narrative.
F. Dermatology Consult
Refer the subject to a dermatologist as soon as possible.
–
For a “severe rash”, the subject must be seen within 1-2 days of reporting the event.
–
For clinically significant rash, the subject should be seen within 3-5 days.
 
The  dermatologist  should  submit  a  biopsy  sample  to  a  certified  dermatopathology  laboratory  
or  to  a pathologist experienced in reviewing skin specimens.
The  site  should  provide  the  dermatologist  with  all  relevant  case  history,  including  copies  of  
clinical photographs and laboratory test results.
3.10 Other
The following AEs, regardless of grade, are considered ECIs and should be reported to the Sponsor 
within 24 hours of the event:
–
Myocarditis
–
Pericarditis
–
Pancreatitis
–
Any additional Grade 3 or higher event which the physician considers to be immune related
All  attempts  should be  made  to  rule  out  other  causes.
Therapeutic specialists should be  
consulted as appropriate. However the AE should be reported regardless of etiology.
Course of Action
Grade 2 events or Grade 1 events that do not improve with symptomatic treatment:
–
Withhold pembrolizumab.
–
Systemic corticosteroids may be indicated.
–
Consider biopsy for confirmation of diagnosis.

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–
If pembrolizumab held and corticosteroid required, manage as per grade 3 below.
Grade 3 events:
–
Hold pembrolizumab
–
Treat with systemic corticosteroids at a dose of 1 to 2 mg/kg prednisone or equivalent once per 
day.
–
When symptoms improve to Grade 1 or less, steroid taper should be started and continued over 
no less than 4 weeks.
–
Permanently discontinue for inability to reduce corticosteroid dose to 10 mg or less of 
prednisone or equivalent per day within 12 weeks. Otherwise, pembrolizumab treatment may 
be restarted and the dose modified as specified in the protocol
Grade 4 events:
–
Treat with systemic corticosteroids at a dose of 1 to 2 mg/kg prednisone or equivalent once per 
day.
–
Discontinue pembrolizumab

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3.11 Infusion Reactions
The following AE terms, regardless of grade, are considered ECIs and should be reported to the 
Sponsor within 24 hours of the event:
–
Allergic reaction
–
Anaphylaxis
–
Cytokine release syndrome
–
Serum sickness
–
Infusion reactions
–
Infusion-like reactions
Please note, the AE should be reported regardless of etiology.
Course of Action
Refer to infusion reaction table in the protocol and below.

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Infusion Reactions
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.
Additional appropriate medical therapy 
may include but is not limited to:
IV fluids
Antihistamines
NSAIDS 
Acetaminophen 
Narcotics
Increase monitoring of vital signs as 
medically indicated until the subject is
deemed medically stable in the opinion of
the investigator.
If symptoms resolve within one hour of 
stopping drug infusion, the infusion may
be restarted at 50% of the original infusion 
rate (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.
Subject may be premedicated
1.5h (± 30 minutes) prior to 
infusion of pembrolizumab 
with:
Diphenhydramine 50 mg p.o. 
(or 
equivalent 
dose 
of 
antihistamine).
Acetaminophen 500-1000 mg 
p.o. (or equivalent dose of 
antipyretic).
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

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Appropriate resuscitation equipment should be available in the room and a physician readily available during the
period of drug administration.
For Further information, please refer to the Common Terminology Criteria for Adverse Events v4.0 (CTCAE) at 
http://ctep.cancer.gov

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3.12 
Follow-up 
to 
Resolution
Subjects should be followed to resolution. The Adverse Experience eCRF should be updated 
with information regarding duration and clinical course of the event. Information obtained from 
the consulting specialist, including diagnosis, should be recorded in the appropriate AE fields. 
Free-text fields should be used to record narrative information:
–
Clinical course of the event
–
Course of treatment
–
Evidence supporting recovery
–
Follow-up to the clinical course
Any treatments administered for the event should also be entered in the Concomitant 
Medication eCRF.