Conditions: Stage III Cutaneous Melanoma Stage IIIA Cutaneous Melanoma Stage IIIB Cutaneous Melanoma Stage IIIC Cutaneous Melanoma Stage IV Cutaneous Melanoma
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 27
Healthy volunteers: no

Brief summary:
This phase II trial studies how well pembrolizumab, ipilimumab, and aspirin work in treating patients with melanoma that has spread to other places in the body or cannot be removed by surgery. Monoclonal antibodies, such as pembrolizumab and ipilimumab, may interfere with the ability of tumor cells to grow and spread. Aspirin may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving pembrolizumab, ipilimumab, and aspirin may work better in treating patients with melanoma.

Detailed description:
PRIMARY OBJECTIVES:

I. To evaluate the overall response rate (ORR) by week 12 in patients with stage III unresectable/stage IV melanoma.

SECONDARY OBJECTIVES:

I. To determine the median progression free survival, overall survival, and toxicity profile of the combination of ipilimumab, pembrolizumab and high dose aspirin in patients with stage III unresectable/IV melanoma.

OUTLINE:

Patients receive pembrolizumab intravenously (IV) over 30 minutes on day 1, ipilimumab IV over 60 minutes on day 1 for courses 1-4, and aspirin orally (PO) twice daily (BID) on days 1-21. Courses repeat every 3 weeks in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 30 days.

Arms:
arm 1: Patients receive pembrolizumab IV over 30 minutes on day 1, ipilimumab IV over 60 minutes on day 1 for courses 1-4, and aspirin PO BID (orally, twice a day) on days 1-21. Courses repeat every 3 weeks in the absence of disease progression or unacceptable toxicity.

Interventions: intervention 1: Aspirin intervention 2: Ipilimumab intervention 3: Laboratory Biomarker Analysis intervention 4: Pembrolizumab
Intervention descriptions: intervention 1: Given PO intervention 2: Given IV intervention 3: Correlative studies intervention 4: Given IV

Protocol document:
Prot_SAP_000.pdf: 
Proprietary and Confidential
The information in this document is considered privileged and confidential, and may not be disclosed to others except 
to the extent necessary to obtain Institutional Review Board approval and informed consent, or as required by 
Federal and State laws.  Persons to whom this information is disclosed should be informed that this information is 
privileged and confidential and that it should not be further disclosed.
Prostaglandin Inhibition and PD-1/CTLA4 blockade in 
melanoma 
Protocol Number:  CC #17854
Study Drugs:  Pembrolizumab, Ipilimumab, Aspirin
Version Number:  7.0
Version Date:  December 12, 2019
IND Number:  Exempt
Principal Investigator (Sponsor-Investigator)
Adil Daud, MD  
University of California San Francisco
 
Statistician
Joan F. Hilton, ScD, MPH  
Revision History
Version 7.0
12/12/2019
Version 6.0
10/02/2019
Version 5.0
05/16/2019
Version 4.0
02/07/2019
Version 3.3
02/06/2018
Version 3.2
12/11/2017
Version 3.1
09/14/2017
Version 3.0
07/24/2017
Version 2.0
05/19/2017
Version 1.0
08/29/2016
NCT# 03396952


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Protocol CC#: 17854
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Page 1 of 62
Protocol Signature Page
Protocol No.: 17854
Version Date: 12/12/2019
1.
I agree to follow this protocol version as approved by the UCSF Protocol Review Committee 
(PRC), Committee on Human Research (CHR), and Data Safety Monitoring Committee 
(DSMC). 
2.
I will conduct the study in accordance with applicable CHR 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 CHR policies, Federal, 
state and local laws and regulations.
UCSF Principal Investigator / Study Chair
Printed Name
Signature
Date


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Abstract
Title
Prostaglandin Inhibition and PD-1/CTLA4 blockade in melanoma
Patient population
Patients with stage III unresectable/ stage IV melanoma
Rationale for Study
Prostaglandin Inhibition may increase the efficacy of immunotherapy
Primary Objective
To evaluate the overall response rate (ORR) by week 12 in patients 
with stage III unresectable/stage IV melanoma.
Secondary 
Objectives
To determine the median progression free survival and the overall 
survival and toxicity profile of this combination.
Study Design
Prospective single arm Simon 2 stage Phase II trial
Number of patients
43
Duration of Follow up
Patients will be followed for 30 days after discontinuation of treatment 
or removal from study
Duration of study
The study is expected to complete accrual at 24 months.
Study Drugs
Aspirin
Pembrolizumab
Ipilimumab
Safety Assessments
CTCAE v. 4 will be used to assess toxicity.
Efficacy 
Assessments
RECIST version 1.1 will be used in this study for assessment of tumor 
response.
Unique Aspects of 
this Study
Combination trial with ipilimumab, pembrolizumab, and aspirin.


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List of Abbreviations
AE
adverse event
ALP
alkaline phosphatase
ALT
alanine aminotransferase
ANC
absolute neutrophil count
AST
aspartate aminotransferase
ATC
Anatomical Therapeutic Chemical (Classification System)
AUC
area under the curve
BUN
blood urea nitrogen
CBC
complete blood cell (count)
CHR
Committee on Human Research (UCSF IRB)
CR
complete response
CRC
Clinical Research Coordinator
CRF
case report form
CSF
cerebral spinal fluid
CT
computerized tomography
CTCEA
Common Terminology Criteria for Adverse Events
CTEP
Cancer Therapy Evaluation Program
CTMS
Clinical Trial Management System
DFS
disease-free survival
DLT
dose limiting toxicity
DSMC
Data and Safety Monitoring Committee
DSMP
Data and Safety Monitoring Plan
ECOG
Eastern Cooperative Oncology Group


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Table of Contents
Protocol Signature Page ...............................................................................................................1
Abstract
2
List of Abbreviations ......................................................................................................................3
Table of Contents ..........................................................................................................................4
1
Introduction...........................................................................................................................7
1.1
Background on Indication.....................................................................................7
1.2
Background on the Immunotherapy Combinations ..............................................7
1.2.1
Pembrolizumab.................................................................................................7
1.2.2
Ipilimumab ........................................................................................................8
1.2.3
Aspirin...............................................................................................................9
1.3
Rationale for the Proposed Study ......................................................................10
1.4
Rationale for Dose Selection/Regimen/Modification ..........................................10
1.5
Correlative Studies.............................................................................................11
2
Objectives of the Study ......................................................................................................12
2.1
Primary ...............................................................................................................12
2.2
Secondary ..........................................................................................................12
2.3
Endpoints ...........................................................................................................12
2.3.1
Primary Endpoints ..........................................................................................12
2.3.2
Secondary Endpoints .....................................................................................12
3
Study Design......................................................................................................................12
3.1
Characteristics....................................................................................................12
3.2
Number of Subjects............................................................................................12
3.3
Eligibility Criteria.................................................................................................12
3.3.1
Inclusion Criteria.............................................................................................13
3.3.2
Exclusion Criteria............................................................................................13
3.4
Duration of Therapy............................................................................................14
3.5
Duration of Follow Up.........................................................................................14
3.6
Study Timeline....................................................................................................14
3.6.1
Primary Completion ........................................................................................14
3.6.2
Study Completion ...........................................................................................14
4
Study Drugs........................................................................................................................15
4.1
Pembrolizumab ..................................................................................................15
4.1.1
Packaging and Labeling Information ..............................................................15
4.1.2
Clinical Supplies Disclosure ...........................................................................15
4.1.3
Storage and Handling Requirements .............................................................15
4.1.4
Returns and Reconciliation.............................................................................15
4.1.5
Safety Information ..........................................................................................15
4.2
Ipilimumab..........................................................................................................15
4.2.1
Packaging and Labeling Information ..............................................................16
4.2.2
Clinical Supplies Disclosure ...........................................................................16
4.2.3
Storage and Handling Requirements .............................................................16
4.2.4
Returns and Reconciliation.............................................................................16
4.2.5
Safety Information ..........................................................................................16
4.3
Aspirin (Acetyl Salicylic Acid) .............................................................................20
4.3.1
Packaging and Labeling Information ..............................................................20


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4.3.2
Clinical Supplies Disclosure ...........................................................................20
4.3.3
Storage and Handling Requirements .............................................................20
4.3.4
Returns and Reconciliation.............................................................................20
4.3.5
Safety Information ..........................................................................................21
5
Treatment Plan...................................................................................................................21
5.1
Dosage and Administration ................................................................................21
5.2
Timing of Dose Administration ...........................................................................21
5.3
Dose Modifications and Dosing Delays..............................................................21
5.3.1
Dose Modification for Pembrolizumab............................................................22
5.3.2
Dose Modification for Ipilimumab ...................................................................26
5.3.3
Dose Modification for Aspirin..........................................................................27
5.4
Rescue Medications & Supportive Care.............................................................27
5.4.1
Supportive Care Guidelines............................................................................27
5.5
Concomitant Medications/Vaccinations (allowed & prohibited)..........................30
5.5.1
Acceptable Concomitant Medications ............................................................31
5.5.2
Prohibited Concomitant Medications ..............................................................31
5.6
Diet/Activity/Other Considerations......................................................................32
5.6.1
Diet .................................................................................................................32
5.6.2
Contraception .................................................................................................32
5.6.3
Use in Pregnancy ...........................................................................................33
5.6.4
Use in Nursing Women...................................................................................33
5.6.5
Subject Withdrawal/Discontinuation Criteria...................................................34
5.6.6
Discontinuation of Study Therapy after CR ....................................................34
5.6.7
Clinical Criteria for Early Trial Termination .....................................................34
6
Study Procedures and Observations .................................................................................35
6.1
Administrative Procedures .................................................................................35
6.1.1
Informed Consent ...........................................................................................35
6.1.2
Inclusion/Exclusion Criteria ............................................................................35
6.1.3
Medical History ...............................................................................................35
6.1.4
Prior and Concomitant Medications Review...................................................36
6.1.5
Disease Details and Treatments ....................................................................36
6.2
Clinical Procedures/Assessments......................................................................36
6.2.1
Adverse Event (AE) Monitoring ......................................................................36
6.2.2
Full Physical Exam .........................................................................................37
6.2.3
Vital Signs.......................................................................................................37
6.2.4
Eastern Cooperative Oncology Group (ECOG) Performance Scale ..............37
6.2.5
Laboratory Procedures/Assessments.............................................................37
6.2.6
Tumor Tissue Collection.................................................................................39
6.2.7
Tumor Imaging ...............................................................................................39
6.3
Other Procedures...............................................................................................39
6.3.1
Withdrawal/Discontinuation ............................................................................39
6.3.2
Visit Requirements .........................................................................................39
6.3.3
Safety Follow-Up Visit ....................................................................................39
6.3.4
Follow-up Visits ..............................................................................................39
7
Assessing and Recording Adverse Events ........................................................................39
7.1
Definition of an Overdose for This Protocol and Reporting of Overdose to the 
Sponsor and to Merck ..........................................................................................................40
7.2
Reporting of Pregnancy and Lactation to the Sponsor and to Merck.................41
7.3
Immediate Reporting of Adverse Events to the Sponsor and to Merck..............41


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7.3.1
Serious Adverse Events .................................................................................41
7.3.2
Events of Clinical Interest ...............................................................................42
7.3.3
Protocol-Specific Exceptions to Serious Adverse Event Reporting................43
7.4
Evaluating Adverse Events ................................................................................43
7.5
Sponsor Responsibility for Reporting Adverse Events.......................................48
8
Statistical Analysis Plan .....................................................................................................48
8.1
Statistical Analysis Plan Summary.....................................................................48
8.2
Sample Size and Accrual Rate Considerations..................................................48
8.2.1
Sample Size and Power Estimate ..................................................................48
8.2.2
Replacement Policy........................................................................................48
8.2.3
Accrual Estimates...........................................................................................48
8.3
Interim Analyses and Stopping Rules ................................................................48
8.4
Statistical Analysis Plan .....................................................................................49
8.4.1
Analysis of Primary Endpoints........................................................................49
8.4.2
Analysis of Secondary Endpoints ...................................................................49
8.4.3
Other Analyses ...............................................................................................49
8.5
Evaluation of Safety ...........................................................................................49
9
Study Management ............................................................................................................50
9.1
Pre-study Documentation...................................................................................50
9.2
Institutional Review Board Approval...................................................................50
9.3
Informed Consent...............................................................................................51
9.4
Changes in the Protocol.....................................................................................51
9.5
Handling and Documentation of Clinical Supplies..............................................51
9.6
Case Report Forms (CRFs) ...............................................................................51
9.7
Oversight and Monitoring Plan...........................................................................52
9.8
Record Keeping and Record Retention..............................................................52
References
53
Appendix 1
Schedule of Study Procedures and Assessments .............................................55
Appendix 2
Performance Status Criteria ...............................................................................57
Appendix 3
Data and Safety Monitoring Plan for a Phase 2 or 3 Institutional Study.............58
Appendix 4
Prohibited Medications .......................................................................................61


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1
Introduction
1.1
Background on Indication
The combination of ipilimumab and nivolumab is considered one of the standard treatments for 
advanced melanoma(1). However, even with this treatment, 40% of patients do not have an 
objective response. Recently, it has been shown in a preclinical model that the addition of a 
cyclooxygenase (COX) inhibitor may reduce PD-1 resistance(2, 3) In the study by Zelenay et al, 
aspirin, which blocks both COX-1 and COX-2), was able to prevent PD-1 resistance in a 
melanoma model. While the initial ipilimumab nivolumab study used nivolumab as the PD-1 
inhibitor, these results have been recently replicated with pembrolizumab, a very similar anti-PD-1 
inhibitor (Long G, et al ASCO 2016).
1.2
Background on the Immunotherapy Combinations
1.2.1 Pembrolizumab
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(4-7).
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(8).
The PD-1 receptor-ligand interaction is a major pathway hijacked by tumors to suppress immune 
control(5). 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 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-


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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.
1.2.2 Ipilimumab
Successful stimulation of T cells by antigen presenting cells require both antigen presentation by 
the MHC molecule-antigen peptide complex to the T cell receptor as well as costimulation by the 
B7 molecule on the antigen presenting cells to the CD 80/86 molecule. Ipilimumab is a humanized 
monoclonal antibody to CTLA-4 which is a decoy receptor. The effect of ipilimumab binding to 
CTLA-4 is to increase costimulation and increase T cell activation.
The two currently approved immune checkpoint blockers are anti-CTLA-4 and anti-PD-1 
antibodies. The first, anti-CTLA4 antibody, ipilimumab was evaluated for treatment of advanced 
melanoma in two phase III trials as a monotherapy, and in combination with dacarbazine(9)(10). 
In these studies, ipilimumab demonstrated an increase overall response rate (ORR), median 
progression free survival (PFS), and median overall survival (OS) compared to a gp100 vaccine 
or in combination with dacarbazine vs. dacarbazine alone. Ipilimumab both at the tested 3mg/kg 
dose and at the 10 mg/kg dose was associated with increased immune related toxicities such as 
colitis, diarrhea, dermatitis, as well as a characteristic immune related hypophysitis(11).
Following the successful development of ipilimumab in melanoma, the development of anti-PD1 
agents proceeded rapidly following the FDA approval of ipilimumab for advanced melanoma. In 
initial phase I clinical trials, two anti-PD-1 agents, pembrolizumab and nivolumab exhibited 
favorable response rates between 20-40% with substantial decreased frequency for grade 3-4 
adverse events (10-15%)(12-13). Subsequent phase III trials showed durable clinical benefit with 
improved ORR, OFS, and OS from both pembrolizumab and nivolumab administered as first line 
therapies when compared to ipilimumab (KEYNOTE-006(14), CheckMate 067 trials(15), 
respectively).
With the anti-tumor benefit of both anti-CTLA4 and anti-PD1 agents administered as 
monotherapies, the logical next step was the administration of both immunotherapies in 
combination. Phase II data of ipilimumab and nivolumab in combination followed by nivolumab 
maintenance exhibited an increased toxicity profile compared to agents administered as 
monotherapies (50% of patients with grade 3-4 adverse events)(16). Yet despite the heightened 
toxicity profile, the clinical benefit seen in the combination was promising with improved ORR and 
PFS when compared to either ipilimumab or nivolumab alone (CheckMate 067)(15). Thus, while 
the clinical benefit has been promising, an increased propensity to develop grade 3/4 adverse 
events remains a strong consideration in choosing the proper context to administer the 
combination of nivolumab and ipilimumab.
The dose of ipilimumab does not appear to play a role in response rate but the dose does appear 
to play a role in side effects and adverse events. A recent trial, the Keynote 029 trial showed that 
the combination of pembrolizumab at the 200 mg dose and ipilimumab 1 mg/kg X 4 was 
associated with a reduced incidence of grade 3/4 AE to ~ 20%and an ORR of 55%(17). This 
reduced ipilimumab dose appears to be a well tolerated and equi-efficacious dose compared to 


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the higher dose ipilimumab regimens. For combination therapies, this is considered to be a good 
regimen.
1.2.3 Aspirin
Aspirin, in the form of leaves from the willow tree, has been used for its health effects for at least 
2,400 years. In 1853, chemist Charles Frédéric Gerhardt synthesized acetyl salicylic acid in the 
lab for the first time. In 1897, scientists at Bayer began studying acetylsalicylic acid as a less-
irritating replacement for common salicylate medicines. In 1899, Bayer had named the drug 
Aspirin(18).
In 1971, British pharmacologist John Robert Vane, showed aspirin suppressed the production of 
prostaglandins and thromboxanes. Aspirin's ability to suppress the production of prostaglandins 
and thromboxanes is due to its irreversible inactivation of the cyclooxygenase enzyme required 
for prostaglandin and thromboxane synthesis. Aspirin acts as an acetylating agent where an 
acetyl group is covalently attached to a serine residue in the active site of the PTGS enzyme. 
Low-dose aspirin use irreversibly blocks the formation of thromboxane A2 in platelets, producing 
an inhibitory effect on platelet aggregation during the lifetime of the affected platelet (8–9 days). 
This antithrombotic property makes aspirin useful for reducing the incidence of heart attacks in 
people who have had a heart attack, unstable angina, ischemic stroke or transient ischemic attack 
40 mg of aspirin a day is able to inhibit a large proportion of maximum thromboxane A2 release 
provoked acutely, with the prostaglandin I2 synthesis being little affected; however, higher doses 
of aspirin are required to attain further inhibition.
COX-1 and COX-2 inhibition
At least two different types of cyclooxygenases, COX-1 and COX-2, are acted on by aspirin. 
Aspirin irreversibly inhibits COX-1 and modifies the enzymatic activity of COX-2. COX-2 normally 
produces prostanoids, most of which are proinflammatory. Aspirin-modified PTGS2 
(prostaglandin synthetase 2) produces lipoxins, most of which are anti-inflammatory
However, several of the new COX-2 inhibitors, such as rofecoxib (Vioxx), have been withdrawn 
in the last decade, after evidence emerged that PTGS2 inhibitors increase the risk of heart attack 
and stroke. Endothelial cells lining the microvasculature in the body are proposed to express 
PTGS2, and, by selectively inhibiting PTGS2, prostaglandin production (specifically, PGI2; 
prostacyclin) is downregulated with respect to thromboxane levels, as PTGS1 in platelets is 
unaffected. Thus, the protective anticoagulative effect of PGI2 is removed, increasing the risk of 
thrombus and associated heart attacks and other circulatory problems. Since platelets have no 
DNA, they are unable to synthesize new PTGS once aspirin has irreversibly inhibited the enzyme, 
an important difference with reversible inhibitors.
Furthermore, aspirin, while inhibiting the ability of COX-2 to form pro-inflammatory products such 
as the prostaglandins, converts this enzyme's activity from a prostaglandin-forming 
cyclooxygenase to a lipoxygenase-like enzyme: aspirin-treated COX-2 metabolizes a variety of 
polyunsaturated fatty acids to hydroperoxy products which are then further metabolized to 
specialized proresolving mediators such as the aspirin-triggered lipoxins, aspirin-triggered 
resolvins, and aspirin-triggered maresins. These mediators possess potent anti-inflammatory 
activity. It is proposed that this aspirin-triggered transition of COX-2 from cyclooxygenase to 
lipoxygenase activity and the consequential formation of specialized proresolving mediators 
contributes to the anti-inflammatory effects of aspirin.
Recently, COX-2 inhibition has been proposed as a mechanism for reducing MDSC activity in 
some models of cancer and thereby assisting PD-1 effectiveness(3). In these preclinical models, 


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COX blockade synergizes with PD-1 inhibition in melanoma, colorectal cancer and in other 
syngeneic immunocompetent models. Furthermore the same COX signature was seen in 
cutaneous melanoma(3). The calculated human dose extrapolated from animal models is 1 gm 
twice daily.  
1.3
Rationale for the Proposed Study
PD-1 inhibition is associated with dramatic and long lasting responses in melanoma. However, 
40-60 % of patients do not respond to anti-PD-1 or anti-PD-L-1 blocking antibodies. Recent 
reports of PD-1+CTLA4 blocking combinations have shown increased response rates. The 
combination of ipilimumab and nivolumab has demonstrated response rates in the ~60% range 
(19). The combination of low dose ipilimumab and standard dose pembrolizumab has been 
explored in a recent clinical trial and shown an ORR of 55%. However, there remains a residual 
40% of patients where this combination is still not effective.
Our analysis has shown that many PD-1 non-responders share certain characteristics such as 
elevated LDH, liver metastasis, as well as increased tumor burden and non-cutaneous origin (21-
23). Collectively, many of these melanoma patients have low fractions of partially exhausted 
cytotoxic T lymphocytes (peCTL).  For these “low peCTL” tumors, ipilimumab + PD-1 combination 
therapy with ipilimumab and PD-1 inhibitors is the current standard of care. We hypothesize that 
the addition of aspirin to this modified ipilimumab pembrolizumab regimen will increase response 
rates.
Recent reports have highlighted other pathways that may be involved (20) such as iNOS, COX-2 
activation, Myeloid Derived Suppressor Cells and Treg activation. A recent report provides 
powerful support for the COX-2 pathway as an escape mechanism(3). These authors showed 
that ablation of the COX-2 pathway or PGE synthetase in mice with the BRAFV600E mutation or 
the NRAS G12D mutation shifts cells towards the classic PD-1 escape pathway and hence 
sensitizes them to anti-PD-1 antibodies. The dose of aspirin was extrapolated from these mouse 
experiments. 
1.4
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 MK-3475. The dose escalation portion of this trial evaluated three dose 
levels, 1 mg/kg, 3 mg/kg, and 10 mg/kg, administered every 2 weeks (Q2W) in subjects with 
advanced solid tumors. All three dose levels were well tolerated and no dose-limiting toxicities 
were observed. This first in human study of MK-3475 showed evidence of target engagement and 
objective evidence of tumor size reduction at all dose levels (1 mg/kg, 3 mg/kg and 10 mg/kg 
Q2W). No MTD has been identified to date. 10.0 mg/kg Q2W, the highest dose tested in PN001, 
will be the dose and schedule utilized in Cohorts A, B, C and D of this protocol to test for initial 
tumor activity. Recent data from other clinical studies within the MK-3475 program has shown 
that a lower dose of MK-3475 and a less frequent schedule may be sufficient for target 
engagement and clinical activity.
PK data analysis of MK-3475 administered Q2W and Q3W showed slow systemic clearance, 
limited volume of distribution, and a long half-life (refer to IB). Pharmacodynamic data (IL-2 
release assay) suggested that peripheral target engagement is durable (>21 days). This early PK 
and pharmacodynamic data provides scientific rationale for testing a Q2W and Q3W dosing 
schedule.
A population pharmacokinetic analysis has been performed using serum concentration time data 
from 476 patients. Within the resulting population PK model, clearance and volume parameters 
of MK-3475 were found to be dependent on body weight. The relationship between clearance and 


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body weight, with an allometric exponent of 0.59, is within the range observed for other antibodies 
and would support both body weight normalized dosing or a fixed dose across all body weights.  
MK-3475 has been found to have a wide therapeutic range based on the melanoma indication.  
The differences in exposure for a 200 mg fixed dose regimen relative to a 2 mg/kg Q3W body 
weight based regimen are anticipated to remain well within the established exposure margins of 
0.5 – 5.0 for MK-3475 in the melanoma indication. The exposure margins are based on the notion 
of similar efficacy and safety in melanoma at 10 mg/kg Q3W vs. the proposed dose regimen of 2 
mg/kg Q3W (i.e. 5-fold higher dose and exposure). The population PK evaluation revealed that 
there was no significant impact of tumor burden on exposure. In addition, exposure was similar 
between the NSCLC and melanoma indications. Therefore, there are no anticipated changes in 
exposure between different indication settings.
The rationale for further exploration of 2 mg/kg and comparable doses of pembrolizumab in solid 
tumors is based on: 1) similar efficacy and safety of pembrolizumab when dosed at either 2 mg/kg 
or 10 mg/kg Q3W in melanoma patients, 2) the flat exposure-response relationships of 
pembrolizumab for both efficacy and safety in the dose ranges of 2 mg/kg Q3W to 10 mg/kg Q3W, 
3) the lack of effect of tumor burden or indication on distribution behavior of pembrolizumab (as 
assessed by the population PK model) and 4) the assumption that the dynamics of 
pembrolizumab target engagement will not vary meaningfully with tumor type.
The choice of the 200 mg Q3W as an appropriate dose for the switch to fixed dosing is based on 
simulations performed using the population PK model of pembrolizumab showing that the fixed 
dose of 200 mg every 3 weeks will provide exposures that 1) are optimally consistent with those 
obtained with the 2 mg/kg dose every 3 weeks, 2) will maintain individual patient exposures in the 
exposure range established in melanoma as associated with maximal efficacy response and 3) 
will maintain individual patients exposure in the exposure range established in melanoma that are 
well tolerated and safe. 
A fixed dose regimen will simplify the dosing regimen to be more convenient for physicians and 
to reduce potential for dosing errors. A fixed dosing scheme will also reduce complexity in the 
logistical chain at treatment facilities and reduce wastage.
The combination of ipilimumab and pembrolizumab is considered one of the most effective 
regimens currently in use (Long et al, ASCO 2016) with an ORR of >50% with reduced grade 3/4 
toxicities compared to the combination of ipilimumab and nivolumab. Given that this current 
combination is adding a drug (ASA), ipilimumab pembrolizumab is a better choice for the baseline 
regimen
The addition of ASA is based on preclinical data showing the effectiveness of ASA in increasing 
responses to anti-PD-1 antibodies(3)In this study mice were administered aspirin orally at 600 
µg/mL. translating this dose to a human dose, approximately 1,800-2,400 mg/day would be 
appropriate. In a twice daily dose this would be 975 mg (total 1,950 mg/day). 
1.5
Correlative Studies
We have recently described the CD8+ CTLA-4 high/PD-1 high fraction in the tumor as being 
directly proportional to the response rate. We plan to determine the proportion of patients with 
this marker <20% who have a response as this will be representative of patients who we would 
not expect to have a response with monotherapy PD-1 alone(21). 


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2
Objectives of the Study
2.1
Primary
To evaluate the overall response rate (ORR) by week 12 in patients with stage III unresectable/ 
stage IV melanoma
2.2
Secondary
To determine the median progression free survival, overall survival, and toxicity profile of the 
combination of ipilimumab, pembrolizumab and high dose aspirin in patients with stage III 
unresectable/IV melanoma.
2.3
Endpoints
2.3.1 Primary Endpoints

Objective Response Rate (ORR)
2.3.2 Secondary Endpoints

Toxicity, according to CTCAE v. 4

Profession Free Survival (PFS)

Overall Survival (OS)
3
Study Design
3.1
Characteristics
This is a single arm, single institution, open label, prospective, Phase II clinical trial with a Simon 
stage II design with an early stopping rule. In the first stage 11 patients will be accrued. If ≤7 
responses are seen here then the trial will be stopped for futility. If >7 responses are seen then 
the trial will be continued and a full 43 patients will be enrolled.
Patients will take aspirin daily and receive combination therapy with pembrolizumab and 
ipilimumab every 3 weeks for 4 cycles. After 4 cycles, ipilimumab will be discontinued and 
patients will receive pembrolizumab every 3 weeks and continue taking aspirin daily.
3.2
Number of Subjects
A total of 43 subjects will be enrolled.
3.3
Eligibility Criteria
Patients must have baseline evaluations performed prior to the first dose of study drug and must 
meet all inclusion and exclusion criteria. In addition, the patient must be thoroughly informed about 
all aspects of the study, including the study visit schedule and required evaluations and all 
regulatory requirements for informed consent. The written informed consent must be obtained 
from the patient prior to enrollment. The following criteria apply to all patients enrolled onto the 
study unless otherwise specified.


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3.3.1 Inclusion Criteria
1.
Patients must have histologically confirmed melanoma that is metastatic or unresectable 
and for which standard curative or palliative measures do not exist or are no longer effective
2.
Age >18 years
3.
Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1.
4.
Requirements for organ and marrow function: 
Adequate bone marrow function:
leukocytes
≥ 3,000/mcL
absolute neutrophil count
≥ 1,500/mcL
platelets
≥ 100,000/mcL
Adequate hepatic function:
total bilirubin
within normal institutional limits
total bilirubin
≤1.5 X institutional upper limit
AST(SGOT)
≤ 2.5 X institutional upper limit of normal
ALT(SGPT)
≤ 2.5 X institutional upper limit of normal
Adequate renal function:
creatinine
≤ 1.5 X ULN 
5.
Women of childbearing potential should have a negative urine or serum pregnancy within 
72 hours prior to receiving the first dose of study drug. If the urine test is positive or cannot 
be confirmed as negative, a serum pregnancy test will be required.
6.
Women of childbearing potential (Section 5.6.2) must be willing to use an adequate method 
of contraception, as outlined in Section 5.6.2 – Contraception, for the course of the study 
through 120 days after the last dose of study medication.
Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for 
the subject.
7.
Men of childbearing potential (Section 5.6.2) must agree to use an adequate method of 
contraception as outlined in Section 5.6.2- Contraception, starting with the first dose of study 
therapy through 120 days after the last dose of study therapy.
Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for 
the subject.
8.
Ability to understand a written informed consent document, and the willingness to sign it.
3.3.2 Exclusion Criteria
1.
Any mental or physical condition or disease or past medical history that mitigates against 
following the protocol
2.
History of active autoimmune diseases such as but not limited to Crohn’s disease, Ulcerative 
colitis, Sjogren’s syndrome, requiring active immune suppression. Patient may have hay 
fever or controlled asthma
3.
Any solid organ transplant or bone marrow transplant
4.
Any other disseminated malignancy. Exceptions include: localized prostate cancer, basal or 
squamous cell skin cancer, localized cervical cancer, and localized breast cancer.


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5.
Uncontrolled CNS metastasis. Patients with CNS metastasis can be eligible if definitively 
treated with radiotherapy or surgery. 
6.
Any coexistent medical condition interfering with drug absorption
7.
History of gastritis or malabsorption syndrome or aspirin intolerance or allergy
8.
Live vaccination within the last 30 days
9.
History of multiple sclerosis, Type 1 DM or Guellian-Barre syndrome
10. Is pregnant or breastfeeding, or expecting to conceive or father children within the projected 
duration of the trial, starting with the screening visit through 120 days after the last dose of 
trial treatment.
3.4
Duration of Therapy
In the absence of treatment delays due to adverse events, treatment may continue until:

Disease progression
o
Note: For a clinically stable subject with first radiologic evidence of disease progression 
(e.g. unconfirmed), it is at the discretion of the primary investigator to continue treating 
the subject. 
o
Note: A subject may be granted an exception, at the discretion of the primary 
investigator, to continue on treatment with confirmed radiographic progression if 
clinically stable or clinically improved.

Inter-current illness that prevents further administration of treatment

Unacceptable adverse event(s)

Patients decides to withdraw from the study

Significant patient non-compliance with protocol

General or specific changes in the patients’ condition render the patient unacceptable for 
further treatment in the judgment of the investigator.
3.5
Duration of Follow Up
Patients will be followed for 30 days after completion of treatment or removal from study, or until 
death, whichever occurs first. Patients removed from study for unacceptable treatment related 
adverse event(s) will be followed until resolution or stabilization of all treatment related adverse 
events to Grade 2 or lower.
3.6
Study Timeline
3.6.1 Primary Completion
The study is expected to complete accrual at 24 months.
3.6.2 Study Completion
The study will reach completion 36 months from the time the study opens to accrual.


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4
Study Drugs
The drugs to be used in this study are outlined below.
4.1
Pembrolizumab
Drug Name & Potency
Dosage Form
Pembrolizumab 50 mg
Lyophilized Powder for Injection
Pembrolizumab 100 mg/ 4mL
Solution for Injection
4.1.1 Packaging and Labeling Information
Clinical supplies will be affixed with a clinical label in accordance with regulatory requirements.
4.1.2 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.
4.1.3 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.
4.1.4 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.
4.1.5 Safety Information
Complete and updated adverse event information for pembrolizumab is available in the 
Investigational Drug Brochure and/or product package insert.
4.2
Ipilimumab
Ipilimumab used in this study will be commercial drug supply. Ipilimumab is to be stored as 
directed below. 
Drug Name & Potency
Dosage Form
Ipilimumab 200 mg (5 mg/mL)
Solution for Injection
40 mL/vial (4 vials/carton)


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4.2.1 Packaging and Labeling Information
Clinical supplies will be affixed with a clinical label in accordance with regulatory requirements.
4.2.2 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.
4.2.3 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. Store at 2° - 8°C. Protect from light and freezing.
Clinical supplies may not be used for any purpose other than that stated in the protocol.
•
Do not shake product.
•
Inspect parenteral drug products visually for particulate matter and discoloration prior to 
administration. Discard vial if solution is cloudy, there is pronounced discoloration (solution 
may have pale-yellow color), or there is foreign particulate matter other than translucent-
to-white, amorphous particles.
Preparation of Solution
•
Allow the vials to stand at room temperature for approximately 5 minutes prior to 
preparation of infusion.
•
Withdraw the required volume of ipilimumab and transfer into an intravenous bag.
•
Dilute with 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP to prepare 
a diluted solution with a final concentration ranging from 1 mg/mL to 2 mg/mL. Mix diluted 
solution by gentle inversion.
•
Store the diluted solution for no more than 24 hours under refrigeration (2°C to 8°C, 36°F 
to 46°F) or at room temperature (20°C to 25°C, 68°F to 77°F).
•
Flush the intravenous line with 0.9% Sodium Chloride Injection, USP or 5% Dextrose 
Injection, USP after each dose.
4.2.4 Returns and Reconciliation
4.2.5 Safety Information
WARNINGS AND PRECAUTIONS
Ipilimumab can result in severe and fatal immune-mediated reactions [see Boxed Warning].
Immune-Mediated Enterocolitis
Immune-mediated enterocolitis, including fatal cases, can occur with ipilimumab.
Monitor patients for signs and symptoms of enterocolitis (such as diarrhea, abdominal pain, 
mucus or blood in stool, with or without fever) and of bowel perforation (such as peritoneal signs 
and ileus). In symptomatic patients, rule out infectious etiologies and consider endoscopic 
evaluation for persistent or severe symptoms.


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Permanently discontinue ipilimumab in patients with severe enterocolitis and initiate systemic 
corticosteroids at a dose of 1 to 2 mg/kg/day of prednisone or equivalent. Upon improvement to 
Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. In clinical 
trials, rapid corticosteroid tapering resulted in recurrence or worsening symptoms of enterocolitis 
in some patients. Consider adding anti-TNF or other immunosuppressant agents for management 
of immune-mediated enterocolitis unresponsive to systemic corticosteroids within 3 to 5 days or 
recurring after symptom improvement.
Withhold ipilimumab dosing for moderate enterocolitis; administer anti-diarrheal treatment and, if 
persistent for more than 1 week, initiate systemic corticosteroids at a dose of 0.5 mg/kg/day 
prednisone or equivalent.
Metastatic Melanoma
In patients receiving ipilimumab 3 mg/kg in Trial 1, severe, life-threatening, or fatal (diarrhea of 7 
or more stools above baseline, fever, ileus, peritoneal signs; Grade 3 to 5) immune-mediated 
enterocolitis occurred in 34 ipilimumab-treated patients (7%), and moderate (diarrhea with up to 
6 stools above baseline, abdominal pain, mucus or blood in stool; Grade 2) enterocolitis occurred 
in 28 ipilimumab -treated patients (5%). Across all ipilimumab-treated patients (n=511), 5 patients 
(1%) developed intestinal perforation, 4 patients (0.8%) died as a result of complications, and 26 
patients (5%) were hospitalized for severe enterocolitis.
The median time to onset of Grade 3 to 5 enterocolitis was 1.7 months (range: 11 days to 3.1 
months) and for Grade 2 enterocolitis was 1.4 months (range: 2 days to 4.3 months).
Immune-Mediated Hepatitis
Immune-mediated hepatitis, including fatal cases, can occur with ipilimumab.
Monitor liver function tests (hepatic transaminase and bilirubin levels) and assess patients for 
signs and symptoms of hepatotoxicity before each dose of ipilimumab. In patients with 
hepatotoxicity, rule out infectious or malignant causes and increase frequency of liver function 
test monitoring until resolution.
Permanently discontinue ipilimumab in patients with Grade 3 to 4 hepatotoxicity and administer 
systemic corticosteroids at a dose of 1 to 2 mg/kg/day of prednisone or equivalent. When liver 
function tests show sustained improvement or return to baseline, initiate corticosteroid tapering 
and continue to taper over 1 month. Across the clinical development program for ipilimumab, 
mycophenolate treatment has been administered in patients who have persistent severe hepatitis 
despite high-dose corticosteroids. Withhold ipilimumab in patients with Grade 2 hepatotoxicity.
Metastatic Melanoma
In patients receiving ipilimumab 3 mg/kg in Trial 1, severe, life-threatening, or fatal hepatotoxicity 
(AST or ALT elevations of more than 5 times the upper limit of normal or total bilirubin elevations 
more than 3 times the upper limit of normal; Grade 3 to 5) occurred in 8 ipilimumab-treated 
patients (2%), with fatal hepatic failure in 0.2% and hospitalization in 0.4% of ipilimumab-treated 
patients. An additional 13 patients (2.5%) experienced moderate hepatotoxicity manifested by 
liver function test abnormalities (AST or ALT elevations of more than 2.5 times but not more than 
5 times the upper limit of normal or total bilirubin elevation of
more than 1.5 times but not more than 3 times the upper limit of normal; Grade 2). The underlying 
pathology was not ascertained in all patients but in some instances included immune- mediated 
hepatitis. There were insufficient numbers of patients with biopsy-proven hepatitis to characterize 
the clinical course of this event.


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Immune-Mediated Dermatitis
Immune-mediated dermatitis, including fatal cases, can occur with ipilimumab.
Monitor patients for signs and symptoms of dermatitis, such as rash and pruritus. Unless an 
alternate etiology has been identified, signs or symptoms of dermatitis should be considered 
immune-mediated.
Permanently discontinue ipilimumab in patients with Stevens-Johnson syndrome, toxic epidermal 
necrolysis, or rash complicated by full thickness dermal ulceration, or necrotic, bullous, or 
hemorrhagic manifestations. Administer systemic corticosteroids at a dose of 1 to 2 mg/kg/day of 
prednisone or equivalent. When dermatitis is controlled, corticosteroid tapering should occur over 
a period of at least 1 month. Withhold ipilimumab dosing in patients with moderate to severe signs 
and symptoms [see Dosage and Administration (2.3)].
For mild to moderate dermatitis, such as localized rash and pruritus, treat symptomatically. 
Administer topical or systemic corticosteroids if there is no improvement of symptoms within 1 
week.
Metastatic Melanoma
In patients receiving ipilimumab 3 mg/kg in Trial 1, severe, life-threatening, or fatal immune- 
mediated dermatitis (e.g., Stevens-Johnson syndrome, toxic epidermal necrolysis, or rash 
complicated by full thickness dermal ulceration, or necrotic, bullous, or hemorrhagic 
manifestations; Grade 3 to 5) occurred in 13 ipilimumab-treated patients (2.5%). One patient 
(0.2%) died as a result of toxic epidermal necrolysis and one additional patient required 
hospitalization for severe dermatitis. There were 63 patients (12%) with moderate (Grade 2) 
dermatitis.
The median time to onset of moderate, severe, or life-threatening immune-mediated dermatitis 
was 22 days and ranged up to 4.0 months from the initiation of ipilimumab.
Seven ipilimumab-treated patients (54%) with severe dermatitis received high-dose 
corticosteroids (median dose 60 mg prednisone/day or equivalent) for up to 3.4 months followed 
by corticosteroid taper. Of these 7 patients, 6 had complete resolution; time to resolution ranged 
up to 3.6 months.
Of the 63 patients with moderate dermatitis, 25 (40%) were treated with systemic corticosteroids 
(median of 60 mg/day of prednisone or equivalent) for a median of 15 days, 7 (11%) were treated 
with only topical corticosteroids, and 31 (49%) did not receive systemic or topical corticosteroids. 
Forty-four patients (70%) with moderate dermatitis were reported to have complete resolution, 7 
(11%) improved to mild (Grade 1) severity, and 12 (19%) had no reported improvement.
Immune-Mediated Neuropathies
Immune-mediated neuropathies, including fatal cases, can occur with ipilimumab.
Monitor for symptoms of motor or sensory neuropathy such as unilateral or bilateral weakness, 
sensory alterations, or paresthesia. Permanently discontinue ipilimumab in patients with severe 
neuropathy (interfering with daily activities) such as Guillain-Barré-like syndromes. Institute 
medical intervention as appropriate for management of severe neuropathy. Consider initiation of 
systemic corticosteroids at a dose of 1 to 2 mg/kg/day prednisone or equivalent for severe 
neuropathies. Withhold ipilimumab dosing in patients with moderate neuropathy (not interfering 
with daily activities) [see Dosage and Administration (2.3)].


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Metastatic Melanoma
In patients receiving ipilimumab 3 mg/kg in Trial 1, 1 case of fatal Guillain-Barré syndrome and 1 
case of severe (Grade 3) peripheral motor neuropathy were reported. Across the clinical 
development program of ipilimumab, myasthenia gravis and additional cases of Guillain-Barré 
syndrome have been reported.
Immune-Mediated Endocrinopathies
Immune-mediated endocrinopathies, including life-threatening cases, can occur with ipilimumab.
Monitor patients for clinical signs and symptoms of hypophysitis, adrenal insufficiency (including 
adrenal crisis), and hyper- or hypothyroidism. Patients may present with fatigue, headache, 
mental status changes, abdominal pain, unusual bowel habits, and hypotension, or nonspecific 
symptoms which may resemble other causes such as brain metastasis or underlying disease. 
Unless an alternate etiology has been identified, signs or symptoms of endocrinopathies should 
be considered immune-mediated.
Monitor clinical chemistries, adrenocorticotropic hormone (ACTH) level, and thyroid function tests 
at the start of treatment, before each dose, and as clinically indicated based on symptoms. In a 
limited number of patients, hypophysitis was diagnosed by imaging studies through enlargement 
of the pituitary gland.
Withhold ipilimumab dosing in symptomatic patients and consider referral to an endocrinologist. 
Initiate systemic corticosteroids at a dose of 1 to 2 mg/kg/day of prednisone or equivalent, and 
initiate appropriate hormone replacement therapy [see Dosage and Administration (2.3)].
Metastatic Melanoma
In patients receiving ipilimumab 3 mg/kg in Trial 1, severe to life-threatening immune-mediated 
endocrinopathies (requiring hospitalization, urgent medical intervention, or interfering with 
activities of daily living; Grade 3 to 4) occurred in 9 ipilimumab-treated patients (1.8%). All 9 
patients had hypopituitarism and some had additional concomitant endocrinopathies such as 
adrenal insufficiency, hypogonadism, and hypothyroidism. Six of the 9 patients were hospitalized 
for severe endocrinopathies. Moderate endocrinopathy (requiring hormone replacement or 
medical intervention; Grade 2) occurred in 12 patients (2.3%) and consisted of hypothyroidism, 
adrenal insufficiency, hypopituitarism, and 1 case each of hyperthyroidism and Cushing’s 
syndrome. The median time to onset of moderate to severe immune-mediated endocrinopathy 
was 2.5 months and ranged up to 4.4 months after the initiation of ipilimumab.
Of the 21 patients with moderate to life-threatening endocrinopathy, 17 patients required long-
term hormone replacement therapy including, most commonly, adrenal hormones (n=10) and 
thyroid hormones (n=13).
Other Immune-Mediated Adverse Reactions, Including Ocular Manifestations
Permanently discontinue ipilimumab for clinically significant or severe immune-mediated adverse 
reactions. Initiate systemic corticosteroids at a dose of 1 to 2 mg/kg/day prednisone or equivalent 
for severe immune-mediated adverse reactions.
Administer corticosteroid eye drops to patients who develop uveitis, iritis, or episcleritis. 
Permanently discontinue ipilimumab for immune-mediated ocular disease that is unresponsive to 
local immunosuppressive therapy [see Dosage and Administration (2.3)].


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Metastatic Melanoma
In Trial 1, the following clinically significant immune-mediated adverse reactions were seen in less 
than 1% of ipilimumab-treated patients: nephritis, pneumonitis, meningitis, pericarditis, uveitis, 
iritis, and hemolytic anemia.
Other Clinical Experience
Across 21 dose-ranging trials administering ipilimumab at doses of 0.1 to 20 mg/kg (n=2478), the 
following likely immune-mediated adverse reactions were also reported with less than 1% 
incidence: angiopathy, temporal arteritis, vasculitis, polymyalgia rheumatica, conjunctivitis, 
blepharitis, episcleritis, scleritis, iritis, leukocytoclastic vasculitis, erythema multiforme, psoriasis, 
arthritis, autoimmune thyroiditis, neurosensory hypoacusis, autoimmune central neuropathy 
(encephalitis), myositis, polymyositis, ocular myositis, hemolytic anemia, and nephritis.
Embryo-fetal Toxicity
Based on its mechanism of action and data from animal studies, ipilimumab can cause fetal harm 
when administered to a pregnant woman. In animal reproduction studies, administration of 
ipilimumab to cynomolgus monkeys from the onset of organogenesis through delivery resulted in 
higher incidences of abortion, stillbirth, premature delivery (with corresponding lower birth weight), 
and higher incidences of infant mortality in a dose-related manner. The effects of ipilimumab are 
likely to be greater during the second and third trimesters of pregnancy. Advise pregnant women 
of the potential risk to a fetus. Advise females of reproductive potential to use effective 
contraception during treatment with a ipilimumab-containing regimen and for 3 months after the 
last dose of ipilimumab [see Use in Specific Populations (8.1, 8.3)].
4.3
Aspirin (Acetyl Salicylic Acid)
Aspirin used in this study will be commercial drug supply. Aspirin is to be stored as directed below.
4.3.1 Packaging and Labeling Information
Aspirin will be provided from a commercial supplier as tablets 325 mg size. 
4.3.2 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. 
4.3.3 Storage and Handling Requirements
Clinical supplies must be stored in a secure, limited-access location at room temperature. Protect 
from light and freezing. Clinical supplies may not be used for any purpose other than that stated 
in the protocol. Receipt and dispensing of trial medication must be recorded by an authorized 
person at the trial site. 
4.3.4 Returns and Reconciliation
Supplies will be tracked by the investigational pharmacist and dispensed directly to the patient. 


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4.3.5 Safety Information
Aspirin is associated with serious side effects including GI bleeding , renal side effects as well as 
platelet and bleeding abnormalities. The FDA has reviewed aspirin side effect  and a 
comprehensive review is at https://www.drugs.com/monograph/aspirin.html. 
5
Treatment Plan
5.1
Dosage and Administration
Table 1 Regimen Description
Drug
Dose/Potency
Dose 
Frequency
Route of 
Administration
Regimen/Treatment 
Period
Use
Pembrolizumab
200 mg
Q3W
IV infusion
Day 1 of each 3 week 
cycle
Experimental
Ipilimumab
1 mg/kg
Q3wk X4
IV infusion
Day 1 of each 3 wk 
cycle, for 4 cycles
experimental
Aspirin
975 mg
PO BID
oral
Each day
experimental
Trial treatment should begin on the day of randomization or as close as possible to the date on 
which treatment is allocated/assigned.
5.2
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 3 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.
Pembrolizumab 200 mg will be administered as a 30 minute IV infusion every 3 weeks. Sites 
should make every effort to target infusion timing to be as close to 30 minutes as possible. 
However, given the variability of infusion pumps from site to site, a window of -5 minutes and +10 
minutes is permitted (i.e., infusion time is 30 minutes: -5 min/+10 min).
Ipilimumab, 1 mg/kg will be administered for 4 cycles as a 60 minute intravenous infusion following 
the pembrolizumab. No premedication is used routinely. If any infusion reaction is suspected, the 
infusion may be stopped and antihistamines may be administered (Benadryl 50 mg PO or 25 mg 
IV) and the infusion restarted. 
Aspirin, 975 mg PO Twice daily is taken orally by the patient. An adequate number of pills will be 
dispensed every 3 weeks and pill counts done to ensure compliance
5.3
Dose Modifications and Dosing Delays
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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5.3.1 Dose Modification for Pembrolizumab
Adverse events (both non-serious and serious) associated with pembrolizumab exposure may 
represent an immunologic etiology. These adverse events may occur shortly after the first dose 
or several months after the last dose of treatment. Pembrolizumab must be withheld for drug-
related toxicities and severe or life-threatening AEs as per 3 below. See Section 5.6 for supportive 
care guidelines, including use of corticosteroids.


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Table 2 Pembrolizumab 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 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
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


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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) 
Grade 2
Continue 
Hyperthyroidism 
Grade 3 or 4 
Withhold or 
permanently discontinue1

Treat with non-selective 
beta-blockers (e.g., 
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


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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).  


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5.3.2 Dose Modification for Ipilimumab
Note that ipilimumab is only used for Cycles 1-4. Therefore in the case of ipilimumab being held, 
Pembrolizumab may be continued if not specifically contraindicated. Aspirin may also be 
continued unless specifically contraindicated 
Table 3 Ipilimumab Dose Modification Guidelines for Drug-Related Adverse Events
Toxicity
Hold 
For 
Grade
Timing for Restarting 
Treatment
Treatment Discontinuation
2
Toxicity resolves to Grade 
0-1
Toxicity does not resolve within 12 weeks of last 
dose or inability to reduce corticosteroid to 10 mg 
or less of prednisone or equivalent per day within 
12 weeks. Patients are to be treated with 1 mg/kg 
prednisone or equivalent if grade 2 or greater 
toxicity and tapered over several weeks
Diarrhea/Colitis
3-4
Permanently discontinue
Permanently discontinue
2
Toxicity resolves to Grade 
0-1
Toxicity does not resolve within 12 weeks of last 
dose
AST, ALT, or 
Increased Bilirubin
3-4
Permanently discontinue
(see exception below)a
Permanently discontinue
Type 1 diabetes 
mellitus (if new 
onset) or 
Hyperglycemia
T1DM 
or 
3-4
Hold ipilimumab for new 
onset Type 1 diabetes 
mellitus or Grade 3-4 
hyperglycemia associated 
with evidence of beta cell 
failure
Discontinue permanently
Hypophysitis
2-4
Toxicity resolves to Grade 
0-1. Therapy with 
pembrolizumab can be 
continued while endocrine 
replacement therapy is 
instituted
Toxicity does not resolve within 12 weeks of last 
dose or inability to reduce corticosteroid to 10 mg 
or less of prednisone or equivalent per day within 
12 weeks
3
Toxicity resolves to Grade 
0-1
Toxicity does not resolve within 12 weeks of last 
dose or inability to reduce corticosteroid to 10 mg 
or less of prednisone or equivalent per day within 
12 weeks
Hyperthyroidism 
4
Permanently discontinue
Permanently discontinue
Hypothyroidism
Therapy with ipilimumab can 
be continued while thyroid 
replacement therapy is 
instituted
Therapy with ipilimumab can be continued while 
thyroid replacement therapy is instituted
2b
Toxicity resolves to Grade 
0-1 
Permanently discontinue if toxicity develops 
despite adequate premedication 
Infusion Reaction
3-4
Permanently discontinue
Permanently discontinue
2
Toxicity resolves to Grade 
0-1
Toxicity does not resolve within 12 weeks of last 
dose or inability to reduce corticosteroid to 10 mg 
or less of prednisone or equivalent per day within 
12 weeks
Pneumonitis
3-4
Permanently discontinue
Permanently discontinue
2
Toxicity resolves to Grade 
0-1
Toxicity does not resolve within 12 weeks of last 
dose or inability to reduce corticosteroid to 10 mg 
or less of prednisone or equivalent per day within 
12 weeks
Renal Failure or 
Nephritis
3-4
Permanently discontinue
Permanently discontinue


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Toxicity
Hold 
For 
Grade
Timing for Restarting 
Treatment
Treatment Discontinuation
3 or 
Severe
Toxicity resolves to Grade 
0-1
Toxicity does not resolve within 12 weeks of last 
dose or inability to reduce corticosteroid to 10 mg 
or less of prednisone or equivalent per day within 
12 weeks
All Other Drug-
Related Toxicityc
4
Permanently discontinue
Permanently discontinue
5.3.3 Dose Modification for Aspirin
Note that aspirin is known to cause GI bleeding, ulceration and hemorrhage. Any evidence of GI 
bleeding or ulceration based on symptoms or endoscopy should be treated as described below. 
For Grade 1 or 2 adverse events, patients may have proton pump inhibitor or sucralfate treatment 
along with aspirin.
Table 4 Aspirin Dose Modification Guidelines for Drug-Related Adverse Events
Toxicity
Hold 
Treatment 
For Grade
Timing for Restarting 
Treatment
Treatment Discontinuation
2
Toxicity resolves to Grade 
0-1
Toxicity does not resolve within 2 weeks, 
or continued bleeding, or life threatening 
or serious Grade 3 or 4 hemorrhage
GI Bleeding
3-4
Permanently discontinue
Permanently discontinue
Renal Failure 
or Nephritis
2
Toxicity resolves to Grade 
0-1
Toxicity does not resolve within 4 weeks
1-2
Use omeprazole or PPI or 
sucralfate if not currently 
being used
May continue aspirin if symptoms resolve 
with treatment
GI Ulceration
3-4  or 
Severe
Toxicity resolves to Grade 
1 or 0
Life threatening or serious Grade 3 or 4 
toxicity
5.4
Rescue Medications & Supportive Care
5.4.1 Supportive Care Guidelines
Subjects should receive appropriate supportive care measures as deemed necessary by the 
treating investigator. Suggested supportive care measures for the management of adverse events 
with potential immunologic etiology are outlined below. Where appropriate, these guidelines 
include the use of oral or intravenous treatment with corticosteroids as well as additional anti-
inflammatory agents if symptoms do not improve with administration of corticosteroids. Note that 
several courses of steroid tapering may be necessary as symptoms may worsen when the steroid 
dose is decreased. For each disorder, attempts should be made to rule out other causes such as 
metastatic disease or bacterial or viral infection, which might require additional supportive care. 
The treatment guidelines are intended to be applied when the investigator determines the events 
to be related to pembrolizumab. 
Note: if after the evaluation the event is determined not to be related, the investigator does not 
need to follow the treatment guidance (as outlined below). Refer to Section 5.3 for dose 
modification. 
It may be necessary to perform conditional procedures such as bronchoscopy, endoscopy, or skin 
photography as part of evaluation of the event. 


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
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, administer oral corticosteroids. 
o
For Grade 3 or 4 diarrhea/colitis, 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. 

Hypophysitis:
o
For Grade 2 events, treat with corticosteroids. When symptoms improve to Grade 
1 or less, steroid taper should be started and continued over no less than 4 weeks. 
Replacement of appropriate hormones may be required as the steroid dose is 
tapered.
o
For Grade 3-4 events, treat with an initial dose of IV corticosteroids followed by 
oral corticosteroids. When symptoms improve to Grade 1 or less, steroid taper 
should be started and continued over no less than 4 weeks. Replacement of 
appropriate hormones may be required as the steroid dose is tapered.

Hyperthyroidism or Hypothyroidism: Thyroid disorders can occur at any time during 
treatment. Monitor patients for changes in thyroid function (at the start of treatment, 
periodically during treatment, and as indicated based on clinical evaluation) and for clinical 
signs and symptoms of thyroid disorders.


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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 Infusion Reactions: Signs and symptoms usually develop during or 
shortly after drug infusion and generally resolve completely within 24 hours of completion 
of infusion.
The table below shows treatment guidelines for subjects who experience an infusion reaction 
associated with administration of pembrolizumab.


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Table 5 Infusion Reaction Treatment Guidelines
NCI CTCAE Grade
Treatment
Premedication at 
subsequent dosing
Grade 1
Mild reaction; infusion interruption not 
indicated; intervention not indicated
Increase monitoring of vital signs as 
medically indicated until the subject is 
deemed medically stable in the opinion of 
the investigator.
None
Grade 2
Requires infusion interruption but 
responds promptly to symptomatic 
treatment (e.g., antihistamines, 
NSAIDS, narcotics, IV fluids); 
prophylactic medications indicated for 
< =24 hrs
Stop Infusion and monitor symptoms.
Additional appropriate medical therapy may 
include but is not limited to:
IV fluids
Antihistamines
NSAIDS
Acetaminophen
Narcotics
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 (MK-
3475) with:
Diphenhydramine 50 mg 
po (or equivalent dose of 
antihistamine).
Acetaminophen 500-1000 
mg po (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
Appropriate resuscitation equipment should be available in the room and a physician readily available during the 
period of drug administration.
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 


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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.
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 
o
Note: Radiation therapy to a symptomatic solitary lesion or to the brain may be 
allowed at the investigator’s discretion.  
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.  Daily or regular use of 
NSAIDs should be avoided except for the aspirin as specified in the trial. Concomitant NSAID use 
more frequently than once per week may be allowed at the investigator’s discretion.  
The Exclusion Criteria describes other medications which are prohibited in this trial.
There are no prohibited therapies for patients after they discontinue study treatment.


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5.6
Diet/Activity/Other Considerations
5.6.1 Diet
Subjects should maintain a normal diet unless modifications are required to manage an AE such 
as diarrhea, nausea or vomiting.
5.6.2 Contraception
Pembrolizumab may have adverse effects on a fetus in utero.  Furthermore, it is not known if 
pembrolizumab has transient adverse effects on the composition of sperm.  
For this trial, male subjects will be considered to be of non-reproductive potential if they have 
azoospermia (whether due to having had a vasectomy or due to an underlying medical condition).  
Female subjects will be considered of non-reproductive potential if they are either: 
1.
 postmenopausal (defined as at least 12 months with no menses without an alternative 
medical cause; in women < 45 years of age a high follicle stimulating hormone (FSH) level 
in the postmenopausal range may be used to confirm a post-menopausal state in women 
not using hormonal contraception or hormonal replacement therapy. In the absence of 12 
months of amenorrhea, a single FSH measurement is insufficient.); 
OR 
2.
have had a hysterectomy and/or bilateral oophorectomy, bilateral salpingectomy or 
bilateral tubal ligation/occlusion, at least 6 weeks prior to screening; 
OR
3.
has a congenital or acquired condition that prevents childbearing.
Female and male subjects of reproductive potential must agree to avoid becoming pregnant or 
impregnating a partner, respectively, while receiving study drug and for 120 days after the last 
dose of study drug by complying with one of the following:  
1.
 practice abstinence† from heterosexual activity; 
OR 
2.
use (or have their partner use) acceptable contraception during heterosexual activity.  
Acceptable methods of contraception are‡:
Single method (one of the following is acceptable):
•
intrauterine device (IUD)
•
vasectomy of a female subject’s male partner 
•
contraceptive rod implanted into the skin
Combination method (requires use of two of the following):


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•
diaphragm with spermicide (cannot be used in conjunction with cervical 
cap/spermicide)
•
cervical cap with spermicide (nulliparous women only)
•
contraceptive sponge (nulliparous women only)
•
male condom or female condom (cannot be used together)
•
hormonal contraceptive: oral contraceptive pill (estrogen/progestin pill or progestin-
only pill), contraceptive skin patch, vaginal contraceptive ring, or subcutaneous 
contraceptive injection
†Abstinence (relative to heterosexual activity) can be used as the sole method of contraception if 
it is consistently employed as the subject’s preferred and usual lifestyle and if considered 
acceptable by local regulatory agencies and ERCs/IRBs. Periodic abstinence (e.g., calendar, 
ovulation, sympto-thermal, post-ovulation methods, etc.) and withdrawal are not acceptable 
methods of contraception. 
‡If a contraceptive method listed above is restricted by local regulations/guidelines, then it does 
not qualify as an acceptable method of contraception for subjects participating at sites in this 
country/region.
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 
subjects of childbearing potential must adhere to the contraception requirement (described above) 
from the day of study medication initiation (or 14 days prior to the initiation of study medication for 
oral contraception) throughout the study period up to 120 days after the last dose of trial therapy. 
If there is any question that a subject of childbearing potential will not reliably comply with the 
requirements for contraception, that subject should not be entered into the study.
5.6.3 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).
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.
5.6.4 Use in Nursing Women
It is unknown whether pembrolizumab is excreted in human milk. Since many drugs are excreted 
in human milk, and because of the potential for serious adverse reactions in the nursing infant, 
subjects who are breast-feeding are not eligible for enrollment.


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5.6.5 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 6.3 - 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.

Confirmed radiographic disease progression
Note: For a clinically stable subject with first radiologic evidence of disease progression (e.g., 
unconfirmed), it is at the discretion of the site investigator to continue treating the subject 
Note: A subject may be granted an exception to continue on treatment with confirmed 
radiographic progression if clinically stable or clinically improved.

Unacceptable adverse experiences as described in Section 7.4

Intercurrent illness that prevents further administration of treatment

Investigator’s decision to withdraw the subject

The subject has a confirmed positive serum pregnancy test

Noncompliance with trial treatment or procedure requirements

The subject is lost to follow-up

Administrative reasons
The End of Treatment and Follow-up visit procedures are listed in Section 6 (Protocol Flow Chart) 
and Section 6.3 - Other Procedures. After the end of treatment, each subject will be followed for 
30 days for adverse event monitoring.
5.6.6 Discontinuation of Study Therapy after CR 
Discontinuation of treatment may be considered for subjects who have attained a confirmed CR, 
at the discretion of the primary investigator.
5.6.7 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
Study Procedures and Observations
The Trial Flow Chart 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.
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.
6.1
Administrative Procedures
6.1.1 Informed Consent
The Investigator must obtain documented consent from each potential subject prior to 
participating in a clinical trial.
General Informed Consent
Consent must be documented by the subject’s dated signature or by the subject’s legally 
acceptable representative’s dated signature on a consent form along with the dated signature of 
the person conducting the consent discussion. 
A copy of the signed and dated consent form should be given to the subject before participation 
in the trial.
The initial informed consent form, any subsequent revised written informed consent form and any 
written information provided to the subject must receive the IRB/ERC’s approval/favorable opinion 
in advance of use. The subject or his/her legally acceptable representative should be informed in 
a timely manner if new information becomes available that may be relevant to the subject’s 
willingness to continue participation in the trial. The communication of this information will be 
provided and documented via a revised consent form or addendum to the original consent form 
that captures the subject’s dated signature or by the subject’s legally acceptable representative’s 
dated signature.
Specifics about a trial and the trial population will be added to the consent form template at the 
protocol level.
The informed consent will adhere to IRB/ERC requirements, applicable laws and regulations and 
Sponsor requirements.
6.1.2 Inclusion/Exclusion Criteria
All inclusion and exclusion criteria will be reviewed by the investigator or qualified designee to 
ensure that the subject qualifies for the trial.
6.1.3 Medical History
A medical history will be obtained by the investigator or qualified designee. Medical history will 
include all active conditions, and any 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.
6.1.4 Prior and Concomitant Medications Review
6.1.4.1 Prior Medications
The investigator or qualified designee will review prior medication use, including any protocol-
specified washout requirement, and record prior medication taken by the subject within 28 days 
before starting the trial. Treatment for the disease for which the subject has enrolled in this study 
will be recorded separately and not listed as a prior medication.
6.1.4.2 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.
6.1.5 Disease Details and Treatments
6.1.5.1 Disease Details
The investigator or qualified designee will obtain prior and current details regarding disease 
status. 
6.1.5.2 Prior Treatment Details
The investigator or qualified designee will review all prior cancer treatments including systemic 
treatments, radiation and surgeries.
6.1.5.3 Subsequent Anti-Cancer Therapy Status
The investigator or qualified designee will review all new anti-neoplastic therapy initiated after the 
last dose of trial treatment. If a subject initiates a new anti-cancer therapy within 30 days after the 
last dose of trial treatment, the 30 day Safety Follow-up visit must occur before the first dose of 
the new therapy. Once new anti-cancer therapy has been initiated the subject will move off-study.
6.2
Clinical Procedures/Assessments
6.2.1 Adverse Event (AE) Monitoring
The investigator or qualified designee will assess each subject to evaluate for potential new or 
worsening AEs as specified in the Trial Flow Chart and more frequently if clinically indicated. 
Adverse experiences will be graded and recorded throughout the study and during the follow-up 
period according to NCI CTCAE Version 4.0. Toxicities will be characterized in terms regarding 
seriousness, causality, toxicity grading, and action taken with regard to trial treatment. 
For subjects receiving treatment all AEs of unknown etiology associated with treatment 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).
Please refer to Section 7 for detailed information regarding the assessment and recording of AEs.


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6.2.2 Full Physical Exam
The investigator or qualified designee will perform a complete physical exam at screening, on 
C1D1 of each treatment cycle, and at discontinuation of treatment, as specified in the Study Flow 
Chart (Section 6.0). Clinically significant abnormal findings should be recorded as medical history.
6.2.3 Vital Signs
The investigator or qualified designee will take vital signs at screening, on C1D1 of each treatment 
cycle, and at discontinuation of treatment as specified in the Study Flow Chart  (Section 6.0). Vital 
signs should include temperature, pulse, respiratory rate, weight and blood pressure. Height will 
be measured at screening only.
6.2.4 Eastern Cooperative Oncology Group (ECOG) Performance Scale
The investigator or qualified designee will assess ECOG status (see Appendix 1) at screening, 
prior to the administration of each dose of trial treatment and at discontinuation of trial treatment 
as specified in the Study Flow Chart.
6.2.5 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 the table below.


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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 thriiodothyronine (T3)
Absolute Neutrophil 
Count
Carbon Dioxide ‡
results are noted
Free tyroxine (T4)
Absolute Lymphocyte 
Count
  (CO2 or biocarbonate)
Urine pregnancy test †
Thyroid stimulating hormone 
(TSH)
Uric Acid
PK
Calcium
Chloride
Blood for correlative studies
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
† 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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Laboratory tests for screening should be performed within 10 days prior to the first dose of 
treatment. After Cycle 1, pre-dose laboratory procedures can be conducted up to 72 hours prior 
to dosing. Results must be reviewed by the investigator or qualified designee and found to be 
acceptable prior to initiation of each treatment cycle.
6.2.6  Tumor Tissue Collection
At screening, patients with archival tissue or fresh tissue samples available will have their 
samples collected and tested for PD-L1 expression. FFPE blocks will be requested from 
specimens containing melanoma tissue and 5 slides of 5uM thickness will be cut from each 
block. The unstained slides will be shipped to Qualtek for staining with the 22C3 antibody. The 
stained samples will be graded according to MEL score.
6.2.7 Tumor Imaging
Prefer imaging of chest/abdomen and pelvis. PET/CT, CT, or MRI are acceptable. Imaging to be 
performed every 12 weeks (every 4 cycles).
6.3
Other Procedures
6.3.1 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. 
6.3.2 Visit Requirements
Visit requirements are outlined in Table 6 Study Flow Chart. Specific procedure-related details 
are provided above in Section 6.2 - Clinical Procedures/Assessments.
6.3.3 Safety Follow-Up Visit
The Safety Follow-Up Visit should be conducted approximately 30 days after the last dose of trial 
treatment or before the initiation of a new anti-cancer treatment, whichever comes first. All AEs 
that occur prior to the Safety Follow-Up Visit should be recorded. 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.
6.3.4 Follow-up Visits
Patients who discontinue treatment will be followed as clinically indicated.
7
Assessing and Recording Adverse Events
An adverse event is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product and which does not necessarily have 
to have a causal relationship with this treatment. An adverse event can therefore be any 
unfavorable and unintended sign (including an abnormal laboratory finding, for example), 


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symptom, or disease temporally associated with the use of a medicinal product or protocol-
specified procedure, whether or not considered related to the medicinal product or protocol-
specified procedure. Any worsening (i.e., any clinically significant adverse change in frequency 
and/or intensity) of a preexisting condition that is temporally associated with the use of the Merck’s 
product, is also an adverse event.
Changes resulting from normal growth and development that do not vary significantly in frequency 
or severity from expected levels are not to be considered adverse events. Examples of this may 
include, but are not limited to, teething, typical crying in infants and children and onset of menses 
or menopause occurring at a physiologically appropriate time.
Merck product includes any pharmaceutical product, biological product, device, diagnostic agent 
or protocol-specified procedure, whether investigational (including placebo or active comparator 
medication) or marketed, manufactured by, licensed by, provided by or distributed by Merck for 
human use.
Adverse events may occur during the course of the use of Merck product in clinical trials, or as 
prescribed in clinical practice, from overdose (whether accidental or intentional), from abuse and 
from withdrawal.
Progression of the cancer under study is not considered an adverse event.
All adverse events that occur after the consent form is signed but before treatment 
allocation/randomization must be reported by the investigator if they cause the subject 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.
From the time of treatment allocation/randomization through 30 days following cessation of 
treatment, all adverse events must be reported by the investigator. Such events will be recorded 
at each examination on the Adverse Event case report forms/worksheets. The reporting 
timeframe for adverse events meeting any serious criteria is described in section 7.3. The 
investigator will make every attempt to follow all subjects with non-serious adverse events for 
outcome.
Adverse events will not be collected for subjects during the pre-screening period (for 
determination of archival tissue status) as long as that subject has not undergone any protocol-
specified procedure or intervention. If the subject requires a blood draw, fresh tumor biopsy etc., 
the subject is first required to provide consent to the main study and AEs will be captured 
according to guidelines for standard AE reporting. 
7.1
Definition of an Overdose for This Protocol and Reporting of Overdose to 
the Sponsor and to Merck
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.


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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 to Merck Global Safety. 
 
7.2
Reporting of Pregnancy and Lactation to the Sponsor and to Merck
Although pregnancy and lactation are not considered adverse events, it is the responsibility of 
investigators or their designees to report any pregnancy or lactation in a subject (spontaneously 
reported to them) that occurs during the trial.
Pregnancies and lactations that occur after the consent form is signed but before treatment 
allocation/randomization must be reported by the investigator if they cause the subject 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 lactations that occur from the time of treatment allocation/randomization through 
120 days following cessation of Sponsor’s product, or 30 days following cessation of treatment if 
the subject 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.
Such events must be reported within 24 hours to the Sponsor and within 2 working days to Merck 
Global Safety.
7.3
Immediate Reporting of Adverse Events to the Sponsor and to Merck
7.3.1 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 an other important medical event 


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
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.
o
Is a new cancer (that is not a condition of the study);
o
Is associated with an overdose.
Refer to Table 8 Evaluating Adverse Events for additional details regarding each of the above 
criteria.
For the time period beginning when the consent form is signed until treatment 
allocation/randomization, 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 must be reported within 24 hours to the Sponsor and within 2 working days to Merck 
Global Safety if it causes the subject 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 allocation/randomization through 30 days following 
cessation of treatment, or at the time that the subject initiates new anticancer therapy, whichever 
is earlier, 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 , whether or not related to the 
Merck product, must be reported within 24 hours to the Sponsor and within 2 working days to 
Merck Global Safety.
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 
following consent through the end of the specified safety follow-up period specified in the 
paragraph above, or at any time outside of the time period specified in the previous paragraph 
also must be reported immediately to the Sponsor and to Merck Global Safety.
All subjects with serious adverse events must be followed up for outcome.
SAE reports and any other relevant safety information are to be forwarded to 
Merck 
Global Safety 
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 
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.
7.3.2 Events of Clinical Interest
Selected non-serious and serious adverse events are also known as Events of Clinical Interest 
(ECI) and must be reported within 24 hours to the Sponsor and within 2 working days to Merck 
Global Safety.


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For the time period beginning when the consent form is signed until treatment 
allocation/randomization, any ECI, or follow up to an ECI, that occurs to any subject must be 
reported within 24 hours to the Sponsor and within 2 working days to Merck Global Safety if it 
causes the subject 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 allocation/randomization through 30 days following 
cessation of treatment, or until the time that a subject 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 24 hours to the Sponsor and within 24 hours to Merck Global Safety.
Events of clinical interest for this trial include:
1.
an overdose of Merck product, as defined in Section 7.1 - 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. 
7.3.3 Protocol-Specific Exceptions to Serious Adverse Event Reporting 
Efficacy endpoints as outlined in this section will not be reported to Merck as described in Section 
7.3 - Immediate Reporting of Adverse Events to the Sponsor and to Merck, unless there is 
evidence suggesting a causal relationship between the drug and the event. Any such event will 
be submitted to the Sponsor within 24 hours and to Merck Global Safety within 2 working days 
either by electronic or paper media.
Specifically, the suspected/actual events covered in this exception include any event that is 
disease progression of the cancer under study.
The Sponsor will monitor unblinded aggregated efficacy endpoint events and safety data to 
ensure the safety of the subjects in the trial. Any suspected endpoint which upon review is not 
progression of the cancer under study will be forwarded to Merck Global Safety as a SAE within 
2 working days of determination that the event is not progression of the cancer under study 
Hospitalization related to convenience (e.g.transportation issues etc.) will not be considered a 
SAE.
7.4
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.


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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:
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.
V4.0 CTCAE 
Grading
Grade 5
Death related to AE
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 for an elective procedure to treat a pre-existing condition that has not worsened is not a serious adverse 
event.  A pre-existing condition is a clinical condition that is diagnosed prior to the use of a Merck product and is documented 
in the patient’s medical history.); 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) (although not serious per ICH definition, is reportable to the Sponsor 
within 24 hours and to Merck within 2 working days to meet certain local requirements); or
Is an overdose (whether accidental or intentional).  Any adverse event associated with an overdose is considered a serious 
adverse event for collection purposes. 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 to the Sponsor and to Merck within 2 working days..
Seriousness
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 Merck product to be discontinued?
Relationship to 
Merck Product 
Did Merck product cause the adverse event? The determination of the likelihood that 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 


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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 Merck product and the AE; the greater 
the correlation with the components and their respective elements (in number and/or intensity), the more likely Merck product 
caused the adverse event (AE):
Exposure
Is there evidence that the subject was actually exposed to 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 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
The following components are to be used to assess the relationship between the test drug and the AE: (continued)
Dechallenge
Was 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 Sponsor’s product; or (3) the trial is a single-dose 
drug trial); or (4) Sponsor’s product(s) is/are only used one time.)
Rechallenge
Was the subject re-exposed to 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) Sponsor’s 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 MERCK PRODUCT, OR IF REEXPOSURE TO 
MERCK PRODUCT POSES ADDITIONAL POTENTIAL SIGNIFICANT RISK TO THE SUBJECT, 
THEN THE RECHALLENGE MUST BE APPROVED IN ADVANCE BY THE SPONSOR AS PER 
DOSE MODIFICATION GUIDELINES IN THE PROTOCOL.
Relationship 
to Merck 
Product 
(continued)
Consistency with 
Trial Treatment 
Profile
Is the clinical/pathological presentation of the AE consistent with previous knowledge regarding 
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.


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Record one of the following
Use the following scale of criteria as guidance (not all criteria must be present to be indicative 
of Merck product relationship).
Yes, there is a reasonable possibility 
of Merck product relationship.
There is evidence of exposure to Merck product.  The temporal sequence of the AE onset relative to 
the administration of Merck product is reasonable.  The AE is more likely explained by Merck product 
than by another cause.
No, there is not a reasonable 
possibility of Merck product 
relationship
Subject did not receive the Merck  product OR temporal sequence of the AE onset relative to 
administration of Merck product is not reasonable OR the AE is more likely explained by another 
cause than the Merck product.  (Also entered for a subject with overdose without an associated AE.)


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7.5
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
Statistical Analysis Plan
8.1
Statistical Analysis Plan Summary
This is a non-randomized prospective Phase II clinical trial with a Simon stage II design with an 
early stopping provision. The primary objective is to evaluate the overall response rate (ORR) by 
week 12 in patients with stage III unresectable/stage IV melanoma.The hypothesis is that the 
study treatment regimen will have a clinical meaningful improvement in ORR by week 12. H0 is 
for an ORR by week 12 = 60% while Ha is for an ORR by week 12= 80%. 60% is used as a 
threshold for the H0 based on published data (19).
8.2
Sample Size and Accrual Rate Considerations
8.2.1 Sample Size and Power Estimate
A two-stage Simon’s optimal design is used for the study to test the null hypothesis that the ORR 
by week 12 is 60% or less versus the alternative hypothesis that the ORR by week 12 is greater 
than 80% using an one-sided test with 5% level of significance with the power of 80% for 
alternative hypothesis. An initial 11 evaluable patients will be accrued at the end of stage 1. If at 
least 4 or more overall responders (CR/PR per RECIST 1.1) from stage 1 are observed, the study 
will continue to enroll additional 32 evaluable patients in the stage 2. The null hypothesis will be 
rejected at the 5% level of significance (one-sided) if there are 30 or fewer ORR by week 12 
among all 43 evaluable patients by  the end of stage 2. If the ORR rate is 60%, the probability of 
ending the study during the first stage is 70%; if the ORR rate is indeed 80%, the probability of 
study will be terminated at the first stage is 16%. The significance level of the study is 0.05 and 
the power is 0.80 for the study design.
8.2.2 Replacement Policy
Patients who are of unknown clinical response and discontinued due to AEs will be treated as 
non-responders. Other missing data will simply be noted as missing on the appropriate table or 
listing. Patients with missing data will not be replaced.
8.2.3 Accrual Estimates
The study is planned to accrue a total of 43 evaluable patients. The accrual rate is expected to 
be approximately 2 to 3 patients per month. It is expected to take about 24 months to accrue all 
43 evaluable patients. We expect to enroll up to 50 patients to offset the potential drop-outs or 
non-evaluable patients in the study.
8.3
Interim Analyses and Stopping Rules
The two stage sequential design of this study has a decision timepoint based on the counts of CR 
or PR (per RECIST 1.1) from stage 1 by at least 4 months post-initial treatment regimen of the 11 
patients with measurable disease at baseline, to either stop or initiate stage 2 of the study. In the 
first stage 11 patients will be accrued. If ≤7 responses are seen here then the trial will be stopped 


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for futility. If >7 responses are seen then the trial will be continued an a full 43 patients will be 
enrolled.
8.4
Statistical Analysis Plan
This is a Simon 2 stage Phase II prospective clinical trial. The statistical plan will be for an optimal 
2 stage design with the P0=0.6 and P1=0.8. If <30 responses are seen then the experimental 
hypothesis has been rejected. The type 1 error is 0.0489 and the power is 0.8024. The probability 
of early stopping if the response rate is P0=20.5 %
8.4.1 Analysis of Primary Endpoints
The primary efficacy endpoint of the study is the objective response rate (ORR), which is defined 
as the proportion of subjects for whom the best overall response by week 12 at the time of data 
cutoff is confirmed CR or PR as per RECIST. RECIST version 1.1 will be used in this study for 
assessment of tumor response. While either CT or MRI may be utilized, as per RECIST 1.1, CT 
is the preferred imaging technique in this study. In the primary analysis, point estimates of ORR 
and 95% confidence intervals will be provided. Subjects who do not have any post-baseline tumor 
assessments will be considered as non-responders. Supportive analysis of ORR may be 
performed to include response based on investigator assessment. If sufficient responses are 
observed, additional supportive analyses may be conducted in subgroups defined by baseline 
characteristics.
8.4.2 Analysis of Secondary Endpoints
For analysis of secondary endpoints, progression-free survival at 6 months is defined as the 
proportion of subjects alive and progression-free 6 months (182 days) after study day 1. Duration 
of PFS is defined as the time from the study day 1 to the earlier of disease progression or death 
due to any cause. The analysis of PFS will include only objective progression events per RECIST 
and clinical progression determined by the investigator may not be considered disease 
progression. Subjects who do not have any post-baseline tumor assessments will be right-
censored on the date of study day 1. Subjects who receive subsequent anti-cancer therapy before 
experiencing an event will be right censored at the data of the last tumor assessment prior to the 
date of initiation of subsequent therapy. Subjects who have not experienced an event (and are 
not otherwise censored) at the time of data cutoff will be right censored on the date of their last 
tumor assessment. PFS will be estimated as a sample proportion based upon the results of 6-
month tumor assessment. Subjects for whom the assessment is not performed will be included 
as failure, even if known to be alive at this timepoint. 95% confidence intervals will be provided. 
Median of PFS and duration of PFS will also be estimated using Kaplan-Meier methods with 
associated confidence intervals. 
For analysis of overall survival, duration of OS is defined as the time from study day 1 to death 
due to any cause. For subjects who are alive at the time of data cutoff or are permanently lost to 
follow-up, duration of OS will be right censored at the date the subject was last known to be 
alive.The median duration of OS will be estimated using the Kaplan-Meier methods with the 
associated confidence intervals.
8.4.3 Other Analyses
8.5
Evaluation of Safety
Each verbatim adverse event (AE) term recorded during the study will be mapped to a system 
organ class and preferred term using the MedDRA Dictionary, version 16.1. The duration of an 


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adverse event will be computed as the stop date/time minus the start date/time, expressed as 
days.
A treatment-emergent adverse event (TEAE) will be defined as one with a start date and time 
which occurred after the date and time of the first study drug administration. If the start date and 
time of an AE is incomplete or missing, the event will be assumed to be treatment emergent, 
unless the incomplete start date and time or the stop date (complete or incomplete) clearly 
indicates that the event started prior to the first dose of study drug. Incomplete/missing information 
will be reported as incomplete/missing in the subject data listings.
The relationship of each AE to study drug will be recorded as “not related,” “probably not related,” 
“possibly related,” “probably related” and “definitely related.” For all analysis “possibly related,” 
“probably related” and “definitely related” will be considered as related to study drug. If a relation 
is missing for a given event, the event will conservatively be assumed as “definitely related” for 
summarization.
The severity of each AE will be classified as mild, moderate, severe, or potentially life threatening.  
All summaries of AEs will present the number and percentage of subjects who experienced at 
least one event overall, by system organ class, and by preferred term. If a subject had multiple 
occurrences of a particular event, the subject was counted only once at the given level of 
summarization (overall, within system organ class, or within preferred term).
For summaries of adverse events by maximum severity or maximum relation to study drug, if a 
subject had multiple occurrences of a particular AE, the subject was counted only once at the 
maximum severity or relation to study drug at the given level of summarization (overall, within 
system organ class, or within preferred term).
9
Study Management
9.1
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.
9.2
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 


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the UCSF Institutional Review Board. 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.
9.3
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.
9.4
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.
9.5
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.
9.6
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. 
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. 


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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.
9.7
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 3 Data and Safety 
Monitoring Plan for a Phase 2 or 3 Institutional Study, for additional information.
9.8
Record Keeping and Record Retention
The Principal Investigator is required to maintain adequate records of the disposition of the drug, 
including dates, quantity, and use by subjects, as well as written records of the disposition of the 
drug when the study ends.  
The Principal Investigator is required to prepare and maintain adequate and accurate case 
histories that record all observations and other data pertinent to the investigation on each 
individual administered the investigational drug or employed as a control in the investigation. Case 
histories include the case report forms and supporting data (e.g., signed and dated consent forms 
and medical records, such as progress notes of the physician, the individual's hospital chart(s), 
and the nurses' notes. The case history for each individual shall document that informed consent 
was obtained prior to participation in the study.
Study documentation includes all CRFs, data correction forms or queries, source documents, 
Sponsor-Investigator correspondence, monitoring logs/letters, and regulatory documents (e.g., 
protocol and amendments, IRB correspondence and approval, signed patient consent forms).
Source documents include all recordings of observations or notations of clinical activities and all 
reports and records necessary for the evaluation and reconstruction of the clinical research study.
In accordance with FDA regulations, the investigator shall retain records for a period of 2 years 
following the date a marketing application is approved for the drug for the indication for which it is 
being investigated; or, if no application is to be filed or if the application is not approved for such 
indication, until 2 years after the investigation is discontinued and FDA is notified.


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References
1. Larkin J et al. Combined Nivolumab and Ipilimumab or Monotherapy in Untreated Melanoma. 
N. Engl. J. Med. 2015;373(1):23–34.
2. Chen EP, Smyth EM. COX-2 and PGE2-dependent immunomodulation in breast cancer. 
Prostaglandins Other Lipid Mediat. 2011;96(0):14–20.
3. Zelenay S et al. Cyclooxygenase-Dependent Tumor Growth through Evasion of Immunity. 
Cell 2015;162(6):1257–1270.
4. Hamid O et al. Safety and tumor responses with lambrolizumab (anti-PD-1) in melanoma. N. 
Engl. J. Med. 2013;369(2):134–144.
5. Ribas A. Tumor Immunotherapy Directed at PD-1. N. Engl. J. Med. 2012;366(26):2517–2519.
6. Bellmunt J et al. Pembrolizumab as Second-Line Therapy for Advanced Urothelial 
Carcinoma. N. Engl. J. Med. [published online ahead of print: February 17, 2017]; 
doi:10.1056/NEJMoa1613683
7. Garon EB et al. Pembrolizumab for the treatment of non-small-cell lung cancer. N. Engl. J. 
Med. 2015;372(21):2018–2028.
8. Pitt JM et al. Targeting the tumor microenvironment: removing obstruction to anticancer 
immune responses and immunotherapy. Ann. Oncol. Off. J. Eur. Soc. Med. Oncol. ESMO 
2016;27(8):1482–1492.
9. Hodi FS et al. Improved Survival with Ipilimumab in Patients with Metastatic Melanoma. N. 
Engl. J. Med. 2010;363(8):711–723.
10. Robert C et al. Ipilimumab plus Dacarbazine for Previously Untreated Metastatic Melanoma. 
N. Engl. J. Med. 2011;364(26):2517–2526.
11. Weber JS, Kähler KC, Hauschild A. Management of Immune-Related Adverse Events and 
Kinetics of Response With Ipilimumab. J. Clin. Oncol. 2012;30(21):2691–2697.
12. Hamid O et al. Safety and Tumor Responses with Lambrolizumab (Anti–PD-1) in Melanoma. 
N. Engl. J. Med. 2013;369(2):134–144.
13. Topalian SL et al. Survival, Durable Tumor Remission, and Long-Term Safety in Patients 
With Advanced Melanoma Receiving Nivolumab. J. Clin. Oncol. 2014;32(10):1020–1030.
14. Robert C et al. Pembrolizumab versus Ipilimumab in Advanced Melanoma. N. Engl. J. Med. 
2015;372(26):2521–2532.
15. Larkin J et al. Combined Nivolumab and Ipilimumab or Monotherapy in Untreated 
Melanoma. N. Engl. J. Med. 2015;373(1):23–34.
16. Wolchok JD et al. Nivolumab plus Ipilimumab in Advanced Melanoma. N. Engl. J. Med. 
2013;369(2):122–133.


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17. Meeting Library | KEYNOTE-029: Efficacy and safety of pembrolizumab (pembro) plus 
ipilimumab (ipi) for advanced melanoma. 
[Internet]http://meetinglibrary.asco.org/record/149330/abstract. cited July 22, 2017
18. Aspirin [Internet]. Wikipedia 
2017;https://en.wikipedia.org/w/index.php?title=Aspirin&oldid=789965748. cited July 22, 2017
19. Wolchok JD et al. Nivolumab plus Ipilimumab in Advanced Melanoma. N. Engl. J. Med. 
2013;369(2):122–133.
20. Wu AA, Drake V, Huang H-S, Chiu S, Zheng L. Reprogramming the tumor 
microenvironment: tumor-induced immunosuppressive factors paralyze T cells [Internet]. 
Oncoimmunology 2015;4(7). doi:10.1080/2162402X.2015.1016700
21. Loo K et al. Partially exhausted tumor-infiltrating lymphocytes predict response to 
combination immunotherapy [Internet]. JCI Insight 2017;2(14). doi:10.1172/jci.insight.93433
22. Tumeh PC, Hellmann MD, Hamid O, et al. Liver Metastasis and Treatment Outcome with 
Anti-PD-1 Monoclonal Antibody in Patients with Melanoma and NSCLC. Cancer Immunol Res. 
April 2017. doi:10.1158/2326-6066.CIR-16-0325.
23. Wolchok JD, Chiarion-Sileni V, Gonzalez R, et al. Overall Survival with Combined 
Nivolumab and Ipilimumab in Advanced Melanoma. N Engl J Med. September 2017. 
doi:10.1056/NEJMoa170968


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Appendix 1 Schedule of Study Procedures and Assessments
a.
Screening procedures to be completed within 28 days of C1D1, except laboratory tests for screening should be performed within 10 days prior 
to the first dose of treatment.  
Trial Period:
Screening 
Phasea
Treatment Cyclesb
End of 
Treatmente
Post-Treatment 
Follow-upf
To be repeated beyond 
8 cycles
Treatment Cycle/Title:
Main Study 
Screening 
1
2 
3
4
5
6
7
8
End of Treatment 
(EOT) visit
Safety Follow-up 
Visit
Scheduling Window (Days):
-28 to -1
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
At time of Discon
30 days post 
discon
Administrative Procedures
Informed Consent
X
Inclusion/Exclusion Criteria
X
Demographics and Medical History
X
Prior and Concomitant Medication Review
X
Post-study anticancer therapy status
X
X
Survival Status
X
X
Trial Treatment Administration
Ipilimumab
X
X
X
X
Pembrolizumab
X
X
X
X
X
X
X
X
Aspirin
X
X
X
X
X
X
X
X
Clinical Procedures/Assessments
Review Adverse Events
X
X
X
X
X
X
X
X
X
X
Full Physical Examination
X
X
X
X
X
X
X
X
X
X
X
Vital Signs and Weight
X
X
X
X
X
X
X
X
X
X
X
ECOG Performance Status
X
X
X
X
X
X
X
X
X
X
X
Laboratory Procedures/Assessments
Pregnancy Test – Urine or Serum-HCGc
X
PT/INR and aPTT
X
CBC with Differential
X
X
X
X
X
X
X
X
X
Comprehensive Serum Chemistry Panel
X
X
X
X
X
X
X
X
X
Urinalysis
X
T3, FT4 and TSH
X
X
X
X
X
X
X
X
X
Tumor Tissue Collectiong
X
Efficacy Measurements
Tumor Imagingd
X
X
X


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b.
Patients will take aspirin daily and receive pembrolizumab and ipilimumab every 3 weeks for 4 cycles. After 4 cycles, ipilimumab will be 
discontinued and patients will continue receiving pembrolizumab every 3 weeks while taking aspirin daily.
c.
Women of childbearing potential: negative urine or serum pregnancy test within 72 hours prior to receiving trial treatment. If urine test is positive 
or non-confirmatory, a serum pregnancy test will be required.
d.
Prefer imaging of chest/abdomen and pelvis. PET/CT, CT, or MRI are acceptable.
e.
End of Treatment (EOT) is defined as date patient and/or treating physician decides to discontinue study treatment. EOT visit and enter the 
post-treatment (follow-up) period. EOT visit should occur within 30 days of last dose of study drug or the decision to discontinue study drug. If a 
patient discontinues study drug at a scheduled visit, the EOT visit can occur the same day. The EOT assessments do not need to be repeated 
if done within the preceding14 days. The EOT visit can be combined with a safety follow-up visit.
f.
Safety follow-up can be combined with the EOT visit.
g.
If available, archival tissue samples will be collected at screening and processed for for PD-L1 expression testing. FFPE blocks will be requested 
from specimens containing melanoma tissue and 5 slides of 5uM thickness will be cut from each block. The unstained slides will be shipped to 
Qualtek for staining with the 22C3 antibody. The stained samples will be graded according to MEL score.


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Appendix 2 Performance Status Criteria
ECOG Performance Status Scale
Karnofsky Performance Scale
Grade
Descriptions
Percent
Description
100
Normal, no complaints, no evidence 
of disease
0
Normal activity
Fully active, able to carry on all 
pre-disease performance 
without restriction
90
Able to carry on normal activity; 
minor signs or symptoms of disease
80
Normal activity with effort; some 
signs or symptoms of disease
1
Symptoms, but ambulatory
Restricted in physically 
strenuous activity, but 
ambulatory and able to carry out 
work of a light or sedentary 
nature (e.g., light housework, 
office work)
70
Cares for self, unable to carry on 
normal activity or to do active work
60
Requires occasional assistance, but 
is able to care for most of his/her 
needs
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
50
Requires considerable assistance 
and frequent medical care
40
Disabled, requires special care and 
assistance
3
In bed > 50% of the time
Capable of only limited self-
care, confined to bed or chair 
more than 50% of waking hours
30
Severely disabled, hospitalization 
indicated
Death not imminent
20
Very sick, hospitalization indicated
Death not imminent
4
100% bedridden
Completely disabled
Cannot carry on any self-care
Totally confined to bed or chair
10
Moribund, fatal processes 
progressing rapidly
5
Dead
0
Dead


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Appendix 3 Data and Safety Monitoring Plan for a Phase 2 or 3 Institutional Study
Data and Safety Monitoring Plan for a Phase II or III Institutional Study
1.         Oversight and Monitoring Plan
The UCSF Helen Diller Family Comprehensive Cancer Center (HDFCCC) Data and Safety 
Monitoring Committee (DSMC) is responsible for auditing data quality and participant safety for 
all HDFCCC institutional clinical studies.  A summary of DSMC activities for this study includes: 

Semiannual auditing (depending on study accrual)

Review of serious adverse events

Minimum of biennial regulatory auditing
2.
Monitoring and Reporting Guidelines
Investigators will conduct a continuous review of data and participant safety at monthly site 
committee meetings where the results of each participant’s treatment are discussed and 
documented in the site committee minutes.  
All institutional Phase II and III studies are designated with a moderate risk assessment.  The 
data is audited semiannually with a random selection of twenty percent of the participants 
audited (or at least three participants if the calculated value is less than three).  The DSMC 
Monitor/Auditor will audit a maximum of 5 cycles of treatment in the participants selected for the 
review, or until the selected participants discontinue study participation or the trial is closed with 
the IRB.  Additionally, the assigned DSMC Monitor/Auditor will review no more than a total of 10 
participant charts during the course of auditing this trial. DSMC Monitor/Auditors will send a 
follow-up report to the study team within 20 business days after the auditing visit is complete for 
the PI and the study team to resolve all action items from this report within 20 business days.  
Additionally, a regulatory audit will occur on a biennial basis to review all regulatory documents 
for the trial.
3.
Review and Oversight Requirements
3.1
Adverse Event Monitoring 
All Grade 3-5 adverse events (AEs), whether or not considered to be expected or 
unexpected and whether or not considered to be associated with the use of the 
investigational agent(s) or study procedure, will be entered into OnCore®, UCSF’s 
Clinical Trial Management System.  
Adverse events are graded according to the Common Terminology Criteria for Adverse 
Events (CTCAE) as developed and revised by the Common Therapy Evaluation 
Program (CTEP) of the National Cancer Institute.  Adverse events are further given an 
assignment of attribution or relationship to investigational agent or study procedure.  
Attribution categories are:


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


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If the SAE involves a subject death, and is determined to be possibly, probably or 
definitely related to the investigational drug or any research related procedure, the event 
must be reported to the DSMC Chair (or Vice Chair) and DSMC Director within one 
business day.  
1.3
Review of Adverse Event Rates
If an increase in the frequency of Grade 3 or 4 adverse events (above the rate reported 
in the Investigator Brochure or package insert) is noted in the study, the Principal 
Investigator will notify the DSMC via report at the time the increased rate is identified.  
The report will indicate if the incidence of adverse events observed in the study is above 
the range stated in the Investigator Brochure or package insert.
If at any time the Investigator voluntarily holds enrollment or stops the study due to 
safety issues, the DSMC Chair (or Vice Chair) and the DSMC Director must be notified 
within one business day and the IRB must be notified as per IRB reporting regulations.
Data and Safety Monitoring Committee Contacts:
Box 1705
UCSF HDFCCC
San Francisco, CA 94158
   DSMC Monitors 
                           Box 0128
   UCSF HDFCCC
San Francisco, CA 
94143


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Appendix 4 Prohibited Medications
Drug
Trade name (if applicable)
Aosetron:
lotronex
Bosentan:
Tracleer
Candesartan:
Atacand
Celecoxib:
Celebrex
Diclofnac:
Volaren
Dronabinol:
Marinol
Flubiprofen:
Ansaid
Fluvastatin:
Lescol
Glimepiride:
Amaryl
Indomethacin:
Indocin
Irbesartan:
Avapro
Losartan:
Cozaar
Meloxicam:
Mobic
Montelukast:
Singulair
Nateglinide:
Starlix
Phenobarbital
Phenytoin:
Dilantin
Piroxicam:
Feldene
Rosiglitazone:
Avandia
Rosuvastatin:
Crestor
Sulfmethoxazole
Tolbutamide
Torsemide:
Demadex
Valsartan:
Diovan
Warfarin:
Coumadin
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


Version date: 12-12-2019
Protocol CC#: 17854
Phase II – Pembrolizumab, Ipilimumab, Aspirin
Page 62 of 62

Investigational agents other than pembrolizumab

Radiation therapy 
o
Note: Radiation therapy to a symptomatic solitary lesion or to the brain may be 
allowed at the investigator’s discretion

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. Daily or regular use of NSAID’s should be avoided except for aspirin as 
specified in the trial. Concomitant NSAID use more frequently than once per week may be 
allowed at the investigator’s discretion. 
The Exclusion Criteria describes other medications which are prohibited in this trial.
There are no prohibited therapies for patients after they discontinue study treatment.