Phase II Study of Pembrolizumab and Ipilimumab Following Initial Anti-PD1/L1 Antibody
Phase: PHASE2
Conditions: Melanoma
Sponsor: University of Chicago

 
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TITLE: Phase II study of pembrolizumab and ipilimumab following initial anti-PD1/L1 
antibody 
 
SPONSOR: Thomas F. Gajewski, MD, PhD – University of Chicago 
 
UC NUMBER: IRB17-0686 
 
IND NUMBER: 129455 
 
PRINCIPAL INVESTIGATOR: 
 
Thomas F. Gajewski, MD, PhD 
Professor of Medicine 
University of Chicago 
5841 S. Maryland Ave. MC2115 
Chicago, IL 60637 
Telephone: (773) 702-4601 
Fax: (773) 702--3163 
 tgajewsk@medicine.bsd.uchicago.edu 
 
Version Date: January 27th, 2016 Initial FDA submission 
 
 
March 15th, 2016 Revision #1 
March 21st, 2016 Revision #2 
April 15th, 2016 Initial IRB submission IRB15-1788 
February 10th, 2017 Amendment #1 
April 5th, 2017 Amendment #2 
May 3rd, 2017 IRB re-submission with a new study number IRB17-0686 
June 13th, 2017 Amednment #3 
January 10th, 2018 Amendment #4 
October 4th, 2018 Amendment #5 
April 10th, 2019 Amendment #6 
 
This study is being conducted by institutional members of the Personalized Cancer Care 
Consortium (PCCC), as well as additional sites.  
 

 
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1.0 TRIAL SUMMARY 
Abbreviated Title 
Pembrolizumab and ipilimumab after anti-PD1/L1 antibody 
Trial Phase 
II 
Clinical Indication 
Melanoma 
Trial Type 
Therapeutic 
Type of control 
Historical 
Route of administration 
IV 
Trial Blinding 
None 
Treatment Groups  
Progression on anti-PD1/L1 antibody (or combination not containing anti-
CTLA4),  
 
Number of trial subjects 
70 
Estimated enrollment period 
2 years 
Estimated duration of trial 
4 years 
Duration of Participation 
2 years 
 
 
 
 
2.0 TRIAL DESIGN 
2.1 
Trial Design 
Phase II study evaluating the benefit of the combination of anti-PD1 (pembrolizumab) 
and anti-CTLA4 (ipilimumab) antibodies in advanced melanoma.  The study will 
determine the response rate of the combination and evaluate other clinical parameters 
such as progression-free survival and safety of the combination following anti-PD1/L1 
antibody.  The study will also provide the opportunity to investigate blood or tumor based 
factors that may predict response to anti-PD1 antibody in combination with anti-CTLA4. 

 
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2.2 
Trial Diagram 
 
3.0 OBJECTIVE(S) & HYPOTHESIS(ES) 
3.1 
Primary Objective(s) & Hypothesis(es) 
(1) Objective: To determine the irRECIST* response rate of pembrolizumab with 
ipilimumab following initial progression to anti-PD1/L1 antibody (or combination not 
containing anti-CTLA4) in subjects with advanced melanoma. 
*For review of irRECIST see Appendix – Section 13.3 
Hypothesis: The combination of pembrolizumab and ipilimumab will induce tumor 
responses in patients who have been previously treated with anti-PD1/L1 antibody  
3.2 
Secondary Objective(s) & Hypothesis(es) 
(1) Objective:  To summarize the progression-free survival (RECIST v1.1 and irRC) of the 
combination following prior treatment with anti-PD1/L1 antibody 
Hypothesis: The combination will lengthen progression-free survival relative to historical 
data for ipilimumab alone.  
(2) Objective:  To assess the safety of the combination following prior treatment with anti-
PD1/L1 antibody 

 
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Hypothesis: The combination will demonstrate a manageable safety profile in patients who 
have been previously treated with anti-PD1/L1 antibody 
3.3 
Exploratory Objective 
(1) 
Objective: To evaluate changes in the tumor microenvironment and other biospecimens 
before and after adding ipilimumab to pembrolizumab. 
Hypothesis: Changes in the tumor microenvironment will be observed that may correlate 
with a more favorable response to combination immunotherapy. 
4.0 BACKGROUND & RATIONALE 
4.1 
Background 
Refer to the Investigator’s Brochure (IB)/approved labeling for detailed background 
information on PEMBROLIZUMAB. 
4.1.1 Pharmaceutical(s) and Therapeutic Background 
The importance of intact immune surveillance in controlling outgrowth of neoplastic 
transformation has been known for decades.  Accumulating evidence shows a correlation 
between tumor-infiltrating lymphocytes (TILs) in cancer tissue and favorable prognosis in 
various malignancies.  In particular, the presence of CD8+ T-cells and the ratio of CD8+ 
effector T-cells / FoxP3+ regulatory T-cells seems to correlate with improved prognosis and 
long-term survival in many solid tumors. 
The PD-1 receptor-ligand interaction is a major pathway hijacked by tumors to suppress 
immune control.  The normal function of PD-1, expressed on the cell surface of activated T-
cells under healthy conditions, is to down-modulate unwanted or excessive immune responses, 
including autoimmune reactions.  PD-1 (encoded by the gene Pdcd1) is an Ig superfamily 
member related to CD28 and CTLA-4 which has been shown to negatively regulate antigen 
receptor signaling upon engagement of its ligands (PD-L1 and/or PD-L2).  The structure of 
murine PD-1 has been resolved.  PD-1 and family members are type I transmembrane 
glycoproteins containing an Ig Variable-type (V-type) domain responsible for ligand binding 
and a cytoplasmic tail which is responsible for the binding of signaling molecules.  The 
cytoplasmic tail of PD-1 contains 2 tyrosine-based signaling motifs, an immunoreceptor 
tyrosine-based inhibition motif (ITIM) and an immunoreceptor tyrosine-based switch motif 
(ITSM).  Following T-cell stimulation, PD-1 recruits the tyrosine phosphatases SHP-1 and 
SHP-2 to the ITSM motif within its cytoplasmic tail, leading to the dephosphorylation of 
effector molecules such as CD3ζ, PKCθ and ZAP70 which are involved in the CD3 T-cell 
signaling cascade.  The mechanism by which PD-1 down modulates T-cell responses is similar 
to, but distinct from that of CTLA-4 as both molecules regulate an overlapping set of signaling 
proteins.  PD-1 was shown to be expressed on activated lymphocytes including peripheral 
CD4+ and CD8+ T-cells, B-cells, T regs and Natural Killer cells.  Expression has also been 
shown during thymic development on CD4-CD8- (double negative) T-cells as well as subsets 
of macrophages and dendritic cells.  The ligands for PD-1 (PD-L1 and PD-L2) are 
constitutively expressed or can be induced in a variety of cell types, including non-

 
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hematopoietic tissues as well as in various tumors.  Both ligands are type I transmembrane 
receptors containing both IgV- and IgC-like domains in the extracellular region and contain 
short cytoplasmic regions with no known signaling motifs.  Binding of either PD-1 ligand to 
PD-1 inhibits T-cell activation triggered through the T-cell receptor.  PD-L1 is expressed at 
low levels on various non-hematopoietic tissues, most notably on vascular endothelium, 
whereas PD-L2 protein is only detectably expressed on antigen-presenting cells found in 
lymphoid tissue or chronic inflammatory environments.  PD-L2 is thought to control immune 
T-cell activation in lymphoid organs, whereas PD-L1 serves to dampen unwarranted T-cell 
function in peripheral tissues.  Although healthy organs express little (if any) PD-L1, a variety 
of cancers were demonstrated to express abundant levels of this T-cell inhibitor.  PD-1 has 
been suggested to regulate tumor-specific T-cell expansion in subjects with melanoma (MEL).  
This suggests that the PD-1/PD-L1 pathway plays a critical role in tumor immune evasion and 
should be considered as an attractive target for therapeutic intervention. 
Pembrolizumab is a potent and highly selective humanized monoclonal antibody (mAb) of the 
IgG4/kappa isotype designed to directly block the interaction between PD-1 and its ligands, 
PD-L1 and PD-L2.  KeytrudaTM (pembrolizumab) has recently been approved in the United 
States for the treatment of patients with unresectable or metastatic melanoma and disease 
progression following ipilumumab and, if BRAF V600 mutation positive, a BRAF inhibitor. 
Ipilimumab (Yervoy®) is an immunoregulatory agent that blocks CTLA -4 to promote anti- 
tumor immunity. In a Phase III study of 676 subjects with unresectable or metastatic melanoma 
whose disease had progressed while receiving prior therapy for metastatic disease, ipilimumab 
administered at 3 mg/kg Q3W for up to 4 doses with or without a gp100 peptide vaccine was 
compared with gp100 alone1. The median overall survival was 10.1 months and 10.0 months 
for the ipilimumab alone and ipilimumab plus gp100 arms respectively, while the median 
overall survival was 6.4 months for the gp100 alone arm (p<0.001). An objective response rate 
of 10.9% was observed in ipilimumab alone arm, while the ipilimumab plus gp100 arm and 
gp100 alone arm had lower response rates, 5.7% and 1.5%, respectively. The median duration 
of response was 11.5 months in the ipilimumab plus gp100 arm, and not reached in the 
ipilimumab alone arm with a median follow -up period of 27.8 months.  The median time to 
progression was 2.86 months for the ipilimumab alone arm and 2.76 months for the other two 
arms. In the ipilimumab alone arm, 97% of the subjects experienced an AE and grade 3/4 AEs 
occurred in 46% of the subjects. The most common AEs related to ipilimumab were immune-
related events, which occurred in approximately 60% of the subjects treated with ipilimumab 
and 32% of the subjects treated with gp100. The frequency of grade 3/4 immune-related AEs 
was 15%. The immune-related AEs most often affected the skin and gastrointestinal tract, 
including pruritus, rash, vitiligo, diarrhea, and colitis. 
Based on the above Phase III trial, ipilimumab was approved by the FDA for treatment of 
subjects with unresectable or metastatic melanoma and by the European Commission for 
treatment of subjects with previously-treated advanced melanoma. The recommended regimen 
is 3 mg/kg administered Q3W for a total of four doses. 
Refer to the approved labeling for detailed background information on ipilimumab. 

 
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4.1.2 Preclinical and Clinical Trial Data 
Refer to the Investigator’s Brochure for Preclinical and Clinical data. 
4.2 
Rationale 
4.2.1 Rationale for the Trial and Selected Subject Population 
Melanoma (MEL) is the sixth most common malignancy in men and the seventh most 
common malignancy in women. The incidence of MEL is increasing worldwide, with a 
growing fraction of subjects with advanced disease for which prognosis remains poor. The 
median survival for subjects with metastatic MEL has been under 1 year. The 5 -year survival 
rate of subjects with visceral involvement is under 10%. Treatment options for metastatic 
MEL have been limited to chemotherapeutic agents such as dacarbazine and high -dose 
interleukin-2 immunotherapy in a small percentage of subjects. In the past few years there 
has been steady progress in the development of targeted therapy and immunotherapy for 
metastatic MEL. Vemurafenib, a BRAF inhibitor, was approved in 2011 for the treatment of 
subjects with unresectable or metastatic MEL with BRAFV600E mutation (only about 50% 
of all melanoma subjects). IPI, an anti-CTLA4 monoclonal antibody, was also approved in 
2011 for the treatment of subjects with unresectable or metastatic MEL. More recently, 
a second BRAF inhibitor (dabrafenib) and a first MEK inhibitor (trametinib) were approved 
for treatment of metastatic melanoma; the median survival for subjects treated with these 
drugs in pivotal trials was still less than 6 months.  In spite of these newly approved therapies, 
overall outlook for subjects with metastatic MEL remains dismal and the development of 
new effective therapy is still needed. 
 
Pembrolizumab has shown clinical activity in several cancers with response rates and disease 
control rates previously unknown to immunotherapy.  While impressive as a single agent in 
melanoma, with a response rate of 38% demonstrated in the phase I experience2, those patients 
that do not achieve response continue to have poor outcomes.  In this context, there continues 
to be an area of unmet need in this non-responding melanoma patient population. 
 
The T cell-inflamed tumor microenvironment may be a predictive biomarker for response to 
multiple immunotherapies including therapeutic vaccines, cytokines and anti-cytotoxic T-
lymphocyte antigen-4 (CTLA-4) antibodies3-8.  Tom Gajewski, MD, PhD at the University of 
Chicago has analyzed the tumor microenvironment in patients with melanoma and described 
that approximately 40% of cases show evidence of spontaneous priming of anti-tumor T cells 
leading to migration of CD8+ effector T cells into tumor sites.  This phenotype has been 
designated the T cell-inflamed tumor microenvironment and is characterized by expression of 
T cell markers, chemokines for T cell recruitment, and transcripts indicative of type I interferon 
(IFN) signaling4,5,7.  A gene expression signature that captures this phenotype has been 
developed including a group of 13 immune related genes and preliminary analysis suggests 
that this signature very closely predicts which tumors respond to anti-PD1 antibody treatment 
(data unpublished). 
 
In addition to response prediction, this gene signature is also potentially useful in identifying 
those that will not respond.  Patients harboring non-inflamed tumors therefore require 

 
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treatment strategies which may modulate the immune response to facilitate the influx of TIL 
and conversion from a non-inflamed to an inflamed tumor.  Several tumor localized treatments 
have been suggested in preclinical models to facilitate such a shift including but not limited to 
radiation9, immune agonists such as those directed against the STING pathway10 and oncolytic 
tumor viruses11.  While locally effective, these treatments are impractical in patients with wide 
spread metastatic disease. 
 
As opposed to local treatment, a systemic treatment that can drive a T cell response into the 
tumors may be CTLA4 blocking antibodies.  Phase III clinical trials evaluating the anti-CTLA4 
antibodies tremelimumab and ipilimumab have documented single agent response rates on the 
order of 10%1,12.  For both tremelimumab and ipilimumab, pre- and post-treatment biopsies 
have demonstrated a significant increase in CD8+ TIL in tumor lesions after anti-CTLA4 
antibody treatment13,14.  In some studies15, there is also indication of modulation with the intra-
tumoral FoxP3+ regulatory T cell population; however this has not been seen uniformly. 
 
Preclinical investigations have supported the concept of combined blockade of PD-1 and 
CTLA-4 achieving more pronounced anti-tumor activity than blockade of either pathway 
alone16.  Specifically, combined PD-1 and CTLA-4 blockade increases effector T-cell 
infiltration of tumors, overall intra-tumoral IFN-ɤ levels, as well as the frequency of CD8+ T 
cells that secrete both IFN-ɤ and TNF-α.  These observations were the basis for the phase I 
study of the ipilimumab with the anti-PD1 antibody nivolumab.  In this study, an increased 
response rate relative to historical controls for either agent was observed and patients who had 
previously progressed on ipilimumab alone were noted to have responses17.  No patients were 
reported who had progressed on anti-PD1 antibody alone; however it was specifically noted 
that tumors from patients that tested negative by immunohistochemistry for PD-L1 (possibly 
a surrogate for the non-inflamed tumor phenotype) obtained responses at only a slightly lower 
response rate compared to those who tested positive for PD-L118.  This suggests that the 
addition of anti-CTLA4 to anti-PD1 therapy may be able to overcome the non-inflamed tumor 
phenotype.   
 
4.2.2 Rationale for Dose Selection/Regimen/Modification  
An open-label Phase I trial (Protocol 001) is being conducted to evaluate the safety and 
clinical activity of single agent pembrolizumab.  The dose escalation portion of this trial 
evaluated three dose levels, 1 mg/kg, 3 mg/kg, and 10 mg/kg, administered every 2 weeks 
(Q2W) in subjects with advanced solid tumors.  All three dose levels were well tolerated and 
no dose-limiting toxicities were observed.  This first in human study of pembrolizumab 
showed evidence of target engagement and objective evidence of tumor size reduction at all 
dose levels (1 mg/kg, 3 mg/kg and 10 mg/kg Q2W).  No MTD has been identified to date.  
Recent data from other clinical studies within the pembrolizumab program has shown that a 
lower dose of pembrolizumab and a less frequent schedule may be sufficient for target 
engagement and clinical activity. 
 
PK data analysis of pembrolizumab 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 

 
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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 pembrolizumab were found to be dependent on body weight. The relationship 
between clearance and body weight, with an allometric exponent of 0.59, is within the range 
observed for other antibodies and would support both body weight normalized dosing or a 
fixed dose across all body weights.  Pembrolizumab has been found to have a wide 
therapeutic range based on the melanoma indication.  The differences in exposure for a 200 
mg fixed dose regimen relative to a 2 mg/kg Q3W body weight based regimen are 
anticipated to remain well within the established exposure margins of 0.5 – 5.0 for 
pembrolizumab in the melanoma indication. The exposure margins are based on the notion of 
similar efficacy and safety in melanoma at 10 mg/kg Q3W vs. the proposed dose regimen of 
2 mg/kg Q3W (i.e. 5-fold higher dose and exposure). The population PK evaluation revealed 
that there was no significant impact of tumor burden on exposure. In addition, exposure was 
similar between the NSCLC and melanoma indications. Therefore, there are no anticipated 
changes in exposure between different indication settings. 
 
The rationale for further exploration doses comparable to 2mg/kg 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. 
In this study, pembrolizumab will be evaluated in combination with 1 mg/kg of ipilimumab. 
The dose schedule of ipilimumab will follow the approved drug label of Q3W.  In a Phase 1 
study, updated by Sznol et al at ESMO 2013, efficacy of nivolumab 3 mg/kg + ipilimumab 
1 mg/kg ([ORR  40% (95% CI 16-68%) and Aggregate Clinical Benefit Rate (defined as CR 
+ PR + uCR+ uPR+ irPR+ SD >24 week + irSD >24 week) 73%] appeared to have similar 
efficacy as nivolumab 1 mg/kg + ipilimumab 3 mg/kg [ORR 53% (95% CI 28-77%) and ACBR 
65%]. In addition, the combination of nivolumab 3 mg/kg + ipilimumab 1 mg/kg showed lower 

 
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rate of drug related Grade 3-4 AEs compared with nivolumab 1 mg/kg + ipilimumab 3 mg/kg 
(44% versus 65%, respectively) [66].    
The combination of pembrolizumab with ipilimumab was evaluated in a phase I study 
presented at ASCO 2015 (KEYNOTE-029)19.  In this study pembrolizumab was administered 
at 2 mg/kg every 3 weeks in conjunction with 1 mg/kg of ipilimumab every 3 weeks x 4 doses.  
Of 19 patients evaluable for dose-limiting toxicity (DLT), 6 patients experienced ≥ 1 DLT.  All 
of these were grade 3 in severity except for one episode of grade 4 lipase elevation.  The only 
event that occurred in ≥1 patient was ALT elevation.  Two patients experienced 2 DLTs each 
including elevated pancreatic enzymes and hyperthyroidism in one patient and increased ALT 
and AST in the other patient.  All DLTs resolved with exception of elevated lipase (on-going 
at time of presentation).  There were no treatment-related deaths and adverse events of any 
attribution led to discontinuation of both pembrolizumab and ipilimumab in 3 (13.6%) of 
patients and ipilimumab only in 5 (18.2%) of patients.  At least 1 grade 3-4 treatment related 
adverse event was observed in 54.5% of patients.  The most common AEs in decreased order 
of frequency were: fatigue (27.3%), diarrhea, liver enzyme elevations, colitis, lipase, nausea, 
abdominal 
pain, 
hypothyroidism, 
rash, 
hypophysitis, 
puritis, 
pyrexia, 
vitiligo, 
hyperthyroidism, hyponatremia, elevated pancreatic enzymes, pneumonitis, syncope and 
uveitis (4.5%).  At the time of data cut off, 17/22 patients had at least one disease assessment 
evaluable for response.  Partial response per RECSITv1.1 by investigator review was reported 
for 3 patients. 
The overall dosing strategy is intended to emphasize dose intensity with pembrolizumab 
rather than ipilimumab, due to the known safety and efficacy profile of both agents. 
4.2.3 Rationale for Endpoints 
Here we propose a clinical trial testing the hypothesis that the addition of anti-CTLA4 antibody 
(ipilimumab) to pembrolizumab will generate clinical responses in patients who have had 
initial progressive disease, or only disease stabilization, to anti-PD1/L1 antibody alone.  
Preclinical and prior clinical data support this hypothesis and from a practical standpoint, 
deferral of the toxicities associated with anti-CTLA4 in those patients who do not require 
exposure to anti-CTLA4 is particularly attractive.   
 
We propose to continue pembrolizumab beyond progression on an anti-PD1/L1 antibody as 
we believe that single agent ipilimumab will overcome the non-inflamed tumor 
microenvironment in only a small percentage of patients while the combination of ipilimumab 
and pembrolizumab may induce responses in as many as 40% of patients based on prior studies.  
The results of this study may suggest that continuous PD-1 blockade is required to optimize 
therapy for advanced melanoma and, through our correlative analysis, we hope to propose a 
model by which we can suggest which patients would benefit from upfront pembrolizumab 
alone or pembrolizumab in combination with anti-CTLA4 antibody. 
 
4.2.3.1 Efficacy Endpoints 
The primary efficacy objective of this trial is to evaluate the anti-tumor activity of the 
combination of pembrolizumab and ipilimumab in subjects with advanced melanoma who 

 
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have previously been treated with an anti-PD1/L1 antibody. Response rates per irRECIST 
will be evaluated. 
 
irRECIST as assessed by the investigator will be used as the primary response rate 
efficacy endpoint. irRECIST will also be used by the local site to determine eligibility and 
make treatment decisions.  The primary efficacy endpoint is response rate based on 
irRECIST.   Secondary endpoints are listed in section 3.2. 
 
Immunotherapeutic agents such as pembrolizumab may produce antitumor effects by 
potentiating endogenous cancer-specific immune responses which may be functionally 
anergic.   The response patterns seen with such an approach may extend beyond the typical 
time course of responses seen with cytotoxic agents, and can manifest a clinical response 
after an initial increase in tumor burden or even the appearance of new lesions.  Standard 
RECIST criteria may not provide a complete response assessment of immunotherapeutic 
agents such as pembrolizumab therefore the irRECIST have been developed to encompass 
this. 
 
Broadly, irRECIST includes the concept of treatment beyond progression, if radiologic 
imaging shows PD, tumor assessment should be repeated ≥ 4 weeks later in order to 
confirm PD with the option of continuing treatment per below while awaiting radiologic 
confirmation of progression.   If repeat imaging shows a reduction in the tumor burden 
compared to the initial scan demonstrating PD, treatment may be continued as per 
treatment calendar.   If repeat imaging confirms progressive disease, subjects will be 
discontinued from trial therapy.    In determining whether or not the tumor burden has 
increased or decreased, Investigators should consider all target lesions as well as non-target 
lesions. 
 
In subjects who have initial evidence of radiological PD, it is at the discretion of the treating 
physician whether to continue a subject on study treatment until repeat imaging is obtained 
a minimum of 4 weeks later.  This decision should be based on the clinical judgment of 
the subject’s overall clinical condition, including performance status, clinical symptoms, 
and laboratory data. Subjects may receive treatment while waiting for confirmation of PD 
if they are clinically stable as defined by the following criteria: 
 
 Absence of signs and symptoms indicating disease progression 
 
 No decline in ECOG performance status 
 
 Absence of rapid progression of disease 
 
 Absence of progressive tumor at critical anatomical sites (e.g., cord compression) 
requiring urgent alternative medical intervention 
 
When feasible, subjects should not be discontinued until progression is confirmed.  This 
allowance to continue treatment despite initial radiologic progression takes into account 
the observation that some subjects can have a transient tumor flare in the first few months 
after the start of immunotherapy, but with subsequent disease response.  Subjects that are 
deemed clinically unstable are not required to have repeat imaging for confirmation of 
progressive disease. 
 

 
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4.2.3.2 Biomarker Research 
Our group has previously described the T cell-inflamed tumor microenvironment as a potential 
predictive biomarker for response to multiple immunotherapies including therapeutic vaccines, 
anti-CTLA-4, and anti-PD-1/PD-L1 antibodies3-8,20.  Our analysis of the tumor 
microenvironment in patients with melanoma suggests that approximately 35-50% of cases 
show evidence of spontaneous priming of anti-tumor T cells leading to migration of CD8+ 
effector T cells into tumor sites.  This phenotype has been designated the T cell-inflamed tumor 
microenvironment and is characterized by expression of T cell markers, chemokines for T cell 
recruitment, and transcripts indicative of type I IFN signaling4,5,7. 
In addition to response prediction, this gene signature is also potentially useful in identifying 
those that will not respond.  Patients harboring non-inflamed tumors therefore require 
treatment strategies which may modulate the immune response to facilitate the influx of tumor 
infiltrating lymphocytes (TIL) and conversion from a non-inflamed to an inflamed tumor.   
Beyond the tumor microenvironment, aspects of the host (patient) and commensal environment 
may also have an essential impact on immunity in response to both radiation and anti-PD1 
antibody.  Host factors of interest regarding the immune response include circulating immune 
subsets as well as germline DNA sequence and polymorphisms.  Further, a growing literature 
supports a role for commensal microbiota in the immune response to infection and cancer 
including development of acute versus chronic immune responses and regulatory mechanisms 
to prevent collateral tissue damage21.  We and others have proposed that manipulation of the 
microbiome has the potential ability to modulate the anti-tumor immune response and promote 
the development of an inflamed tumor microenviroment22,23. 
Considering this background, we propose to collect peripheral blood for serum, peripheral 
blood mononuclear cells, germline DNA, as well as pre-treatment fecal sample and baseline 
tumor tissue on all patients.  Additionally, it is requested that any patients who undergo tumor 
biopsy during the study have any available tissue forwarded for analysis in comparison of 
pretreatment and on-/post-treatment tumor microenvironmental factors. 
Pending available tissue, biomarker analysis may include the following assays listed below: 
Biomarker name  
(Facility performing assay) 
Assay 
Tissue/Body Fluid Tested 
and Timing of Assay 
Interferon inducible genes (IDO, 
PD-L1, FoxP3 etc.) 
University of Chicago Human 
Immunological Monitoring Core 
Gene Array 
Pre- and post-treatment tumor 
tissue 
PD-L1, CD3, CD8, FoxP3, Ki67, 
exome sequencing 
University of Chicago Human 
Immunological Monitoring Core 
IHC, exome sequencing 
Pre-treatment tumor tissue (or 
archived FFPE tissue) 
Germline DNA 
Genotyping for a genome-wide association study 
(results pooled with subjects from other studies) 
Pre-treatment blood 

 
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Biomarker name  
(Facility performing assay) 
Assay 
Tissue/Body Fluid Tested 
and Timing of Assay 
University of Chicago Human 
Immunological Monitoring Core 
Gut microbiome sequencing 
University of Chicago Human 
Immunological Monitoring Core 
Gut microbiome sequencing (results pooled with 
subjects from other studies) 
Pre-treatment stool 
Peripheral blood T cell functional 
activity 
University of Chicago Human 
Immunological Monitoring Core 
ELISA 
for 
IFN-γ 
after 
co-culture 
with 
Staphylococcal enterotoxin A 
Blood before treatment and after 4 
doses of pembrolizumab 
 
5.0 METHODOLOGY 
5.1 
Entry Criteria 
5.1.1 Diagnosis/Condition for Entry into the Trial 
1. Unresectable or metastatic melanoma with known BRAF mutation status 
5.1.2 Subject Inclusion Criteria 
In order to be eligible for participation in this trial, the subject must: 
1. Be willing and able to provide written informed consent for the trial. 
2. Be  18 years of age on day of signing informed consent. 
3. Have experienced disease progression during treatment with an anti-PD1/L1 antibody 
as the treatment regimen immediately prior to accrual to this study or disease 
progression within 6 months of adjuvant anti-PD1 antibody. 
4. Have measurable disease based on irRECIST 1.1.   
5. Have a performance status of 0 or 1 on the ECOG Performance Scale. 
6. Demonstrate adequate organ function as defined in Table 1.   
Table 1  Adequate Organ Function Laboratory Values 
System 
Laboratory Value 
Hematological 
 
Absolute neutrophil count (ANC) 
≥1,500 /mcL 
Platelets 
≥100,000 / mcL 
Hemoglobin 
≥8 g/dL or ≥4.96 mmol/L  
Renal 
 
Serum creatinine OR 
≤1.5 X upper limit of normal (ULN) OR 
 

 
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Measured or calculateda creatinine 
clearance 
(GFR can also be used in place of 
creatinine or CrCl) 
≥60 mL/min for subject with creatinine levels > 1.5 X 
institutional ULN 
Hepatic 
 
Serum total bilirubin 
≤ 1.5 X ULN OR 
 
Direct bilirubin ≤ ULN for subjects with total bilirubin levels > 
1.5 ULN 
AST (SGOT) and ALT (SGPT) 
≤ 2.5 X ULN  OR 
≤ 5 X ULN for subjects with liver metastases 
Albumin 
>2.5 mg/dL 
aCreatinine clearance should be calculated per institutional standard. 
 
7. Female subject of childbearing potential should have a negative urine or serum 
pregnancy within 72 hours prior to receiving the first dose of study medication.  If the 
urine test is positive or cannot be confirmed as negative, a serum pregnancy test will 
be required.   
8. Female subjects of childbearing potential should be willing to use 2 methods of birth 
control or be surgically sterile, or abstain from heterosexual activity for the course of 
the study through 120 days after the last dose of study medication (Reference Section 
5.7.2).  Subjects of childbearing potential are those who have not been surgically 
sterilized or have not been free from menses for > 1 year.  
9. Male subjects should agree to use an adequate method of contraception starting with 
the first dose of study therapy through 120 days after the last dose of study therapy. 
5.1.3 Subject Exclusion Criteria 
The subject must be excluded from participating in the trial if the subject: 
1. Has received study therapy (including investigational device) as part of a clinical trial 
within 4 weeks of the first dose of treatment, with the exclusion of an anti-PD1/L1 
antibody given as either a single agent or non-CTLA-4 antibody containing 
combination. 
2. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any 
other form of immunosuppressive therapy within 7 days prior to the first dose of trial 
treatment. 
 
3. Has a known history of active TB   (Bacillus Tuberculosis) 
 
4. Hypersensitivity to pembrolizumab or any of its excipients. 
5. Has had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to study 
Day 1 (excluding commercial or investigational anti-PD1 or anti-PD-L1 antibodies as 
single agents) or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse 
events due to agents administered more than 4 weeks earlier. 

 
14 
 
Patients who have autoimmune adverse events controlled by replacement therapy (i.e. 
hypothyroidism) due to previous treatment are eligible provided replacement therapy 
has been initiated and toxicity has returned to Grade 1. 
6. Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy 
within 2 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at 
baseline) from adverse events due to a previously administered agent. 
- 
Note:  Subjects with ≤ Grade 2 neuropathy are an exception to this criterion and 
may qualify for the study. 
- 
Note:  If subject received major surgery, they must have recovered adequately 
from the toxicity and/or complications from the intervention prior to starting 
therapy.   
7. Has a known additional malignancy that is progressing or requires active treatment.  
Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the 
skin that has undergone potentially curative therapy or in situ cervical cancer. 
8. Has known active central nervous system (CNS) metastases and/or carcinomatous 
meningitis.  Subjects with previously treated brain metastases may participate provided 
they are stable (without evidence of progression by imaging for at least four weeks 
prior to the first dose of trial treatment and any neurologic symptoms have returned to 
baseline), have no evidence of new or enlarging brain metastases, and are not using 
steroids for at least 7 days prior to trial treatment.  This exception does not include 
carcinomatous meningitis which is excluded regardless of clinical stability.   
9. Has active autoimmune disease that has required systemic treatment in the past 2 years 
(i.e. with use of disease modifying agents, corticosteroids or immunosuppressive 
drugs). Replacement therapy (eg., thyroxine, insulin, or physiologic corticosteroid 
replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form 
of systemic treatment. Patients with previous grade III/IV toxicity from 
immunotherapy that led to treatment discontinuation are excluded. 
10. Patients with uveal/ocular melanoma are excluded. 
 
11. Has known history of, or any evidence of active, non-infectious pneumonitis. 
12. Has an active infection requiring systemic therapy. 
13. Has a history or current evidence of any condition, therapy, or laboratory abnormality 
that might confound the results of the trial, interfere with the subject’s participation for 
the full duration of the trial, or is not in the best interest of the subject to participate, in 
the opinion of the treating investigator.   
14. Has known psychiatric or substance abuse disorders that would interfere with 
cooperation with the requirements of the trial. 

 
15 
 
15. Is pregnant or breastfeeding, or expecting to conceive or father children within the 
projected duration of the trial, starting with the pre-screening or screening visit through 
120 days after the last dose of trial treatment. 
16. Has received prior therapy with an anti-CTLA4 agent in the unresectable or metastatic 
disease setting. Prior treatment with ipilimumab in the adjuvant setting is allowed 
17. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies). 
18. Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA 
[qualitative] is detected). 
19. Has received a live vaccine within 30 days of planned start of study therapy. 
Note:  Seasonal influenza vaccines for injection are generally inactivated flu vaccines 
and are allowed; however intranasal influenza vaccines (e.g., Flu-Mist®) are live 
attenuated vaccines, and are not allowed. 
5.2 
Trial Treatments 
The treatment to be used in this trial is outlined below in Table 2 
Table 2  Trial Treatment 
Drug 
Dose/ 
Potency 
Dose 
Frequency 
Route of 
Administration 
Regimen/ 
Treatment 
Period 
Pembrolizumab 
200 mg per 
dose 
Q3W 
IV infusion 
Day 1 of each 3 
week cycle 
Ipilimumab 
1 mg/kg 
Q3W 
IV infusion 
Day 1 of each 3 
week cycle x 4 
treatments 
5.2.1 Dose Selection/Modification 
5.2.1.1 Dose Selection 
The rationale for selection of doses to be used in this trial is provided in Section 4.0 – 
Background and Rationale.   
The dose amount required to prepare ipilimumab will be based on the subject’s weight in 
kilograms (kg).     
5.2.1.2 Dose Modification  
Adverse events (both non-serious and serious) associated with pembrolizumab and/or 
ipilimumab 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 and ipilimumab must be withheld for drug-related toxicities and severe or life-

 
16 
 
threatening AEs as per Table 3 below. See Section 5.6.1 for supportive care guidelines, 
including use of corticosteroids. 
All Grade 3-5 adverse events considered possibly, probably or definitely related to study 
agent(s) must be discussed with the Principal Investigator.  All treating clinicians involved 
in the protocol are welcomed to discuss complicated cases at any time with the Principal 
Investigator:  
Thomas Gajewski, MD, PhD 
University of Chicago Comprehensive Cancer Center 
 tgajewsk@medicine.bsd.uchicago.edu 
 
 
 

 
17 
 
Table 3 
Dose Modification Guidelines for Drug-Related Adverse Events 
 
Toxicity 
Hold 
Treatment 
For Grade 
Timing for Restarting Treatment 
Discontinue Subject (Includes both drugs unless stated) 
Diarrhea/Colitis 
2-3 
 
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.  
For Grade 3 diarrhea/colitis, permanently discontinue ipilimumab 
4 
Permanently discontinue both 
pembrolizumab and ipilimumab 
Permanently discontinue both pembrolizumab and ipilimumab 
AST, ALT, or 
Increased Bilirubin 
2 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last dose. 
3-4 
Permanently discontinue 
(see exception below)1 
Permanently discontinue both pembrolizumab and ipilimumab 
Type 1 diabetes 
mellitus (if new 
onset) or 
Hyperglycemia 
T1DM or  
3-4 
Hold pembrolizumab for new onset Type 1 
diabetes 
mellitus 
or 
Grade 
3-4 
hyperglycemia associated with evidence of 
beta cell failure.  
 
Resume pembrolizumab when patients are clinically and 
metabolically stable. Permanently discontinue ipilimumab. 
Hypophysitis 
2-3 
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. 
4 
Permanently discontinue both 
pembrolizumab and ipilimumab 
Permanently discontinue both pembrolizumab and ipilimumab 
Hyperthyroidism  
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. 
4 
Permanently discontinue both 
pembrolizumab and ipilimumab 
Permanently discontinue both pembrolizumab and ipilimumab 
Hypothyroidism 
2-4 
Therapy with pembrolizumab can be 
continued while treatment for the thyroid 
disorder is instituted 
Therapy with pembrolizumab and ipilimumab can be continued 
while treatment for the thyroid disorder is instituted. 
Infusion Reaction 
3-4 
Permanently discontinue both 
pembrolizumab and ipilimumab 
Permanently discontinue both pembrolizumab and ipilimumab 
Pneumonitis 
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. 
3-4 
Permanently discontinue both 
pembrolizumab and ipilimumab 
Permanently discontinue both pembrolizumab and ipilimumab 
Renal Failure or 
Nephritis 
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. 
3-4 
Permanently discontinue both 
pembrolizumab and ipilimumab 
Permanently discontinue both pembrolizumab and ipilimumab 
All Other Drug-
Related Toxicity2 
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. 
4 
Permanently discontinue both 
pembrolizumab and ipilimumab 
Permanently discontinue both pembrolizumab and ipilimumab 
Note: Permanently discontinue for any severe or Grade 3 drug-related AE that recurs or any life-threatening event. 
1 For patients with liver metastasis who begin treatment with Grade 2 AST or ALT, if AST or ALT increases by greater than or equal to 50% relative to baseline 
and lasts for at least 1 week then patients should be discontinued. 
2 Patients with intolerable or persistent Grade 2 drug-related AE may hold study medication at physician discretion.  Permanently discontinue study drug for 
persistent Grade 2 adverse reactions for which treatment with study drug has been held, that do not recover to Grade 0-1 within 12 weeks of the last dose.   
 

 
18 
 
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). Ipilimumab should be permanently discontinued for subject’s who fail to 
complete the full treatment course of ipilimumab within 16 weeks from administration of first 
dose. 
 
If a subject’s study treatment has been interrupted for more than 2 doses of pembrolizumab 
and/or ipilimumab, the investigator must contact the Principal Investigator to review the 
subject’s condition in order to resume the treatment. Subjects being treated on combination 
therapy with pembrolizumab plus ipilimumab who require discontinuation of ipilimumab due 
to toxicity may continue treatment with pembrolizumab after approval from the Principal 
Investigator. The reason for discontinuation must be recorded. 
 
5.2.2 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.  Patients will be monitored per 
individual site institutional standard of care policy during administration of ipilimumab and 
pembrolizumab. 
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). Pembrolizumab 
should always be administered first when in combination with ipilimumab. 
The Pharmacy Manual contains specific instructions for the preparation of the pembrolizumab 
infusion fluid and administration of infusion solution. 
Ipilimumab will be administered once every 3 weeks for a total of 4 doses. Ipilimumab may 
be administered as either a 30 or 90 minute IV infusion. For additional instructions regarding 
dosing please refer to the ipilimumab label.  
5.2.3 Trial Blinding/Masking 
This is an open-label trial; therefore, the Sponsor, investigator and subject will know the 
treatment administered. 
5.3 
Randomization or Treatment Allocation 
There is no randomization within the study however study participants will be allocated to a 
treatment arm based on prior progressive disease on anti-PD1/L1 antibody alone or PD1/L1 
combination not including CTLA4 Ab. 

 
19 
 
5.4 
Stratification 
None 
5.5 
Concomitant Medications/Vaccinations (allowed & prohibited) 
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed 
during the ongoing trial.  If there is a clinical indication for one of these or other medications 
or vaccinations specifically prohibited during the trial, discontinuation from trial therapy or 
vaccination may be required.  The investigator should discuss any questions regarding this 
with the Principal Investigator.  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 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 
recorded. 
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  
 Investigational agents other than pembrolizumab and ipilimumab 
 Radiation therapy  
o Note:  Radiation therapy to a symptomatic solitary lesion or to the brain may 
be allowed after discussion between the investigator and Principal Investigator.   
 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 Principal 
Investigator. 

 
20 
 
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. 
Local surgery resulting from disease progression is prohibited.   However, if indicated for 
palliative measure and after Principal Investigator approval, local surgery may be permitted 
after the Week 12 tumor assessment.  Subjects who, in the assessment by the investigator, 
require the use of any of the aforementioned treatments for clinical management should be 
removed from the trial.   Subjects may receive other medications that the investigator deems 
to be medically necessary. 
The Exclusion Criteria describes other medications which are prohibited in this trial. 
There are no prohibited therapies during the Post-Treatment Follow-up Phase. 
5.6 
Rescue Medications & Supportive Care 
5.6.1 Supportive Care Guidelines 
Subjects should receive appropriate supportive care measures as deemed necessary by the 
treating investigator.  Suggested supportive care measures for the management of adverse 
events with potential immunologic etiology are outlined below. 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 and/or ipilimumab.  
It may be necessary to perform conditional procedures such as bronchoscopy, endoscopy, or 
skin photography as part of evaluation of the event.  
 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).   

 
21 
 
 
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 consider early administration of oral 
corticosteroids, especially if symptoms persists greater than 3 days,.  
o For Grade 3 or 4 diarrhea/colitis consider early administration of 
corticosteroids and if symptoms persist > 1 week, treat with intravenous steroids 
followed by high dose oral steroids.   
o When symptoms improve to Grade 1 or less, steroid taper should be started and 
continued over no less than 4 weeks. 
 
 
 Type 1 diabetes mellitus (if new onset, including diabetic ketoacidosis [DKA]) or 
≥ Grade 3 Hyperglycemia, if associated with ketosis (ketonuria) or metabolic 
acidosis (DKA) 
 
o For T1DM or Grade 3-4 Hyperglycemia 
 Insulin replacement therapy is recommended for Type I diabetes 
mellitus and for Grade 3-4 hyperglycemia associated with metabolic 
acidosis or ketonuria.  
 Evaluate patients with serum glucose and a metabolic panel, urine 
ketones, glycosylated hemoglobin, and C-peptide.  
 
 Hypophysitis: 
 
o For Grade 2 events, treat with corticosteroids. When symptoms improve to 
Grade 1 or less, steroid taper should be started and continued over no less than 
4 weeks. Replacement of appropriate hormones may be required as the steroid 
dose is tapered. 
o For Grade 3-4 events, treat with an initial dose of IV corticosteroids followed 
by oral corticosteroids. When symptoms improve to Grade 1 or less, steroid 
taper should be started and continued over no less than 4 weeks. Replacement 
of appropriate hormones may be required as the steroid dose is tapered. 
 
 
 Hyperthyroidism or Hypothyroidism:  
Thyroid disorders can occur at any time during treatment. Monitor patients for changes 
in thyroid function (at the start of treatment, periodically during treatment, and as 
indicated based on clinical evaluation) and for clinical signs and symptoms of thyroid 
disorders. 
 
o Grade 2 hyperthyroidism events (and Grade 2-4 hypothyroidism): 
 In hyperthyroidism, non-selective beta-blockers (e.g. propranolol) are 
suggested as initial therapy. 

 
22 
 
 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.  
 Infusion reactions to ipilimumab will be managed by the investigators according to the 
product labels. 
Table 4 below shows treatment guidelines for subjects who experience an infusion 
reaction associated with administration of pembrolizumab. Infusion reactions to 
ipilimumab will be managed by the investigators according to the product labels. 
Table 4 Infusion Reaction Treatment Guidelines 
NCI CTCAE Grade 
Treatment 
Premedication at subsequent 
dosing 
Grade 1 
Mild reaction; infusion interruption 
not indicated; intervention not 
indicated 
Increase monitoring of vital signs as medically 
indicated until the subject is deemed medically 
stable in the opinion of the investigator. 
None 
Grade 2 
Requires infusion interruption but 
responds promptly to symptomatic 
treatment (e.g., antihistamines, 
NSAIDS, narcotics, IV fluids); 
Stop Infusion and monitor symptoms. 
Additional appropriate medical therapy may 
include but is not limited to: 
IV fluids 
Antihistamines 
NSAIDS 
Subject may be premedicated 1.5h 
(± 30 minutes) prior to infusion of 
pembrolizumab 
(PEMBROLIZUMAB) with: 
 

 
23 
 
NCI CTCAE Grade 
Treatment 
Premedication at subsequent 
dosing 
prophylactic medications indicated for 
< =24 hrs 
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. 
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. 
 
 
 Management of Stevens-Johnson syndrome and Toxic Epidermal Necrolysis: 
To date, approximately 11,000 patients in clinical trials and 27,000 patients in the post-
marketing setting have been treated with KEYTRUDA®. One fatal case of SJS in a clinical 
trial and one fatal case of TEN in the post-marketing setting have been reported in patients 
treated with KEYTRUDA®. Including these cases, there have been 8 cases of SJS (6 in 
clinical trials, and 2 post-marketing) and 2 cases of TEN (both post-marketing) all of which 
were serious. 
 
o For signs or symptoms of SJS or TEN, withhold KEYTRUDA® and refer the patient 
for specialized care for assessment and treatment.  
o If SJS or TEN is confirmed, permanently discontinue KEYTRUDA®.  
 
 Management of Immune-mediated myocarditis: 
A total of 6 cases of myocarditis have been reported in patients treated with KEYTRUDA® in 
clinical trials or in an expanded access program. There were was 1 fatal case reported in a 
clinical trial. 

 
24 
 
o For suspected immune-mediated myocarditis, ensure adequate evaluation to exclude 
other etiologies, and administer corticosteroids as appropriate.  
 
 
5.7 
Diet/Activity/Other Considerations 
5.7.1 Diet 
Subjects should maintain a normal diet unless modifications are required to manage an AE 
such as diarrhea, nausea or vomiting. 
5.7.2 Contraception 
Pembrolizumab and/or ipilimumab may have adverse effects on a fetus in utero.  Furthermore, 
it is not known if pembrolizumab or ipilimumab have transient adverse effects on the 
composition of sperm.  Non-pregnant, non-breast-feeding women may be enrolled if they are 
willing to use 2 methods of birth control or are considered highly unlikely to conceive.  Highly 
unlikely to conceive is defined as 1) surgically sterilized, or 2) postmenopausal (a woman who 
is ≥45 years of age and has not had menses for greater than 1 year will be considered 
postmenopausal), or 3) not heterosexually active for the duration of the study.  The two birth 
control methods can be either two barrier methods or a barrier method plus a hormonal method 
to prevent pregnancy. Subjects should start using birth control from study Visit 1 throughout 
the study period up to 120 days after the last dose of study therapy.  
The following are considered adequate barrier methods of contraception: diaphragm, condom 
(by the partner), copper intrauterine device, sponge, or spermicide.  Appropriate hormonal 
contraceptives will include any registered and marketed contraceptive agent that contains an 
estrogen and/or a progestational agent (including oral, subcutaneous, intrauterine, or 
intramuscular agents). 
Subjects should be informed that taking the study medication may involve unknown risks to 
the fetus (unborn baby) if pregnancy were to occur during the study.  In order to participate in 
the study they must adhere to the contraception requirement (described above) for the duration 
of the study and during the follow-up period defined in section 7.2.2-Reporting of Pregnancy 
and Lactation to the Principal Investigator.  If there is any question that a subject will not 
reliably comply with the requirements for contraception, that subject should not be entered into 
the study. 
5.7.3 Use in Pregnancy 
If a subject inadvertently becomes pregnant while on treatment with pembrolizumab and/or 
ipilimumab, 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 Principal 
Investigator and to Merck without delay and within 24 hours to the Principal Investigator 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).   

 
25 
 
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 Principal Investigator.   
If a male subject impregnates his female partner the study personnel at the site must be 
informed immediately and the pregnancy reported to the Principal Investigator and to Merck 
and followed as described above and in Section 7.2.2. 
5.7.4 Use in Nursing Women 
It is unknown whether pembrolizumab and/or ipilimumab is excreted in human milk.  Since 
many drugs are excreted in human milk, and because of the potential for serious adverse 
reactions in the nursing infant, subjects who are breast-feeding are not eligible for enrollment. 
5.8 
Subject Withdrawal/Discontinuation Criteria 
Subjects may withdraw consent at any time for any reason or be dropped from the trial at the 
discretion of the investigator should any untoward effect occur.  In addition, a subject may be 
withdrawn by the investigator or the Principal Investigator if enrollment into the trial is 
inappropriate, the trial plan is violated, or for administrative and/or other safety reasons.  
Specific details regarding discontinuation or withdrawal are provided in Section 7.1.4 – 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: A subject may be granted an exception to continue on treatment with 
confirmed radiographic progression if clinically stable or clinically improved. Such 
cases should be discussed by the treating physician with the Principal Investigator. 
 Unacceptable adverse experiences as described in Section 5.2.1.2 
 Intercurrent illness that prevents further administration of treatment 
 Investigator’s decision to withdraw the subject 
 The subject has a confirmed positive serum pregnancy test 
 Noncompliance with trial treatment or procedure requirements 
 The subject is lost to follow-up 
 Completed 24 months of uninterrupted treatment with pembrolizumab or 35 
administrations of study medication (which includes both doses of pembrolizumab and 
ipilimumab together for 4 doses followed by pembrolizumab monotherapy), whichever 
is later. 

 
26 
 
Note: 24 months of study medication is calculated from the date of first dose. Subjects 
who stop pembrolizumab after 24 months may be eligible for up to one year of 
additional study treatment if they progress after stopping study treatment provided they 
meet protocol requirements.  
 Administrative reasons 
After the end of treatment, each subject will be followed for 30 days for adverse event 
monitoring. Subjects who discontinue for reasons other than progressive disease will have 
post-treatment follow-up for disease status until disease progression, initiating a non-study 
cancer treatment, withdrawing consent or becoming lost to follow-up.  After documented 
disease progression each subject will be followed by telephone until death, initiating 
subsequent treatment, withdrawal of consent, or the end of the study, whichever occurs first. 
5.8.1 Discontinuation of Study Therapy after CR  
Discontinuation of treatment may be considered for subjects who have attained a confirmed 
CR that have been treated for at least 24 weeks with pembrolizumab and had at least two 
treatments with pembrolizumab beyond the date when the initial CR was declared.  Subjects 
who then experience radiographic disease progression may be eligible for up to one year of 
additional treatment with pembrolizumab via the Second Course Phase at the discretion of the 
investigator if no cancer treatment was administered since the last dose of pembrolizumab, the 
subject meets the safety parameters listed in the Inclusion/Exclusion criteria, and the trial is 
open.  Subjects will resume therapy at the same dose and schedule at the time of initial 
discontinuation.  Additional details are provided in Section 7.1.4.2. 
5.9 
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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Protocol/Amendment No.:   
 
 
 
 
 
 
6.0 TRIAL FLOW CHART 
6.1 
Study Flow Chart 
Trial Period: 
Screening Phase 
Treatment Cyclesa 
End of 
Treatment 
Post-Treatment 
Treatment Cycle/Title: 
Pre-
screening 
(Visit 1) 
Main 
Study 
Screening 
(Visit 2) 
1 
2  
3 
4* 
To be repeated beyond 8 
cycles 
Discon 
Safety 
Follow-up 
Follow Up Visitsb 
Every 12 weeks post 
discon 
5 
6 
7 
8 
Scheduling Window (Days): 
 
-28 to -1 
 
± 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 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Trial Treatment Administration 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Clinical Procedures/Assessments 
Review Adverse Events 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical Examination 
 
X 
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 
X 
ECOG Performance Status 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Laboratory Procedures/Assessments: analysis performed by LOCAL laboratory 
Pregnancy Test – Urine or Serum -HCG 
 
X 
 
 
 
 
 
 
 
 
 
 
 
CBC with Differential 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Comprehensive Serum Chemistry Panel 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Urinalysis 
 
X 
 
 
 
 
 
 
 
 
 
 
 
TSH (with reflexive T3, FT4 as indicated) 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Efficacy Measurements 

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Protocol/Amendment No.:   
 
 
 
 
 
 
Trial Period: 
Screening Phase 
Treatment Cyclesa 
End of 
Treatment 
Post-Treatment 
Treatment Cycle/Title: 
Pre-
screening 
(Visit 1) 
Main 
Study 
Screening 
(Visit 2) 
1 
2  
3 
4* 
To be repeated beyond 8 
cycles 
Discon 
Safety 
Follow-up 
Follow Up Visitsb 
Every 12 weeks post 
discon 
5 
6 
7 
8 
Scheduling Window (Days): 
 
-28 to -1 
 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
At time of 
Discon 
30 days 
post 
discon 
Tumor Imaging (window includes all of 
cycle following drug administration) 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
Tumor Biopsies/Archival Tissue Collection/Correlative Studies Blood 
Archival or Newly Obtained Tissue 
CollectionC 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Correlative Studies Blood CollectionC 
 
X 
X 
 
 
X 
 
 
 
 
X 
 
 
Fecal Sample 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
a – Treatment cycles; *Treatment cycle 4 visit-to allow for the scan any time after infusion of the 4th dose. 
b – Follow up visits for up to 2 years following drug discontinuation 
c – Samples to be collected for correlative blood analysis are detailed in section 8.1.1.11 
 
 
 
 
 

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7.0 REGISTRATION PROCEDURES 
7.1 
General Guidelines 
Prior to registration and any study-specific evaluations being performed, all patients must have 
given written informed consent for the study and must have completed the pre-treatment 
evaluations.  Patients must meet all of the eligibility requirements listed in Section 3. Eligible 
patients will be entered on study centrally by the University of Chicago study coordinator. All 
sites 
should 
call 
the 
study 
coordinator 
at 
(773) 
834-1746 
or 
PhaseIICRA@medicine.bsd.uchicago.edu to verify availability of a slot. 
7.2 
Registration Process 
When a potential patient has been identified, notify the CRA via phone or email to ensure a 
reservation on the study ((773) 834-1746 or PhaseIICRA@medicine.bsd.uchicago.edu). 
Reservations for potential subjects will only be held for subjects who have signed consent for 
that particular study. 
When registering a subject, the following must occur:  
• 
Confirm that the institution has a current IRB approval letter for the correct version of 
protocol/consent and has an annual update on file, if appropriate.  
• 
Submit all required materials (Eligibility Checklist, Source documentation, & signed 
consent form) to confirm eligibility and required pre-study procedures to the CRA a minimum 
of 48 hours prior to the subject’s scheduled therapy start date.  
• 
Source documentation includes copies of all original documents that support each 
inclusion/exclusion criteria.  The eligibility checklist does not serve as source documentation 
but rather as a checklist that original source documentation exists for each criterion. 
• 
Communicate with the CRA to ensure all necessary supporting source documents are 
received and the potential subject is eligible to start treatment on schedule. If there are 
questions about eligibility, the CRA will discuss it with the PI. PI may clarify, but not overturn, 
eligibility criteria.  
• 
Affiliate sites must confirm registration of subjects by obtaining a subject study ID 
number from the CRA via phone, fax or email.  
• 
If a subject does not start on the scheduled day 1 treatment date, promptly inform the 
CRA as the delay in start may deem the subject ineligible and/or require further or repeat 
testing to ensure eligibility.  
• 
The date the patient receives treatment for the first time will be considered the patient’s 
“OnStudy Date.” The patient’s subject ID will be assigned and a confirmation of registration 
will be issued by the CRA on this date. Subjects that sign consent and do not go “OnStudy” 

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Protocol/Amendment No.:   
 
 
 
 
 
 
will be recorded in the database with the date they signed consent and the reason for not going 
“OnStudy” (e.g., Ineligible, Screen Failure or Withdrawn Consent).    
8.0 TRIAL PROCEDURES 
8.1 
Trial Procedures 
The Trial Flow Chart - Section 6.0 summarizes the trial procedures to be performed at each 
visit.  Individual trial procedures are described in detail below.  It may be necessary to perform 
these procedures at unscheduled time points if deemed clinically necessary by the investigator. 
Furthermore, additional evaluations/testing may be deemed necessary by the Principal 
Investigator 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 may require that additional 
informed consent be obtained from the subject.   
8.1.1 Administrative Procedures 
8.1.1.1 Informed Consent 
The Investigator must obtain documented consent from each potential subject prior to 
participating in a clinical trial. 
8.1.1.1.1  General Informed Consent 
Consent must be documented by the subject’s dated signature or by the subject’s legally 
acceptable representative’s dated signature on a consent form along with the dated signature 
of the person conducting the consent discussion.  
A copy of the signed and dated consent form should be given to the subject before participation 
in the trial. 
The initial informed consent form, any subsequent revised written informed consent form and 
any written information provided to the subject must receive the IRB 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 requirements as well as applicable laws and 
regulations. 

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Protocol/Amendment No.:   
 
 
 
 
 
 
 
8.1.1.2 Inclusion/Exclusion Criteria 
All inclusion and exclusion criteria will be reviewed by the investigator or qualified designee 
to ensure that the subject qualifies for the trial.  
8.1.1.3 Medical History 
A medical history will be obtained by the investigator or qualified designee.  Medical history 
will include all active conditions, and any condition diagnosed within the prior 10 years that 
are considered to be clinically significant by the Investigator.  Details regarding the disease for 
which the subject has enrolled in this study will be recorded separately and not listed as medical 
history.   
8.1.1.4 Prior and Concomitant Medications Review 
8.1.1.4.1 Prior Medications 
The investigator or qualified designee will review prior medication use, including any 
protocol-specified washout requirement, and record prior medication taken by the subject 
within 28 days before starting the trial.  Treatment for the disease for which the subject has 
enrolled in this study will be recorded separately and not listed as a prior medication.  
8.1.1.4.2 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 should be recorded as defined in 
Section 7.2. 
8.1.1.5 Disease Details and Treatments 
8.1.1.5.1 Disease Details 
The investigator or qualified designee will obtain prior and current details regarding disease 
status.  
8.1.1.5.2 Prior Treatment Details 
The investigator or qualified designee will review all prior cancer treatments including 
systemic treatments, radiation and surgeries. 
8.1.1.5.3 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 

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Protocol/Amendment No.:   
 
 
 
 
 
 
first dose of the new therapy.  Once new anti-cancer therapy has been initiated the subject will 
move into survival follow-up.  
8.1.1.6 Adverse Event (AE) Monitoring 
The investigator or qualified designee will assess each subject to evaluate for potential new or 
worsening AEs as specified in the Trial Flow Chart and more frequently if clinically indicated.  
Adverse experiences will be graded and recorded throughout the study and during the follow-
up period according to NCI CTCAE Version 4.0 (see Section 11.2).  Toxicities will be 
characterized in terms regarding seriousness, causality, toxicity grading, and action taken with 
regard to trial treatment.  
For subjects receiving treatment with pembrolizumab all AEs of unknown etiology associated 
with pembrolizumab exposure should be evaluated to determine if it is possibly an event of 
clinical interest (ECI) of a potentially immunologic etiology (termed immune-related adverse 
events, or irAEs).  
Please refer to section 7.2 for detailed information regarding the assessment and recording of 
AEs.   
8.1.1.7 Physical Exam 
The investigator or qualified designee will perform a physical exam at protocol specified time 
points as per the Trial Flow Chart (Section 6.0).  Clinically significant abnormal findings 
should be recorded as medical history.  A full physical exam should be performed during 
screening,  
8.1.1.8 Vital Signs 
The investigator or qualified designee will take vital signs at screening, prior to the 
administration of each dose of trial treatment and at treatment discontinuation as specified in 
the Trial Flow Chart (Section 6.0).  Vital signs should include temperature, pulse, respiratory 
rate, weight and blood pressure.  Height will be measured at screening only. 
8.1.1.9 Eastern Cooperative Oncology Group (ECOG) Performance Scale 
The investigator or qualified designee will assess ECOG status (see Section 13.1) at screening, 
prior to the administration of each dose of trial treatment and discontinuation of trial treatment 
as specified in the Trial Flow Chart.   
8.1.1.10 Tumor Imaging and Assessment of Disease 
Baseline and restaging radiologic imaging will be performed to encompass all sites of 
metastatic disease. This will generally include at least CT CAP though the specific imaging 
study can be changed by the treating investigator depending on patient circumstances.  
Radiologic imaging modality should be consistent throughout the study for response 

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Protocol/Amendment No.:   
 
 
 
 
 
 
assessment.  For patients who have known bone metastases at baseline, bone scan should 
additionally be pursued as standard of care for disease assessment. 
8.1.1.11 Tumor Tissue Collection and Correlative Studies Blood Sampling 
The following tables outline the requirements for tissue and blood banking. These will be 
collected and stored for batched future analysis. 
Biospecimen type 
Collection Time Point 
Number of 
samples per 
patient 
Fecal sample 
Pre-treatment:  obtained prior 
treatment on protocol  
On-treatment: obtained at dose 
4 of treatment with 
pembrolizumab 
2 samples 
A paraffin-embedded tissue block of 
the primary tumor taken before 
initiation of treatment (if available). 
Pre-treatment:  obtained prior 
treatment on protocol 
1 historical sample 
Peripheral Blood Mononuclear 
Cells: ~60 ml of anti-coagulated 
whole blood in green top tube  
Pre-treatment: 8-10 tubes taken 
within 21 days prior to 
initiation of treatment. 
Post treatment: 8-10 tubes taken 
day of dose 1 and dose 4 
pembrolizumab and at time of 
progressive disease. 
Up to 30 samples 
total over 3 time 
points 
Whole blood for germline DNA: 8-
10 mL of whole blood in PAXgene 
tube 
Pre-treatment: taken 21 days 
prior to initiation of treatment. 
 
1 sample 
Whole blood for serum analysis: 8-
10 mL of whole blood in red top 
tube 
Pre-treatment: taken within 21 
days prior to initiation of 
treatment. 
 
1 sample 
 
Biospecimens will be shipped and stored in the University of Chicago Human Immune 
Monitoring Core Facility. 
Human Immune Monitoring Core: 

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Protocol/Amendment No.:   
 
 
 
 
 
 
Contact: Yuanyuan Zha 
University of Chicago - Human Immune Monitoring Core 
910 E. 58th St. MKL057 
Chicago, IL 60637 
yzha1@bsd.uchicago.edu 
Phone: 773-702-4812 
 
8.1.2 Laboratory Procedures/Assessments 
Details regarding specific laboratory procedures/assessments to be performed in this trial are 
provided below. Laboratory Safety Evaluations (Hematology, Chemistry and Urinalysis) 
Laboratory tests for hematology, chemistry, urinalysis, and others are specified in Table 5.   

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Protocol/Amendment No.:   
 
 
 
 
 
 
Table 5  Laboratory Tests 
Hematology 
Chemistry 
Urinalysis 
Other 
Hematocrit 
Albumin 
Blood 
Serum β-human chorionic gonadotropin† 
Hemoglobin 
Alkaline phosphatase 
Glucose 
  (β-hCG)† 
Platelet count 
Alanine aminotransferase (ALT) 
Protein 
 
WBC (total and differential) 
Aspartate aminotransferase (AST) 
Specific gravity  
 
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) 
 
Calcium 
 
 
 
Chloride 
 
Blood for correlative studies 
 
Creatinine 
 
 
 
Glucose 
 
  
 
Potassium   
 
  
 
Sodium 
 
  
 
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.   
 
 
 

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Protocol/Amendment No.:   
 
 
 
 
 
 
Laboratory tests for screening or entry into the Second Course Phase 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 each dose of trial 
treatment.  
8.1.3 Other Procedures 
8.1.3.1 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.  Subjects who a) attain a CR or b) complete 24 months of treatment with 
pembrolizumab may discontinue treatment with the option of restarting treatment if they meet 
the criteria specified in Section 7.1.4.2.  After discontinuing treatment following assessment 
of CR, these subjects should return to the site for a Safety Follow-up Visit and then proceed to 
the Follow-Up Period of the study. 
8.1.4 Visit Requirements 
Visit requirements are outlined in Section 6.0 - Trial Flow Chart.   Specific procedure-related 
details are provided above in Section 7.1 - Trial Procedures. 
The mandatory Safety Follow-Up Visit should be conducted approximately 30 days after the 
last dose of trial treatment or before the initiation of a new anti-cancer treatment, whichever 
comes first.  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.  SAEs that occur 
within 90 days of the end of treatment or before initiation of a new anti-cancer treatment should 
also be followed and recorded.  Subjects who are eligible for retreatment with pembrolizumab 
(as described in Section 7.1.4.2) may have up to two safety follow-up visits, one after the 
Treatment Period and one after the Second Course Phase. 
8.1.4.1 Follow-up Visits 
Subjects who discontinue trial treatment for a reason other than disease progression will move 
into the Follow-Up Phase and should be assessed every 12 weeks (± 7 days) by radiologic 
imaging to monitor disease status up to 24 months after the final patients is enrolled or until 
receiving treatment outside of this protocol.  Every effort should be made to collect information 
regarding disease status until the start of new anti-neoplastic therapy, disease progression, 
death, end of the study or if the subject begins retreatment with pembrolizumab as detailed in 
Section 7.1.4.2.  Information regarding post-study anti-neoplastic treatment will be collected 
if new treatment is initiated. 

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Protocol/Amendment No.:   
 
 
 
 
 
 
Subjects who are eligible to receive retreatment with pembrolizumab according to the criteria 
in Section 7.1.4.2 will move from the follow-up phase to the Second Course Phase when they 
experience disease progression.      
8.1.4.2 Second Course Phase (Retreatment Period) 
Subjects who stop pembrolizumab with SD or better may be eligible for up to one year of 
additional pembrolizumab therapy if they progress after stopping study treatment.  This 
retreatment is termed the Second Course Phase of this study and is only available if the study 
remains open and the subject meets the following conditions: 
 Either  
o Stopped initial treatment with pembrolizumab after attaining an investigator-
determined confirmed CR according to RECIST 1.1, and 
 Was treated for at least 24 weeks with pembrolizumab before discontinuing 
therapy 
 Received at least two treatments with pembrolizumab beyond the date when 
the initial CR was declared 
 
 
OR 
o Had SD, PR or CR and stopped pembrolizumab treatment after 24 months of study 
therapy for reasons other than disease progression or intolerability 
AND 
 Experienced an investigator-determined confirmed radiographic disease progression 
after stopping their initial treatment with pembrolizumab 
 Did not receive any anti-cancer treatment since the last dose of pembrolizumab 
 Has a performance status of 0 or 1 on the ECOG Performance Scale 
 Demonstrates adequate organ function as detailed in Section 5.1.2 
 Female subject of childbearing potential should have a negative serum or urine 
pregnancy test within 72 hours prior to receiving retreatment with study medication.   
 Female subject of childbearing potential should be willing to use 2 methods of birth 
control or be surgically sterile, or abstain from heterosexual activity for the course of 
the study through 120 days after the last dose of study medication (Reference Section 
5.7.2).  Subjects of child bearing potential are those who have not been surgically 
sterilized or have been free from menses for > 1 year.  

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Protocol/Amendment No.:   
 
 
 
 
 
 
 Male subject should agree to use an adequate method of contraception starting with the 
first dose of study therapy through 120 days after the last dose of study therapy.   
 Does not have a history or current evidence of any condition, therapy, or laboratory 
abnormality that might interfere with the subject’s participation for the full duration of 
the trial or is not in the best interest of the subject to participate, in the opinion of the 
treating investigator. 
Subjects who restart treatment will be retreated at the same dose and dose interval as when 
they last received pembrolizumab.  Treatment will be administered for up to one additional 
year. 
Visit requirements are outlined in Section 6.0 – Trial Flow Chart. 
8.2 
Assessing and Recording Adverse Events 
An adverse event is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product and which does not necessarily 
have to have a causal relationship with this treatment. An adverse event can therefore be any 
unfavorable and unintended sign (including an abnormal laboratory finding, for example), 
symptom, or disease temporally associated with the use of a medicinal product or protocol-
specified procedure, whether or not considered related to the medicinal product or protocol-
specified procedure.  Any worsening (i.e., any clinically significant adverse change in 
frequency and/or intensity) of a preexisting 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 
within the follow-up period specified by the protocol, or prescribed in clinical practice, from 
overdose (whether accidental or intentional), from abuse and from withdrawal. 
Adverse events may also occur in screened subjects during any pre-allocation baseline period 
as a result of a protocol-specified intervention, including washout or discontinuation of usual 
therapy, diet, placebo treatment or a procedure. 
Progression of the cancer under study is not considered an adverse event unless it is considered 
to be drug related by the investigator. 

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Protocol/Amendment No.:   
 
 
 
 
 
 
All adverse events will be recorded from first day of study drug administration through 30 days 
following cessation of treatment and at each examination on the Adverse Event case report 
forms/worksheets. The reporting timeframe for adverse events meeting any serious criteria is 
described in section 7.2.3.1. 
8.2.1 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. 
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 UC CCC Cancer Clinical Trials Office and Principal Investigator and within 2 working 
days hours to Merck Global Safety. (Attn: Worldwide Product Safety; FAX 215 993-1220) 
8.2.2 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), including the pregnancy of a male subject's female partner that occurs during 
the trial or within 120 days of completing the trial completing the trial, or 30 days following 
cessation of treatment if the subject initiates new anticancer therapy, whichever is earlier.  All 
subjects and female partners of male subjects who become pregnant must be followed to the 
completion/termination of the pregnancy.  Pregnancy outcomes of spontaneous abortion, 
missed abortion, benign hydatidiform mole, blighted ovum, fetal death, intrauterine death, 
miscarriage and stillbirth must be reported as serious events (Important Medical Events).  If 
the pregnancy continues to term, the outcome (health of infant) must also be reported. 
Such events must be reported within 24 hours to the UC CCC Cancer Clinical Trials Office 
and Principal Investigator and within 2 working days to Merck Global Safety. (Attn: 
Worldwide Product Safety; FAX 215 993-1220) 

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Protocol/Amendment No.:   
 
 
 
 
 
 
8.2.3 Immediate Reporting of Adverse Events to the Sponsor and to Merck 
8.2.3.1 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 a new cancer (that is not a condition of the study); 
 Is associated with an overdose; 
 Is an other important medical event  
Refer to Table 6 for additional details regarding each of the above criteria. 
Any serious adverse event, or follow up to a serious adverse event, including death due to any 
cause other than progression of the cancer under study that occurs to any subject from first day 
of study drug administration through 90 days following cessation of treatment, or the initiation 
of new anti-cancer therapy, whichever is earlier, whether or not related to Merck product, must 
be reported within 24 hours to the UC CCC Cancer Clinical Trials Office and Principal 
Investigator and within 2 working days to Merck Global Safety.  
Non-serious Events of Clinical Interest will be forwarded to Merck Global Safety and will be 
handled in the same manner as SAEs.  
Additionally, any serious adverse event, considered by an investigator who is a qualified 
physician to be related to Merck product that is brought to the attention of the investigator at 
any time outside of the time period specified in the previous paragraph also must be reported 
immediately to the UC CCC Cancer Clinical Trials Office and Principal Investigator and to 
Merck. 
SAE reports and any other relevant safety information are to be forwarded to the Merck Global 
Safety facsimile number:  +1-215-993-1220 
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. (Attn: 
Worldwide Product Safety; FAX 215 993-1220) at the time of submission to FDA. 
All subjects with serious adverse events must be followed up for outcome. 

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Protocol/Amendment No.:   
 
 
 
 
 
 
8.2.3.2 Unexpected Events 
Unexpected events are those not listed at the observed specificity or severity in the protocol, 
informed consent, investigator brochure, or FDA-approved package insert.  An event is 
considered unexpected if it is listed as occurring within the class of drugs or otherwise expected 
from the drug’s pharmacological properties but which has not been previously observed with 
this specific investigational agent. 
8.2.3.3 Adverse Reactions 
An adverse event is considered to be an adverse reaction if there evidence to suggest a causal 
relationship to the study agent.  This may include a single occurrence of an event strongly 
associated with drug exposure (e.g. Stevens-Johnson Syndrome), one or more occurrence of 
an event otherwise uncommon is the study population, or an aggregate analysis of specific 
events occurring at greater than expected frequency. 
8.2.3.4 Events of Clinical Interest 
Selected non-serious and serious adverse events are also known as Events of Clinical Interest 
(ECI) and must be recorded as such on the Adverse Event case report forms/worksheets and 
reported within 24 hours to the UC CCC Cancer Clinical Trials Office and Principal 
Investigator and within 2 working days to Merck Global Safety. (Attn: Worldwide Product 
Safety; FAX 215 993-1220)Events of clinical interest for this trial include: 
1.  an overdose of Merck product, as defined in Section 7.2.1 - 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.   
 
Subjects should be assessed for possible ECIs prior to each dose.  Lab results should be 
evaluated and subjects should be asked for signs and symptoms suggestive of an immune-
related event.  Subjects who develop an ECI thought to be immune-related should have 
additional testing to rule out other etiologic causes.  If lab results or symptoms indicate a 
possible immune-related ECI, then additional testing should be performed to rule out other 
etiologic causes.  If no other cause is found, then it is assumed to be immune-related. 
 

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Protocol/Amendment No.:   
 
 
 
 
 
 
 
8.2.4 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. 
All adverse events regardless of CTCAE grade must also be evaluated for seriousness. 

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Protocol/Amendment No.:   
 
 
 
 
 
 
Table 6  Evaluating Adverse Events 
An investigator who is a qualified physician, will evaluate all adverse events as to: 
V4.0 
CTCAE 
Grading 
Grade 1 
Mild; asymptomatic or mid symptoms; clinical or diagnostic observations only; intervention not indicated. 
 
Grade 2 
Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental ADL. 
 
Grade 3 
Severe or medically significant but not immediately life-threatening; hospitalization or prolongation or hospitalization indicated; 
disabling; limiting self-care ADL. 
 
Grade 4 
Life threatening consequences; urgent intervention indicated. 
 
Grade 5 
Death related to AE 
Seriousness 
A serious adverse event is any adverse event occurring at any dose or during any use of Merck product that: 
 
†Results in death; or 
 
†Is life threatening; or places the subject, in the view of the investigator, at immediate risk of death from the event as it occurred (Note: This does not include an 
adverse event that, had it occurred in a more severe form, might have caused death.); or 
 
†Results in a persistent or significant disability/incapacity (substantial disruption of one’s ability to conduct normal life functions); or 
 
†Results in or prolongs an existing inpatient hospitalization (hospitalization is defined as an inpatient admission, regardless of length of stay, even if the 
hospitalization is a precautionary measure for continued observation. (Note: Hospitalization [including hospitalization for an elective procedure] for a preexisting 
condition which has not worsened does not constitute a serious adverse event.); or 
 
†Is a congenital anomaly/birth defect (in offspring of subject taking the product regardless of time to diagnosis);or 
 
Is a new cancer; (that is not a condition of the study) or 
 
Is an overdose (whether accidental or intentional).  Any adverse event associated with an overdose is considered a serious adverse event. An overdose that is not 
associated with an adverse event is considered a non-serious event of clinical interest and must be reported within 24 hours. 
 
Other important medical events that may not result in death, not be life threatening, or not require hospitalization may be considered a serious adverse event when, 
based upon appropriate medical judgment, the event may jeopardize the subject and may require medical or surgical intervention to prevent one of the outcomes 
listed previously (designated above by a †). 
Duration 
Record the start and stop dates of the adverse event. If less than 1 day, indicate the appropriate length of time and units 
Action taken  
Did the adverse event cause the Merck product to be discontinued? 
Relationship to 
test drug  
Did the Merck product cause the adverse event? The determination of the likelihood that the Merck product caused the adverse event will be provided by an 
investigator who is a qualified physician. The investigator’s signed/dated initials on the source document or worksheet that supports the causality noted on the AE 
form, ensures that a medically qualified assessment of causality was done. This initialed document must be retained for the required regulatory time frame. The 
criteria below are intended as reference guidelines to assist the investigator in assessing the likelihood of a relationship between the test drug and the adverse event 
based upon the available information.  
The following components are to be used to assess the relationship between the Merck product and the AE; the greater the correlation with the components and 
their respective elements (in number and/or intensity), the more likely the Merck product caused the adverse event (AE): 
 
Exposure 
Is there evidence that the subject was actually exposed to the Merck product such as: reliable history, acceptable compliance assessment (pill 
count, diary, etc.), expected pharmacologic effect, or measurement of drug/metabolite in bodily specimen? 
 
Time Course 
Did the AE follow in a reasonable temporal sequence from administration of the Merck product?  
Is the time of onset of the AE compatible with a drug-induced effect (applies to trials with investigational medicinal product)? 
 
Likely Cause 
Is the AE not reasonably explained by another etiology such as underlying disease, other drug(s)/vaccine(s), or other host or environmental 
factors 
 

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

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8.2.5 Serious Adverse Event Reporting to the Coordinating Center 
All Adverse Events will be reported to regulatory authorities, IRB/IECs and investigators in 
accordance with all applicable global laws and regulations.  
All serious adverse events and all Events of Clinical Interest that have been specified to require 
expedited reporting occurring on this study require expedited reporting to the University of 
Chicago Comprehensive Cancer Center (UC CCC).  The responsible Research Nurse or other 
designated individual at the treating site should report the SAE to the Principal Investigator 
and the Cancer Clinical Trials Office (CCTO) by the end of the business day when s/he 
becomes aware of the event.  Events occurring after business hours should be reported to the 
CCTO by 12pm (noon) the next business day.  Reports should be made using the ‘Serious 
Event Report’ Form. Please scan and send via email (preferred) or fax to the following: 
University of Chicago Phase II CRA General: 
PhaseIICRA@medicine.bsd.uchicago.edu 
Phone: 773-834-1746 
Fax: 773-702-4889 
 
UC CCC Cancer Clinical Trials Office Quality Assurance: 
qaccto@bsd.uchicago.edu 
 
All unexpected adverse reactions must be reported to the IND holder so that the University of 
Chicago CCTO can inform the FDA.  The responsible Research Nurse or other designated 
individual at the treating site should provide a complete written report using the FDA 
MedWatch 3500A form.  The completed form should be sent to the CCTO at 
qaccto@bsd.uchicago.edu 
and 
to 
the 
Phase 
II 
CRA 
at 
PhaseIICRA@medicine.bsd.uchicago.edu within the specified timelines below regardless of 
whether all information regarding the event is available.  If applicable, a follow-up report 
should be provided to the CCTO if additional information on the event becomes available. 
Participating sites should not forward any adverse event reports directly to the FDA.  The 
CCTO will report all events to the FDA as per the current FDA guidelines.   
Fatal or Life-threatening Events: within 4 calendar days from treating investigator 
knowledge of the event 
All Other Reportable Events: within 10 calendar days of treating investigator 
knowledge of the event 
All serious adverse events should also be reported to the local IRB of record according to 
their policies and procedures.   
 

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8.2.6 Serious Adverse Event Reporting by the Coordinating Center 
The designated UC CCC Regulatory Manager will notify all participating sites of all 
unexpected and serious adverse reactions that occur on this clinical trial and which are reported 
to the FDA and/or UC Institutional Review Board (IRB).  When reported to the FDA, a copy 
of the completed Form 3500A (MedWatch) will be provided to the responsible Regulatory 
Manager by the CCTO IND Coordinator for distribution to all participating sites. 
8.2.7 Serious Adverse Event Reporting to Merck 
Any serious adverse event reported to the UC CCC, whether or not related to Merck product, 
must also be reported within 2 working days to Merck Global Safety by the responsible 
Research Nurse or other designated individual at the treating site.  
Non-serious Events of Clinical Interest will be forwarded to Merck Global Safety and will be 
handled in the same manner as SAEs.  
SAE reports and any other relevant safety information are to be forwarded to the Merck Global 
Safety facsimile number:  +1-215-993-1220. 
9.0 DATA REPORTING 
Data reporting will be performed utilizing the eVelos electronic data capture system.  The 
University of Chicago CRA will provide you with the applicable user registration information.  
All required data must be recorded in the eVelos database at the completion of each cycle.  
AEs are to be entered in real time. SAEs are to be entered on the Serious Event Form within 
24 hours of the site’s knowledge of the event and sent via email (preferred) or fax to the 
University 
of 
Chicago 
(PhaseIICRA@medicine.bsd.uchicago.edu 
or 
qaccto@bsd.uchicago.edu; Fax: 773-702-4889). All case report forms must be completed by 
designated study personnel. Each screened (consented) patient is to be entered into eVelos 
within 48 hours of patient registration. In addition to direct data entry, you may be required to 
provide supporting source documentation. Source records are original documents, data, and 
records (e.g., medical records, raw data collection forms, pharmacy dispensing records, 
recorded data from automated instruments, laboratory data) that are relevant to the clinical 
trial. Each site will prepare and maintain adequate and accurate source documents. These 
documents are designed to record all observations and other pertinent data for each subject 
enrolled in this clinical trial. Source records must be adequate to reconstruct all data transcribed 
onto the case report form.   
10.0 STATISTICAL ANALYSIS PLAN 
10.1 Statistical Analysis Plan  
The primary endpoint of the study will be response rate by irRECIST criteria.  A Simon (Cont 
Clin Trials, 1980), optimal two-stage design will be employed to test the null hypothesis of a 
10% response rate (based on historical ipilimumab alone) vs. a 30% alternative.  Twelve 

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Protocol/Amendment No.:   
 
 
  
 
 
 
patients will be entered into the first stage and if 1 or fewer responses are observed then the 
trial will be terminated for lack of activity.  Otherwise an additional 23 patients will be enrolled 
for a total of 35.  If 5 or fewer responses are observed the treatment will be considered 
insufficiently active whereas if 6 or more (>17%) are seen the null hypothesis will be rejected 
and the treatment considered worthy of further testing.  This design has an alpha level of 0.10 
(1-sided), 90% power, and a 0.65 probability of stopping early if the true response rate is only 
10%.  With the closing of cohort 2, we will enroll an additional 35 patients who had initial 
progression if 6 or more patients respond among the initial 35.  This will bring the total sample 
size to n=70, and provide additional precision for the estimated response rate and other 
secondary endpoints.  For response rate, assuming a true rate of 30%, n=70 subjects will 
provide a 90% confidence interval width of ± 9.0%.   
Evaluable patients will be defined as any eligible patient who receives a dose of 
pembrolizumab in combination with ipilimumab. 
Secondary endpoints will include estimation of progression-free survival using the Kaplan-
Meier method and assessment of changes in biomarkers from pre-post treatment using paired 
t-tests or Wilcoxon signed-rank tests. 
10.2 Sample Size and Expected Accrual 
The total sample size will be 70 patients Patient accrual is projected to be approximately 3 
patients per month.  Thus accrual is likely to proceed for 8 to 24 months. 
11.0 LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL 
SUPPLIES 
11.1 Investigational Product  
The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution and usage of 
investigational product in accordance with the protocol and any applicable laws and 
regulations. 
Clinical Supplies will be provided by Merck as summarized in Table 7. 
Table 7  Product Descriptions 
Product Name & Potency 
Dosage Form 
Pembrolizumab 50 mg 
Lyophilized Powder for Injection 
Pembrolizumab 100 mg/ 4mL 
Solution for Injection 
 

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Protocol/Amendment No.:   
 
 
  
 
 
 
11.2 Packaging and Labeling Information 
Clinical supplies will be affixed with a clinical label in accordance with regulatory 
requirements. 
11.3 Clinical Supplies Disclosure 
This trial is open-label; therefore, the subject, the trial site personnel, the Sponsor and/or 
designee are not blinded to treatment. Drug identity (name, strength) is included in the label 
text; random code/disclosure envelopes or lists are not provided. 
11.4 Storage and Handling Requirements 
Clinical supplies must be stored in a secure, limited-access location under the storage 
conditions specified on the label.   
Receipt and dispensing of trial medication must be recorded by an authorized person at the 
trial site. 
Clinical supplies may not be used for any purpose other than that stated in the protocol. 
11.5 Returns and Reconciliation 
The investigator is responsible for keeping accurate records of the clinical supplies received 
from Merck or designee, the amount dispensed to and returned by the subjects and the amount 
remaining at the conclusion of the trial.  
Upon completion or termination of the study, all unused and/or partially used investigational 
product will be destroyed at the site per institutional policy. It is the Investigator’s 
responsibility to arrange for disposal of all empty containers, provided that procedures for 
proper disposal have been established according to applicable federal, state, local and 
institutional guidelines and procedures, and provided that appropriate records of disposal are 
kept. 
12.0 ADMINISTRATIVE AND REGULATORY DETAILS 
12.1 Institutional Review Board (IRB) Approval and Consent 
Unless otherwise specified, each participating institution must obtain its own IRB approval. It 
is expected that the IRB will have the proper representation and function in accordance with 
federally mandated regulations.  The IRB should approve the consent form and protocol. 
In obtaining and documenting informed consent, the investigator should comply with the 
applicable regulatory requirement(s), and should adhere to Good Clinical Practice (GCP) and 
to ethical principles that have their origin in the Declaration of Helsinki. 

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Before recruitment and enrollment onto this study, the patient will be given a full explanation 
of the study and will be given the opportunity to review the consent form. Each consent form 
must include all the relevant elements currently required by the FDA Regulations and local or 
state regulations. Once this essential information has been provided to the patient and the 
investigator is assured that the patient understands the implications of participating in the 
study, the patient will be asked to give consent to participate in the study by signing an IRB 
approved consent form. 
Prior to a patient’s participation in the trial, the written informed consent form should be signed 
and personally dated by the patient and by the person who conducted the informed consent 
discussion. 
12.2 Food and Drug Administration (FDA) Approval 
This study will be conducted under an IND held by Dr. Thomas Gajewski at the University of 
Chicago.  The University of Chicago CCTO will be responsible for facilitating all 
communications with the FDA on behalf of the IND holder.   Participating sites should not 
communicate directly with the FDA.     
12.3 Required Documentation 
Prior to the selection of a study site that is not a full member of the Personalized Cancer Care 
Consortium, the audit and trial oversight processes for the site must be reviewed and approved 
by the UC CCC Clinical Research Advisory Committee.   
Before the study can be initiated at any site, the following documentation must be provided to 
the Cancer Clinical Trials Office (CCTO) at the University of Chicago Comprehensive Cancer 
Center. 
 A copy of the official IRB approval letter for the protocol and informed consent 
 IRB membership list 
 CVs and medical licensure for the principal investigator and any sub-investigators who 
will be involved in the study. 
 Form FDA 1572 appropriately filled out and signed with appropriate documentation  
 CAP and CLIA Laboratory certification numbers and institution lab normal values 
 Investigational drug accountability standard operating procedures 
 
Additionally, before the study can be initiated at any site, the required executed research 
contract/subcontract must be on file with the University of Chicago. 
12.4 Data and Safety Monitoring 
This study will be remotely monitored by the designated University of Chicago Clinical 
Research Associate (CRA) in accordance with the University of Chicago, Section of 
Hematology/Oncology standard operating procedure titled Monitoring of Multi-Institutional 
Investigator Initiated Clinical Trials. 

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Protocol/Amendment No.:   
 
 
  
 
 
 
Prior to subject recruitment, and unless otherwise specified, a participating site will undergo a 
Site Initiation Teleconference to be conducted by the designated University of Chicago 
research team. The site’s principal investigator and his or her study staff must attend the site 
initiation meeting.  
Monitoring will be conducted to verify the following: 
 Adherence to the protocol 
 Completeness and accuracy of study data and samples collected 
 Compliance with regulations  
 Submission of required source documents  
 
Participating sites will also undergo a site close-out teleconference upon completion, 
termination or cancellation of a study to ensure fulfillment of study obligations during the 
conduct of the study, and to ensure that the site Investigator is aware of his/her ongoing 
responsibilities. 
Unless otherwise specified, this protocol will undergo weekly review at the multi-institutional 
data and safety monitoring teleconference as per procedures specified by the UC CCC NCI-
approved Data and Safety Monitoring Plan. The conference will review: 
 Enrollment rate relative to expectations, characteristics of participants 
 Safety of study participants (Serious Adverse Event & Adverse Event reporting) 
 Adherence to protocol (protocol deviations) 
 Completeness, validity and integrity of study data 
 Retention of study participants 
 
Protocol deviations are to be documented using the Protocol Deviation Form and sent via email 
to PhaseIICRA@medicine.bsd.uchicago.edu. Deviations that are considered major because 
they impact subject safety or alter the risk/benefit ratio, compromise the integrity of the study 
data, and/or affect subjects’ willingness to participate in the study must be reported within 7 
days. 
Please 
contact 
the 
University 
of 
Chicago 
CRA 
(PhaseIICRA@medicine.bsd.uchicago.edu) if you have questions about how to report 
deviations.  All major protocol deviations should also be reported to the local IRB of record 
according to their policies and procedures.  
12.5 Auditing 
In addition to the clinical monitoring procedures, the University of Chicago Comprehensive 
Cancer Center will perform routine Quality Assurance Audits of investigator-initiated clinical 
trials as described in the NCI-approved UC CCC DSM Plan. Audits provide assurance that 
trials are conducted and study data are collected, documented and reported in compliance with 
the protocol. Further, quality assurance audits ensure that study data are collected, documented 
and reported in compliance with Good Clinical Practices (GCP) Guidelines and regulatory 
requirements. The audit will review subjects enrolled at the University of Chicago in 
accordance with audit procedures specified in the UC CCC Data and Safety Monitoring plan. 

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Protocol/Amendment No.:   
 
 
  
 
 
 
For institutions who are formal members of the Personalized Cancer Care Consortium (PCCC), 
the UC CCC will conduct on site quality assurance audits on average every two years during 
the enrollment and treatment phase of the study.  
Auditing procedures for participating sites that are not full members of the PCCC must be 
specified and approved by the UC CCC Clinical Research Advisory Committee.  In general, 
for sites that are not full members of the PCCC, auditing responsibility will be delegated to the 
participating center, with the annual audit report forwarded to the University of Chicago for 
review.   
A regulatory authority (e.g. FDA) may also wish to conduct an inspection of the study, during 
its conduct or even after its completion. If an inspection has been requested by a regulatory 
authority, the site investigator must immediately inform the University of Chicago Cancer 
Clinical Trials Office and Regulatory Manager that such a request has been made. 
12.6 Amendments to the Protocol 
All modifications to the protocol, consent form, and/or questionnaires will be submitted to 
the University of Chicago IRB for review and approval. A list of the proposed modifications 
or amendments to the protocol and/or an explanation of the need of these modifications will 
be submitted, along with a revised protocol incorporating the modifications. Only the Study 
Lead PI can authorize any modifications, amendments, or termination of the protocol. Once 
a protocol amendment has been approved by the University of Chicago IRB, the Regulatory 
Manager will send the amended protocol and consent form (if applicable) to the affiliate 
institutions electronically. Upon receipt of the packet the affiliate institution is expected to 
do the following: 
 The affiliate must reply to the email from the Regulatory Manager indicating that the 
amendment was received by the institution and that it will be submitted to the local 
IRB.  
 
 The amendment should be submitted to the affiliate institution’s IRB as soon as 
possible after receipt. The amendment must be IRB approved by the institution 
within 3 months from the date that it was received.  
 
 The  University  of  Chicago  version  date  and/or  amendment  number  must  
appear  on  the  affiliate consent form and on the affiliate IRB approval letter.  
The version dates can be found on the footer of every page of the protocol and 
consent form.  The amendment number can be found on the University of Chicago 
IRB amendment approval letter that is sent with the protocol/amendment mailing.  
 
The IRB approval for the amendment and the amended consent form (if amended consent is 
necessary) for the affiliate institution must be sent to the designated UC Regulatory Manager as 
soon as it is received. 

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Protocol/Amendment No.:   
 
 
  
 
 
 
12.7 Annual IRB Renewals, Continuing Review and Final Reports 
A continuing review of the protocol will be completed by the University of Chicago IRB and 
the participating institutions’ IRBs at least once a year for the duration of the study. The 
annual IRB renewal approvals for participating institutions should be forwarded promptly 
to the Regulatory Manager. If the institution’s IRB requires a new version of the consent 
form with the annual renewal, the consent form should be included with the renewal letter. 
12.8 Record Retention 
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. 
 
Government agency regulations and directives require that all study documentation pertaining 
to the conduct of a clinical trial must be retained by the study investigator.  In the case of a 
study with a drug seeking regulatory approval and marketing, these documents shall be 
retained for at least two years after the last approval of marketing application in an International 
Conference on Harmonization (ICH) region.  In all other cases, study documents should be 
kept on file until three years after the completion and final study report of this investigational 
study. 
 
12.9 Obligations of Study Site Investigators 
The Study Site Principal Investigator is responsible for the conduct of the clinical trial at the 
site in accordance with Title 21 of the Code of Federal Regulations and/or the Declaration of 
Helsinki.  The Study Site Principal Investigator is responsible for personally overseeing the 
treatment of all study patients.  He/she must assure that all study site personnel, including sub-
investigators and other study staff members, adhere to the study protocol and all 
FDA/GCP/NCI regulations and guidelines regarding clinical trials both during and after study 
completion. 
 
The Study Site Principal Investigator at each institution or site will be responsible for assuring 
that all the required data will be collected and entered into the CRFs. Periodically, monitoring 
visits or audits will be conducted and he/she must provide access to original records to permit 
verification of proper entry of data. 
 
 
 

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Product:  PEMBROLIZUMAB 
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Protocol/Amendment No.:   
 
 
  
 
 
 
13.0 APPENDICES 
13.1 ECOG Performance Status 
Grade 
Description 
0 
Normal activity. Fully active, able to carry on all pre-disease 
performance without restriction. 
1 
Symptoms, but ambulatory. Restricted in physically strenuous 
activity, but ambulatory and able to carry out work of a light or 
sedentary nature (e.g., light housework, office work). 
2 
In bed <50% of the time. Ambulatory and capable of all self-care, but 
unable to carry out any work activities. Up and about more than 50% 
of waking hours. 
3 
In bed >50% of the time. Capable of only limited self-care, confined 
to bed or chair more than 50% of waking hours. 
4 
100% bedridden. Completely disabled. Cannot carry on any self-care. 
Totally confined to bed or chair. 
5 
Dead. 
* As published in Am. J. Clin. Oncol.:  Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E., 
McFadden, E.T., Carbone, P.P.: Toxicity And Response Criteria Of The Eastern Cooperative Oncology 
Group. Am J Clin Oncol 5:649-655, 1982. The Eastern Cooperative Oncology Group, Robert Comis 
M.D., Group Chair. 
 
13.2 Common Terminology Criteria for Adverse Events V4.0 (CTCAE) 
The descriptions and grading scales found in the revised NCI Common Terminology Criteria 
for Adverse Events (CTCAE) version 4.0 will be utilized for adverse event reporting. 
(http://ctep.cancer.gov/reporting/ctc.html) 
13.3 Evaluation of Tumor Response by immune-related Response Evaluation Criteria 
in Solid Tumors (irRECIST)  
Tumor response will be assessed by the irRECIST (Nishino et al, 2013)24.  This standard is a 
reconciliation of RECIST guidelines v1.1 with the original immune-related Response Criteria 
(irRC) (Wolchok et al, 2009)25. The latter standard incorporated principles important for 
assessment of immune-checkpoint blocking immunotherapy for cancer, but fundamentally 
differed from RECIST in using 2-dimensional tumor assessment.  In contrast, irRECIST is 
based on 1-dimensional tumor measurement, but it differs from RECIST guidelines v1.1 in the 
following key ways: 
 Under RECIST guidelines v1.1, the appearance of new lesions indicates PD.  Under 
irRECIST, new measurable lesions are incorporated in the tumor burden, which is used 
to determine immune-related progressive disease (irPD), immune-related partial 

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Protocol/Amendment No.:   
 
 
  
 
 
 
response (irPR), and immune-related complete response (irCR).  New non-measurable 
lesions preclude irCR. 
 Under RECIST guidelines v1.1, there is no confirmation for PD.  In addition, responses 
and irPDs must be confirmed by consecutive scans at least 4 weeks apart, assuming 
no clinical deterioration. 
The following sub-sections describe irRECIST in detail. 
Tumor Burden 
At baseline, the tumor burden is the sum of single diameters (short axis for nodal lesions, 
longest diameter for other lesions) for the target lesions.  In subsequent scans, the diameters of 
new measurable lesions are added to the tumor burden.  If a subject is retreated, then up to 5 
target lesions (perhaps different from the original lesions) will be selected and a new baseline 
tumor burden will be established. 
Overall Response at a Single Time Point 
The table below outlines determination of disease response at a single assessment based on 
irRECIST. 
irRECIST: Overall Response 
Tumor Burden 
(Baseline and New) 
Non-Target Lesions 
(Baseline and New) 
Response 
Disappearance of non-nodal lesions. All 
pathologic lymph nodes < 10 mm (short 
axis) 
Disappearance of non-nodal lesions. All 
pathologic lymph nodes < 10 mm (short 
axis) 
irCRa 
≥ 30% decrease from baseline 
Any 
irPRa 
≥ 20% increase from nadir and at least 5 
mm 
Any 
irPDa 
Neither sufficient decrease to qualify for 
PR, nor sufficient increase to qualify for 
PD 
Any 
irSD 
Disappearance of all non-nodal lesions. All 
pathologic lymph nodes < 10 mm 
Any other than disappearance of all non-
nodal lesions and reduction of pathologic 
lymph nodes < 10 mm 
irPRa 
Not all evaluatedb 
Any 
irNE 
a Selection as best response requires confirmation by 2 consecutive measurments at least 4 weeks apart. 
b If some lesions are measured, response may be inferred from available measurements. For example, growth in evaluated target lesions may 
be sufficient for irPD regardless of status of non-evaluated lesions. 
 

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