Clinical trial NCT03274661
Conditions: Solid Tumor, Adult
Keywords: solid tumor, Pembrolizumab,
Sponsor: Baptist Health South Florida
Start date: 2017-11-03; Completion date: 2022-03-19
Enrollment: 52 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Phase II trial in which patients with metastatic solid tumors experiencing progression after first line standard chemotherapy or for which there is no standard chemotherapy, and for which pembrolizumab does not have an FDA or compendia listing approved indication, will receive pembrolizumab intravenously at a dose of 200 mg every 3 weeks.

Detailed description:
Patients with metastatic or recurrent solid malignancy who have progressed on first line standard of care treatment or for which defined standard of care does not exist or is not readily available are eligible to participate on this trial. Patients for which pembrolizumab has an FDA approved indication and for whom pembrolizumab is covered by their insurance should receive standard commercial pembrolizumab and will not be eligible for this trial.

The primary objective of this trial is to evaluate the Immune-Related Objective Response Rate (IR-ORR) achieved with pembrolizumab in patients with Fanconi Anemia Repair Pathway functionally competent and functionally deficient tumors.

Trial treatment should be administered on Day 1 of each cycle after all procedures/assessments have been completed. Trial treatment may be administered up to 3 days before or after the scheduled Day 1 of each cycle due to administrative reasons.

All trial treatments will be administered on an outpatient basis.

Pembrolizumab 200 mg will be administered as a 30 minute IV infusion every 3 weeks. Target infusion timing is 30 minutes.

Expansion Cohort:

Ten (10) additional subjects with the diagnosis of metastatic or recurrent endometrial carcinoma will be enrolled in the trial at the conclusion of regular enrollment.

Arms: arm 1: Pembrolizumab 200 mg Intravenous Infusion every 3 weeks administered on Day 1 of each 3 week cycle
Interventions: intervention 1: Pembrolizumab 200 mg Q3W
Intervention descriptions: intervention 1: Pembrolizumab 200 mg Intravenous Infusion every 3 weeks administered on Day 1 of each 3 week cycle

Protocol documents:
Prot_SAP_000.pdf: 
 
SPONSOR: MIAMI CANCER INSTITUTE AT BAPTIST HEALTH, INC. 
 
 
 
TITLE: EVALUATING IMMUNE CHECKPOINT INHIBITION IN SOLID TUMOR 
PATIENTS WITH HOMOLOGOUS RECOMBINATION REPAIR DEFICIENCY 
 
 
 
PRINCIPAL INVESTIGATOR:  JOHN DIAZ, MD 
 
 
 
IND NUMBER:  
 
 
136283   
 
 
 
PROTOCOL NUMBER:   
MK-3475-663 
 
 
 
PROTOCOL VERSION DATE:  20 JUL 2020 
PROTOCOL VERSION: 
 
Version 16 
 


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SIGNATURE PAGE 
The signature below constitutes the approval of this protocol and the attachments and 
provides the necessary assurances that this study will be conducted according to all 
stipulations of the protocol, including all statements regarding confidentiality, and according 
to local legal and regulatory requirements and applicable US federal regulations and ICH 
guidelines. 
Principal Investigator: 
Signed:    
  Date:   
 
 
Name:    
 
Title:  
  
  
{Include signature blocks for Clinical Site Investigator(s), when applicable. Duplicate as 
needed} 
 
Clinical Site Investigator: 
Signed:    
  Date:   
 
 
Name:    
 
Title:  
  
  
 
 


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1.0 TRIAL SUMMARY 
 
Abbreviated Title 
Pembrolizumab activity in patients with HR competent and deficient tumors 
Trial Phase 
II 
Clinical Indication 
Solid Tumors  
Trial Type 
Therapeutic 
Type of control 
None 
Route of administration 
Intravenous 
Trial Blinding 
None 
Treatment Groups  
One with stratification 
Number of trial subjects 
32-50 
Estimated enrollment period 
1 year 
Estimated duration of trial 
2 years 
Duration of Participation 
Until tumor progression 
Estimated average length of 
treatment per patient 
6 months 
 
 
 
2.0 TRIAL DESIGN 
Phase II trial in which patients with metastatic solid tumors experiencing progression after first 
line standard chemotherapy or for which there is no standard chemotherapy, and for which 
pembrolizumab does not have an FDA or compendia listing approved indication, will receive 
pembrolizumab intravenously at a dose of 200 mg every 3 weeks.  
The end points are the immune-related objective response rate (primary) and the 20-week 
immune-related progression-free survival rate (secondary). Availability of paraffin embedded 
tumor material and willingness to provide blood for plasma DNA mutational analysis will be 
required for enrollment, as well as standard acceptable organ function and no history of 
autoimmune disease or previous treatment with immune check-point inhibitors.  CT 
assessment at baseline and after every 8 weeks will be obtained to measure immune-related 
objective response rates. Patients will continue treatment until tumor progression or intolerable 
toxicity.   
Stratification based on FANCD2 foci formation in tumor material (see below) to evaluate 
potential differences in activity will be performed.  Exploratory correlatives include evaluation 
of mutation load on tumor and cell free DNA analysis and of gut microbiome composition on 
fecal samples.  


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3.0 OBJECTIVES & HYPOTHESES 
3.1 Hypotheses 
1. The immune checkpoint inhibitor pembrolizumab has clinically meaningful antitumor 
activity in solid tumor patients with functional deficiency in the Fanconi Anemia (FA) 
pathway in their tumors. 
2. The Fanconi Anemia Triple Stain Inmmunofluorescence (FATSI) assay through 
detecting the lack of repair foci formation in the nucleus of proliferating cells will be 
able to identify these patients, and a FATSI negative assay will be associated with a 
better rate of responses than FATSI positive tumors.  
3.2 Primary Objective 
To evaluate the Immune-Related Objective Response Rate (IR-ORR) achieved with 
pembrolizumab in patients with Fanconi Anemia Repair Pathway functionally competent 
and functionally deficient tumors  
3.3 Secondary Objective 
To evaluate immune-related progression-free rate at 20 weeks (irPFS) and Overall Survival 
(OS) achieved with pembrolizumab in patients with Fanconi Anemia Repair Pathway 
functionally competent and functionally deficient tumors. 
3.4. Exploratory Objectives 
      1. To evaluate mutation load and alterations in homologous recombination repair genes or 
other mechanisms of repair in blood specimens. 
      2. To evaluate gut microbiome composition of stool specimens in patients receiving 
pembrolizumab in this trial. 
 
4.0 BACKGROUND & RATIONALE 
 
4.1. Homologous Recombination Repair as an Anticancer Target 
Excitement has been generated following the identification of mutations on the BRCA genes 
as potential predictors of response to PARP inhibitors and recent clinical trials demonstrating 
antitumor activity with PARP inhibitors in cancer patients with germline BRCA deficiency [1-
5]. The rationale behind these observations is that the BRCA genes are involved in homologous 
recombination (HR), an example of double-strand break repair, and patients with inherited 
BRCA germline heterozygocity who developed cancer had acquired BRCA homozygous 
deficiency in their tumors. The resulting genetic instability becomes an advantage for the tumor 
to perpetuate. Targeting an additional repair pathway, such as base excision repair through 
PARP inhibition would induce inability for the tumor to survive, an example of a concept 
commonly called synthetic lethality.  


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The BRCA genes collaborate 
with several others in the 
Fanconi Anemia (FA) HR 
pathway 
[6-15]. 
Seventeen 
complementation groups/genes 
plus other interactive proteins 
have 
been 
described. 
Monoubiquitination of FancD2 
and FancI by an FA core 
complex followed by nuclear 
co-localization with other DNA 
damage response proteins result 
in the formation of nuclear 
repair foci, thus foci formation 
is the focal functional output of this pathway (Fig 1). Based on this, we developed an 
immunofluorescence based method, FancD2/DAPI/Ki67 (Fanconi Anemia Triple Stain 
Immunofluorescence - FATSI), which permits the observation of FancD2 foci formation (or 
lack thereof) in the nucleus of proliferating cells in paraffin embedded tumor tissues [16], and 
screened >600 patients in a clinical trial for foci formation deficiency (Table 1) [17]. 
Functional deficiency was found in 29% of solid tumor patients. We also developed a targeted 
FA sequencing panel to evaluate potential genetic defects resulting in FA functional deficiency 
in our patients, and confirmed the ability of the FATSI test to enrich for patients exhibiting 
these alterations at the genomic level. 
 


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We also showed that it is safe to administer the PARP inhibitor veliparib at doses up to 300 
mg per day to patients with FA deficient tumors, and that veliparib can be safely combined 
with the DNA damaging agent mitomycin C. Activity was seen for the combination in heavily 
pretreated patients [17]. However, veliparib as a single agent, outside of BRCA/RAD51 
germline mutated breast cancer did not show a substantial level of clinical activity. Potential 
reasons for this discrepancy would include: 1- veliparib is a weak PARP-trapping agent 
[18,19]; 2- restoration of FA functionality as a result of systemic treatment received between 
the time of tissue collection and enrollment in the trial [20-23]; or 3- the presence of additional 
mutations to which the repair deficient cell has become addicted (non-oncogenic 
addiction/induced-essentiality) [24-25]. 
4.2 Immune Checkpoint Inhibition as a Therapeutic Strategy 
The importance of intact immune surveillance in controlling outgrowth of neoplastic 
transformation has been known for decades.  Accumulating evidence shows a correlation 
between tumor-infiltrating lymphocytes (TILs) in cancer tissue and favorable prognosis in 
various malignancies.  In particular, the presence of CD8+ T-cells and the ratio of CD8+ 
effector T-cells / FoxP3+ regulatory T-cells seems to correlate with improved prognosis and 
long-term survival in many solid tumors. 
The PD-1 receptor-ligand interaction is a major pathway hijacked by tumors to suppress 
immune control.  The normal function of PD-1, expressed on the cell surface of activated T-
cells under healthy conditions, is to down-modulate unwanted or excessive immune responses, 
including autoimmune reactions.  PD-1 (encoded by the gene Pdcd1) is an Ig superfamily 
member related to CD28 and CTLA-4 which has been shown to negatively regulate antigen 
receptor signaling upon engagement of its ligands (PD-L1 and/or PD-L2).  The structure of 
murine PD-1 has been resolved.  PD-1 and family members are type I transmembrane 
glycoproteins containing an Ig Variable-type (V-type) domain responsible for ligand binding 
and a cytoplasmic tail which is responsible for the binding of signaling molecules.  The 
cytoplasmic tail of PD-1 contains 2 tyrosine-based signaling motifs, an immunoreceptor 
tyrosine-based inhibition motif (ITIM) and an immunoreceptor tyrosine-based switch motif 
(ITSM).  Following T-cell stimulation, PD-1 recruits the tyrosine phosphatases SHP-1 and 
SHP-2 to the ITSM motif within its cytoplasmic tail, leading to the dephosphorylation of 
effector molecules such as CD3ζ, PKCθ and ZAP70 which are involved in the CD3 T-cell 
signaling cascade.  The mechanism by which PD-1 down modulates T-cell responses is similar 
to, but distinct from that of CTLA-4 as both molecules regulate an overlapping set of signaling 
proteins.  PD-1 was shown to be expressed on activated lymphocytes including peripheral 
CD4+ and CD8+ T-cells, B-cells, T regs and Natural Killer cells.  Expression has also been 
shown during thymic development on CD4-CD8- (double negative) T-cells as well as subsets 
of macrophages and dendritic cells.  The ligands for PD-1 (PD-L1 and PD-L2) are 
constitutively expressed or can be induced in a variety of cell types, including non-
hematopoietic tissues as well 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 


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lymphoid tissue or chronic inflammatory environments.  PD-L2 is thought to control immune 
T-cell activation in lymphoid organs, whereas PD-L1 serves to dampen unwarranted T-cell 
function in peripheral tissues.  Although healthy organs express little (if any) PD-L1, a variety 
of cancers were demonstrated to express abundant levels of this T-cell inhibitor.  PD-1 has 
been suggested to regulate tumor-specific T-cell expansion in subjects with melanoma.  This 
suggests that the PD-1/PD-L1 pathway plays a critical role in tumor immune evasion and 
should be considered as an attractive target for therapeutic intervention. 
Pembrolizumab is a potent and highly selective humanized monoclonal antibody (mAb) of the 
IgG4/kappa isotype designed to directly block the interaction between PD-1 and its ligands, 
PD-L1 and PD-L2.  KeytrudaTM (pembrolizumab) is indicated for the treatment of patients with 
unresectable or metastatic melanoma; for the first-line treatment of patients with metastatic 
non-small cell lung cancer (NSCLC) whose tumors have high PD-L1 expression [Tumor 
Proportion Score (TPS) ≥ 50%)] as determined by an FDA-approved test, with no EGFR or 
ALK genomic tumor aberrations; for the treatment of patients with metastatic NSCLC whose 
tumors express PD-L1 (TPS ≥ 1%) as determined by an FDA-approved test, with disease 
progression on or after platinum-containing chemotherapy; for the treatment of patients with 
recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) with disease 
progression on or after platinum-containing chemotherapy based on tumor response rate and 
durability of response; and for the treatment of adult and pediatric patients with refractory 
classical Hodgkin lymphoma, or who have relapsed after 3 or more prior lines of therapy.  
Accelerated approval contingent on verification and description of clinical benefit in 
confirmatory trials was granted for the last two indications.  
4.3 Preclinical and Clinical Trial Data for Pembrolizumab 
Refer to the Investigator’s Brochure for Preclinical and Clinical data. 
4.4 The Interplay between DNA repair deficiency and Immune Checkpoint inhibition. 
Le et al. recently reported a phase 2 study evaluating the clinical activity of pembrolizumab, 
in 41 patients with progressive metastatic carcinoma with or without mismatch-repair 
deficiency (26). The immune-related objective response rate and immune-related progression-
free survival rate were 40% (4 of 10 patients) and 78% (7 of 9 patients), respectively, for 
mismatch repair-deficient colorectal cancers and 0% (0 of 18 patients) and 11% (2 of 18 
patients) for mismatch repair-proficient colorectal cancers. The median progression-free 
survival and overall survival were not reached in the cohort with mismatch repair-deficient 
colorectal cancer but were 2.2 and 5.0 months, respectively, in the cohort with mismatch 
repair-proficient colorectal cancer.  
Interestingly, patients with mismatch repair-deficient non-colorectal cancer had responses 
similar to those of patients with mismatch repair-deficient colorectal cancer (immune-related 
objective response rate, 71% [5 of 7 patients]; immune-related progression-free survival rate, 
67% [4 of 6 patients]). Whole-exome sequencing revealed a mean of 1782 somatic mutations 
per tumor in mismatch repair-deficient tumors, as compared with 73 in mismatch repair-
proficient tumors (P=0.007), and high somatic mutation loads were associated with prolonged 
progression-free survival (P=0.02). Since somatic mutations have the potential to encode "non-


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self" immunogenic antigens the authors hypothesized that tumors with a large number of 
somatic mutations due to mismatch-repair defects may be susceptible to immune checkpoint 
blockade. 
5.0 RATIONALE 
5.1 Rationale for the Trial and Selected Subject Population 
Following the logic behind the sensitivity of patients with mismatch repair-deficient tumors to 
pembrolizumab, tumors with other type of repair deficiency, such as homologous 
recombination repair would plausibly have a large number of somatic mutations and likely be 
susceptible to immune checkpoint blockade.  FATSI, given its ability to differentiate between 
functionally deficient and functionally competent Fanconi Anemia pathway tumors could 
identify additional patients susceptible to pembrolizumab. 
Rather than patient pre-selection, a design that incorporates all comers (repair competent and 
deficient) with a stratification approach would be more suitable for preliminary evaluation of 
this concept. This approach is consistent with the evaluation by Le et al. for mismatch repair 
discussed above. 
5.2 Rationale for Pembrolizumab Dose Selection/Regimen  
An open-label Phase I trial (Protocol 001) evaluated the safety and clinical activity of single 
agent pembrolizumab.  The dose escalation portion of this trial evaluated three dose levels, 1 
mg/kg, 3 mg/kg, and 10 mg/kg, administered every 2 weeks (Q2W) in subjects with advanced 
solid tumors.  All three dose levels were well tolerated and no dose-limiting toxicities were 
observed.  This first in human study of pembrolizumab showed evidence of target engagement 
and objective evidence of tumor size reduction at all dose levels (1 mg/kg, 3 mg/kg and 10 
mg/kg Q2W).  No MTD was identified.  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 durable (>21 days).   
 
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. 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. 


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It is also assumed 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. 
5.3.Rationale for Endpoints 
5.3.1 Efficacy Endpoints 
The primary efficacy endpoint is overall Immune-Related Objective Response Rate (IR-ORR).  
Secondary efficacy endpoints will include Progression Free Survival (PFS) and Overall 
Survival (OS). 
We expect that pembrolizumab will have a higher clinically meaningful antitumor activity, as 
measured by IR-ORR and PFS in patients with solid tumors with functional deficiency in the 
Fanconi Anemia (FA) pathway, compared to those with functionally competent repair. 
Based on our prior screening data, we anticipate that close to 30% of patients with solid tumors, 
depending on tumor type will be FA functionally deficient and that the response rate in these 
patients will be very similar than what was seen for patients with mismatch repair deficient 
colorectal cancer.  The latter will not be included in this trial as we are trying to identifying 
another subset of highly responsive patients. 
5.3.2 Biomarker Research and Correlative Endpoints 
FATSI Assessment. The main hypothesis of this trial is that pembrolizumab has clinically 
meaningful antitumor activity in solid tumor patients with functional deficiency in the Fanconi 
Anemia (FA) pathway in their tumors. We will be performing The FATSI assay, as previously 
described [16,17], in archived paraffin embedded tumors of enrolled patients to assess for 
functional deficiency. We hypothesize that a FATSI negative assay will be associated with a 
better response rate, that those patients able to form FANCD2 repair foci.  However, we will 
not preselect patients to this trial based on FATSI negativity.. The non-selection approach will 
avoid bias in case we observe a higher than expected rate of antitumor response or PFS in our 
treated patients independent of FATSI status. The results will be exploratory in nature, as there 
will not be sufficient statistical power (see Statistics Section). 
 


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Tissue and Blood DNA sequencing. We will obtain a blood sample at the beginning of the 
trial, prior to pembrolizumab therapy in participating patients in order to obtain cell free DNA 
for mutation analysis, and will also perform tumor DNA sequencing in archival tissue material 
in an attempt to search for the gene abnormalities responsible for the FA functional deficiency 
when relevant, as well as an estimation in mutation load.  We will refer for family genetic 
counseling those patients for which germline deficiency is a consideration, either by family 
history or by results of the above tests.   The correlative methods to be utilized are not validated 
for germline mutation and cancer risk analysis, but whenever a consideration is raised by 
results genetic counseling with validation analysis is the best ethical approach. 
 
Microbiome Exploratory Evaluation. It has been suggested that alterations in the 
interactions between gut microbiota and host immunity can influence the outcome of cancer 
immunotherapy [27,28]. For example, in several preclinical cancer models tumor progression 
was controlled by antibodies against CTLA-4 in specific pathogen free but not in germ free 
mice. Moreover, a combination of broad-spectrum antibiotics compromised the antitumor 
effects of CTLA-4–specific antibodies. In germ free or antibiotic-treated mice, activation of 
splenic effector CD4+ T cells and tumor-infiltrating lymphocytes (TILs) induced by antibody 
against CTLA-4 was significantly decreased. Restoration of CTLA-4 antibody activity was 
associated with oral feeding of specific pathogen isolates, compared to others. [27]. 
 
In patients with melanoma, ipilimumab treatment led to changes in the composition of the 
microbiome and fecal transplants composed of different microbiomes based on a clustering 
algorithm from these patients to tumor bearing mice identified sizeable differences in response 
to 
CTLA-4 
blockade. 
Hence, 
ipilimumab 
can 
modify 
the 
abundance 
of 
immunogenic Bacteroides spp. in the gut, which in turn affects its anticancer efficacy [27]. 
 
Similarly, melanoma growth in mice harboring distinct commensal microbiota had differences 
in spontaneous antitumor immunity, which were eliminated upon cohousing or after fecal 
transfer. Sequencing of the 16S ribosomal RNA identified Bifidobacterium as associated with 
the antitumor effects. Oral administration of Bifidobacterium alone improved tumor control to 
the same degree as programmed cell death protein 1 ligand 1 (PD-L1)–specific antibody 
therapy, and combination treatment nearly abolished tumor outgrowth. Augmented dendritic 
cell function leading to enhanced CD8+ T cell priming and accumulation in the tumor 
microenvironment mediated the effect [28].  
 
Not only associations of specific microbiomes with antitumor activity of immune checkpoint 
inhibitors merit considerations, but also potentially toxicity.  A prospective study of patients 
with metastatic melanoma undergoing ipilimumab treatment demonstrated that increased 
representation of bacteria belonging to the Bacteroidetes phylum correlated with resistance to 
the development of checkpoint-blockade-induced colitis [29]. 
The evidence also suggests that it is not enough to look at the microbial profile of the subject, 
but there is a need to understand what genes are expressed by the microbial community, what 
metabolites are released by the microbiome as well as the host as a result of their interaction, 
and how the host genes and markers play a role in this complex web of interactions. If some 
therapies are working well (or poorly) on select patients, it is critical to understand the role of 
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targeted to individual patients. We choose to pick the three most important “omics” data sets 
to generate for the subject cohort, i.e., microbiome, metatranscriptome and metabolome.  
We will gather data in gut pathogens from fecal samples from patients in this trial.  Our unique 
population (65% Hispanics with different ages at immigration to the USA) may offer valuable 
preliminary data of potential associations to be tested in future studies as we anticipate clear 
diversity in the microbiome of these patients, as its composition is likely influenced by 
geography and culture.   
6.0 METHODOLOGY 
6.1 Entry Criteria 
Diagnosis/Condition for Entry into the Trial 
Patients with metastatic or recurrent solid malignancy who have progressed on first line 
standard of care treatment or for which defined standard of care does not exist.  Patients for 
which pembrolizumab has an FDA approved indication and for whom pembrolizumab is 
covered by their insurance should receive standard commercial pembrolizumab and will not 
be eligible for this trial.    
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/assent for the trial. 
2. Be ≥ 18 years of age on day of signing informed consent. 
3. Have measurable disease based on RECIST 1.1.   
4. Be willing to provide consent for retrieval of archival tumor material tissue from a 
previously obtained core or excisional biopsy of a tumor lesion.  Consent will also be 
given to obtain tumor material from any new biopsy or excision planned for standard 
of care during active participation in this trial or when documenting first tumor 
progression after pembrolizumab treatment.  
5. Have a performance status of 0, 1 or 2 on the ECOG Performance Scale. 
6. Have a tumor presentation at screening for which pembrolizumab does not have an 
FDA approved indication for commercial use (see Section 4.2). Those patients for 
which insurance is not available, or insurance denies pembrolizumab will be considered 
in a case by case basis.  
7. Demonstrate adequate organ function as defined in Table 2, all screening labs should 
be performed within 15 days of treatment initiation.   
 


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Table 2.  Adequate Organ Function Laboratory Values 
System 
Laboratory Value 
Hematological 
 
Absolute neutrophil count (ANC) 
≥1,500 /mcL 
Platelets 
≥100,000 / mcL 
Hemoglobin 
≥9 g/dL or ≥5.6 mmol/L without transfusion or EPO dependency (within 
7 days of assessment) 
Renal 
 
Serum creatinine OR 
Measured or calculateda creatinine 
clearance 
(GFR can also be used in place of creatinine 
or CrCl) 
≤1.5 X upper limit of normal (ULN) OR 
 
≥60 mL/min for subject with creatinine levels > 1.5 X institutional ULN 
Hepatic 
 
Serum total bilirubin 
≤ 1.5 X ULN OR 
 
Direct bilirubin ≤ ULN for subjects with total bilirubin levels > 1.5 ULN 
AST (SGOT) and ALT (SGPT) 
≤ 2.5 X ULN  OR 
≤ 5 X ULN for subjects with liver metastases 
Albumin 
>2.5 mg/dL 
Coagulation 
International Normalized Ratio (INR) or 
Prothrombin Time (PT) 
 
Activated Partial Thromboplastin Time 
(aPTT) 
≤1.5 X ULN unless subject is receiving anticoagulant therapy 
as long as PT or PTT is within therapeutic range of intended use of 
anticoagulants 
≤1.5 X ULN unless subject is receiving anticoagulant therapy 
as long as PT or PTT is within therapeutic range of intended use of 
anticoagulants 
aCreatinine clearance should be calculated per institutional standard. 
 
8. 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.   
9. Female subjects of childbearing potential (Section 5.7.2) must be willing to use an 
adequate method of contraception as outlined in Section 5.7.2 – Contraception,  for the 
course of the study through 120 days after the last dose of study medication. 
10. Male subjects of childbearing potential (Section 5.7.1) must agree to use an adequate 
method of contraception as outlined in Section 5.7.1- Contraception, starting with the 
first dose of study therapy through 120 days after the last dose of study therapy. 
Note: For 9 and 10, abstinence is acceptable if this is the usual lifestyle and preferred 
contraception for the subject. 
6.1.1 Expansion Cohort.  
Ten (10) additional subjects with the diagnosis of metastatic or recurrent endometrial 
carcinoma will be enrolled in the trial at the conclusion of regular enrollment with subject with 
the eligibility discussed in 6.1., and as per Sample size Calculation and Statistics Section 
(Section 12).  The following will be necessary criteria for this expansion cohort. 


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1. Diagnosis of Endometrial Carcinoma or Sarcoma which is metastatic and has failed 
standard treatment or is recurrent, or for which standard chemotherapy is 
contraindicated or refused by patient. 
2. Sufficient tissue is available for correlative studies as specified on Section 9.0.2.8. 
3. MSI studies have been performed, either by immunohistochemistry or next generation 
sequencing and results show that patient is MS low or stable. 
4. Patient meet all the inclusion criteria discussed above on 6.1 and none of the exclusion 
criteria discussed below on section 6.2.   
6.2 Subject Exclusion Criteria 
The subject must be excluded from participating in the trial if the subject: 
1. Is currently participating and receiving study therapy or has participated in a study of 
an investigational agent and received study therapy, or used an investigational device 
within 4 weeks of the first dose of treatment. 
2. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any 
other form of immunosuppressive therapy within 7 days prior to the first dose of trial 
treatment. 
 
3. 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 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due 
to agents administered more than 4 weeks earlier. 
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. 


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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 (e.g., thyroxine, insulin, or physiologic corticosteroid 
replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form 
of systemic treatment. 
10. Has immunohistochemically proven mismatch repair deficient cancer (this test is 
standard in our center for colorectal and endometrial cancer patients, and 
documentation will be required to be negative to accept outside referrals with colorectal 
or endometrial cancer for this trial). 
11. Has a history of (non-infectious) pneumonitis that required steroids or current 
pneumonitis 
12. Evidence of interstitial lung disease. 
13. Has an active infection requiring systemic therapy. 
14. 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.   
15. Has known psychiatric or substance abuse disorders that would interfere with 
cooperation with the requirements of the trial. 
16. 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. 
17. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent. 
18. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies). 
19. Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA 
[qualitative] is detected). 
20. Has received a live vaccine within 30 days of planned start of study therapy. 


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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. 
6.3 Trial Treatments 
The treatment to be used in this trial is outlined below in Table 3. 
Table 3.  Trial Treatment 
Drug 
Dose/Potency 
Dose 
Frequency 
Route of 
Administration 
Regimen/ 
Treatment 
Period 
Use 
Pembrolizumab 
200 mg 
Q3W 
IV infusion 
Day 1 of each 3 
week cycle 
Experimental 
 
Trial treatment should begin on the day of randomization or as close as possible to the date on 
which treatment is allocated/assigned. 
6.4 Dose Selection/Modification 
Dose Selection 
The rationale for selection of doses to be used in this trial is provided in Section 4.0 – 
Background and Rationale.   Details on preparation and administration of pembrolizumab 
(MK-3475) are provided in the Package Insert. 
Dose Modification (Escalation/Titration/Other) 
Adverse events (both non-serious and serious) associated with pembrolizumab exposure may 
represent an immunologic etiology.  These adverse events may occur shortly after the first dose 
or several months after the last dose of treatment. Pembrolizumab must be withheld for drug-
related toxicities and severe or life-threatening AEs as per Table 4 below. See Section 6.8.1 
for supportive care guidelines, including use of corticosteroids. 
Table 4. Dose Modification and Toxicity Management Guidelines for Immune-related AEs 
Associated with Pembrolizumab 
General instructions: 
1. Corticosteroid taper should be initiated upon AE improving to Grade 1 or less and continue to taper over at 
least 4 weeks. 
2. For situations where pembrolizumab has been withheld, pembrolizumab can be resumed after AE has been 
reduced to Grade 1 or 0 and corticosteroid has been tapered. Pembrolizumab should be permanently 
discontinued if AE does not resolve within 12 weeks of last dose or corticosteroids cannot be reduced to ≤10 
mg prednisone or equivalent per day within 12 weeks.  
3. For severe and life-threatening irAEs, IV corticosteroid should be initiated first followed by oral steroid. 
Other immunosuppressive treatment should be initiated if irAEs cannot be controlled by corticosteroids. 
 


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Immune-
related AEs 
Toxicity grade 
or conditions 
(CTCAEv4.0) 
Action taken to 
pembrolizumab 
irAE management 
with corticosteroid 
and/or other 
therapies  
Monitor and follow-up 
Pneumonitis  
Grade 2 
Withhold  
• Administer 
corticosteroids 
(initial dose of 1-2 
mg/kg prednisone 
or equivalent) 
followed by taper 
 
• 
Monitor participants for signs 
and symptoms of pneumonitis 
• 
Evaluate participants with 
suspected pneumonitis with 
radiographic imaging and 
initiate corticosteroid treatment 
• 
Add prophylactic antibiotics for 
opportunistic infections 
Grade 3 or 4, 
or recurrent 
Grade 2 
Permanently 
discontinue 
Diarrhea / 
Colitis  
Grade 2 or 3 
Withhold 
• Administer 
corticosteroids 
(initial dose of 1-2 
mg/kg prednisone 
or equivalent) 
followed by taper 
 
• 
Monitor participants for signs 
and symptoms of enterocolitis 
(ie, diarrhea, abdominal pain, 
blood or mucus in stool with or 
without fever) and of bowel 
perforation (ie, peritoneal signs 
and ileus). 
• 
Participants with ≥ Grade 2 
diarrhea suspecting colitis 
should consider GI consultation 
and performing endoscopy to 
rule out colitis.  
• 
Participants with 
diarrhea/colitis should be 
advised to drink liberal 
quantities of clear fluids.  If 
sufficient oral fluid intake is not 
feasible, fluid and electrolytes 
should be substituted via IV 
infusion. 
Grade 4 
Permanently 
discontinue 
AST / ALT 
elevation or 
Increased 
bilirubin 
Grade 2 
Withhold 
• Administer 
corticosteroids 
(initial dose of 0.5- 
1 mg/kg prednisone 
or equivalent) 
followed by taper 
• 
Monitor with liver function 
tests (consider weekly or more 
frequently until liver enzyme 
value returned to baseline or is 
stable 
Grade 3 or 4  
Permanently 
discontinue 
• Administer 
corticosteroids 
(initial dose of 1-2 
mg/kg prednisone 
or equivalent) 
followed by taper 


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Type 1 
diabetes 
mellitus 
(T1DM) or 
Hyperglycem
ia 
 
Newly onset 
T1DM or  
Grade 3 or 4 
hyperglycemia 
associated with 
evidence of β-
cell failure 
Withhold 
• Initiate insulin 
replacement 
therapy for 
participants with 
T1DM  
• Administer anti-
hyperglycemic in 
participants with 
hyperglycemia  
 
• 
Monitor participants for 
hyperglycemia or other signs 
and symptoms of diabetes. 
Hypophysitis 
Grade 2 
Withhold 
• Administer 
corticosteroids and 
initiate hormonal 
replacements as 
clinically 
indicated.   
 
• 
Monitor for signs and 
symptoms of hypophysitis 
(including hypopituitarism and 
adrenal insufficiency)  
Grade 3 or 4  
Withhold or 
permanently 
discontinue1  
Hyperthyroid
ism  
Grade 2 
Continue  
• Treat with non-
selective beta-
blockers (eg, 
propranolol) or 
thionamides as 
appropriate  
• 
Monitor for signs and 
symptoms of thyroid disorders.  
 
Grade 3 or 4  
Withhold or  
permanently 
discontinue1 
Hypothyroidi
sm 
Grade 2-4 
Continue  
• Initiate thyroid 
replacement 
hormones (eg, 
levothyroxine or 
liothyroinine) per 
standard of care 
• 
Monitor for signs and 
symptoms of thyroid disorders.  
 
Nephritis and 
Renal 
dysfunction 
Grade 2 
Withhold  
• Administer 
corticosteroids 
(prednisone 1-2 
mg/kg or 
equivalent) 
followed by taper. 
• 
Monitor changes of renal 
function 
 
Grade 3 or 4  
Permanently 
discontinue 
Myocarditis 
Grade 1 or 2 
Withhold 
• Based on severity 
of AE administer 
corticosteroids 
• 
Ensure adequate evaluation to 
confirm etiology and/or exclude 
other causes 
 
Grade 3 or 4 
Permanently 
discontinue 
All other 
immune-
related AEs 
Intolerable/ 
persistent 
Grade 2 
Withhold 
• Based on type and 
severity of AE 
administer 
corticosteroids  
• 
Ensure adequate evaluation to 
confirm etiology and/or exclude 
other causes 
 
Grade 3 
Withhold or 
discontinue 
based on the type 
of event.  Events 
that require 
discontinuation 
include and not 
limited to:  
Gullain-Barre 
Syndrome, 
encephalitis 


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Grade 4 or 
recurrent 
Grade 3  
Permanently 
discontinue 
1. Withhold or permanently discontinue pembrolizumab is at the discretion of the investigator or treating physician.   
NOTE:  
For participants with Grade 3 or 4 immune-related endocrinopathy where withhold of pembrolizumab is 
required, pembrolizumab may be resumed when AE resolves to ≤ Grade 2 and is controlled with hormonal 
replacement therapy or achieved metabolic control (in case of T1DM).   
 
Dosing interruptions are permitted in the case of medical / surgical events or logistical reasons 
not related to study therapy (e.g., elective surgery, unrelated medical events, patient vacation, 
and/or holidays). Subjects should be placed back on study therapy within 3 weeks of the 
scheduled interruption, unless otherwise discussed with the Sponsor. The reason for 
interruption should be documented in the patient's study record. 
6.5 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 8.0).  Trial treatment may 
be administered up to 3 days before or after the scheduled Day 1 of each cycle due to 
administrative reasons. 
All trial treatments will be administered on an outpatient basis. 
Pembrolizumab 200 mg will be administered as a 30 minute IV infusion every 3 weeks.  Sites 
should make every effort to target infusion timing to be as close to 30 minutes as possible.  
However, given the variability of infusion pumps from site to site, a window of -5 minutes and 
+10 minutes is permitted (i.e., infusion time is 30 minutes: -5 min/+10 min). 
The Package Insert contains specific instructions for the preparation of the pembrolizumab 
infusion fluid and administration of infusion solution. 
6.6 Trial Blinding/Masking 
This is an open-label trial; therefore, the Sponsor, investigator and subject will know the 
treatment administered. 
6.7 Concomitant Medications/Vaccinations (allowed & prohibited) 
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed 
during the ongoing trial.  If there is a clinical indication for one of these or other medications 
or vaccinations specifically prohibited during the trial, discontinuation from trial therapy or 
vaccination may be required.  The investigator should discuss any questions regarding this 
with the Merck Clinical team.  The final decision on any supportive therapy or vaccination 
rests with the investigator and/or the subject's primary physician.  


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6.7.1 Acceptable Concomitant Medications 
All treatments that the investigator considers necessary for a subject’s welfare may be 
administered at the discretion of the investigator in keeping with the community standards of 
medical care.  All concomitant medication will be recorded on the case report form (CRF) 
including all prescription, over-the-counter (OTC), herbal supplements, and IV medications 
and fluids.  If changes occur during the trial period, documentation of drug dosage, frequency, 
route, and date may also be included on the case report form (CRF). 
All concomitant medications received within 28 days before the first dose of trial treatment 
and 30 days after the last dose of trial treatment should be recorded.  Concomitant medications 
administered after 30 days after the last dose of trial treatment should be recorded for SAEs 
and ECIs as defined in Section 11. 
6.7.2 Prohibited Concomitant Medications 
Subjects are prohibited from receiving the following therapies during the Screening and 
Treatment Phase (including retreatment for post-complete response relapse) of this trial: 
• Antineoplastic systemic chemotherapy or biological therapy  
• Immunotherapy not specified in this protocol 
• Chemotherapy not specified in this protocol 
• Investigational agents other than pembrolizumab 
• Radiation therapy  
o Note:  Radiation therapy to a symptomatic solitary lesion or to the brain may 
be allowed at the investigator’s discretion.   
• Live vaccines within 30 days prior to the first dose of trial treatment and while 
participating in the trial.  Examples of live vaccines include, but are not limited to, the 
following: measles, mumps, rubella, varicella/zoster, yellow fever, rabies, BCG, and 
typhoid vaccine.  
• Systemic glucocorticoids for any purpose other than to modulate symptoms from an 
event of clinical interest of suspected immunologic etiology.  The use of physiologic 
doses of corticosteroids may be approved after consultation with the Sponsor. 
Subjects who, in the assessment by the investigator, require the use of any of the 
aforementioned treatments for clinical management should be removed from the trial.  Subjects 
may receive other medications that the investigator deems to be medically necessary. 
The Exclusion Criteria describes other medications which are prohibited in this trial. 
There are no prohibited therapies during the Post-Treatment Follow-up Phase. 
6.8 Rescue Medications & Supportive Care 


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6.8.1 Supportive Care Guidelines 
Subjects should receive appropriate supportive care measures as deemed necessary by the 
treating investigator.  Suggested supportive care measures for the management of adverse 
events with potential immunologic etiology are outlined below. Where appropriate, these 
guidelines include the use of oral or intravenous treatment with corticosteroids as well as 
additional anti-inflammatory agents if symptoms do not improve with administration of 
corticosteroids.   Note that several courses of steroid tapering may be necessary as symptoms 
may worsen when the steroid dose is decreased. For each disorder, attempts should be made to 
rule out other causes such as metastatic disease or bacterial or viral infection, which might 
require additional supportive care. The treatment guidelines are intended to be applied when 
the investigator determines the events to be related to pembrolizumab.  
Note: if after the evaluation the event is determined not to be related, the investigator does not 
need to follow the treatment guidance (as outlined below). Refer to Section 5.2.1 for dose 
modification.  
It may be necessary to perform conditional procedures such as bronchoscopy, endoscopy, or 
skin photography as part of evaluation of the event.  
• Pneumonitis:  
o For Grade 2 events, treat with systemic corticosteroids. When symptoms improve to 
Grade 1 or less, steroid taper should be started and continued over no less than 4 weeks. 
o For Grade 3-4 events, immediately treat with intravenous steroids.  Administer 
additional anti-inflammatory measures, as needed. 
o Add prophylactic antibiotics for opportunistic infections in the case of prolonged steroid 
administration. 
• Diarrhea/Colitis:  
Subjects should be carefully monitored for signs and symptoms of enterocolitis (such as 
diarrhea, abdominal pain, blood or mucus in stool, with or without fever) and of bowel 
perforation (such as peritoneal signs and ileus).   
o All subjects who experience diarrhea/colitis should be advised to drink liberal quantities 
of clear fluids.  If sufficient oral fluid intake is not feasible, fluid and electrolytes should 
be substituted via IV infusion.  For Grade 2 or higher diarrhea, consider GI consultation 
and endoscopy to confirm or rule out colitis. 
o For Grade 2 diarrhea/colitis, administer oral corticosteroids.  
o For Grade 3 or 4 diarrhea/colitis, treat with intravenous steroids followed by high dose 
oral steroids.   
o When symptoms improve to Grade 1 or less, steroid taper should be started and 
continued over no less than 4 weeks. 


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• 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 
o Insulin replacement therapy is recommended for Type I diabetes mellitus and for Grade 
3-4 hyperglycemia associated with metabolic acidosis or ketonuria.  
o 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): 
o In hyperthyroidism, non-selective beta-blockers (e.g. propranolol) are suggested as 
initial therapy. 
o In hypothyroidism, thyroid hormone replacement therapy, with levothyroxine or 
liothyroinine, is indicated per standard of care. 
o Grade 3-4 hyperthyroidism  
o 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). 
o 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. 


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• 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. Table 5 below shows treatment guidelines for subjects who experience an 
infusion reaction associated with administration of pembrolizumab (MK-3475). 
Table 5. Infusion Reaction Treatment Guidelines 
NCI CTCAE Grade 
Treatment 
Premedication at subsequent dosing 
Grade 1 
Mild reaction; infusion interruption not 
indicated; intervention not indicated 
Increase monitoring of vital signs as medically 
indicated until the subject is deemed medically 
stable in the opinion of the investigator. 
None 
Grade 2 
Requires infusion interruption but 
responds promptly to symptomatic 
treatment (e.g., antihistamines, 
NSAIDS, narcotics, IV fluids); 
prophylactic medications indicated for 
< =24 hrs 
Stop Infusion and monitor symptoms. 
Additional appropriate medical therapy may 
include but is not limited to: 
IV fluids 
Antihistamines 
NSAIDS 
Acetaminophen 
Narcotics 
Increase monitoring of vital signs as medically 
indicated until the subject is deemed medically 
stable in the opinion of the investigator. 
If symptoms resolve within one hour of 
stopping drug infusion, the infusion may be 
restarted at 50% of the original infusion rate 
(e.g., from 100 mL/hr to 50 mL/hr).  Otherwise 
dosing will be held until symptoms resolve and 
the subject should be premedicated for the next 
scheduled dose. 
Subjects who develop Grade 2 toxicity 
despite adequate premedication should be 
permanently discontinued from further trial 
treatment administration. 
Subject may be premedicated 1.5h (± 30 
minutes) prior to infusion of 
pembrolizumab with:Diphenhydramine 50 
mg po (or equivalent dose of 
antihistamine). 
 
Acetaminophen 500-1000 mg po (or 
equivalent dose of antipyretic). 
Grades 3 or 4 
Grade 3: 
Prolonged (i.e., not rapidly responsive 
to symptomatic medication and/or 
brief interruption of infusion); 
recurrence of symptoms following 
initial improvement; hospitalization 
indicated for other clinical sequelae 
(e.g., renal impairment, pulmonary 
infiltrates) 
Grade 4: 
Life-threatening; pressor or ventilatory 
support indicated 
Stop Infusion. 
Additional appropriate medical therapy may 
include but is not limited to: 
IV fluids 
Antihistamines 
NSAIDS 
Acetaminophen 
Narcotics 
Oxygen 
Pressors 
Corticosteroids 
Epinephrine 
 
Increase monitoring of vital signs as medically 
indicated until the subject is deemed medically 
stable in the opinion of the investigator. 
Hospitalization may be indicated. 
Subject is permanently discontinued from 
further trial treatment administration. 
No subsequent dosing 
Appropriate resuscitation equipment should be available in the room and a physician readily available during the period of drug 
administration. 
 
 


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


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 Combination method (requires use of two of the following): 
• 
diaphragm with spermicide (cannot be used in conjunction with cervical 
cap/spermicide) 
• 
cervical cap with spermicide (nulliparous women only)   
• 
contraceptive sponge (nulliparous women only)  
• 
male condom or female condom (cannot be used together) 
• 
hormonal contraceptive: oral contraceptive pill (estrogen/progestin pill or progestin-
only pill), contraceptive skin patch, vaginal contraceptive ring, or subcutaneous 
contraceptive injection 
 †Abstinence (relative to heterosexual activity) can be used as the sole method of contraception 
if it is consistently employed as the subject’s preferred and usual lifestyle and if considered 
acceptable by local regulatory agencies and ERCs/IRBs.  Periodic abstinence (e.g., calendar, 
ovulation, sympto-thermal, post-ovulation methods, etc.) and withdrawal are not acceptable 
methods of contraception.  
‡If a contraceptive method listed above is restricted by local regulations/guidelines, then it 
does not qualify as an acceptable method of contraception for subjects participating at sites in 
this country/region. 
Subjects should be informed that taking the study medication may involve unknown risks to 
the fetus (unborn baby) if pregnancy were to occur during the study.  In order to participate in 
the study subjects of childbearing potential must adhere to the contraception requirement 
(described above) from the day of study medication initiation (or 14 days prior to the initiation 
of study medication for oral contraception) throughout the study period up to 120 days after 
the last dose of trial therapy.  If there is any question that a subject of childbearing potential 
will not reliably comply with the requirements for contraception, that subject should not be 
entered into the study. 
6.9.3 Use in Pregnancy 
If a subject inadvertently becomes pregnant while on treatment with pembrolizumab, the 
subject will immediately be removed from the study.  The site will contact the subject at least 
monthly and document the subject’s status until the pregnancy has been completed or 
terminated.  The outcome of the pregnancy will be reported to the Sponsor and to Merck 
without delay and within 24 hours to the Sponsor and within 2 working days to Merck if the 
outcome is a serious adverse experience (e.g., death, abortion, congenital anomaly, or other 
disabling or life-threatening complication to the mother or newborn).   
The study investigator will make every effort to obtain permission to follow the outcome of 
the pregnancy and report the condition of the fetus or newborn to the Sponsor.   If a male 
subject impregnates his female partner the study personnel at the site must be informed 
immediately and the pregnancy reported to the Sponsor and to Merck and followed as 
described above. 


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6.9.4 Use in Nursing Women 
It is unknown whether pembrolizumab is excreted in human milk.  Since many drugs are 
excreted in human milk, and because of the potential for serious adverse reactions in the 
nursing infant, subjects who are breast-feeding are not eligible for enrollment. 
7.0 SUBJECT WITHDRAWAL/DISCONTINUATION CRITERIA 
Subjects may withdraw consent at any time for any reason or be dropped from the trial at the 
discretion of the investigator should any untoward effect occur.  In addition, a subject may be 
withdrawn by the investigator or the Sponsor if enrollment into the trial is inappropriate, the 
trial plan is violated, or for administrative and/or other safety reasons.   
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 
• Unacceptable adverse experiences  
• Intercurrent illness that prevents further administration of treatment 
• Investigator’s decision to withdraw the subject 
• The subject has a confirmed positive serum pregnancy test 
• Noncompliance with trial treatment or procedure requirements 
• The subject is lost to follow-up 
• Completed 24 months of uninterrupted treatment with pembrolizumab or 35 
administrations of study medication, whichever is later. 
• Administrative reasons 
The End of Treatment and Follow-up visit procedures are listed in Section 8 (Protocol Flow 
Chart) and Section 10.0.1 (Visit Requirements).  After the end of treatment, each subject will 
be followed for 30 days for adverse event monitoring (serious adverse events will be collected 
for 90 days after the end of treatment).  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 
for overall survival until death, withdrawal of consent, or the end of the study, whichever 
occurs first. 


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7.1 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.   
7.2 Subject Replacement Strategy 
We anticipate enrollment of 39 patients for which tumor and toxicity assessments following 
pembrolizumab administration can be made. We will replace patients enrolled for which 
clinical trial discontinuation was performed prior to any administration of pembrolizumab or 
those for which pembrolizumab is discontinued due to acute hypersensitivity reactions during 
the first administration of pembolizumab.  An attempt will be made to assess tumor response 
in all enrolled patients as specified in the protocol.  However, patients experiencing clinical 
deterioration after two doses of pembrolizumab, will be considered treatment failures and will 
count as tumor progression.  These patients will not be replaced. 
We are also expecting that 30% of the patients enrolled will be negative on the FATSI assay, 
which will be conducted in batched analyses. 
See section 6.1.1 and 12.0.1 for expansion cohort.   
7.3 Clinical Criteria for Early Trial Termination 
Early trial termination will be the result of the criteria specified below.  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. 
1. Quality or quantity of data recording is inaccurate or incomplete 
2. Poor adherence to protocol and regulatory requirements 
3. Incidence or severity of new adverse pembrolizumab drug reaction as reported by MERCK 
to the FDA indicates a potential health hazard to subjects and lead to modification in the 
drug labeling. The trial could be re-open following the adoption of required modifications 
in administration. 


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8  TRIAL FLOW CHART 
8.1 Table 6. Study Flow Chart 
Trial Period: 
Screening 
Treatment Cycles 
End of Treatment 
Post-Treatment 
Treatment Cycle/Title: 
Main 
Study 
Screening  
1 
2  
3 
4 
To be repeated beyond 8 
cycles 
Discon 
Safety 
Follow-up 
Follow Up 
Visitsb 
Survival 
Follow-
Up 
5 
6 
7 
8 
Scheduling Window (Days): 
-21 to -1 
 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
At time of 
Discon 
30 days 
post 
discon 
Every 8 
weeks post 
discon 
Every 12 
weeks  
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics and Medical History 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
Prior and Concomitant Medication Review 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
Trial Treatment Administration 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
Post-study anticancer therapy status 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
Survival Status 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
Review Adverse Events 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Full Physical Examination 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Directed Physical Examination 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Vital Signs and Weight 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
ECOG Performance Status 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Pregnancy Test – Urine or Serum β-HCG 
Xc 
 
 
 
 
 
 
 
 
 
 
 
 
PT/INR and aPTT 
Xa 
 
 
 
 
 
 
 
 
 
 
 
 
CBC with Differential 
Xa 
Xb 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
Comprehensive Serum Chemistry Panel 
(see Table 9 for lab details) 
Xa 
Xb 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
Urinalysis 
Xa 
 
 
 
 
 
 
 
 
 
 
 
 
T3, FT4 and TSH 
Xa 
 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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a Must be performed within 10 days of the first treatment visit (Cycle 1 Day 1). 
b Hematology (CBC with differential) and Creatinine results must be available and reviewed by the Investigator prior to infusion. 
A spot creatinine result may be used to proceed with treatment, as Chemistry results may not be available.  
c Must be performed within 72 hours of the first treatment visit (Cycle 1 Day 1).   
d Tumor imaging will only be required every 12 weeks for patients that have been on treatment for more than 1 year. 
 
 
 
 
 
 
Efficacy Measurements 
Tumor Imaging 
X 
 
 
X 
 
 
Xd 
 
 
X 
 
 
 
Archival Tissue Collection/Correlative Studies Blood 
Archival or Newly Obtained Tissue 
Collection 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Correlative Studies Blood Collection 
See Protocol Lab Manual. 
X 
X 
X 
X 
 
 
 
 
 
X 
 
 
 


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9.0 TRIAL PROCEDURES 
The Trial Flow Chart - Section 8.0 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 Sponsor and/or 
Merck for reasons related to subject safety. In some cases, such evaluation/testing may be 
potentially sensitive in nature (e.g., HIV, Hepatitis C, etc.), and thus local regulations may 
require that additional informed consent be obtained from the subject.  In these cases, such 
evaluations/testing will be performed in accordance with those regulations. 
9.0.1 Administrative Procedures 
9.0.1.1 Informed Consent 
The Investigator must obtain documented consent from each potential subject prior to 
participating in a clinical trial. 
Consent must be documented by the subject’s dated signature or by the subject’s legally 
acceptable representative’s dated signature on a consent form along with the dated signature 
of the person conducting the consent discussion.  
A copy of the signed and dated consent form should be given to the subject before participation 
in the trial. 
The initial informed consent form, any subsequent revised written informed consent form and 
any written information provided to the subject must receive the IRB/ERC’s 
approval/favorable opinion in advance of use.  The subject or his/her legally acceptable 
representative should be informed in a timely manner if new information becomes available 
that may be relevant to the subject’s willingness to continue participation in the trial.  The 
communication of this information will be provided and documented via a revised consent 
form or addendum to the original consent form that captures the subject’s dated signature or 
by the subject’s legally acceptable representative’s dated signature. 
Specifics about a trial and the trial population will be added to the consent form template at 
the protocol level.   
The informed consent will adhere to IRB/ERC requirements, applicable laws and regulations 
and Sponsor requirements. 
9.0.1.2 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.  
9.0.1.3 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 


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which the subject has enrolled in this study will be recorded separately and not listed as medical 
history.   
9.0.1.4 Prior and Concomitant Medications Review 
9.0.1.4.1 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 21 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.  
9.0.1.4.2 Concomitant Medications 
The investigator or qualified designee will record medication, if any, taken by the subject 
during the trial.  All medications related to reportable SAEs and ECIs should be recorded as 
defined in Section 9.2. 
9.0.1.5 Disease Details and Treatments 
9.0.1.5.1 Disease Details 
The investigator or qualified designee will obtain prior and current details regarding disease 
status.  
9.0.1.5.2 Prior Treatment Details 
The investigator or qualified designee will review all prior cancer treatments including 
systemic treatments, radiation and surgeries. 
9.0.1.5.3 Subsequent Anti-Cancer Therapy Status 
The investigator or qualified designee will review all new anti-neoplastic therapy initiated after 
the last dose of trial treatment.  If a subject initiates a new anti-cancer therapy within 30 days 
after the last dose of trial treatment, the 30 day Safety Follow-up visit must occur before the 
first dose of the new therapy.  Once new anti-cancer therapy has been initiated the subject will 
move into survival follow-up.  
9.0.2 Clinical Procedures/Assessments 
9.0.2.1 Adverse Event (AE) Monitoring 
The investigator or qualified designee will assess each subject to evaluate for potential new or 
worsening AEs as specified in the Trial Flow Chart and more frequently if clinically indicated.  
Adverse experiences will be graded and recorded throughout the study and during the follow-
up period according to NCI CTCAE Version 4.0 (see Section 11.2).  Toxicities will be 
characterized in terms regarding seriousness, causality, toxicity grading, and action taken with 
regard to trial treatment.  
9.0.2.2 Full Physical Exam 
The investigator or qualified designee will perform a complete physical exam during the 
screening period.  Clinically significant abnormal findings should be recorded as medical 
history.  A full physical exam should be performed during screening,  


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9.0.2.3 Directed Physical Exam 
For cycles that do not require a full physical exam per the Trial Flow Chart, the investigator or 
qualified designee will perform a directed physical exam as clinically indicated prior to trial 
treatment administration.   
9.0.2.4 Vital Signs 
The investigator or qualified designee will take vital signs at screening, prior to the 
administration of each dose of trial treatment and at treatment discontinuation as specified in 
the Trial Flow Chart (Section 8).  Vital signs should include temperature, pulse, respiratory 
rate, weight and blood pressure.  Height will be measured at screening only. 
9.0.2.5 Eastern Cooperative Oncology Group (ECOG) Performance Scale 
The investigator or qualified designee will assess ECOG status (see below) at screening, prior 
to the administration of each dose of trial treatment and discontinuation of trial treatment as 
specified in the Trial Flow Chart.   
9.0.2.6 Tumor Imaging and Assessment of Disease 
Tumor assessments will be performed by computer tomography (CT) or Magnetic 
Resonance Imaging (MRI). Measurable disease will be required by computer tomography or 
MRI examination obtained within 21 days of first dose of therapy. Scans obtained prior to 
consenting will be allowed, as long as performed within 21 days of study initiation.  CT Scans 
or MRI’s will be repeated every 2 cycles (3 weeks cycles); that is before every third dose of 
pembrolizumab in order to assess response to therapy.  Tumor imaging will only be required 
every 12 weeks for patients that have been on treatment for more than 1 year. Immune-related 
Response Criteria (irRC) [30] will be utilized for assessment of response to therapy.  
Systematic criteria designated immune-related response criteria were defined based on four 
distinct response patterns seen after administration of ipilumimab: (a) shrinkage in baseline 
lesions, without new lesions; (b) durable stable disease (in some patients followed by a slow, 
steady decline in total tumor burden); (c) response after an increase in total tumor burden; and 
(d) response in the presence of new lesions.  These four patterns were associated with favorable 
survival [30]. 
For the irRC index and measurable new lesions are taken into account to calculate evolving 
tumor burden.  At baseline, the sum of the products of the two largest perpendicular diameters 
(SPD) of all index lesions (five lesions per organ, up to 10 visceral lesions) is calculated. At 
each subsequent tumor assessment, the SPD of the index lesions and of new, measurable 
lesions (up to 5 new lesions per organ; 10 visceral lesions) are added together to provide the 
total tumor burden.  A comparison of the use of SPD in WHO criteria versus the use of tumor 
burden in irRC is presented in Table 8. 
Table 7. Comparison between WHO criteria and the irRC 
 
WHO 
irRC 
New, measurable lesions 
Always represent PD 
Incorporated into tumor burden. 
New, nonmeasurable lesions 
Always represent PD 
Do not define progression                
(but preclude irCR) 


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Non-index lesions 
Changes contribute to defining 
best overall response 
Contribute to defining irCR              
(complete disappearance required) 
CR 
Disappearance of all lesions in 
two consecutive observations not 
less than 4 weeks apart.  
Disappearance of all lesions in 
two consecutive observations not 
less than 4 weeks apart. 
PR 
≥50% decrease in SPD compared 
with baseline in two observations 
at least 4 weeks apart, in absence 
of new lesions or inequivocal 
progression of non-index lesions. 
≥50% decrease in tumor burden 
compared with baseline in two 
observations at least 4 weeks 
apart. 
SD 
50% decrease in SPD compared to 
baseline cannot be established nor 
25% increase compared with 
nadir, in absence of new lesions or 
inequivocal progression of non-
index lesions. 
50% decrease in tumor burden 
compared with baseline cannot be 
established nor 25% increase 
compared with nadir. 
PD 
At least 25% increase in SPD 
compared with nadir and/or 
unequivocal progression of non-
index lesions and/or appearance of 
new lesions (at any single time 
point). 
At least 25% increase in tumor 
burden compared with nadir (at 
any single time point) in two 
consecutive observations at least 4 
weeks apart. 
 
9.0.2.7 Overall response using the irRC 
• irCR: Complete disappearance of all lesions (whether measurable or not, and no new 
lesions) confirmed by a repeat, consecutive assessment no less than 4 weeks from the 
date first documented. 
• Ir PR: Decrease in tumor burden ≥50% relative to baseline confirmed by a consecutive 
assessment at least 4 weeks after first documentation. 
• irSD: Not meeting criteria for irCR or irPR, in absence of irPD. 
• irPD: Increase in tumor burden ≥25% relative to nadir (minimum recorded tumor 
burden) confirmed by a repeat, consecutive assessment no less than 4 weeks from the 
date first documented. 
Major differences with other tumor response criteria include: PR or SD in the presence of new 
lesions, as long as they met the respective threshold of response based on total differences in 
tumor burden; an SD does not require confirmation; however PD requires confirmation by 
another scan at least 4 weeks apart in the absence of rapid clinical deterioration. 
9.0.2.8 Tumor Tissue Collection and Correlative Studies Sampling 
We will evaluate functionality of the Fanconi Anemia pathway in patient tumor samples. 
Formalin fixed paraffin embedded (FFPE) will be obtained from patients participating in the 
trial.  The presence of archival tumor material is part of the criteria for eligibility for this trial. 
FFPE tumor tissue will be cut at 4 microns, placed on positively charged slides and stained 


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with hematoxylin and eosin (HE).  Additional sections for FATSI staining will be placed in a 
60°C oven for 1 h, cooled, deparaffinized and rehydrated through xylenes and graded ethanol 
solutions to water in standard fashion.  Antigen retrieval will be performed by placing slides 
in Dako’s TRS (pH 6.1) antigen retrieval solution (Dako, Carpenteria, CA) in a calibrated 
vegetable steamer (Black and Decker).  Slides then will be placed on a Dako Autostainer for 
automated staining. The tissue sections will be incubated with a primary antibody cocktail of 
rabbit polyclonal FANC-D2 antibody at a dilution of 1:1000 and a monoclonal anti-Ki67 
mouse antibody at a dilution of 1: 150, and incubated for 1 hour at room temperature.  Sections 
then will be co-incubated with a secondary antibody (FITC conjugated to anti-rabbit IgG and 
Alexafluor 594 donkey anti-mouse) at 1:1000 and incubated for 1 hour at room temperature.  
All rinses will be performed on the autostainer with TBST.  The sections will be mounted on 
glass slides using a 4’ 6-diamidino-2-phenylindole (DAPI)–containing embedding medium 
(Vysis Dapi 1, Abbott Laboratories, Downers Grove, IL).  FANCD2 foci positive and negative 
cell lines (MCF-7 and PD20 cells) used as controls will be included on the sample slide during 
the procedure.  The slides will be analyzed under a Nikon E-400 fluorescence microscope. 
Circulating cell-free tumor DNA (ctDNA) carries comprehensive, inherently specific, and 
highly sensitive information.  Studies in melanoma, breast, ovarian, and colon cancers have 
validated the potential applications of ctDNA to monitor tumor burden dynamically and 
precisely during treatment process. A liquid biopsy based on ctDNA could capture the entire 
heterogeneity of the disease longitudinally as well as in real time.  Blood samples collected 
from the patients will be sent to Florida International University (Duan’s lab) for genomic 
analysis. 
All analyses regarding the microbiome will be performed by the Narasimhan laboratory. 
The four “omics” profiles mentioned above will be processed using integrative analysis 
techniques developed by the Narasimhan laboratory on the machines available to BioRG. In 
particular, the method of heterogeneous correlation networks will help identify groups of 
entities from different omics data that tend to occur together or avoid each other. Groups of 
entities from the metagenome, metatranscriptome, metabolome and patient transcriptome will 
help generate useful hypotheses for further investigations. Using the functional annotations of 
the genes, it is possible to determine which microbial taxa are responsible for the functional 
genes of interest that are most differentially expressed. The analysis will also implicate the 
most relevant human pathways of interest. Using the KEGG metabolic pathways database, it 
is possible to hypothesize which microbial taxa are responsible for the most differentially 
abundant metabolites. 
  
9.0.2.9 Laboratory Procedures/Assessments 
Laboratory tests for hematology, chemistry, urinalysis, and others are specified in Table 9.   
 
 
 


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Table 8.  Laboratory Tests 
Hematology 
Chemistry 
Urinalysis 
Other 
Hematocrit 
Albumin 
Blood 
Serum β-human chorionic gonadotropin† 
Hemoglobin 
Alkaline phosphatase 
Glucose 
  (β-hCG)† 
Platelet count 
Alanine aminotransferase (ALT) 
Protein 
PT (INR) 
WBC (total and differential) 
Aspartate aminotransferase (AST) 
Specific gravity  
aPTT 
Red Blood Cell Count 
Lactate dehydrogenase (LDH) 
Microscopic exam (If abnormal 
Total thriiodothyronine (T3) 
Absolute Neutrophil Count 
Carbon Dioxide  
results are noted) 
Free tyroxine (T4) 
Absolute Lymphocyte Count 
  (CO2 or bicarbonate) 
Urine pregnancy test † 
Thyroid stimulating hormone (TSH) 
 
Uric Acid 
 
 
 
Calcium 
 
 
 
Chloride 
 
Blood and stools for correlative studies 
 
Glucose 
 
  
 
Phosphorus 
 
  
 
Potassium   
 
  
 
Sodium 
 
  
 
Magnesium 
 
  
 
Total Bilirubin 
 
  
 
Direct Bilirubin (If total bilirubin is 
elevated above the upper limit of 
normal) 
 
 
 
Total protein 
 
 
 
Blood Urea Nitrogen 
 
 
† Perform on women of childbearing potential only. If urine pregnancy results cannot be confirmed as negative, a serum pregnancy test will be required.   
 


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10.0 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 11 - 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.  After discontinuing treatment following assessment of 
CR, these subjects should return to the site for a Safety Follow-up Visit (described in Section 
10.0.1.0) and then proceed to the Follow-Up Period of the study (described in Section 
10.0.1.1). 
10.0.1 Visit Requirements 
Visit requirements are outlined in Section 8.0 - Trial Flow Chart.   Specific procedure-related 
details are provided above in Section 9 - Trial Procedures. 
10.0.1.0 Safety Follow-Up Visit 
The mandatory Safety Follow-Up Visit should be conducted approximately 30 days after the 
last dose of trial treatment or before the initiation of a new anti-cancer treatment, whichever 
comes first.  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.   
 
10.0.1.1 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 6 weeks (42 ± 7 days) by radiologic 
imaging to monitor disease status.  After 1 year, the imaging time point will occur every 9 
weeks (± 7 days). Every effort should be made to collect information regarding disease status 
until the start of new anti-neoplastic therapy, disease progression, death, or end of the study 
Information regarding post-study anti-neoplastic treatment will be collected if new treatment 
is initiated. 
10.0.1.2 Survival Follow-up 
Once a subject experiences confirmed disease progression or starts a new anti-cancer therapy, 
the subject moves into the survival follow-up phase and should be contacted by telephone 
every 12 weeks to assess for survival status until death, withdrawal of consent, or the end of 
the study, whichever occurs first.  
11.0 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 


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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 pembrolizumab is also an adverse event. 
Progression of the cancer under study is not considered an adverse event.  
All adverse events that occur after the consent form is signed but before treatment 
allocation/randomization must be reported by the investigator if they cause the subject to be 
excluded from the trial, or are the result of a protocol-specified intervention, including but not 
limited to washout or discontinuation of usual therapy, diet, placebo treatment or a procedure. 
From the time of treatment allocation/randomization through 30 days following cessation of 
treatment, all adverse events must be reported by the investigator. Such events will be 
recorded at each examination on the Adverse Event case report forms/worksheets.  The 
investigator will make every attempt to follow all subjects with non-serious adverse events 
for outcome. 
11.0.1 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.   
If an adverse event(s) is associated with (“results from”) the overdose of pembrolizumab, the 
adverse event(s) is reported as a serious adverse event, even if no other seriousness criteria are 
met. 
If a dose of pembrolizumab meeting the protocol definition of overdose is taken without any 
associated clinical symptoms or abnormal laboratory results, the overdose is reported as a non-
serious Event of Clinical Interest (ECI), using the terminology “accidental or intentional 
overdose without adverse effect.” 
All reports of overdose with and without an adverse event must be reported within 24 hours to 
the Sponsor and within 2 working days hours to Merck Global Safety. (Attn: Worldwide 
Product Safety; FAX 215 993-1220) 
11.0.2 Reporting of Pregnancy and Lactation to the Sponsor and to Merck 
Although pregnancy and lactation are not considered adverse events, it is the responsibility of 
investigators or their designees to report any pregnancy or lactation in a subject 
(spontaneously reported to them) that occurs during the trial. 


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Pregnancies and lactations that occur after the consent form is signed but before treatment 
allocation/randomization must be reported by the investigator if they cause the subject to be 
excluded from the trial, or are the result of a protocol-specified intervention, including but not 
limited to washout or discontinuation of usual therapy, diet, placebo treatment or a procedure.   
Pregnancies and lactations that occur from the time of treatment allocation/randomization 
through 120 days following cessation of Sponsor’s product, or 30 days following cessation of 
treatment if the subject initiates new anticancer therapy, whichever is earlier, must be reported 
by the investigator.  All reported pregnancies must be followed to the completion/termination 
of the pregnancy. Pregnancy outcomes of spontaneous abortion, missed abortion, benign 
hydatidiform mole, blighted ovum, fetal death, intrauterine death, miscarriage and stillbirth 
must be reported as serious events (Important Medical Events). If the pregnancy continues to 
term, the outcome (health of infant) must also be reported. 
Such events must be reported within 24 hours to the Sponsor and within 2 working days to 
Merck Global Safety. (Attn: Worldwide Product Safety; FAX 215 993-1220) 
11.0.3 Immediate Reporting of Adverse Events to the Sponsor and to Merck 
11.0.3.1 Serious Adverse Events 
A serious adverse event is any adverse event occurring at any dose or during any use of 
Merck’s product that: 
• Results in death; 
• Is life threatening; 
• Results in persistent or significant disability/incapacity; 
• Results in or prolongs an existing inpatient hospitalization; 
• Is a congenital anomaly/birth defect; 
• Is an other important medical event  
• Note: In addition to the above criteria, adverse events meeting either of the below criteria, 
although not serious per ICH definition, are reportable to the Merck in the same timeframe 
as SAEs to meet certain local requirements. Therefore, these events are considered serious 
by Merck for collection purposes. 
● Is a new cancer (that is not a condition of the study); 
● Is associated with an overdose. 
For the time period beginning when the consent form is signed until treatment 
allocation/randomization, any serious adverse event, or follow up to a serious adverse event, 
including death due to any cause other than progression of the cancer under study  that occurs 
to any subject must be reported within 24 hours to the Sponsor and within 2 working days to 
Merck Global Safety if it causes the subject to be excluded from the trial, or is the result of a 
protocol-specified intervention, including but not limited to washout or discontinuation of 
usual therapy, diet, placebo treatment or a procedure. 
For the time period beginning at treatment allocation/randomization through 90 days following 
cessation of treatment, or 30 days following cessation of treatment if the subject initiates new 


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anticancer therapy, whichever is earlier, any serious adverse event, or follow up to a serious 
adverse event, including death due to any cause other than progression of the cancer under 
study, whether or not related to the Merck product, must be reported within 24 hours to the 
Sponsor and within 2 working days to Merck Global Safety. 
Additionally, any serious adverse event, considered by an investigator who is a qualified 
physician to be related to Merck product that is brought to the attention of the investigator at 
any time following consent through the end of the specified safety follow-up period specified 
in the paragraph above, or at any time outside of the time period specified in the previous 
paragraph also must be reported immediately to the Sponsor and to Merck Global Safety. 
All subjects with serious adverse events must be followed up for outcome. 
SAE reports and any other relevant safety information are to be forwarded to 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, 
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. 
11.0.3.2 Events of Clinical Interest 
Selected non-serious and serious adverse events are also known as Events of Clinical Interest 
(ECI) and must be reported within 24 hours to the Sponsor and within 2 working days to Merck 
Global Safety. (Attn: Worldwide Product Safety; FAX 215 993-1220). 
For the time period beginning when the consent form is signed until treatment 
allocation/randomization, any ECI, or follow up to an ECI, that occurs to any subject must be 
reported within 24 hours to the Sponsor and within 2 working days to Merck Global Safety if 
it causes the subject to be excluded from the trial, or is the result of a protocol-specified 
intervention, including but not limited to washout or discontinuation of usual therapy, diet, 
placebo treatment or a procedure. 
For the time period beginning at treatment allocation/randomization through 90 days following 
cessation of treatment, or 30 days following cessation of treatment if the subject initiates new 
anticancer therapy, whichever is earlier, any ECI, or follow up to an ECI, whether or not related 
to Merck product, must be reported within 24 hours to the Sponsor and within 24 hours to 
Merck Global Safety. 
Events of clinical interest for this trial include: 
1.  An overdose of Merck product, as defined in Section 7.2.1 - 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.  


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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.  
11.0.3.3 Protocol-Specific Exceptions to Serious Adverse Event Reporting.  
Specifically, the suspected/actual events covered in this exception include any event that is 
disease progression of the cancer under study. 
The Sponsor will monitor unblinded aggregated efficacy endpoint events and safety data to 
ensure the safety of the subjects in the trial. Any suspected endpoint which upon review is not 
progression of the cancer under study will be forwarded to Merck Global Safety as a SAE 
within 2 working days of determination that the event is not progression of the cancer under 
study 
Hospitalization related to convenience (e.g.transportation issues etc.) will not be considered a 
SAE. 
 
11.0.4 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. 
An investigator who is a qualified physician, will evaluate all adverse events as to:


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Table 9. Evaluating Adverse Events 
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 for an elective procedure to treat a pre-existing condition that has not 
worsened is not a serious adverse event.  A pre-existing condition is a clinical condition that is diagnosed prior to the use of a Merck product and is documented in the 
patient’s medical history.); or 
 
†Is a congenital anomaly/birth defect (in offspring of subject taking the product regardless of time to diagnosis);or 
 
Is a new cancer (that is not a condition of the study) (although not serious per ICH definition, is reportable to the Sponsor within 24 hours and to Merck within 2 
working days to meet certain local requirements); or 
 
Is an overdose (whether accidental or intentional).  Any adverse event associated with an overdose is considered a serious adverse event for collection purposes. An 
overdose that is not associated with an adverse event is considered a non-serious event of clinical interest and must be reported within 24 hours to the Sponsor and to 
Merck within 2 working days. 
 
Other important medical events that may not result in death, not be life threatening, or not require hospitalization may be considered a serious adverse event when, 
based upon appropriate medical judgment, the event may jeopardize the subject and may require medical or surgical intervention to prevent one of the outcomes listed 
previously (designated above by a †). 
Duration 
Record the start and stop dates of the adverse event. If less than 1 day, indicate the appropriate length of time and units 
Action taken  
Did the adverse event cause Merck product to be discontinued? 
Relationship to 
Merck Product  
Did Merck product cause the adverse event? The determination of the likelihood that Merck product caused the adverse event will be provided by an investigator who 
is a qualified physician. The investigator’s signed/dated initials on the source document or worksheet that supports the causality noted on the AE form, ensures that a 
 
Exposure 
Is there evidence that the subject was actually exposed to Merck product such as: reliable history, acceptable compliance assessment (pill count, 
diary, etc.), expected pharmacologic effect, or measurement of drug/metabolite in bodily specimen? 
 
Time Course 
Did 
the 
AE 
follow 
in 
a 
reasonable 
temporal 
sequence 
from 
administration 
of 
Merck 
product?  
Is the time of onset of the AE compatible with a drug-induced effect (applies to trials with investigational medicinal product)? 
 
Likely Cause 
Is the AE not reasonably explained by another etiology such as underlying disease, other drug(s)/vaccine(s), or other host or environmental factors 
 


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


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11.0.5 Sponsor Responsibility for Reporting Adverse Events 
All Adverse Events will be reported to regulatory authorities, IRB/IECs and investigators in 
accordance with all applicable global laws and regulations.  
12.0 SAMPLE CALCULATION AND STATISTICAL ANALYSIS PLAN 
The primary endpoint is overall immune-related objective response rate. We expect that similar 
to mismatch repair deficient patients, the immune-related objective response will be at or above 
40% in patients with functional FA deficiency (FATSI negative), and less than 10% in patients 
without either homologous recombination repair deficiency or mismatch repair deficiency. 
Patients with mismatch repair deficiency will be excluded from this trial. Based on our prior 
screening data, we anticipate that close to 30% of patients with solid tumors, depending on 
tumor type will be FA functionally deficient.  
We will utilize a two-stage phase II trial design to detect an iORR of at least 20% in the whole 
population tested vs. the null hypothesis that the true iORR is at most 5%, representing a 
response by chance alone, or other infrequent unknown mechanism. Specifically, we will test 
the null hypothesis H0: iORR ≤ 5% vs. H1: iORR ≥ 20% with 90% power and a Type I error 
rate of 10%. The alternative hypothesis of 20% iORR represents a weighted average of the 
anticipated 40% response in FATSI-negative patients and 10% response in FATSI-positive, 
assuming a 3 to 7 ratio of these patient groups. Interim analysis requires that at least two of the 
first 20 evaluable patients enrolled have an objective response. If this occurs, we will accrue 
19 additional patients for a total of 39. Overall rejection criterion of the null hypothesis is 
observing at least 4 responses.  
The proposed two-stage design was chosen instead of the Simon Optimal or Minimax design 
because it has a larger first stage enrollment and thus a higher expected number of FATSI-
negative patients in the interim analysis. Total enrollment of 39 patients is only slightly greater 
than that of the Simon designs but has the advantage of increasing the expected number of 
FATSI-negative patients. Additionally, the proposed design has a higher early stopping 
probability under the null hypothesis. The following table summarizes these operating 
characteristics. 
Table 10: 
Design 
First 
stage 
enrollment 
Expected 
FATSI-
patients, 
1st stage 
PET 
Total 
enrollment 
Total 
expected 
FATSI-
patients 
Actual 
α 
Power 
Expected 
study size 
Optimal 
12 
4 
0.54 
37 
11 
0.093 
90.2% 
23 
Minimax 
18 
5 
0.40 
32 
10 
0.072 
90.1% 
26 
Proposed 
20 
6 
0.74 
39 
12 
0.099 
91.7% 
25 
FATSI-: FATSI negative. PET: Probability of early termination at completion of first stage enrollment. α: Probability of 
false positive finding (type 1 error, falsely rejecting the null hypothesis). 
 


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We will analyze the paraffin embedded tumors of the participating patients for FA functional 
deficiency. Analysis will be conducted in batches.   
 
We will report the 90% confidence interval estimates of iORR both overall and by FATSI 
status using the exact method (Clopper-Pearson). We note, however, that the planned study is 
too small for a well-powered comparison given that we expect only 12 FATSI-negative 
patients. Instead, variation in iORR by FATSI status will be assessed by considering the one-
sided 95% lower confidence limit (95%LCL) for the difference. The following table illustrates 
the 95%LCL for several possible study outcomes in which iORR is higher in FATSI- patients. 
Taking the second rows as an example, an observed increase in iORR for FATSI-negative 
patients of 34.3%, based on 5 out of 12 FATSI- responders compared with 2 out of 27 FATSI+ 
responders, provides 95% confidence that the true increase for patients with FA deficient 
tumors is at least 9.4%, suggesting that further study of Pembrolizumab in FA deficient patients 
is warranted.  
Table 11: 
iORR 
FATSI─ 
FATSI+ 
Difference 
95%LCL 
5 / 12 
41.7% 
1/27 
3.7% 
38.0% 
13.8% 
5 / 12 
41.7% 
2/27 
7.4% 
34.3% 
9.4% 
5 / 12 
41.7% 
3/27 
11.1% 
30.6% 
5.1% 
4 / 12 
33.3% 
1/27 
3.7% 
29.6% 
6.5% 
4 / 12 
33.3% 
2/27 
7.4% 
25.9% 
2.1% 
4 / 12 
33.3% 
3/27 
11.1% 
22.2% 
-2.3% 
 
The incidence of severe (NCI CTCAE v4 grade 3+) adverse events or toxicities will be 
described. Kaplan-Meier curves will be used to estimate the distributions of overall survival 
and immune-related progression-free survival (iPFS). Point estimates and 2-sided 95% 
confidence intervals will be reported for selected times using Greenwood’s variance and the 
log-log transform method. This will include the 20-week iPFS for purposes of comparison with 
the literature. 
12.1 Expansion Cohort 
At the conclusion of the accrual as specified above, an expanded cohort of 10 patients with the 
diagnosis of metastatic or recurrent endometrial carcinoma or endometrial sarcoma will be 
enrolled. These patients need tissue availability and documentation of microsatellite low or 
stable. (see Section 6.1.1 for inclusion/exclusion criteria).  All clinical benefit measure 
parameters and correlatives will be obtained, as per the other patient.  No additional statistical 
inferences, other than comparison between FATSI positives and negatives in terms of clinical 
outcome will be done.    


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12.2 Correlative Data 
Additional correlative data other than FATSI status will be descriptive in nature and hypothesis 
generating.  These include mutation load in tumor and cell free DNA, FA related gene 
mutations and microbiome analysis. For known or predicted deleterious mutations of suspected 
inheritance trait detected during the trial, the process would be aided by making sure that 
patients carrying these mutations get referred for genetic counseling and CLIA certified 
germline analysis.  The Miami Cancer Institute has these services readily available. 
The evaluation of the microbiome in stool samples will be aimed to derive clusters of patients 
with distinct microbiomes and given the geographic and cultural diversity of our special 
population in Miami to preliminary observed differences that could be attributed to 
environment/dietary practices associated with certain ethnicities or by time in life of 
immigration to the USA.  Association to clinical endpoints will be documented, with no formal 
statistics assess, but may serve as hypothesis generating for future studies.   
13.0 LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL 
SUPPLIES 
13.0 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. 
All Miami Cancer Institute investigational drugs are kept in the pharmacy separate from 
routine drug stock and are stored according to the manufacturer and sponsor specifications. 
Investigational products requiring refrigeration are kept in a locked refrigerator designated for 
research drugs only. Room temperature investigational products also kept in the pharmacy in 
a secured research cabinet. Temperature monitoring is reviewed and recorded on a daily basis 
during normal business hours by Isensix, a real-time, wireless system that continuously 
monitors and records temperatures. The system also provides real time automatic alerts when 
sensors record data that is outside of the unit's operating range.  
Table 12. 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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13.1 Packaging and Labeling Information 
Clinical supplies will be affixed with a clinical label in accordance with regulatory 
requirements. 
13.2 Clinical Supplies Disclosure 
This trial is open-label; therefore, the subject, the trial site personnel, the Sponsor and/or 
designee are not blinded to treatment. Drug identity (name, strength) is included in the label 
text; random code/disclosure envelopes or lists are not provided. 
13.3 Storage and Handling Requirements 
Investigational products will be prepared and dispensed by a licensed pharmacist and certified 
pharmacy technician. 
All orders will be checked by 2 pharmacy staff personnel to ensure correct preparation and 
labeling. 
All products that are not received pre-labeled will be labeled according to federal regulations.  
Accountability of investigational products will be performed and documented by pharmacy. 
Investigational products will be stored and monitored in accordance with protocol-specific 
instructions. 
 
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. 
13.4 Returns and Reconciliation 
 
The Miami Cancer Institute has a dedicated Investigational Drug Service (IDS), including a 
dedicated IDS Supervisor who leads the coordination of investigational drugs services for 
clinical research at Miami Cancer Institute.  The IDS team provides required pharmacy 
services for investigational drug studies including oversight of drug storage, handling, 
preparation, deposition, medication dosing, staff education, and other related activities. All 
pharmacists involved in the compounding of investigational products are trained on each 
individual protocol in regards to receipt, preparation, storage, dispensing and administration, 
product reconciliation and source documentation. Additionally, all pharmacists involved in the 
compounding aspect are CITI trained and listed on the delegation of authority.    


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• Disposition and/or destruction of IPs following drug accountability are performed 
according to specific instructions provided by the sponsor and/or protocol. Disposal 
and/or destruction of investigational products on-site are performed in accordance with 
BHM BCH administrative policy  
• All products will be disposed of according to regulatory requirements according to 
institutional policy and in accordance with the Environmental Protection Agency and 
the State of Florida Department of Transportation (DOT) regulations for hazardous and 
non-hazardous pharmaceutical waste.  
• Disposition of the investigational product must be witnessed by two members of the 
research team and documented per institutional policy 
• Documentation of IDS accountability will be performed from the time of initial product 
receipt through the destruction or return of the product to the supplier 
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. 
14.0 ADMINISTRATIVE AND REGULATORY DETAILS 
14.0.1 Confidentiality of Data 
Both the investigator and the Sponsor affirm that information regarding this trial will be 
maintained in confidence, and such information will be divulged to the institutional review 
board, ethics review committee (IRB/ERC) or similar or expert committee; affiliated 
institution and employees, only under an appropriate understanding of confidentiality with 
such board or committee, affiliated institution and employees. Data generated by this trial will 
be considered confidential by the Sponsor and the investigator. 
 
14.0.2 Confidentiality of Subject Records 
 
The investigator agrees that the Sponsor (or Sponsor representative), IRB/ERC, or regulatory 
authority representatives may consult and/or copy trial documents in order to verify 
worksheet/case report form data. By signing the consent form, the subject agrees to this 
process. If trial documents will be photocopied during the process of verifying worksheet/case 


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report form information, the subject will be identified by unique code only; full names/initials 
will be masked prior to transmission to the Sponsor. 
 
The investigator and Sponsor agree to treat all subject data used and disclosed in connection 
with this trial in accordance with all applicable privacy laws, rules and regulations. 
 
14.0.3 Confidentiality of Investigator Information 
 
The investigator recognizes that certain personal identifying information with respect to the 
investigator, and all sub-investigators and trial site personnel, may be used and disclosed for 
trial management purposes, as part of a regulatory submission, and as required by law. This 
information may include: 
 
1. Name, address, telephone number and e-mail address; 
2. Hospital or clinic address and telephone number; 
3. Curriculum vitae or other summary of qualifications and credentials; and 
4. Other professional documentation. 
 
Consistent with the purposes described above, this information may be transmitted to the 
Sponsor, and subsidiaries, affiliates and agents of the Sponsor, in your country and other 
countries, including countries that do not have laws protecting such information. Additionally, 
the investigator’s name and business contact information may be included when reporting 
certain serious adverse events to regulatory authorities or to other investigators. By signing 
this protocol, the investigator expressly consents to these uses and disclosures. 
 
14.0.4 Confidentiality of IRB/IEC Information 
 
The Sponsor is required to record the name and address of each IRB/IEC that reviews and 
approves this trial. The Sponsor is also required to document that each IRB/IEC meets 
regulatory and ICH GCP requirements by requesting and maintaining records of the names and 
qualifications of the IRB/IEC members and to make these records available for regulatory 
agency review upon request by those agencies. 
15.0 Compliance with Financial Disclosure Requirements 
Financial Disclosure requirements are outlined in the US Food and Drug Administration 
Regulations, Financial Disclosure by Clinical Investigators (21 CFR Part 54). It is the 
Sponsor's responsibility to determine, based on these regulations, whether a request for 
Financial Disclosure information is required. It is the investigator's/subinvestigator's 
responsibility to comply with any such request. 
 
The investigator/subinvestigator(s) agree, if requested by the Sponsor in accordance with 21 
CFR Part 54, to provide his/her financial interests in and/or arrangements with the Sponsor to 
allow for the submission of complete and accurate certification and disclosure statements. The 


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investigator/subinvestigator(s) 
further 
agree 
to 
provide 
this 
information 
on 
a 
Certification/Disclosure Form, commonly known as a financial disclosure form, provided by 
the Sponsor. The investigator/subinvestigator(s) also consent to the transmission of this 
information to the Sponsor in the United States for these purposes. This may involve the 
transmission of information to countries that do not have laws protecting personal data. 
 
15.1 Compliance with Law, Audit and Debarment 
The investigator agrees to conduct the trial in an efficient and diligent manner and in 
conformance with this protocol; generally accepted standards of Good Clinical Practice (e.g., 
International Conference on Harmonization of Technical Requirements for Registration of 
Pharmaceuticals for Human Use Good Clinical Practice: Consolidated Guideline and other 
generally accepted standards of good clinical practice); and all applicable federal, state and 
local laws, rules and regulations relating to the conduct of the clinical trial. 
 
The investigator also agrees to allow monitoring, audits, IRB/ERC review and regulatory 
authority inspection of trial-related documents and procedures and provide for direct access to 
all trial-related source data and documents. 
 
The investigator agrees not to seek reimbursement from subjects, their insurance providers or 
from government programs for procedures included as part of the trial reimbursed to the 
investigator by the Sponsor. 
 
The investigator shall prepare and maintain complete and accurate trial documentation in 
compliance with Good Clinical Practice standards and applicable federal, state and local laws, 
rules and regulations; and, for each subject participating in the trial, provide all data, and, upon 
completion or termination of the clinical trial, submit any other reports to the Sponsor as 
required by this protocol or as otherwise required pursuant to any agreement with the Sponsor. 
 
Trial documentation will be promptly and fully disclosed to the Sponsor by the investigator 
upon request and also shall be made available at the trial site upon request for inspection, 
copying, review and audit at reasonable times by representatives of the Sponsor or any 
regulatory authorities. The investigator agrees to promptly take any reasonable steps that are 
requested by the Sponsor as a result of an audit to cure deficiencies in the trial documentation 
and worksheets/case report forms. 
 
The investigator must maintain copies of all documentation and records relating to the conduct 
of the trial in compliance with all applicable legal and regulatory requirements. This 
documentation includes, but is not limited to, the protocol, worksheets/case report forms, 
advertising for subject participation, adverse event reports, subject source data, correspondence 
with regulatory authorities and IRBs/ERCs, consent forms, investigator’s curricula vitae, 
monitor visit logs, laboratory reference ranges, laboratory certification or quality control 
procedures and laboratory director curriculum vitae. The investigator agrees that 
documentation shall be retained until at least 2 years after the last approval of a marketing 


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application in an ICH region or until there are no pending or contemplated marketing 
applications in an ICH region or until at least 2 years have elapsed since the formal 
discontinuation of clinical development of the investigational product.  
 
Because the clinical development and marketing application process is variable, it is 
anticipated that the retention period can be up to 15 years or longer after protocol database 
lock. The Sponsor will determine the minimum retention period and notify the investigator 
when documents may be destroyed. The Sponsor will determine the minimum retention period 
and upon request, will provide guidance to the investigator when documents no longer need to 
be retained. The sponsor also recognizes that documents may need to be retained for a longer 
period if required by local regulatory requirements. All trial documents shall be made available 
if required by relevant regulatory authorities. The investigator must consult with and obtain 
written approval by the Sponsor prior to destroying trial and/or subject files. 
 
ICH Good Clinical Practice guidelines recommend that the investigator inform the subject’s 
primary physician about the subject’s participation in the trial if the subject has a primary 
physician and if the subject agrees to the primary physician being informed. 
 
The investigator will promptly inform the Sponsor of any regulatory authority inspection 
conducted for this trial. 
 
Persons debarred from conducting or working on clinical trials by any court or regulatory 
authority will not be allowed to conduct or work on this Sponsor’s trials. The investigator will 
immediately disclose in writing to the Sponsor if any person who is involved in conducting the 
trial is debarred or if any proceeding for debarment is pending or, to the best of the 
investigator’s knowledge, threatened. 
 
In the event the Sponsor prematurely terminates a particular trial site, the Sponsor will 
promptly notify that trial site’s IRB/IEC. 
 
16.0 Compliance with Trial Registration and Results Posting Requirements 
Under the terms of the Food and Drug Administration Modernization Act (FDAMA) and the 
Food and Drug Administration Amendments Act (FDAAA), the Sponsor of the trial is solely 
responsible for determining whether the trial and its results are subject to the requirements for 
submission to the Clinical Trials Data Bank, http://www.clinicaltrials.gov.  Information posted 
will allow subjects to identify potentially appropriate trials for their disease conditions and 
pursue participation by calling a central contact number for further information on appropriate 
trial locations and trial site contact information.     
The Sponsor agrees to be responsible for implementing and maintaining a quality management 
system with written development procedures and functional area standard operating 
procedures (SOPs) to ensure that trials are conducted and data are generated, documented, and 
reported in compliance with the protocol, accepted standards of Good Clinical Practice, and 


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all applicable federal, state, and local laws, rules and regulations relating to the conduct of the 
clinical trial. 
The Quality Assurance (QA) division in the Miami Cancer Institute Clinical Trials Office is 
responsible for ensuring that industry standards of quality are met and exceeded on an on-
going basis.  The division is responsible for the identification, management, and prevention of 
quality issues, reviewing subject research charts, and mapping out current processes. They 
develop and implement quality and verification checks, including necessary assessment tools 
and checklists used during the QC process. Moreover, they facilitate and advice on corrections 
and corrective and preventive actions related to quality issues, provide guidance on 
interpretation and application of regulations, manage FDA and sponsor site visits, and work 
with site manager to create, implement, and evaluate action plans. 
17.0 DATA MANAGEMENT 
The Miami Cancer Institute Clinical Trials Office oversees record keeping and handling of 
data is to record, store, transfer and, where necessary, convert efficiently and accurately, the 
information gathered on each trial subject into data. 
All steps involved in data management should be documented in order to allow step-by-step 
retrospective assessment of quality of the data and the performance of the clinical trial (the 
“audit paper trail” concept). Documentation is facilitated by methods such as the use of check-
lists and forms giving details of action taken, dates, the individuals responsible, etc. 
In the event of electronic data handling, confidentiality of the database must be secured by 
safety procedures such as passwords and written assurances from all staff involved. Provision 
must be made for the satisfactory maintenance of the database and for back-up procedures. 
17.1 Responsibilities of the investigator 
a)  The investigator has overall responsibility for ensuring the accuracy and completeness 
of data entry. The investigator must ensure that the observations and findings are recorded 
correctly and completely in the case-report forms (CRFs) and signed by the responsible person 
designated in the protocol. When conducting a study and using CRFs to report clinical trial 
data to the sponsor, the investigator must also ensure that the routine requirements for 
recording of data in the source documents (e.g. hospital and laboratory records, consultation 
files) are met, particularly those relating to the treatment given to the subject and adverse 
events. 
b)  If trial data are entered directly into a computer, there must always be an adequate safeguard 
to ensure validation, including a signed and dated print-out and back-up records. Computerized 
systems should be validated and a detailed description for their use be produced and kept up-
to-date. 


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c)  All corrections to CRFs and to raw data must be made in a way which does not obscure the 
original entry. The correct data must be inserted with the reason for the correction (if not 
obvious), the date, and the initials of the investigator or authorized person. For electronic data 
processing, only authorized persons should be permitted to enter or modify data in the 
computer and there should be a record of changes and deletions. If data are altered during 
processing, the alteration must be documented. 
d)  Laboratory values with normal reference ranges, preferably together with the specificity 
and sensitivity of the methods used, should always be recorded on the CRF or be attached to 
it. Values outside a clinically accepted reference range or values that differ significantly from 
previous values must be evaluated and commented upon by the investigator. 
e)  Data other than those required by the protocol may appear on the CRF, provided they are 
clearly marked as additional or optional findings, with an explanation of their significance. 
f)  Units of measurement must always be stated, and conversion of units must always 
be indicated and documented. 
g)  The final report of the trial should be drawn up as defined in the protocol. The report should 
be signed by the sponsor, monitor and investigator(s) as well as the responsible statistician, in 
accordance with the applicable regulations. 
h)  For a period of time defined by national regulations, the investigator should maintain a 
confidential record to allow the translation of the unambiguous code used to conceal the 
identity of the individual subjects in the trial (subject identification code). The investigator 
may submit the subject identification code list to the drug regulatory authority after the trial, 
together with the final report, according to national regulations. 
i)  Theinvestigatorshouldensurethatthesubject’sparticipationintheclinicaltrialisclearly marked 
in his or her medical records. 
 
 


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APPENDICES 
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. 
 
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)