A Multicenter Phase II Study of Pembrolizumab (MK-3475) in Patients With Advanced Small Bowel Adenocarcinomas
Phase: PHASE2
Conditions: Metastatic Small Intestinal Adenocarcinoma, Recurrent Small Intestinal Carcinoma, Unresectable Small Intestinal Carcinoma
Sponsor: Academic and Community Cancer Research United

Addendum 5 
1  
RU021502I 
 
Academic and Community Cancer Research United (ACCRU) 
 
A Multicenter Phase II Study of Pembrolizumab (MK-3475) in Patients with Advanced  
Small Bowel Adenocarcinomas 
 
For any communications regarding this protocol,  
please contact the person listed on the Protocol Resource page. This is a stand-alone document found on 
the ACCRU website (www.ACCRU.org). 
 
Study Chairs 
 
ACCRU: 
Robert R. McWilliams, M.D. 
 
 
Mayo Clinic 
 
 
Rochester, MN 55905 
 
 
mcwilliams.robert@mayo.edu  
 
FDA IND Sponsor/Investigator: 
 
Robert R. McWilliams, M.D. 
   
 
Study Co-chairs: 
   
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
                             Statistician:  
  
 
  
Mayo Clinic 
 
  
  
 
 
Drug Availability  
Drug Company Supplied:  Pembrolizumab (MK-3475Commercial supply provided by Merck) IND #130955 
 
√ Study contributor(s) not responsible for patient care. 
 
NCI: NCT02949219 
Merck MISP# 52192 
 
Research Coordinating Center 
Academic and Community Cancer Research United 
200 First Street Southwest 
Rochester, MN 55905 
FAX# 507-538-0906 
 
Document History 
Effective Date 
Pre-activation ACCRU 
September 30, 2016 
Activation Addendum 1 
February 24, 2017 
Addendum 2 
September 15, 2017 
 
 
 
Addendum 3 
 
 
April 27, 2018 
 
 
 
Addendum 4 
 
 
September 06, 2019 
 
 
 
Addendum 5 
 
 
September 27, 2019

Addendum 5 
2  
RU021502I 
 
 Index 
 
Schema  
  1.0 
Background 
  2.0 
Goals 
  3.0 
Patient Eligibility 
  4.0 
Test Schedule 
  5.0  
Stratification Factors  
  6.0 
Registration Procedures 
  7.0 
Protocol Treatment 
  8.0 
Dosage Modification Based on Adverse Events  
  9.0 
Ancillary Treatment/Supportive Care 
10.0 
Adverse Event (AE) Reporting and Monitoring  
11.0 
Treatment Evaluation Using RECIST Guideline 
12.0 
Descriptive Factors 
13.0 
Treatment/Follow-up Decision at Evaluation of Patient  
14.0 
Body Fluid Biospecimens 
15.0 
Drug Information 
16.0 
Statistical Considerations and Methodology 
17.0 
Pathology Considerations/Tissue Biospecimens 
18.0 
Records and Data Collection Procedures 
19.0 
Budget 
20.0 
References 
 
  
 

Addendum 5 
3  
RU021502I 
 
 
Schema 
 
 
Registration 
 
Treatment  
Pembrolizumab  
200 mg IV q3 weeks (until PD or 
toxicity) 
 (for detailed treatment information see 
Section 7.0) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Primary outcome is response based on RECIST criteria. Secondary endpoints are PFS, OS, and adverse 
events.  
*To permit continued study treatment beyond initial radiographic disease progression, see section 7.6 
Treatment Continuation. 
Cycle length = 21 days  
 
Generic name:   Pembrolizumab 
Brand name(s): Keytruda 
ACCRU Abbreviation:    
  
Availability:   Clinical Research Services, a division of Rx Crossroads by McKesson  
 
 
 
 
 
 
Unacceptable toxicity  
Disease progression 
  Event  
 
Patient refusal 
  Monitoring 
 Event Monitoring 
(Follow-up per Section 
18.0) 

Addendum 5 
4  
RU021502I 
 
 
1.0 
Background   
 
 
Trial Summary 
 
 
Abbreviated Title 
Pembrolizumab in advanced small bowel adenocarcinoma  
Trial Phase 
Phase II 
Clinical Indication 
Treatment of subjects with advanced small bowel 
adenocarcinoma after first-line treatment 
Trial Type 
Interventional  
Type of control 
None 
Route of administration 
Intravenous 
Trial Blinding 
Unblinded, open-label 
Treatment Groups  
All patients receive pembrolizumab 200 mg every 3 weeks. 
Number of trial subjects 
41 patients 
Estimated enrollment period 
The sponsor estimates that the trial will require approximately 
17 months from the first patient enrolling until the final 
patient signs informed consent. 
Estimated duration of trial 
The sponsor estimates that the trial will require approximately 
20 months to allow full accrual and at least the first 4 cycles 
of pembrolizumab. 
Duration of Participation 
Until disease progression, drug intolerance, or 24 months of 
pembrolizumab therapy. 
 
 
1.1 
Pharmaceutical and Therapeutic Background 
 
The importance of intact immune surveillance in controlling outgrowth of neoplastic 
transformation has been known for decades.  Accumulating evidence shows a correlation 
between tumor-infiltrating lymphocytes (TILs) in cancer tissue and favorable prognosis 
in various malignancies.  In particular, the presence of CD8+ T-cells and the ratio of 
CD8+ effector T-cells / FoxP3+ regulatory T-cells seems to correlate with improved 
prognosis and long-term survival in many solid tumors. 
The PD-1 receptor-ligand interaction is a major pathway hijacked by tumors to suppress 
immune control.  The normal function of PD-1, expressed on the cell surface of activated 
T-cells under healthy conditions, is to down-modulate unwanted or excessive immune 
responses, including autoimmune reactions.  PD-1 (encoded by the gene Pdcd1) is an Ig 
superfamily member related to CD28 and CTLA-4 which has been shown to negatively 
regulate antigen receptor signaling upon engagement of its ligands (PD-L1 and/or 
PD-L2).  The structure of murine PD-1 has been resolved.  PD-1 and family members are 
type I transmembrane glycoproteins containing an Ig Variable-type (V-type) domain 
responsible for ligand binding and a cytoplasmic tail which is responsible for the binding 
of signaling molecules.  The cytoplasmic tail of PD-1 contains 2 tyrosine-based signaling 
motifs, an immunoreceptor tyrosine-based inhibition motif (ITIM) and an 
immunoreceptor tyrosine-based switch motif (ITSM).  Following T-cell stimulation, 
PD-1 recruits the tyrosine phosphatases SHP-1 and SHP-2 to the ITSM motif within its 
cytoplasmic tail, leading to the dephosphorylation of effector molecules such as CD3ζ, 
PKCθ and ZAP70 which are involved in the CD3 T-cell signaling cascade.  The 
mechanism by which PD-1 down modulates T-cell responses is similar to, but distinct 
from that of CTLA-4 as both molecules regulate an overlapping set of signaling proteins.  
PD-1 was shown to be expressed on activated lymphocytes including peripheral CD4+ 

Addendum 5 
5  
RU021502I 
 
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 lymphoid tissue or chronic inflammatory environments.  PD-L2 
is thought to control immune T-cell activation in lymphoid organs, whereas PD-L1 serves 
to dampen unwarranted T-cell function in peripheral tissues.  Although healthy organs 
express little (if any) PD-L1, a variety of cancers were demonstrated to express abundant 
levels of this T-cell inhibitor.  PD-1 has been suggested to regulate tumor-specific T-cell 
expansion in subjects with melanoma (MEL).  This suggests that the PD-1/PD-L1 
pathway plays a critical role in tumor immune evasion and should be considered as an 
attractive target for therapeutic intervention. 
Pembrolizumab is a potent and highly selective humanized monoclonal antibody (mAb) 
of the IgG4/kappa isotype designed to directly block the interaction between PD-1 and its 
ligands, PD-L1 and PD-L2.  KeytrudaTM (pembrolizumab) has recently been approved in 
the United Stated for the treatment of patients with unresectable or metastatic melanoma 
and disease progression following ipilimumab and, if BRAF V600 mutation positive, a 
BRAF inhibitor. 
 
1.2  
Preclinical and Clinical Trial Data 
 
Refer to the Investigator’s Brochure for Preclinical and Clinical data. 
Small bowel adenocarcinoma (SBA) is a rare malignancy that is often diagnosed in its 
late stages.  Due to its rarity, it is historically understudied.  As such, there is no clear, 
consistent standard of care.  This is further complicated by a noted heterogeneous 
response to standard chemotherapy regimens. To date, small prospective clinical studies 
have evaluated chemotherapy for SBA the first of which examined the use of mitomycin 
C, Adriamycin, and 5-fluorouracil with minimal therapeutic effect. (Gibson, Holcroft et 
al. 2005).  This study was performed in the early 1980s but not reported until 2005.  
More recently oxaliplatin-based therapies have been demonstrated to have activity and 
have emerged as a standard of care in the front line setting. Overman et al. demonstrated 
a high response rate (50%) with combination therapy of oxaliplatin and capecitabine 
although the trial also included patients with ampullary carcinoma.(Overman, 
Varadhachary et al. 2009) This study showed that small bowel carcinoma is a 
chemosensitive disease with response rates and sensitivity profile similar to other GI 
malignancies, namely fluoropyrimidine and oxaliplatin-based therapy.  A Chinese study 
using FOLFOX showed similar response rates, progression free survival, and overall 
survival to the XELOX study (Table 1).(Xiang, Liu et al. 2012) A recently completed 
multicenter trial, N0543 is a small bowel adenocarcinoma study using a triplet 
combination of irinotecan, oxaliplatin, and capecitabine, with UGT1A1 genotype-based 
therapy.  This study has demonstrated the feasibility of performing a small 
adenocarcinoma study within a cooperative group, in this case the North Central Cancer 
Treatment Group, now part of the Alliance for Clinical Trials in Oncology. 
(McWilliams, Mahoney et al. 2012)  While oxaliplatin-based therapy is widely 
considered the standard for first line therapy, there is no clearly established therapy 
beyond first line treatment for SBA, as no prospective trials have been performed to 
date. 
 

Addendum 5 
6  
RU021502I 
 
 
 
 
 
Table 1. Prospective Trials for Oxaliplatin-based therapy in Metastatic SBA 
Study  
Regimen 
# patients 
PFS (mo.) 
OS (mo.) 
RR (%) 
Overman et al. 
(2009) 
XELOX 
30 
9.4 
15.5 
50 
McWilliams et al 
(2012) 
XELIRINOX 29 
8.7 
13.2 
39 
Xiang (2012) 
FOLFOX 
33 
7.8 
15.2 
48 
 
Similar to patterns seen in colorectal cancer (Gonsalves, Mahoney et al. 2014; Missiaglia, 
Jacobs et al. 2014), there appears to be genetic heterogeneity among sites of small bowel 
adenocarcinoma primary tumor origination. This may correspond with differences in 
overall survival, as we have noted in examining outcomes of 50 small bowel patients 
seen at the Mayo Clinic (Figure 1). (Unpublished data) For instance, tumors deficient in 
DNA mismatch repair and having resulting high microsatellite instability (dMMR/MSI-
H) appear more often in proximal tumors, and KRAS mutations are more common in 
duodenal cancers (57% vs. jejunum (29%) and ileum (14%).(Aparicio, Svrcek et al. 
2013) Her-2 expression levels appear to be lowest in proximal tumors and highest in ileal 
tumors. While several of these genetic mutations that have been noted in small bowel 
adenocarcinomas are potentially targetable with therapy, the frequency is too low, even 
when attempting screening by the above known tumor site characteristics, in this rare 
cancer to allow for feasible clinical study.  
 
 
 

Addendum 5 
7  
RU021502I 
 
Figure 1. Survival by primary tumor site
 
 
1.3  
Rationale for the Trial and Selected Subject Population 
Beyond conventional chemotherapy for these tumors, there are no known SBA-specific 
genetic targets that have been investigated for treatment efficacy. Genetic analyses have 
revealed similar molecular characteristics to colorectal cancer. Recently, a European 
coalition investigated 46 commonly altered cancer genes in 83 cases and found that the 
most common mutations are not therapeutically targeted: KRAS, TP53, APC, and smad4 
(Laforest, Aparicio et al. 2014). There may be a population of Her2, BRAF, or PI3KCA 
patients who may benefit from signaling pathway blockade, but with the rarity of those 
mutations (<15.8%) in a rare disease, trials will be difficult to accrue. There is an urgent 
need to perform larger, coordinated international studies to establish further evidence-
based therapeutic options. 
The relative rarity of adenocarcinoma of the small bowel compared to the colon or 
stomach is postulated to be related to increased immune surveillance in the small 
intestine(Lowenfels 1973) suggesting that, in those tumors that do develop in the small 
bowel, immune checkpoint therapies may be widely useful in re-establishing anti-tumor 
immune function.  
We performed a pilot study of PD-L1 staining of 50 archived small bowel 
adenocarcinoma tumors. In this study, 4 patients (8%) had strong cellular staining for 
PD-L1, while 21/50 (42%) had 3+ or greater staining of intratumoral stroma. In an 
unadjusted survival analysis, tumors that showed cellular staining for PD-L1 were 
associated with a poorer survival (median survival 10 months vs 5.5 years, p = 0.0009 by 
Log-Rank), though the cohort size was too small to draw general conclusions (Figure 2). 
There was no difference in outcome by stromal stating 3+/4+ vs 0, 1+, 2+ (p=0.51). The 
poor survival of PD-L1 staining tumors is similar to what is reported for renal cell 
carcinoma, suggesting impaired immune surveillance and providing the rationale for PD1 
targeted therapy in this disease.(Thompson, Gillett et al. 2004).  
 
 
Jejunum 
Duodenum 
Ileum 

Addendum 5 
8  
RU021502I 
 
 
 
Figure 2. Survival by tumor cell staining for PD-L1 
 
 
It has recently been suggested that dMMR/MSI-H patients may have a superior response 
to anti-PD1 therapy. (Le, Uram et al. 2015) In our preclinical study, seven of the 50 
tumors (14%) were already known clinically to be dMMR/MSI-H. These had a superior 
prognosis to tumors not known to be dMMR/MSI-H (median survival not reached vs 2.5 
years, p=0.028 by Log-Rank), suggesting a unique biology at baseline and is in keeping 
with survival data on Lynch syndrome patients with cancer of the large intestine. While 
the response to PD-1 inhibitors was most prominent in the dMMR cohort of the Le et al. 
study (ORR 40%), a small number of patients with proficient MMR and microsatellite 
stability (pMMR/MSS) did achieve a small response or stable disease, indicating 
potential efficacy in both cohorts.  
Our goal is to evaluate whether pembrolizumab administered to patients with advanced 
small bowel adenocarcinoma in second- or later lines of therapy demonstrates antitumor 
activity as measured by confirmed response rate. Secondary endpoints would include 
response in dMMR vs. pMMR patients, response in PD-L1 (+) vs, PD-L1 (-) expressers, 
progression-free survival (PFS), overall survival (OS), and tolerability.  
 
1.4  
Rationale for Dose Selection/Regimen/Modification  
 
An open-label Phase I trial (Protocol 001) is being conducted to evaluate the safety and 
clinical activity of single agent MK-3475.  The dose escalation portion of this trial 
evaluated three dose levels, 1 mg/kg, 3 mg/kg, and 10 mg/kg, administered every 2 weeks 
(Q2W) in subjects with advanced solid tumors.  All three dose levels were well tolerated 
and no dose-limiting toxicities were observed.  This first in human study of MK-3475 
showed evidence of target engagement and objective evidence of tumor size reduction at 
all dose levels (1 mg/kg, 3 mg/kg and 10 mg/kg Q2W).  No MTD has been identified to 
date.  Recent data from other clinical studies within the MK-3475 program has shown 
that a lower dose of MK-3475 and a less frequent schedule may be sufficient for target 
engagement and clinical activity(Daud, Ribas et al. 2015). 
 
PK data analysis of MK-3475 administered Q2W and Q3W showed slow systemic 
clearance, limited volume of distribution, and a long half-life (refer to IB).  
Pharmacodynamic data (IL-2 release assay) suggested that peripheral target engagement 
is durable (>21 days).  This early PK and pharmacodynamic data provides scientific 
rationale for testing a Q2W and Q3W dosing schedule.   
A population pharmacokinetic analysis has been performed using serum concentration 
time data from 476 patients. Within the resulting population PK model, clearance and 
volume parameters of MK-3475 were found to be dependent on body weight. The 
PD-L1+ 
PD-L1- 

Addendum 5 
9  
RU021502I 
 
relationship between clearance and body weight, with an allometric exponent of 0.59, is 
within the range observed for other antibodies and would support both body weight 
normalized dosing or a fixed dose across all body weights.  MK-3475 has been found to 
have a wide therapeutic range based on the melanoma indication.  The differences in 
exposure for a 200 mg fixed dose regimen relative to a 2 mg/kg Q3W body weight based 
regimen are anticipated to remain well within the established exposure margins of 0.5 – 
5.0 for MK-3475 in the melanoma indication. The exposure margins are based on the 
notion of similar efficacy and safety in melanoma at 10 mg/kg Q3W vs. the proposed 
dose regimen of 2 mg/kg Q3W (i.e. 5-fold higher dose and exposure). The population PK 
evaluation revealed that there was no significant impact of tumor burden on exposure. In 
addition, exposure was similar between the NSCLC and melanoma indications. 
Therefore, there are no anticipated changes in exposure between different indication 
settings. 
 
The rationale for further exploration of 2 mg/kg and comparable doses of pembrolizumab 
in solid tumors is based on: 1) similar efficacy and safety of pembrolizumab when dosed 
at either 2 mg/kg or 10 mg/kg Q3W in melanoma patients, 2) the flat exposure-response 
relationships of pembrolizumab for both efficacy and safety in the dose ranges of 2 
mg/kg Q3W to 10 mg/kg Q3W, 3) the lack of effect of tumor burden or indication on 
distribution behavior of pembrolizumab (as assessed by the population PK model) and 4) 
the assumption that the dynamics of pembrolizumab target engagement will not vary 
meaningfully with tumor type. 
The choice of the 200 mg Q3W as an appropriate dose for the switch to fixed dosing is 
based on simulations performed using the population PK model of pembrolizumab 
showing that the fixed dose of 200 mg every 3 weeks will provide exposures that 1) are 
optimally consistent with those obtained with the 2 mg/kg dose every 3 weeks, 2) will 
maintain individual patient exposures in the exposure range established in melanoma as 
associated with maximal efficacy response and 3) will maintain individual patients 
exposure in the exposure range established in melanoma that are well tolerated and safe.  
A fixed dose regimen will simplify the dosing regimen to be more convenient for 
physicians and to reduce potential for dosing errors.  A fixed dosing scheme will also 
reduce complexity in the logistical chain at treatment facilities and reduce waste. 
 
2.0 
Goals    
 
2.1 
Primary Objective and Endpoint 
 
2.11  
To determine whether pembrolizumab administered to SBA patients 
demonstrates antitumor activity as measured by the confirmed response rate 
 
2.2 
Secondary Objectives and Endpoints 
 
2.21  
To assess survival endpoints (OS, PFS), including stratified analysis by tumor 
site.  
 
2.22 
To assess whether pembrolizumab is safe in SBA patients by assessing adverse 
events.   
 
2.3 
Correlative Research 
 
2.31  
To determine whether PD-L1 expression, as measured by IHC, or MSI status is 
associated with the response rate overall.   
 
2.32  
To determine if Bim levels in tumor-reactive CD11ahighPD-1+CD8+ peripheral 

Addendum 5 
10  
RU021502I 
 
blood T cells can objectively monitor responses to pembrolizumab and to 
determine if excessive release of soluble B7-H1 (sPD-L1) by the tumor leads to 
Bim upregulation and treatment resistance in SBA.   
 
2.33  
To determine if other tissue-based factors, such as total mutational burden, 
correlate with response to pembrolizumab. 
 
 
3.0 
Patient Eligibility    
 
3.1 
Inclusion Criteria  
 
3.11 
Patients must have biopsy-proven adenocarcinoma of the small bowel at any site 
(duodenum, jejunum, ileum), excluding ampullary and appendiceal tumors. 
 
3.12 
Have locally advanced (unresectable) or metastatic small bowel adenocarcinoma. 
 
3.13 
Willing and able to provide written informed consent for the trial. 
 
3.14 
Age ≥ 18 years. 
 
3.15 
Measurable disease based on RECIST 1.1.   
 
3.16 
Had at least one prior line of systemic chemotherapy for metastatic disease. 
Adjuvant therapy would not count toward first-line therapy unless patient recurs 
less than 6 months after completion of that regimen. 
 
3.17 
Willing to provide blood and tissue (can be archival) samples for mandatory 
research purposes (see sections 4.0, 14.0 and 17.0).    
 
3.18 
ECOG Performance Status (PS) 0 or 1.  (Form is available on the ACCRU web 
site) 
 
3.19a 
The following laboratory values obtained ≤28 days prior to registration.   
 
• Absolute neutrophil count (ANC) ≥1500/mm3 (1.50 x 109/L) 
• Platelet count ≥100,000/mm3 (100 x 109/L) 
• Hemoglobin >9.0 g/dL (5.6 mmol/L or 90 g/L) without transfusion or EPO 
dependency (within 7 days of assessment) 
• Serum total bilirubin ≤1.5x upper limit of normal (ULN) OR direct bilirubin  
 ≤ ULN for subjects with total bilirubin levels > 1.5x ULN 
• Aspartate transaminase (AST) and alanine aminotransferase (ALT) ≤2.5x ULN 
OR ≤ 5x ULN for subjects with liver metastases 
• Serum creatinine ≤1.5x upper limit of normal (ULN)  
  
 
OR 
• Measured or calculated creatinine clearance must be ≥60 mL/min for subjects 
with creatinine levels > 1.5 X ULN using the Cockcroft-Gault formula below 
(Glomerular Filtration Rate [GFR] >60 mL/min (1.0 mL/s/m2) can also be used 
in place of creatinine or CrCl):  
 

Addendum 5 
11  
RU021502I 
 
 
3.19b Female subject of childbearing potential have a negative urine or serum 
pregnancy ≤7 days prior to registration. If the urine test is positive or cannot be 
confirmed as negative, a serum pregnancy test will be required.   
Note:  Female subjects of childbearing potential should be willing to use 2 
methods of birth control or be surgically sterile, or abstain from heterosexual 
activity for the course of the study through 120 days after the last dose of study 
medication.  Subjects of childbearing potential are those who have not been 
surgically sterilized or have not been free from menses for > 1 year. Male 
subjects should agree to use an adequate method of contraception starting with 
the first dose of study therapy through 120 days after the last dose of study 
therapy. 
 
 
3.2 
Exclusion Criteria  
 
3.21 
Non-adenocarcinoma histology. 
 
3.22 
Adenocarcinoma originating in the ampulla or appendix. (Duodenal Tumors that 
involve the ampulla but originate in the duodenum are eligible). 
 
3.23 
Currently participating and receiving study therapy, or have participated in a 
study of an investigational agent and received study therapy, or used an 
investigational device ≤4 weeks of registration.  
 
3.24 
Diagnosis of immunodeficiency or be receiving systemic steroid therapy or any 
other form of immunosuppressive therapy ≤7 days prior to registration.  
 
3.25 
History of active TB (Bacillus Tuberculosis). 
 
3.26 
Hypersensitivity to pembrolizumab or any of its excipients. 
 
3.27 
Any of the following: 
• Prior anti-cancer monoclonal antibody (mAb) ≤4 weeks prior to 
registration  
 
3.28 
Prior chemotherapy, targeted small molecule therapy, or radiation therapy ≤2 
weeks prior to registration or who has not recovered to ≤ Grade 1 or baseline 
from adverse events due to the previously administered agent. 
 
Note:  Subjects with ≤ Grade 2 neuropathy are an exception to this criterion and 
may qualify for the study. 
 
3.29a 
Received major surgery ≤2 weeks prior to registration, subject must have 
recovered adequately from the toxicity and/or complications from the 
intervention prior to starting therapy.   
 

Addendum 5 
12  
RU021502I 
 
3.29b Known additional malignancy that is progressing or requires active treatment or 
that may interfere with interpretation of response evaluation, in the judgment of 
the investigator. 
 
3.29c  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 ≤4 weeks 
prior to registration and any neurologic symptoms have returned to baseline), 
have no evidence of new or enlarging brain metastases, and are not using steroids 
≤7 days prior to registration.  This exception does not include carcinomatous 
meningitis which is excluded regardless of clinical stability.   
 
3.29d Active autoimmune disease (including but not limited to: patients with a history 
of inflammatory bowel disease, including ulcerative colitis and Crohn’s Disease, 
patients with a history of symptomatic disease (e.g., rheumatoid arthritis, 
systemic progressive sclerosis [scleroderma], systemic lupus erythematosus, 
autoimmune vasculitis [e.g. Wegener’s Granulomatosis]); CNS or motor 
neuropathy considered of autoimmune origin (e.g., Guillain-Barre Syndrome and 
Myasthenia Gravis, multiple sclerosis)) 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.  
 
3.29e  Known history of or any evidence of active, non-infectious pneumonitis. 
 
3.29f  Active infection requiring systemic therapy. 
 
3.29g 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.   
 
3.29h  Known psychiatric or substance abuse disorders that would interfere with 
cooperation with the requirements of the trial. 
 
3.29i  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. 
 
3.29j  Received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent, or 
other immune checkpoint inhibitor (e.g. anti-CTLA4). 
 
3.29k    History of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies). 
 
3.29l  Known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA 
[qualitative] is detected). 
 
3.29m  Received a live vaccine within 30 days of planned start of study therapy. 
 
Note:  Seasonal influenza vaccines for injection are generally inactivated flu 
vaccines and are allowed; however, intranasal influenza vaccines (e.g., Flu-
Mist®) are live attenuated vaccines and are not allowed. 
 
 

Addendum 5 
 
13 
 
RU021502I 
4.0 
Test Schedule 
 
 
Active Monitoring Phase 
 
 
 
Tests and procedures 
 
 
≤28 days 
prior to 
registration 
 
 
Day 1  
Cycle 1 
 
 
Day 1 
Cycles 2 -8 and 
beyond 
(+/-3 days) 
  
End of  
treatment 
(PD, withdrawal,  
or removal9) 
 (+7days) 
 
History and exam, wt, ECOG PS  
X 
X6,8 
X6 
X 
Height 
X 
 
 
 
Adverse event assessment 
X 
X8 
X 
X 
Concomitant medication review 
X 
X8 
X 
 
Hematology: 
CBC/ differential 
 
X 
 
X 
 
X 
X 
Chemistry:  SGOT (AST), ALT, alk phos, T. 
bili, creatinine, calcium,, Na, K, glucose, LDH, 
bicarbonate, uric acid, Mg,  Phosphorus, total 
protein, blood urea nitrogen, albumin 
 
X 
 
X 
 
X 
 
 
 
PT/INR and aPTT 
X 
 
 
 
Urinalysis3 
X 
 
 
 
T3, FT4 and TSH 
X 
X 
X 
 
Tumor measurement (should include at least a 
CT of the abdomen/pelvis, and appropriate 
imaging of any other target site lesions) 1, 10 
 
X 
 
 
X5 
 
X 
 
CEA 
X 
 
X7 
X 
Pregnancy test 
 X2 
 
 
 
Mandatory blood sample (see Section 14.0) R  
X 
X 
X4 
X 
Mandatory tissue sample (see Section 17.0) 
X 
 
 
 
1. Use same imaging throughout the study. 
2. For women of childbearing potential only.  Must be done ≤7 days prior to registration. 
3. Urine blood, glucose, protein, specific gravity. Microscopic exam if abnormalities on urinalysis results. 
4. Collected   cycles   2, 3, 4, 8   (see Section 14.0). Kits are required for this collection. 
5. Every 4 cycles beginning with end of cycle 4, and at end of treatment. 
6. Directed physical exam only. 
7.  Every even-numbered cycle, beginning with cycle 2, and at end of treatment. 
8.  ≤24 hours prior to treatment. 
9. Continued study treatment beyond initial radiographic disease progression may be allowed; see Section 13.4 for details. These 

Addendum 5 
14  
RU021502I 
 
patients would continue follow-up per test schedule until confirmed progression.  
10. To be submitted <60 days after registration 
R Research funded (see Section 19.0). Mandatory research blood draws should be collected and submitted after the patient is registered 
onto the study, but before beginning study treatment.

Addendum 5 
 
15  
 
 
 
 
 
 
RU021502I 
 
5.0 
Grouping Factor 
 
None 
  
6.0  
Registration Procedures  
 
 
6.1 
To register a patient, access the ACCRU web page at 
 go to the 
Application section and click on “Registration” and enter the registration/randomization 
application.  The registration application is available 24 hours a day, 7 days a week.  
Back up and/or system support contact information is available on the Web site.  If 
unable to access the Web site, call the Academic and Community Cancer Research 
United (ACCRU) Registration Office at 
 between the hours of 8 a.m. and 
4:30 p.m. Central Time (Monday through Friday). 
 
Instructions for the registration/randomization application are available on the above web 
page under the Study Resources section, “Application Training.”   
 
Prior to initiation of protocol study intervention, this process must be completed in its entirety 
and an ACCRU subject ID number must be available as noted in the instructions.  It is the 
responsibility of the individual and institution registering the patient to confirm the process 
has been successfully completed prior to release of the study agent.  Patient registration via 
the registration application can be confirmed in any of the following ways: 
• 
Contact the ACCRU Registration Office 
.  If the patient was fully 
registered, the Registration Office staff can access the information from the 
centralized database and confirm the registration. 
• 
Refer to “Application Training” at 
; click on “Registration, 
Installation & Entry Instructions.”  
 
6.2 
Correlative Research  
 
A mandatory correlative research component is part of this study; the patient will be 
automatically registered onto this component (see Sections 3.17, 14.0 and 17.0). 
 
6.3 
Documentation of IRB approval must be on file in the Registration Office before 
an investigator may register any patients. Approvals should be uploaded using the 
online ACCRU Regulatory Management System (ARMS). 
 
In addition to submitting initial IRB approval documents, ongoing IRB approval 
documentation must be on file (no less than annually) with ACCRU. Approvals should be 
uploaded using the online 
.  If the 
necessary documentation is not submitted in advance of attempting patient registration, 
the registration will not be accepted and the patient may not be enrolled in the protocol 
until the situation is resolved. 
 
Submission of annual IRB approvals is required until the study has been closed through 
your IRB. 
 
6.4 
Prior to accepting the registration, the registration/randomization, the 
registration/randomization application will verify the following: 
• 
IRB approval at the registering institution 
• 
Patient eligibility 

Addendum 5 
 
16  
 
 
 
 
 
 
RU021502I 
 
• 
Existence of a signed consent form 
• 
Existence of a signed authorization for use and disclosure of protected health 
information   
 
 
 
6.5 
At the time of registration, the following will be recorded: 
• 
Patient has/has not given permission to store and use his/her sample(s) for future 
research to learn about, prevent, or treat cancer. 
• 
Patient has/has not given permission to store and use his/her sample(s) for future 
research to learn, prevent, or treat other health problems (for example:  diabetes, 
Alzheimer’s disease, or heart disease). 
• 
Patient has/has not given permission for ACCRU to give his/her sample(s) to outside 
researchers. 
 
6.6 
Treatment cannot begin prior to registration and must begin ≤10 days after registration. 
 
6.7 
Pretreatment tests/procedures (see Section 4.0) must be completed within the guidelines 
specified on the test schedule. 
 
6.8 
All required baseline symptoms (see Section 10.5) must be documented and graded. 
 
6.9a 
Treatment on this protocol must commence at an ACCRU institution under the 
supervision of a medical oncologist.  
 
6.9b 
Study drug is available on site.  
 
6.9c 
Blood draw kit is available on site.  
  
7.0 
Protocol Treatment 
 
 
7.1 
Treatment Schedule   
 
Drug 
Dose/Potency 
Dose 
Frequency 
Route of 
Administration 
Regimen/Treatment 
Period 
Use 
Pembrolizumab 
200 mg 
(flat dosing) 
Q3W 
IV infusion 
Day 1 of each 3 
week cycle 
Experimental 
Note: Trial treatment should begin ≤10 days after registration and as close as possible to the date 
on which treatment is allocated/assigned. 
Note: Details on preparation and administration of pembrolizumab (MK-3475) are provided in 
section 15.0. 
 
7.2 
For this protocol, the patient must return to the consenting ACCRU institution for 
evaluation at least every 21 days (+/- 3 days) during treatment. 
 
7.3 
Dosing interruptions, not due to adverse effects. 
 
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.  The reason for interruption should be 
documented in the patient's study record. 

Addendum 5 
 
17  
 
 
 
 
 
 
RU021502I 
 
 
7.4 
Timing of Dose Administration 
 
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. 
7.5 
Dose Administration 
 
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). 
 
7.6 
Treatment Continuation 
 
 
To permit continued study treatment beyond initial radiographic disease progression the 
following will be required: 
a) 
The patient’s performance status must be stable 
b) 
Clinical symptoms and signs of disease progression must be absent 
c) 
A repeat scan to assess for true disease progression must be performed in 
approximately 4 weeks 
d) 
Any patient with pending organ compromise must be discontinued from 
study treatment 
 
Note: See section 13.4 for patients that have initial progression 
 
7.7 
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.   
 
 
7.71  
Acceptable Concomitant Medications 
 
All treatments that the investigator considers necessary for a subject’s welfare 
may be administered at the discretion of the investigator in keeping with the 
community standards of medical care.  All concomitant medication will be 
recorded on the case report form (CRF) including all prescription, over-the-
counter (OTC), herbal supplements, and IV medications and fluids.  If changes 
occur during the trial period, documentation of drug dosage, frequency, route, 
and date may also be included on the CRF. 
 
 
7.72 
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, biological therapy, immunotherapy, 
not specified in this protocol 

Addendum 5 
 
18  
 
 
 
 
 
 
RU021502I 
 
• 
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 event monitoring.     
 
 7.8 
Diet/Activity/Other Considerations 
 
 
7.81 
Diet 
 
Subjects should maintain a normal diet unless modifications are required to 
manage an AE such as diarrhea, nausea or vomiting. 
 
 
7.82 
Contraception 
 
Pembrolizumab may have adverse effects on a fetus in utero.  Furthermore, it is 
not known if pembrolizumab has transient adverse effects on the composition of 
sperm.  Non-pregnant, non-breast-feeding women may be enrolled if they are 
willing to use 2 methods of birth control or are considered highly unlikely to 
conceive.  Highly unlikely to conceive is defined as 1) surgically sterilized, or 2) 
postmenopausal (a woman who is ≥45 years of age and has not had menses for 
greater than 1 year will be considered postmenopausal), or 3) not heterosexually 
active for the duration of the study.  The two birth control methods can be either 
two barrier methods, or a barrier method plus a hormonal method to prevent 
pregnancy. Subjects should start using birth control from study Visit 1 
throughout the study period up to 120 days after the last dose of study therapy.  
The following are considered adequate barrier methods of contraception: 
diaphragm, condom (by the partner), copper intrauterine device, sponge, or 
spermicide.  Appropriate hormonal contraceptives will include any registered and 
marketed contraceptive agent that contains an estrogen and/or a progestational 
agent (including oral, subcutaneous, intrauterine, or intramuscular agents). 

Addendum 5 
 
19  
 
 
 
 
 
 
RU021502I 
 
Subjects should be informed that taking the study medication may involve 
unknown risks to the fetus (unborn baby) if pregnancy were to occur during the 
study.  In order to participate in the study they must adhere to the contraception 
requirement (described above) for the duration of the study and during the 
follow-up period. If there is any question that a subject will not reliably comply 
with the requirements for contraception, that subject should not be entered into 
the study. 
 
 
7.83 
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 ACCRU without delay and within 24 hours. 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 recorded on the CRF.  
 
 
7.84 
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. 
 
8.0 
Dosage Modification Based on Adverse Events  
 
8.1  
Dose Levels  
 
No dose level adjustments are recommended for any adverse reaction, but the dosing 
interval may be increased by 1 week if required.  
 
8.2  
Dose Modification  
 
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 the table 
below.  

Addendum 5 
 
20  
 
 
 
 
 
 
RU021502I 
 
Dose Modification Guidelines for Drug-Related Adverse Events. Use the NCI Common Terminology Criteria for Adverse Events (CTCAE) v. 4.03  
 
CTCAE 
System/Organ/ 
Class 
(SOC) 
Adverse Event/ 
Toxicity 
Hold 
Treatment 
For Grade 
Timing for Restarting 
Treatment 
Discontinue Subject 
 
Gastrointestinal 
disorders 
Diarrhea/Colitis 
(8.4) 
2-3 
 
Toxicity resolves to Grade 0-1. 
Toxicity does not resolve within 12 weeks of last dose or 
inability to reduce corticosteroid to 10 mg or less of 
prednisone or equivalent per day within 12 weeks. 
4 
Permanently discontinue 
Permanently discontinue 
 
Investigations  
Increased AST 
ALT, or Bilirubin 
2 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last dose. 
3-4 
Permanently discontinue 
(see exception below)1 
Permanently discontinue 
 
 
Metabolism and 
nutrition disorders 
Hyperglycemia 
(8.5) 
2-3 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last dose or 
inability to reduce corticosteroid to 10 mg or less of 
prednisone or equivalent per day within 12 weeks.  
4 
Permanently discontinue 
Permanently discontinue 
 
 
 
 
Endocrine 
disorders  
 
Hyperthyroidism/
Hypothyroidism 
(8.7)  
 
3 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last dose or 
inability to reduce corticosteroid to 10 mg or less of 
prednisone or equivalent per day within 12 weeks. 
4 
Permanently discontinue 
Permanently discontinue 
Other:  
Hypophysitis 
(8.6) 
2 
Withhold 
 Administer corticosteroids and initiate hormonal 
replacements as clinically indicated 
Monitor for signs and symptoms of hypophysitis (including 
hypopituitarism and adrenal insufficiency) 
3-4 
Withhold or permanently 
discontinue 
General disorders 
and administration 
site conditions 
Infusion Reaction 
(8.9) 
3-4 
Permanently discontinue 
Permanently discontinue 

Addendum 5 
 
21  
 
 
 
 
 
 
RU021502I 
 
CTCAE 
System/Organ/ 
Class 
(SOC) 
Adverse Event/ 
Toxicity 
Hold 
Treatment 
For Grade 
Timing for Restarting 
Treatment 
Discontinue Subject 
 
Respiratory, 
thoracic and 
mediastinal 
disorders 
Pneumonitis 
(8.3) 
2-4 
Permanently discontinue 
Permanently discontinue 
 
Renal and urinary 
disorders  
Renal Failure or 
Nephritis 
(8.9a) 
2 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last dose or 
inability to reduce corticosteroid to 10 mg or less of 
prednisone or equivalent per day within 12 weeks. 
3-4 
Permanently discontinue 
Permanently discontinue 
 
 
Cardiac disorders 
Myocarditis 
 
1-2 
 
Withhold 
Based on severity of the AE administer corticosteroids. 
Ensure adequate evaluation to confirm etiology and/or 
exclude other causes  
3-4 
Permanently discontinue 
Permanently discontinue 
 
All other 
immune-related 
AEs 
2 
Withhold 
Based on type and severity of AE administer corticosteroids 
Ensure adequate evaluation to confirm etiology and/or 
exclude other causes 
3 
Withhold or discontinue based 
on the type of event; Events 
that require discontinuation 
include and not limited to: 
Guillain-Barre Syndrome, 
encephalitis 
 
Recurrent grade 3 
Permanently discontinue 
4 
Permanently discontinue 
Permanently discontinue 
 
All Other Drug-
Related Toxicity2 
3 (Severe) 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last dose or 
inability to reduce corticosteroid to 10 mg or less of 
prednisone or equivalent per day within 12 weeks. 

Addendum 5 
 
22  
 
 
 
 
 
 
RU021502I 
 
CTCAE 
System/Organ/ 
Class 
(SOC) 
Adverse Event/ 
Toxicity 
Hold 
Treatment 
For Grade 
Timing for Restarting 
Treatment 
Discontinue Subject 
4 
Permanently discontinue 
Permanently discontinue 
 
Note: Permanently discontinue for any severe or Grade 3 drug-related AE that recurs or any life-threatening event. 
1 For patients with liver metastasis who begin treatment with Grade 2 AST or ALT, if AST or ALT increases by greater than or 
equal to 50% relative to baseline therapy should be held up to 3 weeks.  If this does not resolve to grade 2, therapy should be 
discontinued.   Steroids can be used to treat elevated AST/ ALT (see section 8.7).  Resolution to grade 2 with steroid treatment 
will be allowed continuation on therapy.  
2 Patients with intolerable or persistent Grade 2 drug-related AE may hold study medication at physician discretion.  Permanently 
discontinue study drug for persistent Grade 2 adverse reactions for which treatment with study drug has been held, that do not 
recover to Grade 0-1 within 12 weeks of the last dose.   

Addendum 5 
23  
RU021502I 
 
8.3 
Pneumonitis 
 
• 
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. 
• 
For Grade 3-4 events, immediately treat with intravenous steroids.  Administer 
additional anti-inflammatory measures, as needed. 
• 
Add prophylactic antibiotics for opportunistic infections in the case of prolonged 
steroid administration. 
 
8.4 
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).   
 
• 
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. 
• 
For Grade 2 diarrhea/colitis that persists greater than 3 days, administer oral 
corticosteroids.  
• 
For Grade 3 or 4 diarrhea/colitis that persists > 1 week, treat with intravenous 
steroids followed by high dose oral steroids.   
• 
When symptoms improve to Grade 1 or less, steroid taper should be started and 
continued over no less than 4 weeks. 
 
8.5 
Type 1 diabetes mellitus (if new onset, including diabetic ketoacidosis [DKA]) or ≥ 
Grade 3 Hyperglycemia, if associated with ketosis (ketonuria) or metabolic acidosis 
(DKA) 
 
For T1DM or Grade 3-4 Hyperglycemia 
• 
Insulin replacement therapy is recommended for Type I diabetes mellitus and for 
Grade 3-4 hyperglycemia associated with metabolic acidosis or ketonuria.  
• 
Evaluate patients with serum glucose and a metabolic panel, urine ketones, 
glycosylated hemoglobin, and C-peptide.  
 
8.6 
Hypophysitis 
 
• 
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. 
• 
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. 
 
 
 
 
 
 

Addendum 5 
24  
RU021502I 
 
 
8.7 
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. 
 
Grade 2 hyperthyroidism events (and Grade 2-4 hypothyroidism): 
• 
In hyperthyroidism, non-selective beta-blockers (e.g. propranolol) are suggested as 
initial therapy. 
• 
In hypothyroidism, thyroid hormone replacement therapy, with levothyroxine or 
liothyronine, is indicated per standard of care. Treatment with pembrolizumab may 
be continued. 
 
Grade 3-4 hyperthyroidism  
• 
Treat with an initial dose of IV corticosteroid followed by oral corticosteroids. When 
symptoms improve to Grade 1 or less, steroid taper should be started and continued 
over no less than 4 weeks. Replacement of appropriate hormones may be required as 
the steroid dose is tapered. 
 
8.8 
Hepatitis or Hepatic function decline 
 
For Grade 2 events, monitor liver function tests more frequently until returned to 
baseline values (consider weekly). 
• 
Treat with IV or oral corticosteroids 
For Grade 3-4 events, treat with intravenous corticosteroids for 24 to 48 hours.  
• 
When symptoms improve to Grade 1 or less, a steroid taper should be started and 
continued over no less than 4 weeks. 
 
8.9a 
Renal Failure or Nephritis 
 
For Grade 2 events, treat with corticosteroids. 
For Grade 3-4 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.  
 
8.9b  
Management of Infusion Reactions: Signs and symptoms usually develop during or 
shortly after drug infusion and generally resolve completely within 24 hours of 
completion of infusion. The table below shows treatment guidelines for subjects who 
experience an infusion reaction associated with administration of pembrolizumab (MK-
3475). 
 
 

Addendum 5 
25  
RU021502I 
 
 
 Infusion Reaction Treatment Guidelines 
 
NCI CTCAE Grade 
Treatment 
Premedication at 
subsequent dosing 
Grade 1 
Mild reaction; infusion 
interruption not indicated; 
intervention not indicated 
Increase monitoring of vital signs as 
medically indicated until the subject 
is deemed medically stable in the 
opinion of the investigator. 
None 
Grade 2 
Requires infusion 
interruption but responds 
promptly to symptomatic 
treatment (e.g., 
antihistamines, NSAIDS, 
narcotics, IV fluids); 
prophylactic medications 
indicated for < =24 hrs. 
Stop Infusion and monitor 
symptoms. 
Additional appropriate medical 
therapy may include but is not 
limited to: 
IV fluids 
Antihistamines 
NSAIDS 
Acetaminophen 
Narcotics 
Increase monitoring of vital signs as 
medically indicated until the subject 
is deemed medically stable in the 
opinion of the investigator. 
If symptoms resolve within one 
hour of stopping drug infusion, the 
infusion may be restarted at 50% of 
the original infusion rate (e.g., from 
100 mL/hr to 50 mL/hr).  Otherwise 
dosing will be held until symptoms 
resolve and the subject should be 
premedicated for the next scheduled 
dose. 
Subjects who develop Grade 2 
toxicity despite adequate 
premedication should be 
permanently discontinued from 
further trial treatment 
administration. 
Subject may be 
premedicated 1.5h (± 
30 minutes) prior to 
infusion of 
pembrolizumab (MK-
3475) with: 
 
Diphenhydramine 50 
mg P.O. (or equivalent 
dose of antihistamine). 
 
Acetaminophen 500-
1000 mg P.O. (or 
equivalent dose of 
antipyretic). 
Grades 3 or 4 
Grade 3: 
Prolonged (i.e., not rapidly 
responsive to symptomatic 
medication and/or brief 
interruption of infusion); 
recurrence of symptoms 
following initial 
improvement; 
hospitalization indicated for 
other clinical sequelae (e.g., 
renal impairment, 
pulmonary infiltrates) 
Grade 4: 
Life-threatening; pressor or 
ventilator 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 
No subsequent dosing 

Addendum 5 
26  
RU021502I 
 
NCI CTCAE Grade 
Treatment 
Premedication at 
subsequent dosing 
is deemed medically stable in the 
opinion of the investigator. 
Hospitalization may be indicated. 
Subject is permanently 
discontinued from further trial 
treatment administration. 
Appropriate resuscitation equipment should be available in the room and a physician readily 
available during the period of drug administration. 
 
 
 
9.0 
Ancillary Treatment/Supportive Care 
 
9.1 
Supportive Care Guidelines 
Subjects should receive appropriate supportive care measures as deemed necessary by the 
treating investigator.  Suggested supportive care measures for the management of adverse 
events with potential immunologic etiology are outlined below and in greater detail in 
section 8.0.  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.  
 
All blood products and concomitant medications such as antidiarrheals, analgesics, and/or 
antiemetics received from the first day of study treatment administration until 30 days 
after the final dose will be recorded in the medical records. 
 
Note: if after the evaluation the event is determined not to be related, the site investigator 
is instructed to follow the reporting guidance but does not need to follow the treatment 
guidance. Refer to the table in section 8.1 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.   
 
10.0 
Adverse Event (AE) Reporting and Monitoring 
 
The site principal investigator is responsible for reporting any/all serious adverse events to the 
sponsor as described within the protocol. Refer to the adverse event and serious adverse event 
sections of the protocol for detailed information..  
 
The sponsor/sponsor-investigator is responsible for notifying FDA and all participating 
investigators in a written safety report of any of the following:  
 
• 
Any suspected adverse reaction that is both serious and unexpected.  
 
• 
Any findings from laboratory animal or in vitro testing that suggest a significant risk for 
human subjects, including reports of mutagenicity, teratogenicity, or carcinogenicity.  

Addendum 5 
27  
RU021502I 
 
• 
Any findings from epidemiological studies, pooled analysis of multiple studies, or 
clinical studies, whether or not conducted under an IND and whether or not conducted by 
the sponsor, that suggest a significant risk in humans exposed to the drug.  
 
• 
Any clinically important increase in the rate of a serious suspected adverse reaction over 
the rate stated in the protocol or Investigator’s Brochure (IB).  
 
Definitions 
 
Adverse Event 
Any untoward medical occurrence associated with the use of a drug in humans, whether 
or not considered drug related.  
 
Suspected Adverse Reaction 
Any adverse event for which there is a reasonable possibility that the drug caused the 
adverse event. 
 
Expedited Reporting 
Events reported to sponsor within 24 hours, 5 days or 10 days of study team becoming 
aware of the event. 
 
Routine Reporting 
Events reported to sponsor via case report forms 
 
Events of Interest 
Events that would not typically be considered to meet the criteria for expedited reporting, 
but that for a specific protocol are being reported via expedited means in order to 
facilitate the review of safety data (may be requested by the FDA or the sponsor).  
 
10.1 
Adverse Event Characteristics 
 
CTCAE term (AE description) and grade:  The descriptions and grading scales found 
in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 
4.03 will be utilized for AE reporting.  All appropriate treatment areas should have 
access to a copy of the CTCAE version 4.03.  A copy of the CTCAE version 4.03 can be 
downloaded from the CTEP website.(  
 
a. Adverse event monitoring and reporting is a routine part of every clinical trial.   
 
b. Identify the grade and severity of the event using the CTCAE version 4.03.   
 
c. Determine whether the event is expected or unexpected (see Section 10.2).  
 
d. Determine if the adverse event is related to the study intervention (agent, treatment or 
procedure) (see Section 10.3). 
 
e. Determine whether the event must be reported as an expedited report. If yes, 
determine the timeframe/mechanism (see Section 10.4).  
 
f. Determine if other reporting is required (see Section 10.5). 
g. Note: All AEs reported via expedited mechanisms must also be reported via the 
routine data reporting mechanisms defined by the protocol (see Sections 10.6 and 
18.0). 

Addendum 5 
28  
RU021502I 
 
 
Each CTCAE term in the current version is a unique representation of a specific event 
used for medical documentation and scientific analysis and is a single MedDRA Lowest 
Level Term (LLT). 
 
NOTE:  A severe AE, as defined by the above grading scale, is NOT the same as serious 
AE which is defined in the table in Section 10.4. 
 
10.2  
Expected vs. Unexpected Events  
 
Expected events - are those described within the Section 15.0 of the protocol, the study 
specific consent form, package insert (if applicable), and/or the investigator brochure, (if 
an investigator brochure is not required, otherwise described in the general 
investigational plan).  
 
Unexpected adverse events or suspected adverse reactions are those not listed in Section 
15.0 of the protocol, the study specific consent form, package insert (if applicable), or in 
the investigator brochure (or are not listed at the specificity or severity that has been 
observed); if an investigator brochure is not required or available, is not consistent with 
the risk information described in the general investigational plan. 
 
Unexpected also refers to adverse events or suspected adverse reactions that are 
mentioned in the investigator brochure as occurring with a class of drugs but have not 
been observed with the drug under investigation. 
 
10.3 
Assessment of Attribution 
 
When assessing whether an adverse event is related to a medical treatment or 
procedure, the following attribution categories are utilized: 
 
Definite - The adverse event is clearly related to the agent(s). 
Probable - The adverse event is likely related to the agent(s). 
Possible - The adverse event may be related to the agent(s). 
Unlikely - The adverse event is doubtfully related to the agent(s). 
Unrelated - The adverse event is clearly NOT related to the agent(s). 
 
Events determined to be possibly, probably or definitely attributed to a 
medical treatment suggest there is evidence to indicate a causal relationship 
between the drug and the adverse event.  
 
10.31  EXPECTED Serious Adverse Events: Protocol Specific Exceptions 
to Expedited Reporting   
 
For this protocol only, the following Adverse Events/Grades are expected to occur within 
this population and do not require Expedited Reporting. These events must still be 
reported via Routine Reporting (see Section 10.5). * 
 
 
 
 

Addendum 5 
29  
RU021502I 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
These exceptions only apply if the adverse event does not result in hospitalization. If the adverse 
event results in hospitalization, then the standard expedited adverse events reporting requirements 
must be followed.  
 
The following hospitalizations are not considered to be SAEs because there is no 
“adverse event” (i.e., there is no untoward medical occurrence) associated with the 
hospitalization: 
 
• 
Hospitalizations for respite care 
• 
Planned hospitalizations required by the protocol or to administer protocol directed 
treatment (i.e. 131I therapy) 
• 
Hospitalization planned before informed consent (where the condition requiring 
hospitalization has not changed post study drug administration) 
• 
Hospitalization for administration of study drug or insertion of access for administration 
of study drug 
• 
Hospitalization for routine maintenance of a device (e.g., battery replacement) that was in 
place before study entry  
 
 
System Organ 
Class (SOC) 
 
Adverse event/ Symptoms 
 
CTCAE Grade at which the 
event will not require expedited 
reporting. 
 
Endocrine disorders 
 
Hypothyroidism 
1,2,3 
Other, specify: 
1,2,3 
Gastrointestinal 
disorders  
Enterocolitis 
1, 2 
Intra-abdominal hemorrhage  
1,2 
Other, specify: 
1,2 
Respiratory, 
thoracic and 
mediastinal 
disorders 
Pneumonitis 
1,2 
Dyspnea 
1,2 
Cough 
1,2 
Respiratory failure 
1,2 
 
Other, specify  
 
 
1,2 
Renal and urinary 
disorders  
Nephritis 
1, 2 
Hematuria 
1,2 
Proteinuria 
1,2 
Investigations 
Increased AST/ALT 
1,2,3 
Increased bilirubin  
1,2,3 
Creatinine increased 
1,2 
Infections and 
infestations  
Hepatitis viral  
1,2,3 

Addendum 5 
30  
RU021502I 
 
 * Report any clinically important increase in the rate of a serious suspected adverse reaction (at 
your study) site over that which is listed in the protocol or investigator brochure as an 
expedited event.  
 
* Report an expected event that is greater in severity or specificity than expected as an    
expedited event  
 
* An investigational agent/intervention might exacerbate the expected AEs associated with a 
commercial agent.  Therefore, if an expected AE (for the commercial agent) occurs with a higher 
degree of severity or specificity, expedited reporting is required.   
 
A list of known/expected AEs is reported in the investigator brochure, package insert or the 
literature, including AEs resulting from a drug overdose. 
 
10.331 Death 
• 
Any death occurring within 30 days of the last dose, 
regardless of attribution to an agent/intervention under an 
IND/IDE requires expedited reporting within 24-hours. 
 
• 
Any death occurring greater than 30 days with an attribution 
of possible, probable, or definite to an agent/intervention 
under an IND/IDE requires expedited reporting within 24-
hours. 
 
• 
Reportable categories of Death  
 
• 
Death attributable to a CTCAE term. 
 
• 
Death Neonatal:  A disorder characterized by 
cessation of life during the first 28 days of life. 
 
• 
Death NOS:  A cessation of life that cannot be 
attributed to a CTCAE term associated with Grade 5. 
 
• 
Sudden death NOS:  A sudden (defined as instant or 
within one hour of the onset of symptoms) or an 
unobserved cessation of life that cannot be attributed 
to a CTCAE term associated with Grade 5. 
 
• 
Death due to progressive disease should be reported 
as Grade 5 “Neoplasms benign, malignant and 
unspecified (including cysts and polyps) – Other 
(Progressive Disease)” under the system organ class 
(SOC) of the same name.  Evidence that the death 
was a manifestation of underlying disease (e.g., 
radiological changes suggesting tumor growth or 
progression: clinical deterioration associated with a 
disease process) should be submitted. 
 
 
 
 

Addendum 5 
31  
RU021502I 
 
10.332 Secondary Malignancy 
 
• 
A secondary malignancy is a cancer caused by treatment for a 
previous malignancy (e.g., treatment with investigational 
agent/intervention, radiation or chemotherapy).  A secondary 
malignancy is not considered a metastasis of the initial neoplasm. 
 
• 
All secondary malignancies that occur following treatment with an 
agent under an IND/IDE to be reported. Three options are available to 
describe the event: 
 
o Leukemia secondary to oncology chemotherapy (e.g., Acute 
Myeloctyic Leukemia [AML]) 
 
o Myelodysplastic syndrome (MDS) 
 
o Treatment-related secondary malignancy 
 
• 
Any malignancy possibly related to cancer treatment (including 
AML/MDS) should also be reported via the routine reporting 
mechanisms outlined in each protocol. 
 
10.333 Second Malignancy 
 
• 
A second malignancy is one unrelated to the treatment of a prior 
malignancy (and is NOT a metastasis from the initial malignancy).  
Second malignancies require ONLY routine reporting. 
 
10.334 Pregnancy  
 
Prior to obtaining private information about a pregnant woman and her infant, the 
investigator must obtain consent from the pregnant woman and the newborn 
infant’s parent or legal guardian before any data collection can occur.  A consent 
form will need to be submitted to the IRB for these subjects if a pregnancy 
occurs. If informed consent is not obtained, no information may be collected. 
In cases of fetal death, miscarriage or abortion the mother is the patient. In cases 
where the child/fetus experiences a serious adverse event other than fetal death, 
the child/fetus is the patient. 
 
NOTE: When submitting ACCRU Adverse Event Report reports for 
“Pregnancy”, “Pregnancy loss”, or “Neonatal loss”, the potential risk of exposure 
of the fetus to the investigational agent(s) or chemotherapy agent(s) should be 
documented in the “Description of Event” section. Include any available medical 
documentation.  
 
10.335 Study drug overdose ≥1000mg is the accidental or intentional use of the 
drug in the amount higher than the starting dose being studied. 
 
10.3351 Any study drug overdose during the study should be noted on the 
CRF (AE Log found in the Forms Packet). 
 
10.3352 All AEs associated with an overdose should both be entered on 
the Adverse Event CRF and reported using the procedures 

Addendum 5 
32  
RU021502I 
 
detailed in Reporting of SAEs, even if the events do not meet 
serious criteria. If the AE associated with an overdose does not 
meet serious criteria, it must still be reported using the SAE form 
and in an expedited manner but should be noted as non-serious 
on the SAE form and the Adverse Event CRF. 
 
 
 

Addendum 5 
33  
RU021502I 
 
10.4 
Expedited Adverse Event Reporting Requirements for IND Agents 
 
10.41  Phase 1 and Early Phase 2 Studies:  Expedited Reporting via the ACCRU 
Adverse Event Expedited Report Form for Adverse Events That Occur Within 
30 Days1 of the Last Dose of the Investigational Agent 
 
FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312) 
NOTE:  Investigators MUST immediately report to the sponsor ANY Serious Adverse Events, whether or not they 
are considered related to the investigational agent(s)/intervention (21 CFR 312.64) 
An adverse event is considered serious if it results in ANY of the following outcomes:   
1) 
Death 
2) 
A life-threatening adverse event  
3) 
An adverse event that results in inpatient hospitalization or prolongation of existing hospitalization for ≥ 24 
hours  
4) 
A persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions  
5) 
A congenital anomaly/birth defect.  
6) 
Important Medical Events (IME) that may not result in death, be life threatening, or require hospitalization 
may be considered serious when, based upon medical judgment, they may jeopardize the patient or subject 
and may require medical or surgical intervention to prevent one of the outcomes listed in this definition. (FDA, 
21 CFR 312.32; ICH E2A and ICH E6). 
ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported to the sponsor within 
the timeframes detailed in the table below. 
Hospitalization 
Grade 1 and Grade 2 Timeframes 
Grade 3-5 
Timeframes 
Resulting in 
Hospitalization       
≥ 24 hrs 
7 Calendar Days 
24-Hour / 3 Calendar 
Days 
Not resulting in 
Hospitalization       
≥ 24 hrs 
Not required 
Expedited AE reporting timelines are defined as: 
o “24-Hour / 3 Calendar Days” - The AE must initially be reported within 24 hours of learning of the AE, 
followed by a complete expedited report within 3 calendar days of the initial 24-hour report. 
o 
7 Calendar Days” - A complete expedited report on the AE must be submitted within 7 calendar days 
of learning of the AE. 
1Serious adverse events that occur more than 30 days after the last administration of investigational 
agent/intervention and have an attribution of possible, probable, or definite require reporting as follows:  
Expedited 24-hour notification followed by complete report within 3 calendar days for: 
• All Grade 3, 4, and Grade 5 AEs 
Expedited 7 calendar day reports for: 
• Grade 2 AEs resulting in hospitalization or prolongation of hospitalization 
2 For studies using PET or SPECT IND agents, the AE reporting period is limited to 10 radioactive half-lives, 
rounded UP to the nearest whole day, after the agent/intervention was last administered.  Footnote “1” above 
applies after this reporting period. 
Effective Date:  May 5, 2011 
 
 

Addendum 5 
34  
RU021502I 
 
Special Instructions:  
 
• Follow site-specific reporting guidelines. 
 
• Submit the ACCRU Adverse Event Expedited Report Form to the ACCRU SAE 
Coordinator via fax 
 or email 
.  The 
ACCRU SAE Coordinator will provide copies to Merck Global Safety by fax (
within 2 working days of SAE occurring or being noted.  
 
• Other relevant safety information, drug overdoses, and Non-Serious Events of Clinical 
Interest should be handled in the same manner as SAEs. A copy of all 15 Day Reports 
and Annual Progress Reports is submitted as required by FDA, European Union (EU), 
Pharmaceutical and Medical Devices Agency (PMDA), or other local regulators. 
Investigators will cross-reference this submission according to local regulations to the 
Merck Investigational Compound Number (IND, CSA, etc.) at the time of submission. 
Additionally, investigators will submit a copy of these reports to Merck & Co., Inc. 
(Attn: Worldwide Product Safety; FAX 
) at the time of submission to 
the FDA. 
 
• The ACCRU SAE Coordinator will forward to 
 as 
appropriate. The ACCRU IND Coordinator will assist the sponsor-investigator in 
notifying the FDA if required.  
 
10.5 
Other Required Reporting 
 
10.51 Unanticipated Problems Involving Risks to Subjects or Others (UPIRTSOS) in 
general, include any incident, experience, or outcome that meets all of the 
following criteria: 
 
1. Unexpected (in terms of nature, severity, or frequency) given (a) the research 
procedures that are described in the protocol-related documents, such as the 
IRB-approved research protocol and informed consent document; and (b) the 
characteristics of the subject population being studied; 
 
2. Related or possibly related to participation in the research (in this guidance 
document, possibly related means there is a reasonable possibility that the 
incident, experience, or outcome may have been caused by the procedures 
involved in the research); and 
 
3. Suggests that the research places subjects or others at a greater risk of harm 
(including physical, psychological, economic, or social harm) than was 
previously known or recognized. 
 
Some unanticipated problems involve social or economic harm instead of the 
physical or psychological harm associated with adverse events.  In other cases, 
unanticipated problems place subjects or others at increased risk of harm, but no 
harm occurs. 
 
Note: If there is no language in the protocol indicating that pregnancy is not 
considered an adverse experience for this trial, and if the consent form does not 
indicate that subjects should not get pregnant/impregnate others, then any 
pregnancy in a subject/patient or a male patient’s partner (spontaneously 

Addendum 5 
35  
RU021502I 
 
reported) which occurs during the study or within 120 days of completing the 
study should be reported as a UPIRTSO. 
If the event meets the criteria for an UPIRTSO, submit to your IRB as required 
by your institutional policies.   
  
10.52 Baseline and Adverse Events Evaluations 
 
 
Pre-treatment symptoms/conditions to be graded at baseline and adverse events 
to be graded at each evaluation per the CTCAE v4.03 grading unless otherwise 
stated in the table below: 
 
System Organ 
Class (SOC) 
CTC Adverse Event Term 
(CTCAE v.4.03) 
Baseline At each evaluation 
Investigations 
 
 
 
 
  Aspartate aminotransferase (AST) increased 
X 
X 
Alanine aminotransferase (ALT) increased 
X 
X 
Blood bilirubin increased  
X  
X  
Alkaline phosphatase increased 
X  
X  
 
Endocrine Disorders 
 
 
 
Hyperthyroidism  
X 
X 
Hypothyroidism  
X 
X 
Other:  Specify hypophysitis 
 
X 
 
X 
 
 
10.53  Case Report Forms - Academic and Community Cancer Research United 
(ACCRU) 
 
 
Submit the following AEs not specified in Section 10.5 (paper or electronic, as 
applicable)  
 
 
10.531 Grade 2 AEs deemed possibly, probably, or definitely related to the study 
treatment or procedure. 
 
10.532 Grade 3 and 4 AEs regardless of attribution to the study treatment or 
procedure. 
 
10.533 Grade 5 AEs (Deaths) 
10.5331 Any death within 30 days of the patient’s last study treatment or 
procedure regardless of attribution to the study treatment or 
procedure. 
 
10.5332 Any death more than 30 days after the patient’s last study 
treatment or procedure that is felt to be at least possibly 
treatment related must also be submitted as a Grade 5 AE, with a 
CTCAE type and attribution assigned. 
 
 
 

Addendum 5 
36  
RU021502I 
 
10.54 Late Occurring Adverse Events 
 
Refer to the instructions in the Forms Packet (or electronic data entry screens, as 
applicable) regarding the submission of late occurring AEs following completion 
of the Active Monitoring Phase (i.e., compliance with Test Schedule in Section 
4.0). 
  
11.0 
Treatment Evaluation  
 
NOTE:  This study uses protocol RECIST v1.1 template dated 2/16/2011.  See the footnote for 
the table regarding measureable disease in Section 11.44, as it pertains to data collection 
and analysis. 
 
Response and progression will be evaluated in this study using the international criteria proposed 
by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guidelines (version 1.1)1 
Changes in the largest diameter (unidimensional measurement) of the tumor lesions and the short 
axis measurements in the case of lymph nodes are used in the RECIST guideline. Evaluations will 
be performed by the investigator at the times of treatment.  
 
11.1 
Schedule of Evaluations:  For the purposes of this study, patients should be reevaluated 
every 12 weeks (i.e. 4 cycles),  
 
11.2 
Definitions of Measurable and Non-Measurable Disease 
 
11.21   Measurable Disease 
 
11.211 A non-nodal lesion is considered measurable if its longest diameter can be 
accurately measured as ≥2.0 cm with chest x-ray, or as ≥1.0 cm with CT 
scan, CT component of a PET/CT, or MRI.  
 
11.212 A superficial non-nodal lesion is measurable if its longest diameter is ≥ 
1.0 cm in diameter as assessed using calipers (e.g. skin nodules) or 
imaging.  In the case of skin lesions, documentation by color 
photography, including a ruler to estimate the size of the lesion, is 
recommended. 
 
11.213 A malignant lymph node is considered measurable if its short axis is >1.5 
cm when assessed by CT scan (CT scan slice thickness recommended to 
be no greater than 5 mm).   
 
Note:  Tumor lesions in a previously irradiated area are not considered 
measurable disease.   
 
11.22 Non-Measurable Disease 
 
11.221 All other lesions (or sites of disease) are considered non-measurable 
disease, including pathological nodes (those with a short axis ≥1.0 to <1.5 
cm).  Bone lesions, leptomeningeal disease, ascites, pleural/pericardial 
effusions, lymphangitis cutis/pulmonis, inflammatory breast disease, and 
abdominal masses (not followed by CT or MRI), are considered as non-
measurable as well. 
 

Addendum 5 
37  
RU021502I 
 
Note:  ‘Cystic lesions’ thought to represent cystic metastases can be 
considered as measurable lesions, if they meet the definition of 
measurability described above. However, if non-cystic lesions are present 
in the same patient, these are preferred for selection as target lesions.  In 
addition, lymph nodes that have a short axis <1.0 cm are considered non- 
pathological (i.e., normal) and should not be recorded or followed. 
 
11.3 
Guidelines for Evaluation of Measurable Disease 
 
11.31 Measurement Methods:   
 
• 
All measurements should be recorded in metric notation (i.e., decimal 
fractions of centimeters) using a ruler or calipers. 
 
• 
The same method of assessment and the same technique must be used to 
characterize each identified and reported lesion at baseline and during follow-
up. For patients having only lesions measuring at least 1 cm to less than 2 cm 
must use CT imaging for both pre- and post-treatment tumor assessments.  
  
• 
Imaging-based evaluation is preferred to evaluation by clinical examination 
when both methods have been used at the same evaluation to assess the 
antitumor effect of a treatment.  
 
11.32 Acceptable Modalities for Measurable Disease:       
 
• 
Conventional CT and MRI:  This guideline has defined measurability of 
lesions on CT scan based on the assumption that CT slice thickness is 5 mm 
or less. If CT scans have slice thickness greater than 5 mm, the minimum size 
for a measurable lesion should be twice the slice thickness.     
 
• 
As with CT, if an MRI is performed, the technical specifications of the 
scanning sequences used should be optimized for the evaluation of the type 
and site of disease.  The lesions should be measured on the same pulse 
sequence.  Ideally, the same type of scanner should be used and the image 
acquisition protocol should be followed as closely as possible to prior scans.  
Body scans should be performed with breath-hold scanning techniques, if 
possible. 
 
• 
PET-CT:  If the site can document that the CT performed as part of a PET-CT 
is of identical diagnostic quality to a diagnostic CT (with IV and oral 
contrast), then the CT portion of the PET-CT can be used for RECIST 
measurements and can be used interchangeably with conventional CT in 
accurately measuring cancer lesions over time.   
 
• 
Physical Examination:  For superficial non-nodal lesions, physical 
examination is acceptable, but imaging is preferable, if both can be done. In 
the case of skin lesions, documentation by color photography, including a 
ruler to estimate the size of the lesion, is recommended. 
 
• 
FDG-PET:  FDG-PET scanning is allowed to complement CT scanning in 
assessment of progressive disease [PD] and particularly possible 'new' disease.  
A ‘positive’ FDG-PET scanned lesion is defined as one which is FDG avid 
with an update greater than twice that of the surrounding tissue on the 

Addendum 5 
38  
RU021502I 
 
attenuation corrected image; otherwise, an FDG-PET scanned lesion is 
considered ‘negative.’  New lesions on the basis of FDG-PET imaging can be 
identified according to the following algorithm: 
 
a. Negative FDG-PET at baseline with a positive FDG-PET at follow-up is a 
sign of PD based on a new lesion. 
 
b.   No FDG-PET at baseline and a positive FDG-PET at follow-up:   
 
i. 
If the positive FDG-PET at follow-up corresponds to a new site of 
disease confirmed by CT, this is PD.   
 
ii. If the positive FDG-PET at follow-up is not confirmed as a new site 
of disease on CT at the same evaluation, additional follow-up CT 
scans (i.e., additional follow-up scans at least 4 weeks later) are 
needed to determine if there is truly progression occurring at that site. 
In this situation, the date of PD will be the date of the initial abnormal 
PDG-PET scan.   
 
iii If the positive FDG-PET at follow-up corresponds to a pre-existing 
site of disease on CT that is not progressing on the basis of the 
anatomic images, it is not classified as PD. 
 
11.33 Measurement at Follow-up Evaluation:   
 
• 
A subsequent scan must be obtained at least four weeks following initial 
documentation of an objective status of either complete response (CR) or 
partial response (PR).  
 
• 
In the case of stable disease (SD), follow-up measurements must have met the 
SD criteria at least once after study entry at a minimum interval of 6 weeks 
(see Section 11.44). 
 
• 
The cytological confirmation of the neoplastic origin of any effusion that 
appears or worsens during treatment when the measurable tumor has met 
criteria for response or stable disease is mandatory to differentiate between 
response or stable disease (an effusion may be a side effect of the treatment) 
and progressive disease. 
 
• 
Cytologic and histologic techniques can be used to differentiate between PR 
and CR in rare cases (e.g., residual lesions in tumor types such as germ cell 
tumors, where known residual benign tumors can remain.) 
 
11.4 
Measurement of Effect 
 
11.41 Target Lesions & Target Lymph Nodes 
 
• 
Measurable lesions (as defined in Section 11.21) up to a maximum of 5 
lesions, representative of all involved organs, should be identified as “Target 
Lesions” and recorded and measured at baseline.  These lesions can be non-
nodal or nodal (as defined in 11.21), where no more than 2 lesions are from 
the same organ and no more than 2 malignant nodal lesions are selected.  
 

Addendum 5 
39  
RU021502I 
 
Note: If fewer than 5 target lesions and target lymph nodes are identified (as 
there often will be), there is no reason to perform additional studies beyond 
those specified in the protocol to discover new lesions.   
 
• 
Target lesions and target lymph nodes should be selected on the basis of their 
size, be representative of all involved sites of disease, but in addition should 
be those that lend themselves to reproducible repeated measurements.  It may 
be the case that, on occasion, the largest lesion (or malignant lymph node) 
does not lend itself to reproducible measurements in which circumstance the 
next largest lesion (or malignant lymph node) which can be measured 
reproducibly should be selected.   
 
• 
Baseline Sum of Dimensions (BSD): A sum of the longest diameter for all 
target lesions plus the sum of the short axis of all the target lymph nodes will 
be calculated and reported as the baseline sum of dimensions (BSD).  The 
BSD will be used as reference to further characterize any objective tumor 
response in the measurable dimension of the disease.   
 
• 
Post-Baseline Sum of the Dimensions (PBSD):  A sum of the longest diameter 
for all target lesions plus the sum of the short axis of all the target lymph 
nodes will be calculated and reported as the post-baseline sum of dimensions 
(PBSD).  If the radiologist is able to provide an actual measure for the target 
lesion (or target lymph node), that should be recorded, even if it is below 0.5 
cm.  If the target lesion (or target lymph node) is believed to be present and is 
faintly seen but too small to measure, a default value of 0.5 cm should be 
assigned.  If it is the opinion of the radiologist that the target lesion or target 
lymph node has likely disappeared, the measurement should be recorded as 0 
cm. 
 
• 
Minimum sum of the dimensions (MSD): The minimum of the BSD and the 
PBSD. 
 
• 
Sum of Perpendicular Diameters: The sum of the products of the two largest 
perpendicular diameters of a lesion will be calculated and reported. The SPD 
will be used to calculate the total measurable tumor burden per irRC 
assessment. 
 
• 
Total Measurable Tumor Burden: per the irRC, all index and measurable new 
lesions are taken into account. The SPD of the two largest index lesions (five 
lesions per organ, up to 10 visceral lesions) is calculated at baseline and at 
each subsequent reassessment. The SPD of new, measurable lesions (>5 x 5 
mm; up to five new lesions per organ, 10 total visceral lesions) are added 
together for the total tumor burden. 
 
 
11.42  Non-Target Lesions & Non-Target Lymph Nodes 
 
Non-measurable sites of disease (Section 11.22) are classified as non- target 
lesions or non-target lymph nodes and should also be recorded at baseline.  These 
lesions and lymph nodes should be followed in accord with 11.433. 
 
 
 
 

Addendum 5 
40  
RU021502I 
 
11.43 Response Criteria 
 
11.431 All target lesions and target lymph nodes followed by 
 
CT/MRI/PET-CT/Chest X-ray/physical examination must be measured 
on re-evaluation at evaluation times specified in Section 11.1.  
Specifically, a change in objective status to either a PR or CR cannot be 
done without re-measuring target lesions and target lymph nodes.  
 
Note: Non-target lesions and non-target lymph nodes should be 
evaluated at each assessment, especially in the case of first response or 
confirmation of response.  In selected circumstances, certain non-target 
organs may be evaluated less frequently.  For example, bone scans may 
need to be repeated only when complete response is identified in target 
disease or when progression in bone is suspected. 
 
 

Addendum 5 
41  
RU021502I 
 
 
11.432 Evaluation of Target Lesions 
 
 
Target lesions will be assessed using RECIST criteria for all primary  
 
endpoints (see table below). 
 
Response Criteria per RECIST 1.1  
 
 
RECIST 1.1* 
Complete Response 
(CR) 
Disappearance of all target lesions AND 
each target lymph node must have short-
axis reduction to <1.0 cm 
Partial Response (PR) 
At least 30% decrease in PBSD (sum of 
the longest diameter for all target lesions 
plus the sum of the short axis of all the 
target lymph nodes at current evaluation) 
taking the BSD as reference (see Section 
11.41). 
Progression (PD) 
At least one of the following must be true: 
 
a. At least one new malignant lesion, 
which also includes any lymph node that 
was normal at baseline (< 1.0 cm short 
axis) and increased to > 1.0 cm short axis 
during follow-up 
 
b. At least a 20% increase in PBSD (sum 
of the longest diameter for all target 
lesions plus the sum of the short axis of all 
the target lymph nodes at current 
evaluation) taking as reference the MSD 
(Section 11.41).  In addition, the PBSD 
must also demonstrate an absolute 
increase of at least 0.5 cm from the MSD. 
 
c. See Section 11.32 for details in regards 
to the requirements for PD via FDG-PET 
imaging 
Stable Disease (SD) 
Neither sufficient shrinkage to qualify for 
PR, nor sufficient increase to qualify for 
PD taking as reference the MSD. 
*Primary endpoint. 
**Secondary endpoint. Tumor burden includes index, non-index, and emerging 
lesions while on therapy. 
 
 
 

Addendum 5 
42  
RU021502I 
 
11.433 Evaluation of Non-Target Lesions & Non-target Lymph Nodes 
 
• Complete Response (CR): 
All of the following must be true: 
 
a. Disappearance of all non-target 
lesions.  
 
b. Each non-target lymph node must 
have a reduction in short axis to <1.0 
cm. 
• Non-CR/Non-PD: 
Persistence of one or more non-target 
lesions or non-target lymph nodes. 
 
• Progression (PD): 
At least one of the following must be true: 
 
a. At least one new malignant lesion, 
 
which also includes  any lymph node 
 
that was normal at baseline (< 1.0 cm 
 
short axis) and increased to ≥ 
 
1.0 cm short axis during follow-up.   
 
b. Unequivocal progression of existing 
non-target lesions and non-target 
lymph nodes.  (NOTE:  Unequivocal 
progression should not normally 
trump target lesion and target lymph 
node status.  It must be representative 
of overall disease status change.)  
   
c. See Section 11.32 for details in 
regards to the requirements for PD 
via FDG-PET imaging. 
 
 
 

Addendum 5 
43  
RU021502I 
 
11.44 Overall Objective Status 
 
 
The overall objective status for an evaluation is determined by combining the 
patient’s status on target lesions, target lymph nodes, non-target lesions, non-target 
lymph nodes, and new disease as defined in the following table:  
 
 Overall Responses by RECIST 1.1 
 
Target Lesions & 
Target Lymph Nodes 
Non-Target Lesions & 
Non-Target Lymph 
Nodes 
New  
Sites of Disease 
Overall Objective 
Status 
CR 
CR 
No 
CR 
CR 
Non-CR/Non-PD 
No 
PR 
PR 
CR 
Non-CR/Non-PD 
No 
PR 
CR/PR 
Not All Evaluated* 
No 
PR** 
SD 
CR 
Non-CR/Non-PD 
Not All Evaluated* 
No 
SD 
Not all Evaluated 
CR 
Non-CR/Non-PD 
Not All Evaluated* 
No 
Not Evaluated 
(NE) 
PD 
Unequivocal PD 
CR 
Non-CR/Non-PD 
Not All Evaluated* 
Yes or No 
PD 
CR/PR/SD/PD/Not all 
Evaluated 
Unequivocal PD 
Yes or No 
PD 
CR/PR/SD/PD/Not all 
Evaluated 
CR 
Non-CR/Non-PD 
Not All Evaluated* 
Yes 
PD 
*See Section 11.431 
** NOTE:  This study uses the protocol RECIST v1.1 template dated 2/16/2011.  For data collection 
and analysis purposes the objective status changed from SD to PR in the ACCRU protocol RECIST 
v1.1 template as of 2/16/2011 and to match RECIST v1.1 requirements. 
 
***NOTE: For those patients who have initial PD, a confirmation scan will be required around 4 
weeks later to confirm PD, assuming the patient is eligible to remain on treatment after initial PD (see 
13.4 for further details).  If progression is confirmed then the date of disease progression will be the 
first date the patient met the criteria for progression based on standard RECIST 1.1 criteria. 
 
  
11.45 Symptomatic Deterioration: Patients with global deterioration of health status 
requiring discontinuation of treatment without objective evidence of disease 
progression at that time, and not either related to study treatment or other medical 
conditions, should be reported as PD due to “symptomatic deterioration.”  Every 
effort should be made to document the objective progression even after 
discontinuation of treatment due to symptomatic deterioration.  A patient is 
classified as having PD due to “symptomatic deterioration” if any of the 
following occur that are not either related to study treatment or other medical 
conditions: 
• Weight loss >10% of body weight. 
• Worsening of tumor-related symptoms. 
• Decline in performance status of >1 level on ECOG scale. 

Addendum 5 
44  
RU021502I 
 
12.0 
Descriptive Factors   
 
 
12.1 
Type of Prior chemotherapy 
 
 
 
All prior lines of chemotherapy (adjuvant vs. palliative, or both) and identities of prior 
drug regimens administered (FOLFOX vs. XELOX, etc.) should be noted for each 
patient. Of note, no prior immunotherapies may have been given. 
 
 
12.2    Number of lines of prior chemotherapy  
 
 
 
0 vs. 1 vs. 2 vs. 3 vs. 4 or more prior treatment courses. 
 
 
 
12.3 
Site of primary tumor:   
 
 
 
Duodenal vs. jejunal vs. ileal 
 
 
12.4 
Prior Radiation Therapy:   
 
 
 
Yes vs. no, including specific notation whether prior radiation therapy had been 
previously administered to the abdomen/pelvis. 
 
 
12.5 
MSI status  
 
 
 
MSS vs MSI-L vs MSI-H, vs. unknown 
 
 
 
13.0 
Treatment/Follow–up Decision at Evaluation of Patient   
 
 
 
13.1 
A patient is deemed ineligible if after registration, it is determined that at the time of 
registration, the patient did not satisfy each and every eligibility criteria for study entry.  
The patient may continue treatment off-protocol at the discretion of the physician as long 
as there are no safety concerns, and the patient was properly registered. The patient will 
go directly to the event-monitoring phase of the study (or off study, if applicable).  
• 
If the patient received treatment, all data up until the point of confirmation of 
ineligibility must be submitted.  Event monitoring will be required per Section 18.0 
of the protocol.  
• 
If the patient never received treatment, on-study material must be submitted. Event 
monitoring will be required per Section 18.0 of the protocol.  
  
13.2 
A patient is deemed a major violation, if protocol requirements regarding treatment in 
cycle 1 of the initial therapy are severely violated such that evaluating for primary end 
point is in question.  All data up until the point of confirmation of a major violation must 
be submitted.  The patient will go directly to the event-monitoring phase of the study.  
The patient may continue treatment off-protocol at the discretion of the physician as long 
as there are no safety concerns, and the patient was properly registered.  Event 
monitoring will be required per Section 18.0 of the protocol. 
 
13.3 
A patient is deemed a cancel if he/she is removed from the study for any reason before 
any study treatment is given.  On-study material will be required per Section 18.0 of the 
protocol and the End of Active Treatment/Cancel Notification Form must be submitted.  
No further data submission is necessary. 
 
13.4 
Patients will continue on treatment until disease progression, intolerable toxicity, or 
patient refusal.  To permit continued study treatment beyond initial radiographic disease 

Addendum 5 
45  
RU021502I 
 
progression the following will be required: 
a) 
The patient’s performance status must be stable 
b) 
Clinical symptoms and signs of disease progression must be absent 
c) 
A repeat scan to assess for true disease progression must be performed in 
approximately 4 weeks 
d) 
Any patient with pending organ compromise must be discontinued from study 
treatment 
 
After discontinuation of treatment or once a patient has confirmed disease progression, 
patients will continue in event monitoring only follow-up as outlined in section18.   
 
 13.5 
Subject Withdrawal/Discontinuation Criteria 
 
Subjects may withdraw consent at any time for any reason or be dropped from the trial at 
the discretion of the investigator should any untoward effect occur.  In addition, a subject 
may be withdrawn by the investigator or the Sponsor if enrollment into the trial is 
inappropriate, the trial plan is violated, or for administrative and/or other safety reasons.  . 
 
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 (but remain on trial for long term 
survival) 
• 
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. 
 
Note: 24 months of study medication is calculated from the date of first dose. Subjects 
who stop pembrolizumab after 24 months may be eligible for up to one year of additional 
study treatment if they progress after stopping study treatment. To permit continued 
study treatment beyond initial radiographic disease progression, see section 7.6 
Treatment Continuation. 
 
Administrative reasons 
 
Subjects who discontinue trial treatment for any reason will move into the event-
monitoring phase and should be assessed every 3 months until progression and every 6 
months after progression for a maximum follow-up time of 5 years from study entry.   
 
 
13.6  
Discontinuation of Study Therapy after CR  
 
Discontinuation of treatment may be considered for subjects who have attained a 
confirmed CR that have been treated for at least 24 weeks with pembrolizumab and had 
at least two treatments with pembrolizumab beyond the date when the initial CR was 
declared.  Subjects who then experience radiographic disease progression may be eligible 
for up to one year of additional treatment with pembrolizumab via the Second Course 

Addendum 5 
46  
RU021502I 
 
Phase at the discretion of the investigator if no cancer treatment was administered since 
the last dose of pembrolizumab, the subject meets the safety parameters listed in the 
Inclusion/Exclusion criteria, and the trial is open.  Subjects will resume therapy at the 
same dose and schedule at the time of initial discontinuation.   
 
13.7 
Subject Replacement Strategy 
 
 
 
A subject that discontinues from the trial will not be replaced. 
 
13.8 
Clinical Criteria for Early Trial Termination 
Early trial termination will be the result of the criteria specified below: 
 
1. Quality or quantity of data recording is inaccurate or incomplete; 
2. Poor adherence to protocol and regulatory requirements; 
3. Incidence or severity of adverse drug reaction in this or other studies indicates 
a potential health hazard to subjects; 
4. Plans to modify or discontinue the development of the study drug. 
 
In the event of Merck decision to no longer supply study drug, ample notification will be 
provided so that appropriate adjustments to subject treatment can be made. 
 
 
13.9 
Second Course Phase (Retreatment Period) 
 
Subjects who stop pembrolizumab with SD or better may be eligible for up to one year of 
additional pembrolizumab therapy if they progress after stopping study treatment.  This 
retreatment is termed the Second Course Phase of this study and is only available if the 
study remains open and the subject meets the following conditions: 
 
• 
Either  
o Stopped initial treatment with pembrolizumab after attaining an investigator-
determined confirmed CR according to RECIST 1.1, and 
 
Was treated for at least 24 weeks with pembrolizumab before 
discontinuing therapy 
 
Received at least two treatments with pembrolizumab beyond the 
date when the initial CR was declared 
 
 
Or 
 
o Had SD, PR or CR and stopped pembrolizumab treatment after 24 months of 
study therapy for reasons other than disease progression or intolerability 
AND 
 
• 
Experienced an investigator-determined confirmed radiographic disease progression 
after stopping their initial treatment with pembrolizumab 
• 
Did not receive any anti-cancer treatment since the last dose of pembrolizumab 
• 
Has a performance status of 0 or 1 on the ECOG Performance Scale 
• 
Demonstrates adequate organ function as detailed 
• 
Female subject of childbearing potential should have a negative serum or urine 
pregnancy test within 72 hours prior to receiving retreatment with study medication.   
• 
Female subject of childbearing potential should be willing to use 2 methods of birth 
control or be surgically sterile, or abstain from heterosexual activity for the course of 
the study through 120 days after the last dose of study medication (Reference Section 
5.7.2).  Subjects of child bearing potential are those who have not been surgically 
sterilized or have been free from menses for > 1 year.  

Addendum 5 
47  
RU021502I 
 
• 
Male subject should agree to use an adequate method of contraception starting with 
the first dose of study therapy through 120 days after the last dose of study therapy.   
• 
Does not have a history or current evidence of any condition, therapy, or laboratory 
abnormality that might interfere with the subject’s participation for the full duration 
of the trial or is not in the best interest of the subject to participate, in the opinion of 
the treating investigator. 
Subjects who restart treatment will be retreated at the same dose and dose interval as 
when they last received pembrolizumab.  Treatment will be administered for up to one 
additional year. 
 
Visit requirements are outlined in Section 4.0.

Addendum 5 
48  
RU021502I 
 
14.0 
Body Fluid Biospecimens   
 
14.1Summary Table of Research Blood/Blood Products to Be Collected for This Protocol  
 
Specimen 
mandatory 
or 
optional? 
Collection 
Tube 
Volume to 
collect per 
tube 
(number of 
tubes to be 
collected) 
Blood 
product 
being 
processed 
and 
submitted 
Baseline  
 
 
 
 
 
 
Cycles 1-4 
and 8 
 
 
 
 
End 
of 
Treat
ment  
Additional 
processing 
required 
at site 
after 
draw? 
Storage/ 
shipping 
conditions1 
Analysis Plan 
Mandatory 
Sodium 
heparin 
10 mL (6) 
Whole 
blood 
X  
 
 
X 
 
 
 
X 
No 
Room 
(ambient) 
temperature 
– DO NOT 
FREEZE 
Immunological 
analyses, 
germline DNA, 
and optional 
banking 
Mandatory 
Streck cell 
free DNA 
BCT 
10 mL (2) 
plasma 
X  
 
X 
 
X 
Yes 
Room 
(ambient) 
temperature 
– DO NOT 
FREEZE 
Cell free DNA 
analysis 
*Note: Blood draws should not be collected and submitted until after the patient is registered/randomized to the study. 
 
After all samples have been processed according to kit instructions, ship all specimens according to shipping instructions (see Section 
14.27 for detailed shipping instructions).  
 
14.2 
Kits will be used for this study and will contain supplies for collecting and shipping specimens. 
 
14.21 Participating institutions may obtain kits by e-mailing 
 at 
 
 
E-mail requests should include the site address and phone number, contact information and number of kits being 
requested. 
 
14.22 Kits will be sent via FedEx® Ground at no additional cost to the  participating institutions. Please allow 1-2 weeks to 
receive the kits. 
 

Addendum 5 
49  
RU021502I 
 
14.23    Specimens may be collected Monday through Thursday.  If a Friday collection is needed please make arrangements with 
 ahead of time to make arrangements (1-2 weeks prior, if possible).  
 
14.24  Label specimen tubes with protocol number, ACCRU patient ID number, and time and date blood drawn. 
 
14.25  Collect all blood/blood products according to specific kit instructions.  
 
14.26 Any questions concerning sample collection and shipments can be directed to 
 at the Research Base by 
phone 
 or e-mail 
 
 
14.27 Shipping  
 
14.271 Verify ALL sections of the ACCRU Blood Specimen Submission Form, and specimen collection labels are 
completed and filled in correctly.  Enter information from the ACCRU Blood Specimen Submission Form into the 
remote data entry system ≤7 days after specimen collection (see Forms Packet). 
 
14.272 Send heparin tubes and Streck cell free DNA ambient or at room temperature to:   
 
 
 
 
 
 
14.273 Notify Michael Thompson at the Research Base by phone 
 or e-mail 
that blood has been shipped. 
 
14.3Study Methodology and Storage Information 
 
14.31 Blood/blood product samples will be collected for the following research  
 
14.311 Nucleic acid extraction and storage of DNA and/or RNA for future pharmacogenetic assays will be performed by 
 laboratory,   
 
 will store DNA will be 
stored frozen at -70ºC, according to patient consent information (see Section 6.5) until specific analyses are 
identified.  As protocols are developed, they will be presented for ACCRU and IRB review and approval.  (This 
collection is part of a general strategy of investigation for the majority of ACCRU studies.) 

Addendum 5 
50  
RU021502I 
 
 
14.312 A portion of the serum/plasma will initially be analyzed for the presence of immunologic markers and cell free 
DNA in 
 laboratory using standard laboratory protocols.  According to patient consent information 
(see Sections 6.2 and 6.5), remaining serum/plasma will be stored frozen at -70ºC by BAP, until specific analyses 
are identified.  As protocols are developed, they will be presented for ACCRU and IRB review and approval.  
(This collection is part of a general strategy of investigation for the majority of ACCRU studies.) 
 
14.4 
Return of Genetic Testing Research Results 
 
 
If, at any time, genetic results are obtained that may have clinical relevance, IRB review and approval will be sought regarding the 
most appropriate manner of disclosure and whether or not validation in a CLIA-certified setting will be required.  Sharing of 
research data with individual patients should only occur when data have been validated by multiple studies and testing has been 
done in CLIA-approved laboratories.

Addendum 5 
51  
RU021502I 
 
15.0 
Drug Information 
 
 
15.1 
Pembrolizumab (Keytruda®) - IND #130955 
 
 
 
Investigator Brochure available on the ACCRU web site. 
 
 
  
15.11 Background: Pembrolizumab is a potent humanized IgG4 monoclonal antibody 
with high specificity of binding to the PD-1 receptor thus inhibiting its 
interaction with PD-L1 and PD-L2. Based on preclinical in vitro data, 
pembrolizumab has a high affinity and potent receptor blocking activity for PD-
1. 
 
15.12 Formulation: Pembrolizumab is available as a liquid, 25mg/ml (4ml), 100 
mg/vial. Pembrolizumab is available as for subcutaneous injection as 165 mg/mL 
and 130 mg/mL liquid sterile solutions. 
 
15.13 Preparation and storage: Vials should be stored in the refrigerator at 
temperatures between 2°C to 8°C. Drug concentrate is further diluted with 
normal saline (or 5% dextrose) in the concentration range of 1 to 10. 
mg/mL The infusion solution in the IV bag should be immediately 
administered. Diluted pembrolizumab should be stored at room 
temperature for a cumulative period of up to 6 hours. This includes room 
temperature storage of admixture solutions in the IV bags and the duration 
of infusion. In addition, IV bags can be stored at 2°C to 8°C for a 
cumulative time of 24 hours. This 24-hour total hold time from 
reconstitution may include up to 6 hours at room temperature. IV bags 
must be allowed to come to room temperature before use. 
 
15.14 Administration:  Pembrolizumab is administered by intravenous infusion over 
30 minutes through a 0.22 micron in-line filter. The final infusion volume must 
be between 1 and 10 mg/mL. Maximum rate of infusion should not exceed 6.7 
mL/minute through a peripheral or indwelling catheter. Flush the line with 0.9% 
NaCL following the completion of the infusion. 
 
15.15 Pharmacokinetic information: 
 
 
Absorption – Because Pembrolizumab is administered intravenously, it is 
immediately and completely bioavailable. Steady-state concentrations of 
Pembrolizumab are reached by 16 weeks of repeated dosing with a Q3 
regimen and the systemic accumulation is 2.1-fold. The peak 
concentration, trough concentration, and area under the plasma 
concentration versus time curve at steady state of pembrolizumab 
increased dose proportionally in the dose range of 2 to 10 mg/kg Q3W. 
 
 
Distribution – Pembrolizumab has a limited volume of distribution.  
 
 
Excretion – The terminal elimination half-life (t½) is estimated to be 22 days 
at steady state. 
 
 
Metabolism – Pembrolizumab is catabolized through non-specific 
pathways; metabolism does not contribute to its CL. 

Addendum 5 
52  
RU021502I 
 
 
15.16 Potential Drug Interactions:  There are no known significant drug 
interactions. 
 
15.17 Known potential toxicities:   
 
 
Very common known potential toxicities, ≥10%: 
Gastrointestinal disorders; diarrhea, nausea, abdominal pain 
Skin and subcutaneous tissue disorders; rash, pruritis 
General disorders and administration site conditions: fatigue 
 
  
Common known potential toxicities, ≥1%≤10%:   
 
 
Blood and lymphatic system disorders; anemia 
Immune system disorders: infusion related reaction 
 
Endocrine disorders: hyperthyroidism, hypothyroidism 
Metabolism and nutrition disorders: decreased appetite 
Nervous system disorders: headache, dizziness, dysgeusia 
Respiratory, thoracic, and mediastinal disorders: pneumonitis, dyspnea, 
cough 
Gastrointestinal disorders: colitis, vomiting, constipation, dry mouth 
Skin and subcutaneous tissue disorders: severe skin reactions,  
vitiligo, dry skin, erythema 
Musculoskeletal and connective tissue disorders: arthralgia,  
myositis, musculoskeletal pain, pain in extremity 
 
General disorders and administration site conditions: asthenia,  
edema, pyrexia, influenza like illness, chills 
Investigations: alanine aminotransferase increased, aspartate  
aminotransferase increased, blood alkaline phosphatase increased, blood 
creatinine increased 
 
 
Uncommon known potential toxicities, ≥0.1% - 1%: 
 
Infusion related reactions:  
Blood and lymphatic system disorders: neutropenia, thrombocytopenia, 
leukopenia, lymphopenia, eosinophilia 
Endocrine disorders: hypophysitis, adrenal insufficiency, thyroiditis, 
hypopituitarism 
Metabolism and nutrition disorders: type I diabetes mellitus, 
hyponatremia, hypokalemia, hypocalcemia 
Psychiatric disorders: insomnia, confusional state 
 
 
 
Nervous system disorders: epilepsy, lethargy, peripheral  
neuropathy 
Eye disorders: uveitis, dry eye 
Cardiac disorders: myocarditis, atrial fibrillation 
Vascular disorders: hypertension 
Gastrointestinal disorders: pancreatitis 
Hepatobiliary disorders: hepatitis 
Skin and subcutaneous tissue disorders: lichenoid keratosis, psoriasis, 
alopecia, dermatitis, dermatitis acneiform, eczema, hair color changes, 
papule 

Addendum 5 
53  
RU021502I 
 
Musculoskeletal and connective tissue disorders: tenosynovitis 
Renal and urinary disorders: nephritis, acute kidney injury 
Investigations: blood bilirubin increased, amylase increased, 
hypercalcemia 
 
 
Rare known potential toxicities, <0.1% (Limited to important or life-
threatening): 
 
 
Blood and lymphatic system disorders: immune thrombocytopenic 
purpura, hemolytic anemia 
 
 
Immune system disorders: sarcoidosis 
Nervous system disorders: Guillain-Barre syndrome, myasthenic syndrome 
Gastrointestinal disorders: small intestinal perforation, exacerbation of 
myasthenia gravis 
Skin and subcutaneous tissue disorders: toxic epidermal necrolysis, Stevens-
Johnson syndrome, erythema nodosum 
 
The risk profile for Pembrolizumab also includes two important potential 
risks: a) myasthenic syndrome, and b) an increased risk of severe 
complications (such as early severe graft versus host disease and veno 
occlusive disease) of allogeneic transplant in patients with hematologic 
malignancies who have previously been treated with PD-1 inhibitors.  
 
Patients with multiple myeloma who were treated with pembrolizumab in 
combination with either pomalidomide or lenalidomide and 
dexamethasone, had an increased number of serious side effects and deaths 
as compared to patients who received only dexamethasone and either 
pomalidomide or lenalidomide. The benefit-risk profile is unfavorable for 
the combination of pembrolizumab, pomalidomide, and dexamethasone in 
relapsed refractory multiple myeloma, and the combination of 
pembrolizumab, lenalidomide, and dexamethasone in newly diagnosed 
treatment-naive multiple myeloma. 
 
Post marketing reports identified Vogt-Koyanagi-Harada syndrome and 
hemophagocytic lymphohistiocytosis. 
 
15.18 Drug procurement:   
Each participating ACCRU treating location will be responsible for monitoring 
the supply of pembrolizumab and will use the Drug Order Request Form on the 
ACCRU web site to order additional supplies as needed. Before registration of 
first patient fax a drug order request form to procure a starter supply. Fax the 
completed form to the following: 
 
Clinical Research Services, a division of Rx Crossroads by McKesson  
Fax: 
  
 
Outdated or remaining drug is to be destroyed on-site as per procedures in place 
at each institution. 
 

Addendum 5 
54  
RU021502I 
 
15.19  Nursing guidelines:    
 
15.191 Pembrolizumab side effects vary greatly from those of traditional 
chemotherapy and can vary in severity from mild to life threatening. 
Instruct patients to report any side effects to the study team immediately. 
Side effects may be immediate or delayed up to months after 
discontinuation of therapy. Most side effects are reversible with prompt 
intervention of corticosteroids. 
15.192 Diarrhea can be seen, however, it is less common than that seen with 
anti-CTLA-4 agents. However it can be severe, leading to colonic 
perforation. Instruct patients to report ANY increase in the number of 
stools and/or change in baseline, blood in the stool, abdominal pain to the 
study team immediately.  
15.193 Rash/pruritis/dermatitis is seen. Patients should report any rash to the 
study team. Treat per section 9.0 and monitor for effectiveness.  
15.194 Monitor LFT’s closely as elevations in these levels could indicate early 
onset autoimmune hepatitis. Patients should also be instructed to report 
any jaundice, or right upper quadrant pain to the study team immediately. 
15.195 Pneumonitis can be seen and may be mild (only seen on imaging) to 
severe. Patients should be instructed to report any shortness of breath, 
dyspnea, cough, chest pain, etc. to the study team immediately. Patients 
reporting these symptoms should have a pulse oximetry checked and 
consider immediate imaging per the treating physician. 
15.196 Endocrinopathies (including hypopituitarism, hypothyroidism, 
hypophysitis, and adrenal insufficiency) are seen with this agent. Patients 
may present only with the vague sense of fatigue and “not feeling well.” 
Additional symptoms may be that of nausea, sweating and decreased 
activity tolerance. Instruct patients to report these signs or symptoms 
immediately and obtain appropriate labs as ordered by the treating 
physician.  
15.197 Patients who are started on steroid therapy for any side effects of 
pembrolizimab toxicity should be instructed to take the steroids as 
ordered, and not to discontinue abruptly as symptoms may return and be 
severe. Patients may be on steroid therapy for weeks. Instruct patients to 
report any increase or change in side effects with any dosage decrease as 
patients may need a slower taper.  
15.198 Fatigue is common and may or may not be associated with immune 
related side effects. Assess patient’s fatigue level prior to each cycle of 
therapy and report any changes to the study team. 
15.199a Patients should avoid receiving live vaccines within 30 days of study 
drug administration or per other study guidelines.  
15.199b Patients who have undergone an allogenic bone marrow transplant, have 
an increased risk of severe complications including early GVHD, and 
veno-occlusive disease, if they have previously been treated with 
pembrolizumab. 
15.199c Myocarditis has been reported and associated with pembrolizumab. 
Instruct patients to report chest pain, shortness of breath, or dyspnea to 
study team immediately and/or seek emergency medical attention. 
15.199d Autoimmune hematologic disorders including ITP and hemolytic 
anemia have been reported. Monitor blood counts closely and report any 
abnormalities to the study team. 

Addendum 5 
55  
RU021502I 
 
15.199e Rare neurologic disorders including Guillain-Barre syndrome and 
myasthenia gravis have been reported. Instruct patients to report any 
neurologic symptoms including weakness, parathesias or numbness, 
tingling to the study team immediately. 
 
 
16.0  
Statistical Considerations and Methodology  
 
16.1 Study Overview   
This study will assess the confirmed response rate associated   with Pembrolizumab (MK-
3475) in small bowel adenocarcinoma. Additional endpoints consist of progression-free 
survival (PFS), overall survival (OS), and adverse events.  Translational endpoints will be 
assessed as well using an exploratory analysis, given the small sample size.   
 
16.2 Primary Endpoint   
This study will assess the confirmed response rate associated with MK-
3475/Pembrolizumab in small bowel adenocarcinoma.  Confirmed response rate will be 
defined as meeting RECIST 1.1 criteria on two consecutive evaluations at least 4 weeks 
apart.  Confirmed response will be evaluated using the first year of treatment (first 18 
cycles of treatment). All patients meeting the eligibility criteria who have a signed consent 
form and have begun treatment will be evaluable for response.   
 
16.3   Study Design for Primary Endpoint   
 
 16.31 
Ho vs. Ha Hypothesis for the Primary Endpoint  
To evaluate the confirmed response rate we will be using a 1-stage design to test 
the hypothesis of the treatment being ineffective (Ho: p< 10%) vs. the hypothesis 
of the treatment being clinically effective (Ha: p > 30%).  
   
 
16. 32  
Final Analysis Decision Rule  
 
Enter a total of 35 evaluable patients.  If 6 or fewer of these 35 patients have a 
confirmed response, we will conclude that this treatment is insufficiently active 
in this population.  If 7 or more of these 35 patients have a confirmed response 
(20%), this will be considered adequate evidence of efficacy of this treatment and 
may be recommended for further testing in subsequent studies.   
 
 
16.33  
Sample Size and Power   
 
We anticipate accruing an additional 5 patients to account for ineligibilities, 
cancellations, major violations, or other reasons. Therefore, maximum accrual is 
41 patients. This design has a significance level of 0.06 when the confirmed 
response rate is 10%, and 94% power to detect a confirmed response rate of 30%.  
 
16.4 
Total Sample Size   
 
35 evaluable patients will be enrolled, if the study reaches full accrual.  We anticipate 
accruing an additional 5 patients to account for ineligibility’s, cancellations, major 
violations, or other reasons. Therefore, maximum accrual is 41 patients. 
 

Addendum 5 
56  
RU021502I 
 
16.5 
Accrual time and Study Duration  
 
The anticipated accrual rate is approximately 3 patients per month.  Therefore, the 
accrual period for this phase II study is expected to be approximately 14 months, if the 
study goes to full accrual.  The final analysis can begin approximately 30 months after 
the trial begins, i.e. as soon as the last patient has been monitored for 12 months plus data 
clean-up and analysis.   
 
16.6  
Secondary endpoints   
 
These endpoints include progression-free survival (PFS), overall survival (OS), and 
adverse events.  
• 
Progression-free survival (PFS) is defined as the time from study entry to the first of 
either disease progression or death from any cause, where disease progression will be 
determined based on RECIST 1.1 criteria.  PFS will be estimated using the Kaplan-
Meier method.      
• 
Overall survival (OS) is defined as the time from study entry to death from any 
cause.  OS will be estimated using the Kaplan-Meier method.    
• 
Adverse events:  The maximum grade for each type of adverse event will be 
summarized using CTCAE version 4.03.  The frequency and percentage of grade 3+ 
adverse events will be summarized.   
 
16.7 
Translational studies   
 
All translational research will be exploratory and hypothesis generating due to the small 
sample size.  We will correlate clinical data (i.e. response, OS, PFS, adverse events) with 
translational marker data (i.e. MMR/MSI, PDL1 expression, Cell free DNA, genetic 
sequencing data, blood markers, Bim levels, T cell markers, sPD-L1, total mutational 
burden, etc.).  These correlations will be done using the Chi-square or Fisher’s exact test 
for categorical data and Kaplan-Meier methods (including the log-rank test) for the 
survival endpoints.   Univariate Cox regression models will also be done to assess for 
marker effects on survival endpoints.  Descriptive statistics and graphical methods will be 
used to summarize the data as well.  All these analyses will be done overall and by 
MMR/MSI status.    
 
Genetic/genomic testing performed for clinical purposes will be requested for patients 
from the local sites, and will be deidentified for inclusion in analyses. 
 
16.8 
Data & Safety Monitoring 
 
The principal investigator(s) and the study statistician will review the study at least twice 
a year to identify accrual, adverse event, and any endpoint problems that might be 
developing. The trial is monitored continually by the study team who are notified of 
every grade 4 and 5 event in real time. The Mayo Clinic Cancer Center (MCCC) Data 
Safety Monitoring Board (DSMB) is responsible for reviewing accrual and safety data for 
this trial at least twice a year, based on reports provided by the MCCC Statistical Office.  
 
16.9a AE Stopping Rule  
 
The stopping rule specified below is based on the knowledge available at study 
development. We note that the Adverse Event Stopping Rule may be adjusted in the event 

Addendum 5 
57  
RU021502I 
 
of either (1) the study re-opening to accrual after any temporary suspension or (2) at any 
time during the conduct of the trial and in consideration of newly acquired information 
regarding the adverse event profile of the treatment(s) under investigation. The study team 
may also choose to suspend accrual because of unexpected adverse event profiles that 
have not crossed the specified rule below. 
Accrual will be temporarily suspended to this study if at any time we observe events 
considered at least possibly related to study treatment (i.e., an adverse event with attribute 
specified as "possible", "probable", or "definite") that satisfy any of the following criteria 
across both cohorts combined.   
 
• 
If at any time, 4 of the initial 10 treated patients or 40% or more of all patients (i.e. 
when accrual is greater than 10 patients) have experienced a grade 4 non-hematologic 
adverse event.  
• 
If at any time, 2 patients have experienced a grade 5 adverse event (non -progressive 
disease). 
• 
In addition, each grade 5 event will be reviewed on a case by case basis in a real time 
fashion to determine whether study accrual should be suspended.  We may suspend 
accrual after just 1 grade 5 AE, if needed. 
 
16.9b Accrual Monitoring Stopping Rule   
 
Given the expected accrual rate is around 3 patients per month, it is expected that the study 
will take around 14 months to fully accrue.  We plan to monitor the accrual continually 
and if we only end up accruing 5 patients or less in the first year (after study activation), 
we will consider stopping the trial for slow accrual. 
 
16.9c 
Primary Endpoint Completion Time Estimation (For clinicaltrails.gov reporting)   
 
The primary endpoint is the confirmed response rate, evaluated over the first year of 
treatment.  The final analysis is expected to take place around 30 months after the study 
begins, so we expect that the primary endpoint completion time to be around 30 months 
after study activation.    
 
16.9d Inclusion of Women and Minorities   
 
This study will be available to all eligible patients, regardless of race, gender, or ethnic 
origin.  There is no information currently available regarding differential effects of this 
regimen in subsets defined by race, gender, or ethnicity, and there is no reason to expect 
such differences to exist.  Based on prior studies involving similar disease sites, we 
expect about 10% of patients will be classified as minorities by race and about 30% of 
patients to be women.  Expected sizes of racial by gender subsets are shown in the 
following table: 
 
Accrual Targets 
Ethnic Category 
Sex/Gender 
Females 
Males 
Total 
Hispanic or Latino 
0 
0 
0 
Not Hispanic or Latino 
13 
28 
41 
Ethnic Category: Total of all subjects 
13 
28 
41 
Racial Category 

Addendum 5 
58  
RU021502I 
 
Accrual Targets 
Ethnic Category 
Sex/Gender 
Females 
Males 
Total 
American Indian or Alaskan Native 
1 
0 
1 
Asian 
0 
1 
1 
Black or African American 
0 
1 
1 
Native Hawaiian or other Pacific Islander 
0 
1 
1 
White 
11 
25 
36 
Racial Category: Total of all subjects 
13 
28 
41 
 
Ethnic 
Categories: 
Hispanic or Latino – a person of Cuban, Mexican, Puerto Rican, South or Central 
American, or other Spanish culture or origin, regardless of race. The term “Spanish 
origin” can also be used in addition to “Hispanic or Latino.” 
Not Hispanic or Latino 
Racial 
Categories: 
American Indian or Alaskan Native – a person having origins in any of the original 
peoples of North, Central, or South America, and who maintains tribal affiliations or 
community attachment. 
Asian – a person having origins in any of the original peoples of the Far East, 
Southeast Asia, or the Indian subcontinent including, for example, Cambodia, China, 
India, Japan, Korea, Malaysia, Pakistan, the Philippine Islands, Thailand, and 
Vietnam. (Note: Individuals from the Philippine Islands have been recorded as Pacific 
Islanders in previous data collection strategies.)  
Black or African American – a person having origins in any of the black racial 
groups of Africa. Terms such as “Haitian” or “Negro” can be used in addition to 
“Black or African American.” 
Native Hawaiian or other Pacific Islander – a person having origins in any of the 
original peoples of Hawaii, Guam, Samoa, or other Pacific Islands. 
White – a person having origins in any of the original peoples of Europe, the Middle 
East, or North Africa. 
 
 
 

Addendum 5 
59  
RU021502I 
 
17.0  
Pathology Considerations/Tissue Biospecimens  
 
17.1 
Tissue Biospecimen Submission 
 
  
17.11 Summary Table of Tissue Biospecimens for This Protocol 
If an institution is not able to provide the tissue, it does not cause the patient to be 
ineligible; however, the collection of these tissues is strongly recommended. 
 
17.2 
Paraffin Embedded Tissue Blocks/Slides (mandatory for research tissue) 
 
17.21 
Submit one formalin fixed paraffin-embedded (FFPE) tumor tissue block from 
the primary or recurrent/metastatic Small Bowel Adenocarcinoma. A 
corresponding H&E slide from the submitted block must be provided to permit 
quality assessment (QA) of tissue block. 
 
17.22 
The FFPE tissue block is preferred; however, if an institution is unable to 
provide a tissue block, cut 20 five-micron unstained slides and mount on 
charged glass slides and 10 ten-micron unstained slides mounted on uncharged 
slides. Label the slides with the ACCRU patient ID number, accession 
number, and order of sections (i.e., 1-11).  H&E stain the first cut slide 
(i.e., slide labeled 1). Please do not re-label over the original label.  For 
samples containing less than 7square millimeters of tumor tissue, multiple 
sections should be mounted onto each slide to ensure that the appropriate 
amount of tumor tissue is available. Ideally, each slide must have a minimum 
of 75% tumor tissue on the slide to be deemed adequate for study. Do not bake 
or place cover slips on the slides.  
 
 
 
 
 
Type of tissue 
biospecimen 
to submit 
 
 
 
Mandatory or 
optional 
 
 
 
When to 
submit 
 
 
Reason for submission 
(background/methodology 
section) 
Where to 
find specific 
details for  
biospecimen 
submission 
  
  
   
    
  
Formalin-fixed 
paraffin-
embedded 
(FFPE) tissue 
blocks with 
corresponding 
H&E OR 30 
5- or 10-
micron 
unstained 
slides with 
corresponding 
H&E) 
*Can be 
archival tissue 
Mandatory 
≤60 days 
after 
registration 
Correlative studies (Section 
17.3) 
Section 17.2 

Addendum 5 
60  
RU021502I 
 
17.23 
The following materials below are mandatory (unless indicated otherwise) and 
required for shipment: 
 
• 
Paraffin embedded tissue blocks with corresponding H&E (or 30 slides) 
per instructions in section 17.22 
 
• 
Research Tissue Specimen Submission Form 
 
• 
Surgical Pathology Report 
 
• 
Operative Report-Optional 
 
17.24 
Ship all block/slide tissue specimens and accompanying materials to the 
following: 
 
 
 
 
 
17.3 
Study Methodology and Storage Information 
 
17.31 Tissue microarray testing. FFPE tumor tissue blocks/slides will be collected in 
order to assess correlation of responses to treatment with PDL1 staining by 
immunohistochemistry (IHC).  For tissue blocks received, tissue microarrays 
(TMAs) may be constructed and analyzed.  For TMA constructions, the donor 
block remains intact except for 6 small (0.6mm) holes where the cores were 
taken.  This process has minimal impact on the utility of the block for future 
clinical diagnostic needs.  TMA construction and IHC stains will be performed in 
the Pathology Research Core Lab, Mayo Clinic Rochester.  FISH analyses will 
be performed in the laboratory of 
. 
 
17.32 Immunohistochemical analyses. The following protein biomarkers will be 
assessed by immunohistochemistry (IHC) on tumor samples obtained at baseline: 
 
• 
MMR (MLH1, MSH2, MSH6, PMS2) 
• 
PDL1 staining  
• 
Lymphocyte-specific markers (CD4, CD8, Bim, etc.) 
 
PD-L1 staining will be performed. All other IHC testing will be performed in the 
laboratory of 
 
  Analysis of 
all IHC slides, pathologic assessment will be performed by 
 
 
17.33 Nucleic acid analyses. PCR analysis for DNA mismatch repair 
deficiency/microsatellite insufficiency will be performed retroactively at the 
central lab on all tissue samples using the Promega MSI Analysis assay.    

Addendum 5 
61  
RU021502I 
 
 
Genomic analyses (whole exome, RNA-Seq, etc.) may be performed at a future 
date for further characterization of total mutational burden, biomarkers, etc. DNA 
and/or RNA will be extracted and stored as stated in 17.54. 
 
17.34 At the completion of the study, any unused/remaining material will be stored in 
the ACCRU Central Operations Office (Attn:  Pathology Coordinator) for future 
research according to the patient consent permission (see Section 6.0).  Potential 
future research may include immunohistochemistry (IHC) analyses, DNA 
extraction, and/or tissue microarray (TMA) construction to analyze predictive 
biomarkers, changes in expression pattern with therapy, and correlation with 
response and/or adverse events.  For TMAs, the donor block remains intact 
except for 6 small (0.6mm) holes where the cores were taken.  This process has 
minimal impact on the utility of the block for future clinical diagnostic needs. 
When a protocol is developed, it will be presented for IRB review and approval. 
 
17.35 Banking of tumor tissue, according to the patient consent permission     is for 
future research.  As protocols are developed, they will be presented for ACCRU 
and IRB review and approval.  (This collection is part of a general strategy of 
investigation for Mayo Clinic Cancer Center studies.) 
 
17.36 The institutional pathologist will be notified by the ACCRU Operations Office 
(Pathology Coordinator) if the block may be depleted. 
 
17.37 Blocks requested to accommodate individual patient management will be  
returned promptly upon request. 
 
17.4 
Return of Genetic Testing Research  
 
Because the results generated by the genetic testing included in this section are not 
currently anticipated to have clinical relevance to the patient or their family members, the 
genetic results will not be disclosed to the patients or their physicians. 
 
If, at any time, genetic results are obtained that may have clinical relevance, IRB review 
and approval will be sough regarding the most appropriate manner of disclosure and 
whether or not validation in a CLIA certified setting will be required.  Sharing of research 
data with individual patients should only occur when data have been validated by 
multiple studies and testing has been done in CLIA-approved laboratories. 

Addendum 5 
62  
RU021502I 
 
18.0 
Records and Data Collection Procedures 
 
All data must be entered by Remote Data Entry (RDE) and completed by qualified and authorized 
personnel. Access the RAVE RDE system through the iMedidata portal at 
.  All data on the CRF must reflect the corresponding source document.  
Please refer to the ACCRU website for instructions 
.  NOTE: All reports 
must be de-identified and labeled with the study number, ACCRU patient ID number and initials. 
 
18.1 Submission Timetables 
 
Initial Material(s) -  
CRF 
 
 
Active-Monitoring Phase 
(Compliance with Test Schedule Section 4.0) 
 
On-Study   
 
 
 
 
≤2 weeks  after registration 
Adverse Event Baseline   
 Research Blood Submission - Baseline  
(see Section 14.0)  
Research Tissue Submission - Baseline  
(see Section 17.0) 
Concomitant Medication - Baseline   
  Path Reporting  (see Section 17.0)1 
RECIST Measurement – Baseline  
End of Active Treatment/Cancel Notification   
Submit ≤2 weeks  after registration if withdrawal/refusal 
occurs prior to beginning protocol therapy 
1.  Attach a copy of OP and path reports in RAVE using the Supporting Documentation Form for 
documentation of disease. This is in addition to the pathology material requirements for tissue 
submission (Section 17.0) 
Test Schedule Material(s) 
CRF 
Active-Monitoring Phase 
(Compliance with Test Schedule Section 4.0) 
 
At each evaluation during 
treatment 
At end of treatment 
  
Evaluation/Treatment   
X2 
X 
Adverse Event Form 
X 
X 
RECIST Measurement   
X1 
X1 
Research Blood Submission   
X (see Section 14.0) 
 
Pathology Submission  
 
 
Concomitant Medication   
X 
X 
End of Active Treatment/Cancel Notification 
Form 
 
X 
Deviation Form3 
X 
 
ADR/AER 
At each occurrence 
(see Section 10.0) 
 

Addendum 5 
63  
RU021502I 
 
1. Attach a copy in RAVE for documentation of response or progression on the Supporting 
Documentation Form. 
2. Complete at each evaluation during Active Treatment (see Section 4.0).  
3. Submit only if applicable. 
 
 
Follow-up Materia(s) 
CRF 
Event Monitoring Phase1 
 
 
q. 3  
months 
until PD 
 
 
 
At PD 
After 
PD  
q. 6 
mos. 
 
 
 
Death 
 
 
 
New Primary 
Event Monitoring Form 
X2 
X2 
X 
X 
At each occurrence 
1. If a patient is still alive 5_years after registration, no further follow-up is required. 
2. Attach a copy in RAVE for documentation of progression on the Supporting Documentation Form. 
 
19.0  
Budget 
 
19.1 
Each site should review the test schedule (Section 4.0), taking into account local and 
regional coverage policies, to determine which items are standard of care and which are 
research at their site.  Refer to the payment synopsis for funding provided per accrual for 
covering study costs, as well as any additional invoiceables that may be allowed. 
 
 
19.2 
Tests to be research funded:  
 
19.21 Mandatory blood samples done for research. 
 
19.22 Mandatory blood samples done for future research.  
 
19.3 
Other budget concerns: The study agent, pembrolizumab will be provided by Merck at no 
charge. 
 
 

Addendum 5 
64  
RU021502I 
 
20.0 
References 
 
Aparicio, T., M. Svrcek, et al. (2013). "Small bowel adenocarcinoma phenotyping, a 
clinicobiological prognostic study." British journal of cancer 109(12): 3057-3066. 
 
Daud, A., A. Ribas, et al. (2015). Long-term Efficacy of Pembrolizumab in a Pooled Analysis of 
655 Patients with Advanced Melanoma Enrolled in KEYNOTE-001. ASCO Annual Meeting, 
Chicago, IL. 
 
Gibson, M. K., C. A. Holcroft, et al. (2005). "Phase II study of 5-fluorouracil, doxorubicin, and 
mitomycin C for metastatic small bowel adenocarcinoma." The oncologist 10(2): 132-137. 
 
Gonsalves, W. I., M. R. Mahoney, et al. (2014). "Patient and tumor characteristics and BRAF and 
KRAS mutations in colon cancer, NCCTG/Alliance N0147." Journal of the National Cancer 
Institute 106(7). 
 
Laforest, A., T. Aparicio, et al. (2014). "ERBB2 gene as a potential therapeutic target in small 
bowel adenocarcinoma." European journal of cancer 50(10): 1740-1746. 
 
Le, D. T., J. N. Uram, et al. (2015). "PD-1 Blockade in Tumors with Mismatch-Repair 
Deficiency." The New England journal of medicine 372(26): 2509-2520. 
 
Lowenfels, A. B. (1973). "Why are small-bowel tumours so rare?" Lancet 1(7793): 24-26. 
 
McWilliams, R. R., M. R. Mahoney, et al. (2012). Pharmacogenetic dosing by UGT1A1 genotype 
as first-line therapy for advanced small-bowel adenocarcinoma: A North Central Cancer 
Treatment Group (NCCTG) trial. Gastrointestinal Cancers Symposium, San Francisco, CA. 
 
Missiaglia, E., B. Jacobs, et al. (2014). "Distal and proximal colon cancers differ in terms of 
molecular, pathological, and clinical features." Annals of oncology : official journal of the 
European Society for Medical Oncology / ESMO 25(10): 1995-2001. 
 
Overman, M. J., G. R. Varadhachary, et al. (2009). "Phase II study of capecitabine and oxaliplatin 
for advanced adenocarcinoma of the small bowel and ampulla of Vater." J Clin Oncol 27(16): 
2598-2603. 
 
Thompson, R. H., M. D. Gillett, et al. (2004). "Costimulatory B7-H1 in renal cell carcinoma 
patients: Indicator of tumor aggressiveness and potential therapeutic target." Proceedings of the 
National Academy of Sciences of the United States of America 101(49): 17174-17179. 
 
Wolchok, J. D., A. Hoos, et al. (2009). "Guidelines for the evaluation of immune therapy activity 
in solid tumors: immune-related response criteria." Clinical cancer research : an official journal of 
the American Association for Cancer Research 15(23): 7412-7420. 
 
Xiang, X. J., Y. W. Liu, et al. (2012). "A phase II study of modified FOLFOX as first-line 
chemotherapy in advanced small bowel adenocarcinoma." Anti-cancer drugs 23(5): 561-566.