Conditions: Neuroendocrine Tumors
Keywords: Metastatic High grade
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 21
Healthy volunteers: no

Brief summary:
The purpose of this research study is to test if pembrolizumab is safe and effective for treating patients with metastatic high-grade neuroendocrine tumors who have failed platinum based chemotherapy.The study drug, pembrolizumab has been FDA approved for treating a type of skin cancer called melanoma and for metastatic non-small cell lung cancer. However, it is not approved for treatment of metastatic high-grade neuroendocrine tumors.

Detailed description:

Arms:
arm 1: Monotherapy with PD-1 antibody pembrolizumab

Interventions: intervention 1: Pembrolizumab
Intervention descriptions: intervention 1: Pembrolizumab given intravenously at a fixed dose of 200mg every 3 weeks

Protocol document:
Prot_SAP_000.pdf: 
Copyright© 2016 Fox Chase Cancer Center® Clinical Trials Operations.  All rights reserved. 
Version Date 03/03/17 
i 
 
 
 
GI-087 A Phase 2, Open-label Study of Pembrolizumab Monotherapy in Patients 
with Previously Treated Metastatic High Grade Neuroendocrine tumors 
 
 
Supported by (Merck) 
 
 
 
Sponsor Investigator: 
 
Namrata Vijayvergia 
                                                            Fox Chase Cancer Center 
 
 
 
 
 
333 Cottman Ave 
Philadelphia, PA 19111 
 
 
 
 
 
Suite C307 
 
 
 
 
 
Phone: 215-214-4283 
 
 
 
 
 
Fax: 215-728-6900 
 
 
 
 
 
Email: Namrata.Vijayvergia@fccc.edu 
 
Co-Investigators: 
 
 
Paul F Engstrom, MD 
 
 
 
 
 
Fox Chase Cancer Center 
 
 
 
 
 
333 Cottman Ave 
Philadelphia, PA 19111 
 
 
 
 
 
Phone: 215-728-2989 
 
 
 
 
 
Fax: 215-728-3639 
 
 
 
 
 
Email: Paul.Engstrom@fccc.edu 
 
Sub-Investigators: 
 
 
Efrat Dotan, MD 
 
 
 
 
 
Crystal S Denlinger, MD 
 
 
 
 
 
Igor Astsaturov, MD PhD 
 
 
 
 
 
Michael J Hall, MD 
 
 
 
 
 
Wafik El-Deiry, MD PhD 
 
 
 
 
 
Correlative Studies: 
Kerry Campbell, PhD  
 
 
Fox Chase Cancer Center 
 
333 Cottman Avenue  
 
Philadelphia PA  19111 
 
Phone: 215-728-7761 
 
Email: kerry.campbell@fccc.edu 
 


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Statistician:  
 
 
Eric A. Ross, Ph.D. 
Fox Chase Cancer Center 
333 Cottman Ave. 
Philadelphia, Pa 19111 
Phone: (215)728-2891 
Fax: (215)728-2553 
Email: eric.ross@fccc.edu  
 
  
 
 
 
 
 
 
IND Number: 
 
130857 
 
Version Date: 03/03/17 
 
 
 


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Table of Contents 
1.0 Trial Summary 
vii 
2.0 Trial Design 
vii 
3.0 Objectives 
9 
 
Primary Objective 
9 
 
Secondary Objectives 
9 
 
Exploratory objectives 
9 
4.0 Introduction 
10 
 
Study Disease 
10 
 
Agent under Investigation/intervention 
10 
 
Pre-clinical and Clinical Trials: 
11 
 
Study Rationale 
11 
 
Rationale for Dose Selection/Regimen/Modification 
13 
 
Rationale for endpoints 
14 
4.6.1. 
Primary endpoint 
14 
4.6.2. 
Safety Endpoint 
14 
 
Rationale for Correlative Testing 
14 
5.0 Study Plan 
15 
 
Description of Study Design, Population and Duration of Study Therapy 
15 
 
Inclusion Criteria 
15 
 
Exclusion Criteria 
17 
 
Inclusion of Women and Minorities 
18 
 
Patient Registration 
18 
6.0 Treatment Plan 
19 
 
Trial Treatments 
19 
 
Dose Selection 
19 
 
Dose Administration 
19 
 
Concomitant Medications, Supportive Care, Excluded Therapies and Restrictions 
20 
6.4.1. 
Acceptable Concomitant Medications 
20 
6.4.2. 
Prohibited Concomitant Medications 
21 
6.4.3. 
Rescue Medications & Supportive Care 
22 
 
Diet/Activity/Other Considerations 
25 
6.5.1. 
Diet 
25 
6.5.2. 
Contraception 
25 
6.5.3. 
Use in Pregnancy 
26 


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6.5.4. 
Use in Nursing Women 
26 
 
Participant Withdrawal/Discontinuation Criteria 
27 
 
Discontinuation of Study Therapy after CR 
27 
 
Treatment beyond Disease Progression 
28 
7.0 Dose Modifications 
28 
 
General Principles 
28 
8.0 Trial Procedures 
30 
 
Administrative Procedures 
31 
8.1.1. 
Informed Consent 
31 
8.1.2. 
Inclusion/Exclusion Criteria 
31 
8.1.3. 
Medical History 
31 
8.1.4. 
Prior and Concomitant Medications Review 
31 
8.1.5. 
Disease Details and Treatments 
31 
 
Clinical Procedures/Assessments 
32 
8.2.1. 
Adverse Event (AE) Monitoring 
32 
8.2.2. 
Physical Exam 
32 
8.2.3. 
Vital Signs 
32 
8.2.4. 
Eastern Cooperative Oncology Group (ECOG) Performance Scale 
32 
8.2.5. 
Tumor Imaging and Assessment of Disease 
32 
8.2.6. 
Tumor Tissue Collection and Correlative Studies Blood Sampling 
32 
 
Laboratory Procedures/Assessments 
33 
8.3.1. 
Biomarker Evaluations 
34 
 
Other Procedures 
34 
8.4.1. 
Withdrawal/Discontinuation 
34 
 
Visit Requirements 
35 
8.5.1. 
Screening Period 
35 
8.5.2. 
Treatment Period 
35 
8.5.3. 
Post-Treatment Visits 
35 
8.5.4. 
Second Course Phase (Retreatment Period) 
36 
8.5.5. 
Treatment Beyond Disease Progression 
37 
9.0 Adverse Events 
38 
 
Definitions: 
38 
9.1.1. 
Adverse Events 
38 
9.1.2. 
Serious Adverse Events 
38 
9.1.3. 
Definition of Overdose for This Protocol 
39 
9.1.4. 
Severity Rating 
39 
9.1.4.1. 
Attribution/Relationship to study drug 
39 
9.1.5. 
Expectedness 
39 
9.1.6. 
Events of Clinical Interest 
40 
 
Assessing, Recording and Reporting Adverse Events 
40 
9.2.1. 
Investigative site recording responsibilities: 
40 
9.2.2. 
Investigative site reporting responsibilities: 
40 
9.2.3. 
Additional reporting guidelines for investigative sites: 
41 


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9.2.4. 
Sponsor Reporting Responsibilities: 
42 
9.2.5. 
Sponsor Reporting Responsibilities to Merck: 
43 
10.0 
Study Calendar 
44 
 
Initial Treatment Phase 
44 
 
Retreatment Phase (Second Course of Treatment) 
46 
11.0 
Labeling, Packaging, Storage and Return of Clinical Supplies 
49 
 
Investigational Product 
49 
 
Packaging and Labeling Information 
49 
 
Clinical Supplies Disclosure 
49 
 
Storage and Handling Requirements 
49 
 
Returns and Reconciliation 
49 
12.0 
Measures of Effect 
49 
 
Definitions 
50 
 
Disease Parameters 
50 
 
Methods for Evaluation of Measurable Disease 
51 
 
Response Criteria 
52 
 
Objective response rate (ORR) 
54 
 
Duration of Response 
54 
13.0 
Statistical Considerations 
55 
 
Study Design/Endpoints 
55 
 
Sample Size/Accrual Rate 
56 
 
Stratification Factors 
56 
 
Reporting and Exclusions 
56 
14.0 
Data and Safety Monitoring Plan 
56 
 
Monitoring Plan 
56 
 
Data Safety Monitoring Board 
57 
15.0 
Administrative 
57 
 
Data Reporting 
57 
 
Retention of Records 
57 
 
Informed Consent 
57 
16.0 
References 
59 
17.0 
Appendices 
62 


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ECOG Performance Status 
62 
 
Collection, Shipment, and Processing of Blood Samples and Tissue for Correlative 
studies 63 
 
Management of immune related adverse events from Pembrolizumab. 
65 
 
Common Terminology Criteria for Adverse Events V4.0 (CTCAE) 
65 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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1.0  Trial Summary 
 
 
2.0 Trial Design 
This is a single-arm, open label phase 2 study exploring monotherapy with the PD-1 
antibody pembrolizumab (or MK-3475) given intravenously at a fixed dose of 200mg 
every 3 weeks for patients with high grade neuroendocrine tumors (except any high grade 
NETs of large or small cell type of lung/thymus origin and merkel cell carcinoma.), who 
have received at least 1 prior systemic therapy containing a platinum agent.  The primary 
endpoint of the study is objective response rate. Secondary outcomes are progression free 
and overall survival and rate of toxicities. Patients will be assessed for response with CT 
scans every 9 weeks during the first year and every 12 weeks thereafter, using the RECIST 
1.1 criteria. Correlative endpoints will be exploratory and assess PD-1 expression on 
peripheral blood mononuclear cells; peripheral blood NK-cell functional assays; PD-1 and 
PD-L1 expression on tumor tissue as well as mutational analysis of archived tumor tissue.  
 
 
Abbreviated Title 
Pembrolizumab for previously treated high grade NETs 
Trial Phase 
Phase 2 
Clinical Indication 
Previously treated High Grade Neuroendocrine tumors 
Trial Type 
Open-label single arm 
Type of control 
None 
Route of administration 
Pembrolizumab given intravenously at a fixed dose of 
200mg every 3 weeks 
Trial Blinding 
None 
Treatment Groups  
Single arm 
Number of trial subjects 
21 
Estimated duration of trial 3.5 years 
Duration of Participation 
2 years 


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Metastatic high grade 
Neuroendocrine tumors 
Eligibility: 
• 
Histologically 
confirmed HGNET 
with Ki67>20% 
• 
Disease progression 
or recurrence after 
at least 1 platinum 
containing 
chemotherapy 
regimen 
• 
PS : ECOG 0-1 
• 
Informed consent 
• 
Measurable disease 
• 
Exclude any high 
grade NETs of large 
or small cell type of 
lung/thymus origin, 
merkel cell 
carcinoma. 
Estimated 
N=21 
 
Single arm study 
pembrolizumab 
200 mg IV over 
30 min given 
every 3 weeks 
 
Treat until 
progression 
defined by 
RECIST 1.1 
(every 9 weeks 
for 1 year, then 
every 12 weeks) 
or unacceptable 
toxicity* or for 
a total of 35 
cycles 
* Pts may be treated beyond first progression under protocol defined circumstances 
Screening period 
(within 28 days) 
Treatment 
assignment 
On treatment 
period 
Treatment Schema 
Follow up visit 
for toxicity (at 
1 month) and 
survival follow 
up (every 12 
weeks) 
Follow-up 
period 


 
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3.0 Objectives 
 Primary Objective 
To estimate objective response rate (ORR), using RECIST 1.1, in previously treated 
metastatic High Grade Neuroendocrine Tumors (HGNET) patients treated with 
pembrolizumab monotherapy  
 
 
 Secondary Objectives  
 To evaluate progression free survival (PFS) (using RECIST 1.1) in metastatic 
HGNET patients treated with pembrolizumab monotherapy. 
 To evaluate overall survival (OS) in metastatic HGNET patients treated with 
pembrolizumab monotherapy. 
 Incidence of toxicity, graded according to National Cancer Institute Common 
Toxicity Criteria (NCI-CTC) version 4.0. 
 
 
 Exploratory objectives 
• To correlate biomarkers related to PD-1 blockade in tumor samples (such as TILs, 
PD-1, PD-L1) with overall response rate, progression free survival, and overall 
survival  
• To characterize molecular and biological profile of tumors that respond to 
pembrolizumab by performing genomic analysis of tumor samples and by evaluating 
the expression levels of  PD-L1, PD-L2 on tumor cells; PD-L1, PD-1 on TILs and  T-
regulatory cells (T-regs) in the tumor microenvironment.To compare PD-1 
expression and leukocyte activation markers on circulating T-regs pre-treatment, at 
week 6, and at time of disease progression 
• To compare functional responses (degranulation) by NK cells pre-treatment, at week 
6, and at end of treatment. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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4.0 Introduction 
 Study Disease 
Neuroendocrine tumors (NETs) consist of a spectrum of malignancies that can arise from 
neuroendocrine cells throughout the body. They are currently classified as well differentiated 
(low-grade to intermediate-grade) NETs and poorly differentiated or HGNET based on 
morphology and the proliferation rate.[1] NETs are rare tumors with an incidence of 3.5-
5/100000 per year[2] and HGNETs account for about 10% to 20% of malignant digestive 
NETs.[3] HGNETs are defined as tumors with poorly differentiated morphology and a higher 
proliferation rate (Ki67 > 20%) than well differentiated NETs. They are characterized by a 
high proclivity for metastatic dissemination even among patients with clinically localized 
tumors.[4] Well and poorly differentiated NETs are grouped together in the general class of 
NET only because of generic neuroendocrine marker expression (ie, detection of 
synaptophysin and/or chromogranin by immunohistochemistry).[5]  
Recent molecular discoveries have led to therapeutic advances in well differentiated NETs 
with the approval of targeted therapies like everolimus and sunitinib.[6] In contrast, much 
less is known about HGNETs, and no prospective studies have evaluated HGNETs 
originating outside of the lung. These are aggressive carcinomas that typically present at a 
late stage and have a dismal median overall survival of only 10 months.[2] To date, and even 
for the current standard of care regimen, no prospective trial has been conducted to guide 
treatment for this disease and current treatment recommendations are extrapolated from the 
small cell lung cancer literature.[7] These are generally managed with platinum-based 
chemotherapy with a modest PFS (4months) and OS (11 months) benefit.[7-11] After first-
line treatment, no further standard therapy has been established for HGNETs. No prospective 
trials have been conducted and a few small, retrospective, studies with chemotherapy 
(temozolamide, oxaliplatin, taxanes etc.) have quoted a response rate between 0-20% in the 
second line setting and <5% in the third line setting[11-14]. The responses, however, are of 
short duration. Data pertaining to histologic classification and tumor biology are also 
extremely limited making the care of patients with this disease entity a significant challenge. 
Prospective studies evaluating potential treatment options with associated correlative studies 
to better understand the histologic and molecular features of these carcinomas are therefore 
desperately needed. 
 
  Agent under Investigation/intervention 
The importance of intact immune surveillance in controlling outgrowth of neoplastic 
transformation has been known for decades[15]. Accumulating evidence shows a 
correlation between tumor-infiltrating lymphocytes (TILs) in cancer tissue and favorable 
prognosis in various malignancies[16-20]. 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 
Tcells 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 


 
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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) 
[21, 22]. The structure of murine PD-1 has been resolved [23]. 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[22, 24-26]. 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[27, 28]. PD-1 was 
shown to be expressed on activated lymphocytes including peripheral CD4+ and CD8+ T-
cells, B-cells, T regs and Natural Killer cells[29, 30]. Expression has also been shown 
during thymic development on CD4-CD8- (double negative) T-cells as well as subsets of 
macrophages and dendritic cells[31]. 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[28, 32-34]. 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 Tcell 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[28]. 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 renal cell carcinoma[35]. 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 (MK-3475), previously 
known as SCH 900475, 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.   
 
 Pre-clinical and Clinical Trials:  
Refer to the Investigator’s Brochure for Preclinical and Clinical data. 
  Study Rationale  
Immune checkpoint blockade is a rapidly advancing therapeutic approach in the field of 
immuno-oncology and treatment with investigational agents targeting this mechanism has 
induced regressions in several types of cancer. These agents are tolerable and adverse effects 
(AEs) are generally manageable in patients. They have shown activity in wide range of 


 
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malignancies including melanoma, renal cell carcinoma and lung cancer, and more data is 
emerging by the day.[36-38] No published studies have evaluated PD-L1 expression in high 
grade NET. In SCLC, PD-L1 expression on tumor cells is reported to be low (0-27%) but 
18.5% show PD-L1 expression in tumor-infiltrating macrophages and 48% harbor PD-1 
positive lymphocytes.[39, 40] Immune checkpoint blockers have not been studied in NETs 
but are being actively investigated in SCLC and Merkel Cell Carcinoma with promising 
results. In a recently reported interim analysis of a study using Nivolumab+/- Ipilimumab in 
pretreated advanced small cell lung cancer, researchers reported a partial response in 15% 
and stable disease (SD) in 22.5% patients. In the combination arm, complete response was 
seen in 5%, partial response in 20% and stable disease in 30% patients.[41] In the 
KEYNOTE-028 study, rate of PD-L1 positivity in small cell lung cancer was found to be 
around 27%. In the cohort of 17 evaluable patients treated with pembrolizumab, there were 
no treatment-related deaths or discontinuations due to AEs. 25% patients had a partial 
response and 7% had stable disease, resulting in a disease control rate of 31%.[40] 
(NCT02054806) In the initial phase I study of Pembrolizumab, a patient with Merkel cell 
carcinoma experienced complete responses of 56+ weeks' duration[42]. This led to the phase 
II study in advanced merkel cell carcinoma where the objective response rate with 
pembrolizumab was 71%, which included a complete response in 2 of 14 patients[43]. The 
drug is currently being investigated as a first line therapy for patients with locally 
advanced/metastatic merkel cell carcinoma. (NCT02267603). Both these tumor types (small 
cell lung cancer and merkel cell carcinoma) are thought to be of neuroendocrine lineage and 
are treated similarly with frontline platinum/etoposide combinations, just like other high 
grade neuroendocrine carcinomas. The impressive activity of pembrolizumab in these 
tumors, presents a strong argument for investigating its role in HGNETs. 
 
Snyder et.al.described the importance of tumor genetics in defining the basis of the clinical 
benefit from checkpoint blockade. In their study, mutational load correlated with improved 
overall survival and response to immunotherapy[44]. Preliminary data from our in-house 
IRB approved study, that utilized an NGS platform to detect somatic mutations in 50 cancer-
related genes on archived tissue, found a staggering 77% (16/21) rate of mutations in the 
HGNETs with 44% of the tumors having more than one mutation (on the limited 50 gene 
panel). We enrolled 21 patients with HGNETs over 15 months in this study.[45] This 
provides another rationale for testing pembrolizumab in HGNETs. 
 
As discussed in section 4.1, after first-line treatment, no further standard therapy has been 
established for HGNETs. Several small, retrospective, studies with chemotherapy 
(temozolamide, oxaliplatin, taxanes etc.) have quoted short lived responses after the first line 
setting. 
In summary, the lack of second line treatment options for HGNETs highlights the unmet 
need for drug development in this rare tumor type. The higher mutational load exhibited by 
HGNETs and promising activity of checkpoint blockers in small cell lung cancer and merkel 
cell carcinoma provide strong rationale for studying pembrolizumab, a highly selective, 
humanized monoclonal antibody against PD-1, in HGNETs with respect to efficacy and 
toxicity. Therefore, we propose a phase II, open-label study of pembrolizumab monotherapy 


 
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in patients with metastatic HGNETs who have progressed on at least one platinum containing 
regimen. 
We hypothesize that administration of pembrolizumab to patients with metastatic HGNETs 
will result in a clinically meaningful response rate and that it will have an acceptable safety 
profile when given as a single agent to patients with metastatic, HGNETs. 
 Rationale for Dose Selection/Regimen/Modification 
Previously, an open-label Phase I trial (NCT01848834) was conducted to evaluate the safety 
and clinical activity of single agent Pembrolizumab (MK-3475).  The dose escalation portion 
of the trial evaluated three dose levels, 1 mg/kg, 3 mg/kg, and 10 mg/kg, administered every 
2 weeks (Q2W) in subjects with advanced solid tumors.  All three dose levels were well 
tolerated and no dose-limiting toxicities were observed.  This first in human study of 
pembrolizumab showed evidence of target engagement and objective evidence of tumor size 
reduction at all dose levels (1 mg/kg, 3 mg/kg and 10 mg/kg Q2W).  No MTD has been 
identified to date.  Recent data from other clinical studies within the pembrolizumab program 
has shown that a lower dose of pembrolizumab and a less frequent schedule may be sufficient 
for target engagement and clinical activity.  
 
 
PK data analysis of pembrolizumab administered Q2W and Q3W showed slow systemic 
clearance, limited volume of distribution, and a long half-life (refer to IB).  
Pharmacodynamic data (IL-2 release assay) suggested that peripheral target engagement is 
durable (>21 days).  This early PK and pharmacodynamic data provides scientific rationale 
for testing a Q2W and Q3W dosing schedule.   
 
A population pharmacokinetic analysis has been performed using serum concentration time 
data from 476 patients. Within the resulting population PK model, clearance and volume 
parameters of pembrolizumab were found to be dependent on body weight. The relationship 
between clearance and body weight, with an allometric exponent of 0.59, is within the range 
observed for other antibodies and would support both body weight normalized dosing or a 
fixed dose across all body weights.  Pembrolizumab has been found to have a wide 
therapeutic range based on the melanoma indication.  The differences in exposure for a 200 
mg fixed dose regimen relative to a 2 mg/kg Q3W body weight based regimen are anticipated 
to remain well within the established exposure margins of 0.5 – 5.0 for pembrolizumab in 
the melanoma indication. The exposure margins are based on the notion of similar efficacy 
and safety in melanoma at 10 mg/kg Q3W vs. the proposed dose regimen of 2 mg/kg Q3W 
(i.e. 5-fold higher dose and exposure). The population PK evaluation revealed that there was 
no significant impact of tumor burden on exposure. In addition, exposure was similar 
between the NSCLC and melanoma indications. Therefore, there are no anticipated changes 
in exposure between different indication settings. 
 
The rationale for further exploration of 2 mg/kg and comparable doses of Pembrolizumab in 
solid tumors was 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 


 
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behavior of Pembrolizumab (as assessed by the population PK model) and 4) the assumption 
that the dynamics of Pembrolizumab target engagement will not vary meaningfully with 
tumor type. 
The choice of the 200 mg Q3W as an appropriate dose for the switch to fixed dosing is based 
on simulations performed using the population PK model of Pembrolizumab showing that 
the fixed dose of 200 mg every 3 weeks will provide exposures that 1) are optimally 
consistent with those obtained with the 2 mg/kg dose every 3 weeks, 2) will maintain 
individual patient exposures in the exposure range established in melanoma as associated 
with maximal efficacy response and 3) will maintain individual patients exposure in the 
exposure range established in melanoma that are well tolerated and safe.  
A fixed dose regimen will simplify the dosing regimen to be more convenient for 
physicians and to reduce potential for dosing errors.  A fixed dosing scheme will also 
reduce complexity in the logistical chain at treatment facilities and reduce wastage. 
 
 Rationale for endpoints 
4.6.1. Primary endpoint 
The primary efficacy objective of this trial is to evaluate the anti-tumor activity of 
pembrolizumab (MK-3475) (200 mg Q3W) monotherapy in subjects with previously 
treated metastatic high grade neuroendocrine tumors. Objective response rate (ORR) based 
on RECIST 1.1 will be used as the primary efficacy endpoint. Secondary endpoints in this 
study is progression free survival (per RECIST 1.1), and overall survival. 
 
4.6.2. Safety Endpoint 
The safety endpoint in this study is to characterize the safety and tolerability of 
Pembrolizumab in patients with previously treated metastatic high grade neuroendocrine 
tumors. Adverse events and laboratory test values observed in this study are also safety 
endpoints. The primary safety analysis will be based on subjects who experienced toxicities 
requiring discontinuation of therapy as defined by the protocol (section 7.0). Safety will be 
assessed by quantifying the toxicities and grades experienced by subjects who have 
received pembrolizumab (MK-3475), including serious adverse events (SAEs) and events 
of clinical interest (ECIs). Safety will be assessed by reported adverse experiences using 
CTCAE, Version 4.0. The attribution to drug, time-of-onset, duration of the event, its 
resolution, and any concomitant medications administered will be recorded. AEs will be 
analyzed including but not limited to all AEs, SAEs, fatal AEs, and laboratory changes. 
Furthermore, specific immune-related adverse events (irAEs) will be collected and 
designated as immune-related events of clinical interest (ECIs) as described in Section 
9.1.7. 
 
 Rationale for Correlative Testing 
We will assess the expression level of PD-1, PD-L1 and PD-L2 and Tumor Infiltrating 
Lymphocytes  (TIL) content in tumor samples and its correlation with response to 
investigational therapy. Initial studies suggest that baseline PD-L1 tumor cell expression 


 
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could serve as a key biomarker for response to PD-1 pathway inhibition. Tumor PD-L1 up-
regulation has been the factor most strongly correlated with response to PD-1 blockade. 
Biopsy specimen analysis will endeavor to serve this question in HGNETs. We will utilize 
archived tumor tissue to perform the analysis and patients without available archived 
tissue; may undergo an optional fresh biopsy at enrollment. Tumor infiltrating lymphocytes 
(TILs) will be evaluated by H&E immunohistochemical staining. Guided by our 
preliminary work (section 4.4-study rationale)[45], mutational analysis of tumors using 
next gen sequencing platform will be conducted to identify predictive biomarkers and 
guide future therapy beyond checkpoint inhibitors. 
 
Additionally, using peripheral blood samples, we will assess PD-1 expression and leukocyte 
activation markers on circulating lymphocytes as well as NK- and T-cell function pre-
treatment, during treatment as well as at time of progression in order to assess potential 
associations with treatment response and outcome. Preliminary studies of immune cell 
biomarkers, including PD-1, on peripheral blood mononuclear cells in renal cell carcinoma 
by our group have indicated that PD-1 expression on fresh peripheral blood leukocytes may 
provide a useful marker for disease progression. Furthermore, the results suggest that 
measuring PD-1 levels in peripheral blood may assist in identifying patients likely to respond 
to PD-1 blocking antibodies.  
5.0 Study Plan  
 Description of Study Design, Population and Duration of Study Therapy  
This is a single arm phase II study of pembrolizumab in patients with metastatic high grade 
neuroendocrine carcinoma (except small cell and merkel cell carcinoma) who have failed 
therapy with a platinum agent.  Objective response rate will be measured with disease 
imaging following every 3 cycles for the first year and then every 4 cycles.  Patients will 
continue treatment until disease progression, unacceptable toxicity or for a total of 35 cycles.  
Overall survival will be assessed every 12 weeks during long term follow up.   
 
Patient Selection Inclusion & Exclusion 
 Inclusion Criteria   
5.2.1.  Patients must have histologically or cytologically confirmed metastatic, high 
grade NET (Ki67 >20%), excluding any high grade NETs of large or small cell 
type of lung/thymus origin and merkel cell carcinoma 
  
5.2.2.  Patients must have measurable disease, defined as at least one lesion that can be 
accurately measured in at least one dimension in accordance with RECIST criteria 
v. 1.1 as described in detail in section 12.0 
 
5.2.3.  Has received prior therapy with at least 1 platinum-containing regimen 
 
5.2.4.  Age > 18 years. 
 
5.2.5.  ECOG performance status 0 or 1 


 
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5.2.6.  Patients must have normal organ and marrow function as defined below in table 1 
 
Table 1: Adequate Organ Function Laboratory Values 
 
System 
Laboratory Value 
Hematological 
 
Absolute neutrophil count (ANC) 
≥1,500 /mcL 
Platelets 
≥100,000 / mcL 
Hemoglobin 
≥8 g/dL or ≥5.6 mmol/L without transfusion or EPO dependency 
(within 7 days of assessment) 
Renal 
 
Serum creatinine OR 
Measured or calculateda creatinine 
clearance 
(GFR can also be used in place of 
creatinine or CrCl) 
≤1.5 X upper limit of normal (ULN) OR 
 
≥50 mL/min for subject with creatinine levels > 1.5 X 
institutional ULN 
Hepatic 
 
Serum total bilirubin 
≤ 1.5 X ULN OR 
 
Direct bilirubin ≤ ULN for subjects with total bilirubin levels > 
1.5 ULN 
AST (SGOT) and ALT (SGPT) 
≤ 2.5 X ULN  OR 
≤ 5 X ULN for subjects with liver metastases 
Albumin 
>2.5 mg/dL 
Coagulation 
International Normalized Ratio (INR) or 
Prothrombin Time (PT) 
 
Activated Partial Thromboplastin Time 
(aPTT) 
≤1.5 X ULN unless subject is receiving anticoagulant therapy 
as long as PT or PTT is within therapeutic range of intended use 
of anticoagulants 
≤1.5 X ULN unless subject is receiving anticoagulant therapy 
as long as PT or PTT is within therapeutic range of intended use 
of anticoagulants 
aCreatinine clearance should be calculated per institutional standard. 
 
5.2.7.  Female participants of childbearing potential must have a  negative serum 
pregnancy within 72 hours prior to receiving the first dose of study medication). 
They should also 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.  
Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception 
for the subject. 
 
5.2.8.  Male participants must 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 
Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception 
for the subject. 
 
5.2.9.  Ability to understand and willingness to sign a written informed consent and 
HIPAA consent document 


 
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 Exclusion Criteria   
5.3.1.  Known active central nervous system (CNS) metastases and/or carcinomatous 
meningitis. Subjects with previously treated brain metastases may participate 
provided they are stable (without evidence of progression by imaging for at least 
four weeks prior to the first dose of trial treatment and any neurologic symptoms 
have returned to baseline), have no evidence of new or enlarging brain metastases, 
and are not using steroids for at least 7 days prior to trial treatment.  This exception 
does not include carcinomatous meningitis which is excluded regardless of clinical 
stability.  
 
5.3.2.  Is currently participating and receiving study therapy or has participated in a study 
of an investigational agent and received study therapy or used an investigational 
device within 4 weeks of the first dose of treatment. 
 
5.3.3.  Diagnosis of immunodeficiency or receiving systemic steroid therapy or any other 
form of immunosuppressive therapy within 7 days prior to the first dose of trial 
treatment. 
 
5.3.4.  Prior anti-cancer therapy with a monoclonal antibody (mAb) within 4 weeks prior 
to study Day 1 or not recovered from adverse events (improved to grade 1 or less) 
due to mAbs administered more than 4 weeks earlier. 
 
5.3.5.  Prior chemotherapy, targeted small molecule therapy, or radiation therapy within 
2 weeks (12 weeks for measurable sites of CNS disease) prior to study Day 1 or 
not recovered from adverse events (improved to grade 1 or less) due to a previously 
administered agent. 
 
Note: Subjects with neuropathy or ≤ Grade 2 alopecia are an exception to this criterion 
and may qualify for the study. 
Note: If subject received major surgery, they must have recovered adequately from the 
toxicity and/or complications from the intervention prior to starting therapy. 
 
5.3.6.  Known additional malignancy that is progressing or requires active treatment 
except superficial malignancies of the skin and in situ cervical cancer 
 
5.3.7.  Has an active autoimmune disease that has required systemic treatment in the 
past 2 years (i.e. with use of disease modifying agents, corticosteroids or 
immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or 
physiologic corticosteroid replacement therapy for adrenal or pituitary 
insufficiency, etc.) is not considered a form of systemic treatment.  
 
5.3.8.  Has history of (non-infectious) pneumonitis that required steroids, evidence of 
interstitial lung disease or active non-infectious pneumonitis.  
 


 
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5.3.9.  Active infection requiring systemic therapy at enrollment.  
 
5.3.10. Has a known history of active TB   (Bacillus Tuberculosis) 
 
5.3.11. Hypersensitivity to pembrolizumab or any of its excipients 
 
5.3.12. Has received a live virus vaccine within 30 days of planned start of trial 
treatment. 
 
5.3.13. Pregnant, breastfeeding, or expecting to conceive or father children within the 
projected duration of the trial, starting with the screening period through 120 
days after the last dose of trial treatment 
 
5.3.14. Prior therapy with an anti-programmed cell death 1 (PD-1), anti-programmed 
cell death 1 ligand (PDL-1), anti-PD-L2,  or with an agent directed to another co-
inhibitory T-cell receptor (e.g. CTLA-4, OX-40, CD137) 
 
5.3.15. Known history of human immunodeficiency virus (HIV) 
 
5.3.16. Known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA 
[qualitative]). 
 
5.3.17. Has known psychiatric or substance abuse disorders that would interfere with 
cooperation with the requirements of the trial 
 
5.3.18. Has a history or current evidence of any condition, therapy, or laboratory 
abnormality that might confound the results of the trial, interfere with the 
subject’s participation for the full duration of the trial, or is not in the best 
interest of the subject to participate, in the opinion of the treating investigator. 
 
  Inclusion of Women and Minorities 
Men and women, regardless of race, ethnic group or sexual orientation are eligible for this 
study.   
 
 Patient Registration 
Participants may be registered from 8:00 am to 4:00 pm EST excluding holidays by emailing 
the study monitor at: FCCC.MONITOR@fccc.edu. Eligible participants will be entered on 
study centrally once the following items have been received by email: 
 
• 
Completed registration form  
• 
Consent and HIPAA signature pages  
• 
Eligibility checklist 
 
Following registration, participants must begin protocol treatment within 7 days of 
registration.  Issues that would cause treatment delays must be discussed with the Principal 


 
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Investigator.  If a registered participant does not receive protocol therapy following 
registration, the participant will be recorded as withdrawn from study.  The Study Monitor 
must be notified as soon as possible if a participant does not begin protocol treatment as 
scheduled. For additional registration questions, please email FCCC.MONITOR@fccc.edu 
or call (215) 728-5544. 
 
The study monitor or their designee will notify the site by email once registration is 
confirmed and the sequence number has been assigned.  Participants must be registered and 
have received a sequence number prior to the initiation of treatment.   
 
Exceptions to the current registration policies will not be permitted.  
 
6.0 Treatment Plan 
No stratification based on age, sex or other characteristics will be used in this trial. Treatment 
will be administered on an outpatient basis.  Treatment will be administered as described 
below.  Dose delays and modifications should only be done following protocol guidelines 
described in section 7.0.  If treatment delays are > 42 days study therapy will be discontinued.   
 
 Trial Treatments 
 
Agent 
Dose 
Route 
Schedule 
Cycle Length 
Use 
Pembrolizumab 
200 
mg 
IV infusion  Q 3 
weeks 
3 weeks (21 
days) 
Experimental 
 
 
 Dose Selection 
The rationale for selection of doses to be used in this trial is provided in Section 4.5 –
Rationale.   
Details on preparation and administration of pembrolizumab (MK-3475) are provided in the 
Pharmacy Manual.  
 
 Dose Administration 
Trial treatment should be administered on Day 1 of each cycle after all procedures/ 
assessments have been completed as detailed on the study calendar (Section 10.0).  Trial 
treatment may be administered up to 3 days before or after the scheduled Day 1 of each cycle 
due to administrative reasons. All trial treatments will be administered on an outpatient basis. 
Pembrolizumab will be administered as a 30 minute IV infusion (treatment cycle intervals 
may be increased due to toxicity as described in Section 7.0).  Sites should make every effort 
to target infusion timing to be as close to 30 minutes as possible.  However, given the 


 
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variability of infusion pumps from site to site, a window of -10 minutes and +10 minutes is 
permitted (i.e., infusion time is 30 minutes: -10 min/+10 min). 
 
The following infusion set materials are compatible with (pembrolizumab): 
•      PVC Infusion set that is plasticized using DEHP 
•      PVC and tri-(2-ethylhexyl) trimellitate (TOTM) infusion set 
•      Polyethylene lined PVC infusion set 
•      PVC Infusion set that is plasticized using Di-2-ethylhexyl Terephthalate (DEHT) 
•      Polyurethane set. 
 
A sterile, non-pyrogenic, low-protein binding 0.2 to 5 µm in-line filter made of 
polyethersulfone (PES) must be used during administration to remove any adventitious 
particles.  If the infusion set does not contain 0.2 to 5 µm in-line filter, it is recommended to 
use 0.2 to 5 µm add-on filter which may contain an extension line. Attach the infusion line 
to the pump and prime the line, either with normal saline (at least 25 mL) or with infusion 
solution as per local SOP, before starting the infusion. Infuse pembrolizumab (MK-3475) 
over approximately 30 minutes, with a window of -10 and +10 minutes, through a peripheral 
line or indwelling catheter. Ensure the entire contents of the bag are dosed and all remaining 
drug solution in the line is administered according to institutional guidelines for saline 
flushing. Document volume administered according to data entry guidelines. Vital signs will 
be monitored every 15 minutes during the infusion and at 60 minutes after completion of 
each infusion. In case of infusion reactions, infusion rate may differ; refer to protocol for 
specific instructions. 
  
Whenever possible, the lowest infusion rate should be used that will allow completion of the 
infusion within the 30 minutes. Maximum rate of infusion should not exceed 6.7 mL/min. 
through a peripheral line or indwelling catheter. However, when it is necessary to infuse a 
larger volume (i.e. 250 mL), the flow rate may go as high as 10 mL/min (maximum) in order 
to keep the infusion within the window as defined above 
 
 Concomitant Medications, Supportive Care, Excluded Therapies and 
Restrictions 
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed 
during the ongoing trial. If there is a clinical indication for any medication or vaccination 
specifically prohibited during the trial, discontinuation from trial therapy or vaccination may 
be required. The final decision on any supportive therapy or vaccination rests with the 
investigator and/or the subject's primary physician.  
 
6.4.1. Acceptable Concomitant Medications 
All treatments that the investigator considers necessary for a subject’s welfare may be 
administered at the discretion of the investigator in keeping with the community standards 
of medical care. All concomitant medication received within 28 days before the first dose of 
trial treatment and 30 days after the last dose of trial treatment, will be recorded on the case 
report form (CRF) including all prescription, over-the-counter (OTC), herbal supplements, 


 
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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. Patients may 
receive supportive blood products or antibiotics when appropriate. Patients requiring other 
supportive or adjunctive therapies, including but not limited to percutaneous drainage or 
biliary or genitourinary stent placement, may be considered on an individual patient basis to 
be permitted to hold investigational therapy for up to 42 days. Palliative radiation therapy is 
permitted for irradiating small areas of painful metastases (bony, or otherwise) or bleeding 
from a solitary site that cannot be managed adequately using systemic or local analgesics, as 
long as the treating clinician feels the patient is otherwise clinically benefitting and would 
more likely than not continue to garner benefit at the conclusion of this localized therapy. 
 
Concomitant medications administered after 30 days after the last dose of trial treatment 
should be recorded for SAEs and ECIs as defined in Section 9.0. 
6.4.2. Prohibited Concomitant Medications 
Subjects are prohibited from receiving the following therapies during the Screening and 
Treatment Phase of this trial: 
 Antineoplastic systemic chemotherapy or biological therapy  
 Immunotherapy not specified in this protocol 
 Chemotherapy not specified in this protocol 
 Investigational agents other than pembrolizumab 
 Radiation therapy  
Note:  Radiation therapy to a symptomatic solitary lesion or to the brain may be 
allowed at the investigator’s discretion.   
 Live vaccines within 30 days prior to the first dose of trial treatment and while 
participating in the trial.  Examples of live vaccines include, but are not limited to, 
the following: measles, mumps, rubella, varicella/zoster, yellow fever, rabies, BCG, 
and typhoid vaccine.  
 Systemic glucocorticoids for any purpose other than to modulate symptoms from an 
event of clinical interest of suspected immunologic etiology.  The use of physiologic 
doses of corticosteroids may be approved after consultation with the Sponsor. 
Subjects who, in the assessment by the investigator, require the use of any of the 
aforementioned treatments for clinical management should be removed from the trial.  
Subjects may receive other medications that the investigator deems to be medically 
necessary. 
The Exclusion Criteria describes other medications which are prohibited in this trial. 
There are no prohibited therapies during the Post-Treatment Follow-up Phase 
 


 
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6.4.3. Rescue Medications & Supportive Care 
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 
appendix (section 17.3). Where appropriate, these guidelines include the use of oral or 
intravenous treatment with corticosteroids as well as additional anti-inflammatory agents if 
symptoms do not improve with administration of corticosteroids.   Note that several courses 
of steroid tapering may be necessary as symptoms may worsen when the steroid dose is 
decreased. For each disorder, attempts should be made to rule out other causes such as 
metastatic disease or bacterial or viral infection, which might require additional supportive 
care. The treatment guidelines are intended to be applied when the investigator determines 
the events to be related to Pembrolizumab.  
Note: if after the evaluation the event is determined not to be related, the investigator may 
follow the AE reporting guidance but does not need to follow the treatment guidance (as 
outlined in appendix 17.3). Refer to section 7.0 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. Suggested conditional procedures, as 
appropriate, can be found in the ECI guidance document. 
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. 
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. 
 


 
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Type 1 diabetes mellitus (if new onset, including diabetic ketoacidosis [DKA]) or ≥ 
Grade 3 Hyperglycemia, if associated with ketosis (ketonuria) or metabolic acidosis 
(DKA) 
 
• Insulin replacement therapy is recommended for Type I diabetes mellitus and for Grade 
3-4 hyperglycemia associated with metabolic acidosis or ketonuria.  
• Evaluate patients with serum glucose and a metabolic panel, urine ketones, 
glycosylated hemoglobin, and C-peptide.  
 
Hypophysitis: 
 
• 
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. 
 
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 3-4 hypothyroidism): 
o In hyperthyroidism, non-selective beta-blockers (e.g. propranolol) are suggested as 
initial therapy. 
o In hypothyroidism, thyroid hormone replacement therapy, with levothyroxine or 
liothyroinine, is indicated per standard of care. 
 
• 
Grade 3-4 hyperthyroidism  
o Treat with an initial dose of IV corticosteroid followed by oral corticosteroids. When 
symptoms improve to Grade 1 or less, steroid taper should be started and continued 
over no less than 4 weeks. Replacement of appropriate hormones may be required 
as the steroid dose is tapered. 
 
Hepatic: 
• 
For Grade 2 events, monitor liver function tests more frequently until returned to 
baseline values (consider weekly). 
o 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. 
 
Renal Failure or Nephritis: 


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


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


 
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• diaphragm with spermicide (cannot be used in conjunction with cervical 
cap/spermicide) 
• cervical cap with spermicide (nulliparous women only)   
• contraceptive sponge (nulliparous women only)  
• male condom or female condom (cannot be used together) 
• hormonal contraceptive: oral contraceptive pill (estrogen/progestin pill or progestin-
only pill), contraceptive skin patch, vaginal contraceptive ring, or subcutaneous 
contraceptive injection 
  
†Abstinence (relative to heterosexual activity) can be used as the sole method of 
contraception if it is consistently employed as the subject’s preferred and usual lifestyle and 
if considered acceptable by local regulatory agencies and ERCs/IRBs.  Periodic abstinence 
(e.g., calendar, ovulation, sympto-thermal, post-ovulation methods, etc.) and withdrawal 
are not acceptable methods of contraception.  
  
‡If a contraceptive method listed above is restricted by local regulations/guidelines, then it 
does not qualify as an acceptable method of contraception for subjects participating at sites 
in this country/region. 
 
Subjects should be informed that taking the study medication may involve unknown risks 
to the fetus (unborn baby) if pregnancy were to occur during the study.  In order to 
participate in the study subjects of childbearing potential must adhere to the contraception 
requirement (described above) from the day of study medication initiation (or 14 days prior 
to the initiation of study medication for oral contraception) throughout the study period up 
to 120 days after the last dose of trial therapy.  If there is any question that a subject of 
childbearing potential will not reliably comply with the requirements for contraception, that 
subject should not be entered into the study. 
 
6.5.3. Use in Pregnancy 
If a subject inadvertently becomes pregnant while on treatment with pembrolizumab, the 
subject will immediately be removed from the study.  The site will contact the subject at 
least monthly and document the subject’s status until the pregnancy has been completed or 
terminated.  The outcome of the pregnancy will be reported to Merck without delay and 
within 2 working days to Merck if the outcome is a serious adverse experience (e.g., death, 
abortion, congenital anomaly, or other disabling or life-threatening complication to the 
mother or newborn).   
The study investigator will make every effort to obtain permission to follow the outcome of 
the pregnancy and report the condition of the fetus or newborn to Merck.   If a male subject 
impregnates his female partner the study personnel at the site must be informed immediately 
and the pregnancy reported to Merck and followed as described above and in section 9.2. 
6.5.4. Use in Nursing Women 
It is unknown whether pembrolizumab is excreted in human milk.  Since many drugs are 
excreted in human milk, and because of the potential for serious adverse reactions in the 
nursing infant, subjects who are breast-feeding are not eligible for enrollment. 


 
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 Participant Withdrawal/Discontinuation Criteria 
Participants 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 
participant may be withdrawn by the investigator if enrollment into the trial is 
inappropriate, the trial plan is violated, or for administrative and/or other safety reasons.  
Specific details regarding discontinuation or withdrawal are provided in section 8.4 – Other 
Procedures. 
A participant 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. 
 Disease progression (for definition see Section12 ) 
 Unacceptable adverse experiences as described in Section 7.0 
 Intercurrent illness that prevents further administration of treatment 
 Investigator’s decision to withdraw the subject 
 The participant has a confirmed positive serum pregnancy test 
 Noncompliance with trial treatment or procedure requirements 
 The subject is lost to follow-up 
 Completed 35 cycles of treatment with pembrolizumab  
Note: Subjects who stop pembrolizumab after 35 cycles may be eligible for up to 18 
cycles of additional study treatment if they progress after stopping study treatment 
provided they meet the requirements detailed in Section8.5.4. 
 Administrative reasons 
The End of Treatment and Follow-up visit procedures are listed in Section 10 (Study 
calendar) and Section 8.5 (Visit Requirements).  After the end of treatment, each subject will 
be followed for 120 days for adverse event monitoring (events of clinical interest will be 
collected for 120 days after the end of treatment).  Subjects who discontinue for reasons other 
than progressive disease will have post-treatment follow-up for disease status until disease 
progression, initiating a non-study cancer treatment, withdrawing consent or becoming lost 
to follow-up.  After documented disease progression each subject will be followed by 
telephone for overall survival until death, withdrawal of consent, or the end of the study, 
whichever occurs first. 
 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 


 
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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 18 
cycles of additional treatment with pembrolizumab via the Second Course Phase at the 
discretion of the investigator if no cancer treatment was administered since the last dose of 
pembrolizumab, the subject meets the safety parameters listed in the Inclusion/Exclusion 
criteria, and the trial is open.  Subjects will resume therapy at the same dose and schedule 
at the time of initial discontinuation.  Additional details are provided in Section 8.5. 
 
 Treatment beyond Disease Progression 
Immunotherapeutic agents such as pembrolizumab (MK-3475) may produce antitumor 
effects by reactivating endogenous cancer-specific immune responses, which may be 
functionally exhausted. The response patterns seen with such therapies may extend beyond 
the typical time course of responses seen with cytotoxic agents, and can manifest a clinical 
response after an initial increase in tumor burden or even the appearance of new lesions. 
Standard RECIST criteria may not provide an accurate or complete response assessment of 
immunotherapeutic agents such as pembrolizumab (MK-3475). Data from previous trials has 
clearly demonstrated a phenomenon in which patients treated with PD-1 inhibitors may 
derive 
clinical 
benefit 
despite 
initial 
radiologic 
evidence 
of 
disease 
progression[46].Therefore, RECIST 1.1 will be used with the following adaptation: 
If radiologic imaging by local/site assessment shows PD, tumor assessment may be repeated  
> 4 weeks later in order to confirm PD with the option of continuing treatment per below 
while awaiting radiologic confirmation of progression. If repeat imaging shows SD, PR or 
CR, treatment may be continued as per treatment calendar. If repeat imaging still meets the 
threshold for PD (≥ 20% increase in tumor burden compared to nadir) but shows a reduction 
in tumor burden compared to the previous time point, treatment may be continued as per 
treatment calendar after consultation with Sponsor Investigator. If repeat imaging confirms 
progressive disease without reduction in tumor burden compared to the previous time point, 
subjects will be discontinued from study therapy. In determining whether or not the tumor 
burden has increased or decreased, investigators should consider all target lesions as well as 
non-target lesions. 
 
The decision to continue study treatment after the 1st evidence of disease progression is at 
the Investigator’s discretion based on the clinical status of the subject as described in 
Section 8.5.5.  
 
7.0 Dose Modifications 
 General Principles  
Dose modifications will be made based only on the guidelines described in Section 7.0.  
Patients requiring treatment to be held > 42 days for recovery from toxicity must discontinue 
protocol treatment. Adverse events (both non-serious and serious) associated with 
Pembrolizumab exposure may represent an immunologic etiology.  These adverse events 
may occur shortly after the first dose or several months after the last dose of treatment. 
Pembrolizumab must be withheld for drug-related toxicities and severe or life-threatening 
AEs as per Table 3 below. See Section 6.4 (Supportive Care Guidelines), Table 2 and 


 
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Appendix 17.3 for supportive care guidelines, including use of corticosteroids. For subjects 
whose dose interval was increased due to toxicity, subjects may resume Pembrolizumab upon 
resolution of toxicity to Grade 0-1 or baseline. This dose would be considered Day 1 of the 
next cycle and should be in alignment with the new schedule 
 
Table 3. Dose Modification Guidelines for Pembrolizumab-Related Adverse Events 
 
Toxicity 
Hold 
Treatment 
For Grade 
Timing for Restarting Treatment 
Discontinue Subject if 
Diarrhea/Colitis 
2-3 
 
Toxicity resolves to Grade 0-1. 
Toxicity does not resolve to grade 0-1 within 6 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 
AST, ALT, or 
Increased 
Bilirubin 
2-3 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve to grade 0-1 within 6 weeks of last 
dose. 
4 
Permanently discontinue 
 
Permanently discontinue 
Type 1 diabetes 
mellitus (if new 
onset) or 
Hyperglycemia 
T1DM or  
3-4 
Hold Pembrolizumab for new onset 
Type 1 diabetes mellitus or Grade 3-
4 hyperglycemia associated with 
evidence of beta cell failure.  
 
Resume Pembrolizumab when patients are clinically and 
metabolically stable. 
Hypophysitis 
2-3 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve to grade 0-1 within 6 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 
Hyperthyroidism  
3 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve to grade 0-1 within 6 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 
Hypothyroidism 
 
Therapy with Pembrolizumab can be 
continued while treatment for the 
thyroid disorder is instituted 
Therapy with Pembrolizumab can be continued while treatment 
for the thyroid disorder is instituted. 
Infusion Reaction 
3-4 
Permanently discontinue 
Permanently discontinue 


 
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Toxicity 
Hold 
Treatment 
For Grade 
Timing for Restarting Treatment 
Discontinue Subject if 
Pneumonitis 
2 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve to grade 0-1 within 6 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 
Renal Failure or 
Nephritis 
2 
Toxicity resolves to Grade 0-1 
Toxicity does not resolveto grade 0-1 within 6 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 
All Other Drug-
Related 
Toxicity1,2 
3 or Severe 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve to grade 0-1 within 6 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 
Note: Permanently discontinue for persistent grade 2 or 3 adverse reactions (excluding endocrinopathies controlled with hormone 
replacement therapy) that do not recover to Grade 0-1 within 6 weeks after last dose of Pembrolizumab 
1 Pembrolizumab-specific exclusions to grade 3 non-hematologic toxicity as DLT include:   
1. 
Grade 3 rash in the absence of desquamation, no mucosal involvement, does not require steroids, and resolves to Grade 
1 by the next scheduled dose of pembrolizumab. 
2. 
Transient Grade 3 AST or ALT elevation, defined as no more than 3 days with or without steroid use 
2 Pembrolizumab-specific DLT: Episcleritis, uveitis, or iritis of Grade 2 or higher 
 
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 6 weeks 
of the scheduled interruption, unless otherwise discussed with the PI. The reason for 
interruption should be documented in the patient's study record. 
8.0 Trial Procedures 
The study calendar - Section 10.0 summarizes the trial procedures to be performed at each 
visit.  Individual trial procedures are described in detail below.  It may be necessary to 
perform these procedures at unscheduled time points if deemed clinically necessary by the 
investigator. 


 
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Furthermore, additional evaluations/testing may be deemed necessary by the investigator for 
reasons related to subject safety.  
 
 Administrative Procedures 
8.1.1.  Informed Consent 
The Investigator must obtain documented consent from each potential subject prior to 
participating in a clinical trial. 
8.1.2.  Inclusion/Exclusion Criteria 
All inclusion and exclusion criteria will be reviewed by the investigator or qualified designee 
to ensure that the subject qualifies for the trial.  
8.1.3. Medical History 
A medical history will be obtained by the investigator or qualified designee.  Medical history 
will include all active conditions, and any condition diagnosed within the prior 10 years that 
are considered to be clinically significant by the Investigator.  Details regarding the disease 
for which the subject has enrolled in this study will be recorded separately and not listed as 
medical history.   
8.1.4. Prior and Concomitant Medications Review 
  Prior Medications 
The investigator or qualified designee will review prior medication use, including any 
protocol-specified washout requirement, and record prior medication taken by the subject 
within 28 days before starting the trial.  Treatment for the disease for which the subject has 
enrolled in this study will be recorded separately and not listed as a prior medication.  
 
 Concomitant Medications 
The investigator or qualified designee will record medication, if any, taken by the subject 
during the trial.  All medications related to reportable SAEs and ECIs should be recorded 
as defined in Section 9.2. 
 
8.1.5. Disease Details and Treatments 
  Disease Details 
The investigator or qualified designee will obtain prior and current details regarding 
disease status.  
 
8.1.6. Prior Treatment Details 
The investigator or qualified designee will review all prior cancer treatments including 
systemic treatments, radiation and surgeries. 
 


 
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  Subsequent Anti-Cancer Therapy Status 
The investigator or qualified designee will review all new anti-neoplastic therapy initiated 
after the last dose of trial treatment.  If a subject initiates a new anti-cancer therapy within 
30 days after the last dose of trial treatment, the 30 day Safety Follow-up visit must occur 
before the first dose of the new therapy.  Once new anti-cancer therapy has been initiated 
the subject will move into survival follow-up.  
 Clinical Procedures/Assessments 
8.2.1. Adverse Event (AE) Monitoring 
The investigator or qualified designee will assess each subject to evaluate for potential new 
or worsening AEs as specified in the Trial Flow Chart and more frequently if clinically 
indicated.   
All AEs of unknown etiology associated with pembrolizumab exposure should be evaluated 
to determine if it is possibly an event of clinical interest (ECI) of a potentially immunologic 
etiology (irAE).  See Section 6.4 regarding the identification, evaluation and management 
of AEs of a potential immunological etiology (also Appendix- section 17.3).   
8.2.2. Physical Exam 
The investigator or qualified designee will perform a complete physical exam during the 
screening period.  Clinically significant abnormal findings should be recorded as medical 
history.  A full physical exam should be performed during screening.  
8.2.3. Vital Signs 
The investigator or qualified designee will take vital signs at screening, prior to the 
administration of each dose of trial treatment and at treatment discontinuation as specified 
in the study calendar (Section 10.0).  Vital signs should include temperature, pulse, 
respiratory rate, weight and blood pressure.  Height will be measured at screening only. 
8.2.4. Eastern Cooperative Oncology Group (ECOG) Performance Scale 
The investigator or qualified designee will assess ECOG status (see Appendix- section 17.1) 
at screening, prior to the administration of each dose of trial treatment and discontinuation 
of trial treatment as specified in the Trial Flow Chart.   
8.2.5. Tumor Imaging and Assessment of Disease 
Scans will be performed at baseline, and every 9 weeks (± 7 days) while on treatment for 
the first year and every 12 weeks (± 7 days) thereafter.  Imaging during follow up is outlined 
in section 8.5.3.  
8.2.6. Tumor Tissue Collection and Correlative Studies Blood Sampling 
For details in regards to tumor tissue collection please see Section 8.3.1 Tumor tissue 
processing, and shipment instructions are provided in the Appendix – section 17.2 . 


 
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Peripheral blood samples will be collected immediately prior to the first dose of 
pembrolizumab (time 1), at cycle 3 (immediately prior to dose 3; time 2) and at time of 
progression (time 3) for correlative studies as outlined in Section 10.0 (study calendar). 
 
Processing of blood samples will occur at FCCC as outlined in Appendix (section 17.2). 
Blood samples will be shipped to Protocol Support Laboratory (PSL) at Fox Chase as 
outlined in Appendix. Samples will be distributed from the PSL at Fox Chase to Kerry 
Campbell’s lab. Remaining cells will be stored in the PSL 
 
 Laboratory Procedures/Assessments 
Details regarding specific laboratory procedures/assessments to be performed in this trial 
are provided below.  
 
Laboratory tests for hematology, chemistry, urinalysis, and others are specified in Table 4.  
 
Table 4.  Laboratory Tests 
Hematology 
Chemistry 
Urinalysis 
Other 
Hematocrit 
Albumin 
Blood 
Serum β-human chorionic 
gonadotropin† 
Hemoglobin 
Alkaline phosphatase 
Glucose 
  (β-hCG)† 
Platelet count 
Alanine aminotransferase 
(ALT) 
Protein 
PT (INR) 
WBC (total and 
differential) 
Aspartate aminotransferase 
(AST) 
Specific gravity  
aPTT 
Red Blood Cell Count 
Total Bilirubin  
Microscopic exam (If 
abnormal)  
Total thriiodothyronine (T3) 
Absolute Neutrophil 
Count 
Carbon Dioxide  
results are noted 
Free tyroxine (T4) 
Absolute Lymphocyte 
Count 
  (CO2 or biocarbonate) 
 
Thyroid stimulating hormone 
(TSH) 
 
Blood Urea Nitrogen  
 
Lipase 
 
Calcium 
 
HIV antibody 
 
Chloride 
 
Blood for correlative studies 
 
Glucose 
 
HepBsAg 
 
Potassium   
 
HCV RNA 
 
Sodium 
 
  
 
Direct Bilirubin (If total 
bilirubin is elevated above 
the upper limit of normal) 
 
 
 
Total protein 
 
 
 
 
 
 
† Perform on women of childbearing potential only.  
 


 
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Laboratory tests for screening will be performed within 10 days prior to the first dose of 
treatment.  After Cycle 1, pre-dose laboratory procedures can be conducted up to 72 hours 
prior to dosing.  Results must be reviewed by the investigator or qualified designee and found 
to be acceptable prior to each dose of trial treatment.  
 
8.3.1. Biomarker Evaluations 
Blood Collection for correlative studies/biomarkers 
Sample collection, processing, storage, and shipment instructions for samples is provided in 
the Appendix (section 17.2). 
 
Tumor tissue collection for correlative studies 
Pathology samples from archived tumor biopsies (or optional fresh biopsy done before 
treatment initiation, if no archived tissue available) are to be submitted within 28 days of 
starting cycle 1. Representative FFPE tumor tissue blocks specimen  are to be submitted to 
the Fox Chase Cancer Center PSL.  
 
The following pathology material needs to be submitted: 
 Paraffin embedded biopsy or cell block, and  
 Any available pathology report related to that tumor sample 
 
NOTE: If a block is unavailable for submission, slides are to be submitted. All slides must 
be adequately labeled, with slides numbered sequentially in the order cut. Alternative 
submission requirement:  
 One (1) H&E slide, and  
 Ten  (10) 4 μm unstained air-dried on plus slides. 
 
Shipment of pathology samples is outlined in the Appendix (section 17.2) 
         
  Other Procedures 
8.4.1. Withdrawal/Discontinuation 
When a subject discontinues/withdraws prior to trial completion, all applicable activities 
scheduled for the final trial visit should be performed at the time of discontinuation.  Any 
adverse events which are present at the time of discontinuation/withdrawal should be 
followed in accordance with the safety requirements outlined in Section 9.2 - Assessing and 
Recording Adverse Events.  Subjects who a) attain a CR or b) complete 35 cycles of 
treatment with pembrolizumab may discontinue treatment with the option of restarting 
treatment if they meet the criteria specified in Section 8.5.4.  After discontinuing treatment 
following assessment of CR, these subjects should return to the site for a Safety Follow-up 
Visit (described in Section 8.5.3) and then proceed to the Follow-Up Period of the study. 
 


 
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 Visit Requirements 
Visit requirements are outlined in Section 10.0 – study calendar.   Specific procedure-related 
details are provided above in Section 8.0 - Trial Procedures. 
 
8.5.1. Screening Period 
Subjects will be screened within 28 prior to protocol treatment. Study procedures and 
information regarding the nature of the study will be reviewed with potential subjects and 
written informed consent will be obtained prior to any study related procedures. Screening 
procedures are described in Section 10.0 – study calendar. 
 
8.5.2. Treatment Period 
Subjects will be treated every 3 weeks of Pembrolizumab for up to 35 cycles. During the 
treatment phase patients will be evaluated clinically before each dose of Pembrolizumab for 
toxicities and radiologically every 9 weeks for disease progression as outlined in detail in 
Section 10.0 – study calendar. 
 
8.5.3. Post-Treatment Visits 
Safety Follow-Up Visit 
The mandatory Safety Follow-Up Visit should be conducted approximately 30 days after the 
last dose of trial treatment or before the initiation of a new anti-cancer treatment, whichever 
comes first.  All AEs that occur prior to the 120 day Safety Follow-Up Visit should be 
recorded.  Subjects with an AE of Grade > 1 will be followed until the resolution of the AE 
to Grade 0-1 or until the beginning of a new anti-neoplastic therapy, whichever occurs first.  
SAEs that occur within 120 days of the end of treatment or before initiation of a new anti-
cancer treatment should also be followed and recorded.  Subjects who are eligible for 
retreatment with pembrolizumab (as described in Section 8.5.4) may have up to two safety 
follow-up visits, one after the Treatment Period and one after the Second Course Phase. 
 
           Follow-up Visits 
Subjects who discontinue trial treatment for a reason other than disease progression will 
move into the Follow-Up Phase and should be assessed every 9 weeks (63 ± 7 days) by 
radiologic imaging to monitor disease status.  After 1 year, the imaging time point will occur 
every 12 weeks (± 7 days). Every effort should be made to collect information regarding 
disease status until the start of new anti-neoplastic therapy, disease progression, death, end 
of the study or if the subject begins retreatment with pembrolizumab as detailed in Section 
8.5.4.  Information regarding post-study anti-neoplastic treatment will be collected if new 
treatment is initiated. 
 
           Survival Follow-up 
Once a subject experiences confirmed disease progression or starts a new anti-cancer 
therapy, the subject moves into the survival follow-up phase and should be contacted by 
telephone every 12 weeks to assess for survival status until death, withdrawal of consent, or 
the end of the study, whichever occurs first.  


 
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8.5.4. Second Course Phase (Retreatment Period) 
Subjects who stop pembrolizumab with SD or better may be eligible for up to 18 cycles 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 35 cycles of study 
therapy for reasons other than disease progression or intolerability 
AND 
 Experienced an investigator-determined confirmed radiographic disease progression 
after stopping their initial treatment with pembrolizumab 
 Did not receive any anti-cancer treatment since the last dose of pembrolizumab 
 Has a performance status of 0 or 1 on the ECOG Performance Scale 
 Demonstrates adequate organ function as detailed in Section 6.1 
 Female subject of childbearing potential should have a negative serum 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 (Section 6.5.2).  
Subjects of child bearing potential are those who have not been surgically sterilized 
or have been free from menses for > 1 year.  
 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. 


 
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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 18 additional 
cycles. 
 
Visit requirements are outlined in Section 10.0 – study calendar. 
 
8.5.5. Treatment Beyond Disease Progression 
See section 6.8  for further details. The decision to continue study treatment after the 1st 
evidence of disease progression is at the Investigator’s discretion based on the clinical status 
of the subject as described in table 5. Confirmatory imaging maybe performed as early as 28 
days later; alternatively, the scan performed at the next scheduled time point (every 42 days 
± 7 days) may be used as confirmation. Subjects may receive study treatment while waiting 
for confirmation of PD if they are clinically stable as defined by the following criteria: 
o Absence of signs and symptoms (including worsening of laboratory values) 
indicating 
o disease progression 
o No decline in ECOG performance status 
o Absence of rapid progression of disease 
o Absence of progressive tumor at critical anatomical sites (e.g., cord compression) 
o Requiring urgent alternative medical intervention 
o Subjects exhibiting toxicity from trial therapy requiring discontinuation of trial 
therapy as outlined in Section 6.4.and 7.0 may NOT continue to receive trial therapy. 
 
Table 5 
 
Clinically stable 
Clinically unstable 
Imaging 
Treatment 
Imaging 
Treatment 
1st radiologic 
evidence of PD 
Repeat imaging at > 
4 weeks at site to 
confirm PD 
May continue study 
treatment at the 
Investigator’s discretion 
while awaiting 
confirmatory scan by site 
Repeat imaging at > 
4 weeks to confirm PD per 
physician discretion only 
Discontinue treatment 
Repeat scan 
confirms PD (no 
reduction in tumor 
burden from prior 
scan) 
No additional 
imaging required 
 
Discontinue treatment 
No additional imaging 
required 
NA 
Repeat scan 
confirms PD 
(reduction in tumor 
burden from prior 
scan) 
Continue regularly 
scheduled imaging 
assessments 
Continue study treatment 
after consultation with 
Sponsor Investigator 
Continue regularly 
scheduled imaging 
assessments 
May restart study 
treatment if condition has 
improved and/or 
clinically stable per 
Investigator and Sponsor 
Investigators’s discretion 
Repeat scan shows 
SD, PR or CR 
Continue regularly 
scheduled imaging 
assessments 
Continue study treatment 
at the Investigator’s 
discretion 
Continue regularly 
scheduled imaging 
assessments 
May restart study 
treatment if condition has 
improved and/or 
clinically stable per 
Investigator’s discretion 
NOTE: If a subject with confirmed radiographic progression (i.e. 2 scans at least 28 days 
apart demonstrating progressive disease) is clinically stable or clinically improved, and 
there is no further increase in the tumor dimensions at the confirmatory scan (as assessed 
by the investigator/site radiologist), an exception may be considered to continue treatment 
upon consultation with the Sponsor Investigator. All decisions to treat beyond progression 


 
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must be approved by the PI and the rationale must be clearly documented within the study 
records. 
Upon radiographic or clinical evidence of second progression, defined as an additional 20% 
or greater increase in total sum of tumor burden, patients must discontinue study therapy 
 
9.0 Adverse Events 
 Definitions: 
9.1.1. Adverse Events 
An adverse event is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product and which does not necessarily 
have to have a causal relationship with this treatment. An adverse event can therefore be 
any unfavorable and unintended sign (including an abnormal laboratory finding, for 
example), symptom, or disease temporally associated with the use of a medicinal product 
or protocol-specified procedure, whether or not considered related to the medicinal product 
or protocol-specified procedure.   
 
Any worsening (i.e., any clinically significant adverse change in frequency and/or 
intensity) of a preexisting condition that is temporally associated with the use of the 
pembrolizumab is also an adverse event. 
 
Changes resulting from normal growth and development that do not vary significantly in 
frequency or severity from expected levels are not to be considered adverse events.  
Examples of this may include, but are not limited to, teething, typical crying in infants and 
children and onset of menses or menopause occurring at a physiologically appropriate time. 
 
9.1.2. Serious Adverse Events 
Serious Adverse Event (SAE) is an AE that is fatal or life threatening, requires inpatient 
hospitalization or prolongation of existing hospitalization (for > 24 hours), persistent or 
significant incapacity or substantial disruption of the ability to conduct normal life 
functions, or is a congenital anomaly/ birth defect, or results in any important medical 
event that may not result in death, be life threatening, or require hospitalization may be 
considered an SAE when, based upon appropriate medical judgment, may jeopardize the 
subject and may require medical or surgical intervention to prevent any of the above 
outcomes.  A “life-threatening” adverse event places the patient at immediate risk of death 
in the judgment of the investigator or sponsor. 
 
Note: In addition to the above criteria, adverse events meeting either of the below criteria, 
although not serious per ICH definition, are considered serious for the purpose of this study 
and therefore must be reported in the same timeframe as SAEs.  
●  Is a new cancer (that is not a condition of the study); 
●  Is associated with an overdose.  
 


 
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9.1.3. Definition of Overdose for This Protocol 
For purposes of this trial, an overdose of pembrolizumab will be defined as any dose of 
1,000 mg or greater (≥5 times the indicated dose).  No specific information is available on 
the treatment of overdose of pembrolizumab. Appropriate supportive treatment should be 
provided if clinically indicated. In the event of overdose, the subject should be observed 
closely for signs of toxicity.  Appropriate supportive treatment should be provided if 
clinically indicated. 
 
9.1.4.  Severity Rating  
The investigator will evaluate the severity of each adverse event.  NCI Common 
Terminology Criteria for Adverse Events (CTCAE v.4.0) or study specific toxicity tables 
provided in the protocol define severity.  If not included in CTCAE v.4.0, severity is 
expressed in numerical grade using the following definitions: 
1. Grade 1: Mild-asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated. 
2. Grade 2: Moderate-minimal, local or noninvasive intervention indicated; limiting 
age appropriate instrumental ADL. 
3. Grade 3: Severe-severe or medically significant but not immediately life-
threatening; hospitalization or prolongation of hospitalization indicated; disabling; 
limiting self care ADL. 
4. Grade 4: Life-threatening consequences; urgent intervention indicated.  
5. Grade 5: Death related to AE 
 
9.1.4.1. 
Attribution/Relationship to study drug  
1. 
Definite – clearly related 
2. 
Probable – likely related 
3. 
Possible – may be related 
4. 
Unlikely – doubtfully related 
5. 
Unrelated – clearly not related 
 
9.1.5. Expectedness 
An Expected Adverse Event is one where the specificity or severity is consistent with the 
current information available from the resources. 
An Unexpected Adverse Event is one where the nature, severity, or frequency of the event 
is related to participation in the research is not consistent with either: 
1. The known or foreseeable risk of adverse events associated with the procedures 
involved in the research that are described in (a) the protocol-related documents, 
such as the IRB-approved research protocol, any applicable investigator brochure, 
and the current IRB-approved informed consent document, and (b) other relevant 
sources of information, such as product labeling and package inserts: or 


 
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2. The expected natural progression of any underlying disease, disorder, or condition of 
the subject (s) experiencing the adverse event and the subjects(s) predisposing risk 
factor profile for the adverse event. 
 
(OHRP Guidance on reviewing unanticipated problems 2007) 
 
9.1.6. Events of Clinical Interest 
Selected non-serious and serious adverse events are also known as Events of Clinical 
Interest (ECI).  
 
Events of clinical interest for this trial include: 
1.  An overdose of Merck product that is not associated with clinical symptoms or 
abnormal laboratory results.  
2.  an elevated AST or ALT lab value that is greater than or equal to 3X the upper limit 
of normal and an elevated total bilirubin lab value that is greater than or equal to 2X 
the upper limit of normal and, at the same time, an alkaline phosphatase lab value that 
is less than 2X the upper limit of normal, as determined by way of protocol-specified 
laboratory testing or unscheduled laboratory testing.* 
*Note:  These criteria are based upon available regulatory guidance documents. The 
purpose of the criteria is to specify a threshold of abnormal hepatic tests that may 
require an additional evaluation for an underlying etiology.  
 
 Assessing, Recording and Reporting Adverse Events 
 
9.2.1. Investigative site recording responsibilities: 
 
1. Upon identification of an AE or SAE, the site investigator will utilize the above 
definitions to properly classify the event.  Each category listed above; in section 9.1; 
must be recorded for each event. Adverse events will be recorded from the time of 
treatment initiation through 120 days following cessation of treatment. 
 
2. All AEs and SAEs will be recorded in the “AE case report forms” (CRF) and in progress 
reports with details about the grade and attribution of each episode, action taken with 
respect to the study drug, and the patient’s outcome will be recorded in the CRF.  All 
events will be recorded on case report forms for the duration of the study until they 
resolve. 
 
3. All SAEs will be recorded on the FDA MedWatch form 3500a.  After submitting the 
initial report it may be necessary to submit follow up reports to the Sponsor, Merck and 
the FDA should the event require further investigation. 
 
9.2.2. Investigative site reporting responsibilities: 
1. The investigator/ site is responsible to report all SAEs that occur on or after the first day 
of study treatment to the IST Regulatory Specialist within 24 hours of becoming aware 


 
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of the event.   
 
 
Each investigator is responsible to report all SAEs to their local IRB following 
guidelines set by that IRB.  The FCCC OCR reserves the right to request an event be 
reported to the IRB at their discretion.  Copies of events reviewed by the IRB must be 
sent email to SAE.FCCC@fccc.edu.  
 
2. If the investigator or IRB feels the event warrants a revision to the informed consent that 
was not already initiated by the OCR, draft revisions will be made in track changes and 
submitted to the OCR for consideration.  Any consent revisions must receive OCR 
approval prior to submission to the IRB. 
 
3. Any investigator who is in doubt of whether a particular AE needs to be reported is 
directed to call the Study Monitor for confirmation with the Sponsor Investigator. 
 
4. If the results of an investigator or OCR investigation show an adverse event not initially 
determined to be reportable is so reportable, the investigator will report the event 
following the above guidelines based on the date the determination is made. 
 
5. Copies of all related correspondence and reporting documents must be submitted to the 
ISRU and will be maintained in the trial master file.  
 
Participating sites should report events to: 
 
Investigator-Sponsored Research Unit 
Office of Clinical Research 
Fox Chase Cancer Center 
SAE.FCCC@fccc.edu 
 
 
9.2.3. Additional reporting guidelines for investigative sites: 
 
Following events must be reported by investigative sites to IST Regulatory Specialist 
within 24 hours of being aware of the event: 
 
 Serious Adverse Events  
For the time period beginning at treatment initiation through 120 days following cessation 
of treatment, or 30 days following cessation of treatment if the subject initiates new 
anticancer therapy, whichever is earlier, any serious adverse event, or follow up to a serious 
adverse event, including death due to any cause other than progression of the cancer under 
study whether or not related to the pembrolizumab must be reported. 
 
 Overdose 


 
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If an adverse event(s) is associated with (“results from”) the overdose of a pembrolizumab, 
the adverse event(s) is reported as a serious adverse event, even if no other seriousness 
criteria are met. 
 
If a dose of pembrolizumab meeting the protocol definition of overdose is taken without 
any associated clinical symptoms or abnormal laboratory results, the overdose is reported 
as a non-serious Event of Clinical Interest (ECI), using the terminology “accidental or 
intentional overdose without adverse effect.” 
 
 New cancer Incident  
If a new type of cancer is detected, which is not a condition of the study, it should be 
reported as a serious adverse event. 
 
 Pregnancies and Lactations 
Pregnancies and lactations that occur from the time of treatment initiation through 120 days 
following cessation of pembrolizumab, or 30 days following cessation of treatment if the 
subject initiates new anticancer therapy, whichever is earlier, must be reported . 
All reported pregnancies must be followed to the completion/termination of the pregnancy. 
Pregnancy outcomes of spontaneous abortion, missed abortion, benign hydatidiform mole, 
blighted ovum, fetal death, intrauterine death, miscarriage and stillbirth must be reported as 
serious events (Important Medical Events). If the pregnancy continues to term, the outcome 
(health of infant) must also be reported. 
 
 Events of Clinical Interest (ECIs) 
For the time period beginning at treatment initiation through 120 days following cessation 
of treatment, or 30 days following cessation of treatment if the subject initiates new 
anticancer therapy, whichever is earlier, any ECI, or follow up to an ECI, whether or not 
related to pembrolizumab must be reported. 
 
9.2.4. Sponsor Reporting Responsibilities: 
1. Adverse events which meet all of the following criteria must be reported to all 
participating institutions for IRB submission within 2 weeks of notification of the 
event:   
i. 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; 
ii. Possibly related to participation in the research (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 


 
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iii. Serious (refer to above definition) or otherwise one that suggests that the research 
places subjects or others at a greater risk of physical or psychological harm than 
was previously known or recognized. 
 
2. Copies of all related correspondence and reporting documents will be maintained in a 
centralized regulatory file for this study at OCR. 
 
3. SAEs that are related, unexpected, fatal, or life-threatening are reportable through the 
Food and Drug Administration (FDA) MedWatch program by telephone or fax no later 
than 7 calendar days after initial receipt of the information.  Further information on the 
timing of submissions are as directed by FDA 
guidelines.(http://www.fda.gov/medwatch/index.html).  Serious, unexpected events that 
suggest significant clinical risk will be submitted to within 15 calendar days after initial 
receipt of this information. 
 
Food and Drug Administration: 
Central Document Room  
Center for Drug Evaluation and Research  
Food and Drug Administration  
5901-B Ammendale Road  
Beltsville, MD 20705  
 
 (301) 827-3169 for any further questions regarding where to 
send drug mandatory reporting forms  
 
9.2.5. Sponsor Reporting Responsibilities to Merck: 
Sponsor must report the following to Merck Global Safety within 2 working days of 
notification by investigative sites: 
 Serious Adverse Events 
 All reports of overdose with and without an adverse event 
 Pregnancy and Lactation 
 Events of Clinical Interest (ECIs) 
 
SAE reports and any other relevant safety information are to be forwarded to the 
Merck Global Safety (Attn: Worldwide Product Safety; FAX 215 993-1220) 
 
A copy of all 15 Day Reports and Annual Progress Reports is submitted as required by 
FDA, Investigators will cross reference this submission according to local regulations to 
the Merck Investigational Compound Number (IND, CSA, etc.) at the time of submission.  
Additionally investigators will submit a copy of these reports to Merck & Co., Inc. (Attn: 
Worldwide Product Safety; FAX 215 993-1220) at the time of submission to FDA. 
 


 
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10.0 
Study Calendar 
 Initial Treatment Phase 
 
Trial Period: 
Screening Phase 
Treatment Cyclesa 
End of 
Treatmentm 
 
Post-Treatment 
Treatment Cycle/Title: 
Study Screening  
1 
2  
3 
Cycle 4 and  
beyond   
 
35 cycles 
completed 
OR  
At time of 
Discon 
Safety 
Follow-up 
 
Follow Up 
Visitsb  
Survival 
Follow-
Up 
Safety 
Follow-up 
Scheduling Window (Days): 
-28 to -1 
 
± 3 
± 3 
± 3 
30 days 
post discon 
120 days 
post discon 
 
Every 12 
weeks  
Administrative Procedures 
Informed Consent 
x 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
x 
 
 
 
 
 
 
 
 
 
Demographics and Medical History 
X 
 
 
 
 
 
 
 
 
 
Prior and Concomitant Medication Review 
X 
x 
x 
x 
x 
x 
X 
 
 
 
Pembrolizumab Administration 
 
x 
x 
x 
x 
 
 
 
 
 
Post-study anticancer therapy status 
 
 
 
 
 
 
 
 
x 
x 
Survival Status 
 
 
 
 
 
 
 
 
 
x 
Review Adverse Events 
 
x 
x 
x 
x 
x 
x 
x 
 
 
Full Physical Examination  
x 
X 
X 
x 
X 
x 
x 
 
 
 
Vital Signs i and Weight 
x 
x 
x 
x 
x 
x 
x 
 
 
 
Height 
x 
 
 
 
 
 
 
 
 
 
ECOG Performance Status 
x 
x 
x 
x 
x 
x 
x 
 
 
 
Laboratory Procedures/Assessments: analysis performed by LOCAL laboratory 
Pregnancy Test –Serum B-HCG 
x h 
 
 
 
 
 
 
 
 
 
PT/INR and aPTT 
x g 
 
 
 
 
 
 
 
 
 
CBC with Differential 
x g 
x 
x 
x 
x 
x 
x 
 
 
 


 
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Trial Period: 
Screening Phase 
Treatment Cyclesa 
End of 
Treatmentm 
 
Post-Treatment 
Treatment Cycle/Title: 
Study Screening  
1 
2  
3 
Cycle 4 and  
beyond   
 
35 cycles 
completed 
OR  
At time of 
Discon 
Safety 
Follow-up 
 
Follow Up 
Visitsb  
Survival 
Follow-
Up 
Safety 
Follow-up 
Scheduling Window (Days): 
-28 to -1 
 
± 3 
± 3 
± 3 
30 days 
post discon 
120 days 
post discon 
 
Every 12 
weeks  
 
HIV antibody 
x 
 
 
 
 
 
 
 
 
 
HepBsAg 
x 
 
 
 
 
 
 
 
 
 
HCV RNA 
x 
 
 
 
 
 
 
 
 
 
Comprehensive Serum Chemistry Panel j 
x g 
x 
x 
x 
x 
x 
x 
 
 
 
Urinalysis 
x g 
 
 
 
 
 
 
 
 
 
T3, FT4 and TSH 
x g 
xc 
x 
x 
 
 
 
Efficacy Measurements 
Tumor Imagingd 
x 
Xe 
 
 
 
Xl 
 
Tumor Biopsies/Archival Tissue Collection/Correlative Studies Blood 
Archival Tissue requestedk 
x 
 
 
 
 
 
 
 
 
 
Correlative Studies Blood Collection f 
 
x 
 
x 
 
x 
 
 
 
 
Optional blood collection for future 
studiesn 
x 
x 
x 
 
 
 
 
a Total of 35 treatment cycles. Treatment cycles are 3 weeks (21-days) 
b Patients should be assessed every 9 weeks (63 ± 7 days) for the first 1 year (or until disease progression) for disease status. After 1 year, patients should be assessed 
every 12 weeks (± 7 days). Once a subject experiences confirmed disease progression or starts a new anti-cancer therapy they move into survival follow-up  
c Check during treatment phase every 3 cycles (screening, cycle 3, 6, 9, 12, 15, 18, etc.) 
d Preferably a contrast-enhanced CT scan of chest/abdomen and pelvis (If cannot receive contrast, can substitute for CT chest without contrast and MRI abdomen/pelvis 
with contrast). Subsequent imaging should be of the same modality as the imaging at baseline. Imaging studies will be done every 9 weeks (± 7 days) after initiating 
treatment for the first year; subsequent imaging will be every 12 weeks (± 7days) thereafter during the treatment phase. 
e Imaging studies will be done every 9 weeks (± 7 days) after initiating treatment for the first year; subsequent imaging will be every 12 weeks (± 7 days) thereafter during 
the treatment phase. 


 
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Trial Period: 
Screening Phase 
Treatment Cyclesa 
End of 
Treatmentm 
 
Post-Treatment 
Treatment Cycle/Title: 
Study Screening  
1 
2  
3 
Cycle 4 and  
beyond   
 
35 cycles 
completed 
OR  
At time of 
Discon 
Safety 
Follow-up 
 
Follow Up 
Visitsb  
Survival 
Follow-
Up 
Safety 
Follow-up 
Scheduling Window (Days): 
-28 to -1 
 
± 3 
± 3 
± 3 
30 days 
post discon 
120 days 
post discon 
 
Every 12 
weeks  
f Peripheral blood samples will be collected immediately prior to cycle 1 , immediately prior to dose 1 (time 1), prior to dose 3, cycle 3 day 1 ( time 2) and at time of 
progression (time 3). For sampling, handling, processing, and shipping, please see Appendix (Section 17.2) 
g Within 10 days of treatment initiation 
h Within 72 hours of treatment initiation if participant is a woman of child bearing potential 
i Vital signs consist of temperature, pulse, respiration, and blood pressure and will be monitored every 15 minutes during the infusion and at 60 minutes after completion 
of each infusion.  
j A direct bilirubin must be performed if the total bilirubin is above the upper limit of normal. This will also include Lipase testing.  
k If archival tissue is not available, patient may undergo an optional fresh biopsy of tumor before day 1 of therapy. All archived tissues must be received within 28 days of 
starting cycle 1. 
l In subjects who discontinue study therapy without documented disease progression, every effort should be made to continue monitoring their disease status by 
radiologic imaging every 9 weeks (63 ± 7days) in the first year and every 12 weeks (84 ± 7 days) after year 1 until (1) the start of new anti-cancer treatment, (2) disease 
progression as assessed by the investigator/site radiologist, (3) death, or (4)the end of the study, whichever occurs first. 
m End of treatment procedures will be conducted at the time of treatment discontinuation or at the end of 35 cycles, whichever occurs sooner 
n Optional blood collections in consenting patients for sera, plasma and red blood cells for future research. In consenting patients, blood will be drawn prior to cycle 1, 
every other assessment, and at the end of treatment for future research. 
 
 
Retreatment Phase (Second Course of Treatment) 
Trial Period: 
 
Screening 
Treatment Cyclesa 
End of 
Treatment 
Post-Treatment 
Treatment Cycle/Title: 
 
       Pre-Re-Tx 
1 
2  
3 
 
Cycle 4 and 
beyond 
Discon 
Safety 
Follow-up 
 
Follow Up 
Visitsb 
Survival 
Follow-Up 
 
Safety 
Follow-up 
Scheduling Window (Days): 
 
 
 
± 3 
± 3 
± 3 
At time of 
Discon 
30 days post 
discon 
120 days post 
discon 
 
Every 12 
weeks  
Eligibility criteria 
X 
 
 
 
 
 
 
 
 
 


 
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Trial Period: 
 
Screening 
Treatment Cyclesa 
End of 
Treatment 
Post-Treatment 
Treatment Cycle/Title: 
 
       Pre-Re-Tx 
1 
2  
3 
 
Cycle 4 and 
beyond 
Discon 
Safety 
Follow-up 
 
Follow Up 
Visitsb 
Survival 
Follow-Up 
 
Safety 
Follow-up 
Scheduling Window (Days): 
 
 
 
± 3 
± 3 
± 3 
At time of 
Discon 
30 days post 
discon 
120 days post 
discon 
 
Every 12 
weeks  
Prior and Concomitant Medication Review 
X 
X  
X 
X 
X 
X 
X 
 
 
 
Pembrolizumab Administration 
 
X 
X 
X 
X 
 
 
 
 
 
Post-study anticancer therapy status 
 
 
 
 
 
 
 
 
X 
X 
Survival Status 
 
 
 
 
 
 
 
 
 
X 
Review Adverse Events 
 
X 
X 
X 
X 
X 
X 
X 
 
 
Full Physical Examination 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Vital Signs and Weighti 
X 
X 
X 
X 
X 
X 
X 
 
 
 
ECOG Performance Status 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Pregnancy Test –Serum -HCG 
Xh 
 
 
 
 
 
 
 
 
 
PT/INR and aPTT 
Xg 
 
 
 
 
 
 
 
 
 
CBC with Differential 
Xg 
X 
X 
X 
X 
X 
X 
 
 
 
Comprehensive Serum Chemistry Panelj 
Xg 
X 
X 
X 
X 
X 
X 
 
 
 
HIV antibody 
x 
 
 
 
 
 
 
 
 
 
HepBsAg 
x 
 
 
 
 
 
 
 
 
 
HCV RNA 
x 
 
 
 
 
 
 
 
 
 
Urinalysis 
Xg 
 
 
 
 
 
 
 
 
 
T3, FT4 and TSH 
Xg 
Xc 
 
X 
 
 
 
Tumor Imagingd, 
X 
Xe 
Xf 
 
 
Xk 
 
a Treatment cycles are 3 weeks (21-days) 
b Patients should be assessed every 9 weeks (63 ± 7 days) for the first 1 year (or until disease progression) for disease status. After 1 year, patients should be assessed every 
12 weeks (± 7 days). Once a subject experiences confirmed disease progression or starts a new anti-cancer therapy they move into survival follow-up  
c Check during treatment phase every 3 cycles (screening, cycle 3, 6, 9, 12, 15, 18, etc.) 
d Preferably a contrast-enhanced CT scan of chest/abdomen and pelvis done within 28 days of restarting treatment(If cannot receive contrast, can substitute for CT chest 
without contrast and MRI abdomen/pelvis with contrast). Subsequent imaging should be of the same modality as the imaging at baseline.   


 
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Trial Period: 
 
Screening 
Treatment Cyclesa 
End of 
Treatment 
Post-Treatment 
Treatment Cycle/Title: 
 
       Pre-Re-Tx 
1 
2  
3 
 
Cycle 4 and 
beyond 
Discon 
Safety 
Follow-up 
 
Follow Up 
Visitsb 
Survival 
Follow-Up 
 
Safety 
Follow-up 
Scheduling Window (Days): 
 
 
 
± 3 
± 3 
± 3 
At time of 
Discon 
30 days post 
discon 
120 days post 
discon 
 
Every 12 
weeks  
e Imaging studies will be done every 9 weeks (± 7 days) after initiating treatment for the first year; subsequent imaging will be every 12 weeks (± 7days) thereafter during 
the treatment phase. 
f In subjects who discontinue study therapy without confirmed disease progression, a radiologic evaluation should be performed at the time of treatment discontinuation 
(i.e., date of discontinue ± 4 week window). If a previous scan was obtained within 4 weeks prior to the date of discontinuation, then a scan at treatment discontinuation 
isn’t mandatory. 
g Within 10 days of treatment initiation 
h Within 72 hours of treatment initiation if participant is a woman of child bearing potential 
i Vital signs consist of temperature, pulse, respiration, and blood pressure and will be monitored every 15 minutes during the infusion and at 60 minutes after completion of 
each infusion.  
j A direct bilirubin must be performed if the total bilirubin is above the upper limit of normal. This will also include Lipase testing. k In subjects who discontinue study 
therapy without documented disease progression, every effort should be made to continue monitoring their disease status by radiologic imaging every 9 weeks (63 ± 7days) 
in the first year and every 12 weeks (84 ± 7 days) after year 1 until (1) the start of new anti-cancer treatment, (2) disease progression as assessed by the investigator/site 
radiologist, (3) death, or (4)the end of the study, whichever occurs first 
 


 
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11.0 
Labeling, Packaging, Storage and Return of Clinical Supplies 
 Investigational Product  
The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution and usage of 
investigational product in accordance with the protocol and any applicable laws and 
regulations. 
Clinical Supplies will be provided by Merck as summarized in Table 6. 
Table 6. Product Descriptions 
Product Name & Potency 
Dosage Form 
Pembrolizumab 50 mg 
Lyophilized Powder for Injection 
Pembrolizumab 100 mg/ 4mL 
Solution for Injection 
 
 Packaging and Labeling Information 
Clinical supplies will be affixed with a clinical label in accordance with regulatory 
requirements. 
 
 Clinical Supplies Disclosure 
This trial is open-label 
 
 Storage and Handling Requirements 
Clinical supplies must be stored in a secure, limited-access location under the storage 
conditions specified on the label.   
Receipt and dispensing of trial medication must be recorded by an authorized person at the 
trial site. 
Clinical supplies may not be used for any purpose other than that stated in the protocol. 
 
 Returns and Reconciliation 
The investigator is responsible for keeping accurate records of the clinical supplies received 
from Merck or designee, the amount dispensed to and returned by the subjects and the 
amount remaining at the conclusion of the trial.  
Upon completion or termination of the study, all unused and/or partially used investigational 
product will be destroyed at the site per institutional policy. It is the Investigator’s 
responsibility to arrange for disposal of all empty containers, provided that procedures for 
proper disposal have been established according to applicable federal, state, local and 
institutional guidelines and procedures, and provided that appropriate records of disposal are 
kept. 
 
12.0 
Measures of Effect 
Response Evaluation Criteria in Solid Tumors (RECIST)  


 
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The Response Evaluation Criteria in Solid Tumors (RECIST 1.1) criteria will be used for 
objective tumor response assessment. Assessments will be performed after  every 3 cycles for 
the first year and then every 4 cycles. Once protocol treatment has been completed subjects 
will be assessed every twelve weeks or sooner as indicated and judged by treating physicians. 
 Definitions 
Evaluable for adverse events.  All patients will be evaluable for adverse events from the 
time of their first treatment with pembrolizumab. 
 
Evaluable for objective response.  Only those patients who have measurable disease present 
at baseline, have received at least one cycle of therapy, and have had their disease re-
evaluated will be considered evaluable for response.  These patients will have their response 
classified according to the definitions stated below.  (Note:  Patients who exhibit objective 
disease progression prior to the end of cycle 1 will also be considered evaluable.) 
 
Evaluable Non-Target Disease Response.  Patients who have lesions present at baseline that 
are evaluable but do not meet the definitions of measurable disease, have received at least 
one cycle of therapy, and have had their disease re-evaluated will be considered evaluable 
for non-target disease.  The response assessment is based on the presence, absence, or 
unequivocal progression of the lesions.  
 
 Disease Parameters 
Measurable disease.  Measurable lesions are defined as those that can be accurately 
measured in at least one dimension (longest diameter to be recorded) as >20 mm by chest x-
ray, as >10 mm with CT scan or MRI, or >10 mm with calipers by clinical exam.  All tumor 
measurements must be recorded in millimeters (or decimal fractions of centimeters). 
 
Note:  Tumor lesions that are situated in a previously irradiated area might or might not be 
considered measurable.   
 
Malignant lymph nodes.  To be considered pathologically enlarged and measurable, a lymph 
node must be >15 mm in short axis when assessed by CT scan (CT scan slice thickness 
recommended to be no greater than 5 mm).  At baseline and in follow-up, only the short axis 
will be measured and followed. 
 
Non-measurable disease.  All other lesions (or sites of disease), including small lesions 
(longest diameter <10 mm or pathological lymph nodes with ≥ 10 to <15 mm short axis), 
are considered non-measurable disease.  Bone lesions, leptomeningeal disease, ascites, 
pleural/pericardial effusions, lymphangitis cutis/pulmonitis, inflammatory breast disease, 
and abdominal masses (not followed by CT or MRI), are considered as non-measurable. 
 
Note:  Cystic lesions that meet the criteria for radiographically defined simple cysts should 
not be considered as malignant lesions (neither measurable nor non-measurable) since they 
are, by definition, simple cysts. 
 


 
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‘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. 
 
Target lesions.  All measurable lesions up to a maximum of 2 lesions per organ and 5 
lesions in total, representative of all involved organs, should be identified as target lesions 
and recorded and measured at baseline.  Target lesions should be selected on the basis of 
their size (lesions with the longest diameter), be representative of all involved organs, but 
in addition should be those that lend themselves to reproducible repeated measurements.  It 
may be the case that, on occasion, the largest lesion does not lend itself to reproducible 
measurement in which circumstance the next largest lesion which can be measured 
reproducibly should be selected.  A sum of the diameters (longest for non-nodal lesions, 
short axis for nodal lesions) for all target lesions will be calculated and reported as the 
baseline sum diameters.  If lymph nodes are to be included in the sum, then only the short 
axis is added into the sum.  The baseline sum diameters will be used as reference to further 
characterize any objective tumor regression in the measurable dimension of the disease. 
 
Non-target lesions.  All other lesions (or sites of disease) including any measurable lesions 
over and above the 5 target lesions should be identified as non-target lesions and should 
also be recorded at baseline.  Measurements of these lesions are not required, but the 
presence, absence, or in rare cases unequivocal progression of each should be noted 
throughout follow-up.  
 
 Methods for Evaluation of Measurable Disease 
All measurements should be taken and recorded in metric notation using a ruler or calipers.  
All baseline evaluations should be performed as closely as possible to the beginning of 
treatment and never more than 4 weeks before the beginning of the treatment. 
 
The same method of assessment and the same technique should be used to characterize 
each identified and reported lesion at baseline and during follow-up. Imaging-based 
evaluation is preferred to evaluation by clinical examination unless the lesion(s) being 
followed cannot be imaged but are assessable by clinical exam. 
 
Clinical lesions  Clinical lesions will only be considered measurable when they are 
superficial (e.g., skin nodules and palpable lymph nodes) and 10 mm diameter as assessed 
using calipers (e.g., skin nodules).  In the case of skin lesions, documentation by color 
photography, including a ruler to estimate the size of the lesion, is recommended.  
 
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.  MRI is also acceptable in certain situations (e.g. for body scans).   
 


 
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MRI has excellent contrast, spatial, and temporal resolution; however, there are many 
image acquisition variables involved in MRI, which greatly impact image quality, lesion 
conspicuity, and measurement.  Furthermore, the availability of MRI is variable globally.  
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.  Furthermore, as 
with CT, the modality used at follow-up should be the same as was used at baseline and the 
lesions should be measured/assessed on the same pulse sequence.  It is beyond the scope of 
the RECIST guidelines to prescribe specific MRI pulse sequence parameters for all 
scanners, body parts, and diseases.  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  At present, the low dose or attenuation correction CT portion of a combined PET-
CT is not always of optimal diagnostic CT quality for use with RECIST measurements.  
However, 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.  
Note, however, that the PET portion of the CT introduces additional data which may bias 
an investigator if it is not routinely or serially performed.   
 
 Response Criteria 
Evaluation of Target Lesions 
 
Complete Response (CR): Disappearance of all target lesions.  Any pathological lymph 
nodes (whether target or non-target) must have reduction in short axis to <10 mm. 
 
Partial Response (PR): 
At least a 30% decrease in the sum of the diameters of target 
lesions, taking as reference the baseline sum diameters 
 
Progressive Disease (PD): At least a 20% increase in the sum of the diameters of target 
lesions, taking as reference the smallest sum on study (this includes the baseline sum if that 
is the smallest on study).  In addition to the relative increase of 20%, the sum must also 
demonstrate an absolute increase of at least 5 mm.  (Note:  the appearance of one or more 
new lesions is also considered progressions). 
 
Stable Disease (SD): 
Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest sum diameters while on study 
 
Evaluation of Non-Target Lesions 
 
Complete Response (CR): Disappearance of all non-target lesions and normalization of 
tumor marker level.  All lymph nodes must be non-pathological in size (<10 mm short axis  
Note:  If tumor markers are initially above the upper normal limit, they must normalize for 
a patient to be considered in complete clinical response. 


 
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Non-CR/Non-PD:  
Persistence of one or more non-target lesion(s) and/or maintenance 
of tumor marker level above the normal limits 
 
Progressive Disease (PD): Appearance of one or more new lesions and/or unequivocal 
progression of existing non-target lesions.  Unequivocal progression should not normally 
trump target lesion status.  It must be representative of overall disease status change, not a 
single lesion increase.     
 
Although a clear progression of “non-target” lesions only is exceptional, the opinion of the 
treating physician should prevail in such circumstances, and the progression status should 
be confirmed at a later time by the review panel (or Principal Investigator). 
 
For Patients with Measurable Disease (i.e., Target Disease) 
 
Note:  If tumor markers are initially above the upper normal limit, they must normalize for 
a patient to be considered in complete clinical response. 
 
Non-CR/Non-PD:  
Persistence of one or more non-target lesion(s) and/or maintenance 
of tumor marker level above the normal limits 
 
Progressive Disease (PD): Appearance of one or more new lesions and/or unequivocal 
progression of existing non-target lesions.  Unequivocal progression should not normally 
trump target lesion status.  It must be representative of overall disease status change, not a 
single lesion increase.     
 
Although a clear progression of “non-target” lesions only is exceptional, the opinion of the 
treating physician should prevail in such circumstances, and the progression status should 
be confirmed at a later time by the review panel (or Principal Investigator). 
 
For Patients with Measurable Disease (i.e., Target Disease) 
 
Target 
Lesions 
Non-Target 
Lesions 
New Lesions 
Overall 
Response 
Best Overall Response when 
Confirmation is Required* 
CR 
CR 
No 
CR 
>4 wks. Confirmation** 
CR 
Non-CR/Non-PD 
No 
PR 
 
>4 wks. Confirmation** 
CR 
Not evaluated 
No 
PR 
PR 
Non-CR/Non-PD 
/not evaluated 
No 
PR 
SD 
Non-CR/Non-PD 
/not evaluated 
No 
SD 
documented at least once >4 wks. 
from baseline** 
PD 
Any 
Yes or No 
PD 
 
no prior SD, PR or CR 
Any 
PD*** 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
*      See RECIST 1.1 manuscript for further details on what is evidence of a new lesion. 
**    Only for non-randomized trials with response as primary endpoint. 
***  In exceptional circumstances, unequivocal progression in non-target lesions may be accepted as 
disease progression. 


 
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For Patients with Non-Measurable Disease (i.e., Non-Target Disease) 
 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD* 
Not all evaluated 
No 
not evaluated 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
*  ‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since 
SD is increasingly used as an endpoint for assessment of efficacy in some trials so 
to assign this category when no lesions can be measured is not advised 
 
   Objective response rate (ORR) 
Objective response rate (ORR) is defined as the proportion of subjects with metastatic high 
grade NETs who achieve a best response of complete response (CR) or partial response 
(PR) using the RECIST1.1 criteria. It will be determined by the investigator for each 
subject as either CR or PR and will be calculated as percentage CR + PR.  
 
 Duration of Response 
Duration of overall response:  The duration of overall response is measured from the time 
measurement criteria are met for CR or PR (whichever is first recorded) until the first date 
that recurrent or progressive disease is objectively documented (taking as reference for 
progressive disease the smallest measurements recorded since the treatment started). 
 
The duration of overall CR is measured from the time measurement criteria are first met for 
CR until the first date that progressive disease is objectively documented.  
 
Duration of stable disease:  Stable disease is measured from the start of the treatment until 
the criteria for progression are met, taking as reference the smallest measurements recorded 
since the treatment started, including the baseline measurements.  
 
Progression-Free Survival: Progression free survival is defined as the duration of time from 
start of treatment to time of progression or death, whichever occurs first. 
Note: 
Patients with a global deterioration of health status requiring discontinuation of 
treatment without objective evidence of disease progression at that time should be reported as 
“symptomatic deterioration.”  Every effort should be made to document the objective 
progression even after discontinuation of treatment. 


 
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13.0 
Statistical Considerations 
 Study Design/Endpoints 
The primary objective will be measured by the primary endpoint of Objective Response Rate 
(per RECIST 1.1) among all treated subjects. Secondary endpoints include PFS (per RECIST 
1.1) and OS. As discussed in the background, no second line treatments have been studied 
prospectively for high grade neuroendocrine carcinomas and small retrospective studies have 
shown dismal results with chemotherapy[11-13]. Hence we decided to proceed with a single 
stage statistical design given minimal if any, harm associated with ineffective therapy to 
study participants. 
 
A proportion of patients with favorable response less than 5.0% will be of no interest. The 
investigational agent would be of interest if the ORR is at least 20.0%. Estimates are based 
on historical controls from published data {Hentic, 2012 #70;Olsen, 2012 #71;{Sorbye, 2013 
#36}. Only those patients who have measurable disease present at baseline, have received at 
least one cycle of therapy, and have had their disease re-evaluated will be considered 
evaluable for response. (Note:  Patients who exhibit objective disease progression prior to 
the end of cycle 1 will also be considered evaluable.) Patients who are not evaluable for 
response will be replaced. However, all patients who received at least 1 dose of the study 
drug will be included in the safety analysis. Twenty-one patients would be needed to test the 
null hypothesis: p <= 0.05 against the alternative hypothesis: p >= 0.20 at the 8.5% level of 
significance and with 82.1% power.  After 21 patients are evaluated if 3 or more patients 
with favorable response are observed then the null hypothesis is rejected.  
 
Early stopping rules for safety/adverse events:  
 
Adverse events will be assessed continuously throughout the study. If 6 of the first 12 patients 
have to discontinue study treatment due to treatment related adverse events the study will be 
interrupted for consideration of dose reduction or termination. If ever 8 of the 21 eligible 
patients have to discontinue study treatment due to treatment related adverse events the study 
will be suspended and early termination for excess toxicity will be considered after careful 
investigation of the causes of the higher than expected toxicities. Once the root of the higher 
than anticipated toxicities has been determined, the study team will confer with the FCCC 
DSMC and IRB to make a determination whether accrual can be resumed or the study will 
be terminated early. The chance of early termination with a true toxicity of 50% is 61%. The 
chance of early termination in error, when true toxicity is <20% is 1.9%. The overall chance 
of study termination under the null of 20% true toxicity is 2.7% and is 83% if true toxicity is 
50%. 
 
As discussed earlier, no second line therapies have been prospectively evaluated in high 
grade neuroendocrine carcinomas and small retrospective studies have shown dismal results 
with chemotherapy [11-13]. Hence we decided to proceed without a definite stopping rule 
for futility, given minimal if any, harm associated with ineffective therapy to study 
participants. ]  
 


 
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Correlative studies: Due to this limited sample size, all exploratory analyses of associations 
of biomarkers with outcomes and changes in marker levels pre- and during treatment will 
be largely descriptive in nature.  
 
 Sample Size/Accrual Rate 
We plan to accrue 21 eligible patients. The expected monthly accrual rate is 1-2 patients. 
Thus, accrual is anticipated to take approximately 2 years. 
 
 Stratification Factors 
No stratification factors are pre-defined within the protocol 
 
 Reporting and Exclusions 
13.4.1 Evaluation of toxicity: All patients will be evaluable for toxicity from the time 
of their first treatment with pembrolizumab 
 
13.4.2 Evaluation of response:  All patients included in the study must be assessed for 
response to treatment, even if there are major protocol treatment deviations or if 
they are ineligible.  Each patient will be assigned one of the following 
categories:  1) complete response, 2) partial response, 3) stable disease, 4) 
progressive disease, 5) early death from malignant disease, 6) early death from 
toxicity, 7) early death because of other cause, or 9) unknown (not assessable, 
insufficient data).  [Note:  By arbitrary convention, category 9 usually 
designates the “unknown” status of any type of data in a clinical database.] 
 
All of the patients who met the eligibility criteria (with the possible exception of 
those who received no study medication) should be included in the main 
analysis of the response rate.  Patients in response categories 4-9 should be 
considered to have a treatment failure (disease progression).  Thus, an incorrect 
treatment schedule or drug administration does not result in exclusion from the 
analysis of the response rate.  Precise definitions for categories 4-9 will be 
protocol specific.  
 
14.0 
Data and Safety Monitoring Plan 
 Monitoring Plan  
FCCC ISRU will monitor the medical and study records of each participant accrued 
throughout the course of the study.  In addition, the ISRU will collect and report data to the 
study Sponsor Investigator who will review these data on a regular basis at a rate dependent 
on subject accrual.  All serious adverse events (SAEs) will be reviewed on a real time basis 
first by the study site PI and subsequently by the ISRU and Sponsor Investigator as 
applicable. 
 


 
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 Data Safety Monitoring Board   
Interim analysis of toxicity, outcome and ongoing scientific investigations may be performed 
at least every 3 months by the Fox Chase Cancer Center Data Safety Monitoring Committee 
(FCCCDSMB).  In this capacity the FCCCDSMB will serve as an advisory committee to the 
Sponsor Investigator.  The FCCCDSMB will review those aspects of this trial that are 
outlined in the responsibilities section of the Data and Safety Monitoring Plan (DSMP).  If 
the committee decides that changes should be made to this trial, it will make 
recommendations in writing to the Sponsor Investigator, the Associate Director of Clinical 
Research, and the Protocol Management Executive Committee, which, in turn, have the 
authority to approve or disapprove these recommendations.  These changes will be discussed 
with the Sponsor Investigator before they are implemented.  These changes may include 
early termination of accrual.  Other changes might include altering the accrual goals or 
changing the eligibility criteria for the trial. 
 
15.0 
Administrative   
This study will be conducted in accordance will local, state and Federal regulations and 
according to accepted good clinical practice guidelines. 
 
 Data Reporting 
The FCCC Study Monitor will request eCRF to be completed within 2 weeks of the 
protocol visit.  Participating sites are responsible to respond to queries prior to the next 
scheduled monitoring visit  
 
The ISRU is responsible for compiling and submitting data to the Sponsor Investigator and 
statistician on an ongoing basis for monitoring as described in the data safety monitoring 
plan and reporting to the Data and Safety Monitoring Board. 
 
All patient information will be stored in an EDC system accessible only to the study team 
members for the purpose of entering, reviewing and analyzing data.  Any paper records, such 
as case report files, produced will be stored in a secure location.  
 
The ISRU is responsible for distributing and tracking review of all IND Action Letters, 
Safety Reports, study specific Serious Adverse Events. 
 
 Retention of Records   
In all cases the Study Monitor must be notified of any plans to move records to an offsite 
location prior to doing so. 
 
 Informed Consent 
The IRB approved informed consent documents must be signed by the patient, or the 
patient’s legally authorized representative, before his or her participation in the study.  The 
case history for each patient shall document that informed consent was obtained prior to 
participation in the study.  A copy of the informed consent documents must be provided to 


 
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the patient or the patient’s legally authorized representative.  If applicable, they will be 
provided in a certified translation of the local language. 
 
Original signed consent forms must be filed in each patient’s study file or medical record 
with a copy in the study file. 
 
 


 
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16.0 
References 
 
1. 
Klöppel, G., et al., ENETS Consensus Guidelines for the Standards of Care in 
Neuroendocrine Tumors: Towards a Standardized Approach to the Diagnosis of 
Gastroenteropancreatic Neuroendocrine Tumors and Their Prognostic 
Stratification. Neuroendocrinology, 2009. 90(2): p. 162-166. 
2. 
Yao, J.C., et al., One hundred years after "carcinoid": epidemiology of and 
prognostic factors for neuroendocrine tumors in 35,825 cases in the United 
States. J Clin Oncol, 2008. 26(18): p. 3063-72. 
3. 
Lepage, C., et al., European disparities in malignant digestive endocrine tumours 
survival. International Journal of Cancer, 2010. 126(12): p. 2928-2934. 
4. 
Galanis, E., S. Frytak, and R.V. Lloyd, Extrapulmonary small cell carcinoma. 
Cancer, 1997. 79(9): p. 1729-1736. 
5. 
Smith, J. and D. Reidy-Lagunes, The Management of Extrapulmonary Poorly 
Differentiated (High-Grade) Neuroendocrine Carcinomas. Seminars in Oncology, 
2013. 40(1): p. 100-108. 
6. 
Kunz, P.L., Carcinoid and Neuroendocrine Tumors: Building on Success. Journal 
of Clinical Oncology, 2015. 
7. 
Walenkamp, A.M., G.S. Sonke, and D.T. Sleijfer, Clinical and therapeutic 
aspects of extrapulmonary small cell carcinoma. Cancer treatment reviews, 2009. 
35(3): p. 228-236. 
8. 
Moertel, C.G., et al., Treatment of neuroendocrine carcinomas with combined 
etoposide and cisplatin. Cancer, 1991. 68(2): p. 227-232. 
9. 
Rindi, G., F. Inzani, and E. Solcia, Pathology of gastrointestinal disorders. 
Endocrinology and metabolism clinics of North America, 2010. 39(4): p. 713-
727. 
10. 
Mitry, E., et al., Treatment of poorly differentiated neuroendocrine tumours with 
etoposide and cisplatin. British Journal of Cancer, 1999. 81(8): p. 1351. 
11. 
Sorbye, H., et al., Predictive and prognostic factors for treatment and survival in 
305 patients with advanced gastrointestinal neuroendocrine carcinoma (WHO 
G3): The NORDIC NEC study. Annals of Oncology, 2013. 24(1): p. 152-160. 
12. 
Olsen, I.H., et al., Temozolomide as second or third line treatment of patients with 
neuroendocrine carcinomas. ScientificWorldJournal, 2012. 2012: p. 170496. 
13. 
Hentic, O., et al., FOLFIRI regimen: an effective second-line chemotherapy after 
failure of etoposide-platinum combination in patients with neuroendocrine 
carcinomas grade 3. Endocr Relat Cancer, 2012. 19(6): p. 751-7. 
14. 
Sorbye, H., et al., Gastroenteropancreatic high‐grade neuroendocrine carcinoma. 
Cancer, 2014. 120(18): p. 2814-2823. 
15. 
Disis, M.L., Immune regulation of cancer. J Clin Oncol, 2010. 28(29): p. 4531-8. 
16. 
Thompson, R.H., et al., PD-1 is expressed by tumor-infiltrating immune cells and 
is associated with poor outcome for patients with renal cell carcinoma. Clin 
Cancer Res, 2007. 13(6): p. 1757-61. 
17. 
Francisco, L.M., P.T. Sage, and A.H. Sharpe, The PD-1 pathway in tolerance and 
autoimmunity. Immunol Rev, 2010. 236: p. 219-42. 


 
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18. 
Brown, J.A., et al., Blockade of programmed death-1 ligands on dendritic cells 
enhances T cell activation and cytokine production. J Immunol, 2003. 170(3): p. 
1257-66. 
19. 
Sharpe, A.H. and G.J. Freeman, The B7-CD28 superfamily. Nat Rev Immunol, 
2002. 2(2): p. 116-26. 
20. 
Dong, H., et al., Tumor-associated B7-H1 promotes T-cell apoptosis: a potential 
mechanism of immune evasion. Nat Med, 2002. 8(8): p. 793-800. 
21. 
Usubutun, A., et al., Prognostic factors in renal cell carcinoma. J Exp Clin 
Cancer Res, 1998. 17(1): p. 77-81. 
22. 
Talmadge, J.E., M. Donkor, and E. Scholar, Inflammatory cell infiltration of 
tumors: Jekyll or Hyde. Cancer Metastasis Rev, 2007. 26(3-4): p. 373-400. 
23. 
Al-Shibli, K.I., et al., Prognostic effect of epithelial and stromal lymphocyte 
infiltration in non-small cell lung cancer. Clin Cancer Res, 2008. 14(16): p. 5220-
7. 
24. 
Galon, J., et al., Type, density, and location of immune cells within human 
colorectal tumors predict clinical outcome. Science, 2006. 313(5795): p. 1960-4. 
25. 
Diez, M., et al., Histopathologic prognostic score in colorectal adenocarcinomas. 
Anticancer Res, 1998. 18(1b): p. 689-94. 
26. 
Deschoolmeester, V., et al., Tumor infiltrating lymphocytes: an intriguing player 
in the survival of colorectal cancer patients. BMC Immunol, 2010. 11: p. 19. 
27. 
Nobili, C., et al., Prolonged survival of a patient affected by pancreatic 
adenocarcinoma with massive lymphocyte and dendritic cell infiltration after 
interleukin-2 immunotherapy. Report of a case. Tumori, 2008. 94(3): p. 426-30. 
28. 
Hiraoka, N., Tumor-infiltrating lymphocytes and hepatocellular carcinoma: 
molecular biology. Int J Clin Oncol, 2010. 15(6): p. 544-51. 
29. 
Kloor, M., Lymphocyte infiltration and prognosis in colorectal cancer. Lancet 
Oncol, 2009. 10(9): p. 840-1. 
30. 
Hodi, F.S. and G. Dranoff, The biologic importance of tumor-infiltrating 
lymphocytes. J Cutan Pathol, 2010. 37 Suppl 1: p. 48-53. 
31. 
Hillen, F., et al., Leukocyte infiltration and tumor cell plasticity are parameters of 
aggressiveness in primary cutaneous melanoma. Cancer Immunol Immunother, 
2008. 57(1): p. 97-106. 
32. 
Nishimura, H., T. Honjo, and N. Minato, Facilitation of beta selection and 
modification of positive selection in the thymus of PD-1-deficient mice. J Exp 
Med, 2000. 191(5): p. 891-8. 
33. 
Leffers, N., et al., Prognostic significance of tumor-infiltrating T-lymphocytes in 
primary and metastatic lesions of advanced stage ovarian cancer. Cancer 
Immunol Immunother, 2009. 58(3): p. 449-59. 
34. 
Lee, H.E., et al., Prognostic implications of type and density of tumour-infiltrating 
lymphocytes in gastric cancer. Br J Cancer, 2008. 99(10): p. 1704-11. 
35. 
Liotta, F., et al., Frequency of regulatory T cells in peripheral blood and in 
tumour-infiltrating lymphocytes correlates with poor prognosis in renal cell 
carcinoma. BJU Int, 2011. 107(9): p. 1500-6. 
36. 
Wolchok, J.D., et al., Nivolumab plus ipilimumab in advanced melanoma. New 
England Journal of Medicine, 2013. 369(2): p. 122-133. 


 
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37. 
Motzer, R.J., et al. Nivolumab for metastatic renal cell carcinoma (mRCC): 
Results of a randomized, dose-ranging phase II trial. in ASCO Annual Meeting 
Proceedings. 2014. 
38. 
Brahmer, J., et al., Nivolumab versus docetaxel in advanced squamous-cell non–
small-cell lung cancer. New England Journal of Medicine, 2015. 373(2): p. 123-
135. 
39. 
Schultheis, A.M., et al., PD-L1 expression in small cell neuroendocrine 
carcinomas. Eur J Cancer, 2015. 51(3): p. 421-6. 
40. 
Patrick Alexander Ott, M.E.E.F., Pembrolizumab (MK-3475) in patients (pts) 
with extensive-stage small cell lung cancer (SCLC): Preliminary safety and 
efficacy results from KEYNOTE-028. . J Clin Oncol (Meeting Abstracts), 2015. 
33(no. 15_suppl 7502). 
41. 
Antonia, S.J., et al., Phase I/II study of nivolumab with or without ipilimumab for 
treatment of recurrent small cell lung cancer (SCLC): CA209-032. J Clin Oncol 
(Meeting Abstracts), 2015. 33(15_suppl): p. 7503-. 
42. 
Patnaik, A., et al., Phase I Study of Pembrolizumab (MK-3475; Anti-PD-1 
Monoclonal Antibody) in Patients with Advanced Solid Tumors. Clin Cancer Res, 
2015. 21(19): p. 4286-93. 
43. 
Nghiem, P., et al. Activity of PD-1 blockade with pembrolizumab as first systemic 
therapy in patients with advanced Merkel cell carcinoma. in EUROPEAN 
JOURNAL OF CANCER. 2015. ELSEVIER SCI LTD THE BOULEVARD, 
LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND. 
44. 
Snyder, A., et al., Genetic Basis for Clinical Response to CTLA-4 Blockade in 
Melanoma. New England Journal of Medicine, 2014. 371(23): p. 2189-2199. 
45. 
Vijayvergia, N.E., P.F., Molecular profiling of neuroendocrine tumors (NETs): 
The Fox Chase Cancer Center (FCCC) experience. . J Clin Oncol (Meeting 
Abstracts) January 2015 vol. 33 no. 3_suppl 245  
46. 
Wolchok, J.D., et al., Guidelines for the evaluation of immune therapy activity in 
solid tumors: immune-related response criteria. Clin Cancer Res, 2009. 15(23): p. 
7412-20. 
 
 
 


 
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17.0 
Appendices 
 ECOG Performance Status 
 
Grade 
Description 
0 
Normal activity. Fully active, able to carry on all pre-disease 
performance without restriction. 
1 
Symptoms, but ambulatory. Restricted in physically strenuous 
activity, but ambulatory and able to carry out work of a light or 
sedentary nature (e.g., light housework, office work). 
2 
In bed <50% of the time. Ambulatory and capable of all self-care, but 
unable to carry out any work activities. Up and about more than 50% 
of waking hours. 
3 
In bed >50% of the time. Capable of only limited self-care, confined 
to bed or chair more than 50% of waking hours. 
4 
100% bedridden. Completely disabled. Cannot carry on any self-care. 
Totally confined to bed or chair. 
5 
Dead. 
* As published in Am. J. Clin. Oncol.:  Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E., 
McFadden, E.T., Carbone, P.P.: Toxicity And Response Criteria Of The Eastern Cooperative Oncology 
Group. Am J Clin Oncol 5:649-655, 1982. The Eastern Cooperative Oncology Group, Robert Comis M.D., 
Group Chair. 
 


 
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 Collection, Shipment, and Processing of Blood Samples and Tissue for 
Correlative studies 
Optional blood collection and storage of leftover tumor tissue sample for future 
exploratory research will be done only after obtaining informed consent from patients for 
future unspecified biomedical research. This consent will be a part of the informed 
consent process at the time of study entry. 
 
Blood Sample Collection:   
Three peripheral blood samples (up to 60 ml each) will be serially collected from each 
patient at the following time points: 
1. Immediately prior to the first treatment, for a baseline assessment. 
2. Immediately prior to the third treatment, which would occur at cycle 3. 
3. When disease progression is observed, either during or post-treatment. 
 
Instructions for Collection, Processing and Shipping Procedures for Blood and Tissue 
Specimens 
 
Blood will be drawn by a physician, registered nurse or licensed phlebotomist prior to 
receiving the Pembrolizumab at the predefined time points. For correlative studies, blood 
will be drawn into two (2) sodium heparin green top tubes (about 20 ml) at the three 
time points. Also, one (1) red top tube and one (1) EDTA tube for cell free plasma (20 
ml) will be drawn before cycle 1, every other assessment, and at the end of treatment for 
future research.  
All blood samples for PBMC preparation will be processed in the Protocol Support 
Laboratory. Flow cytometry processing and analysis will be performed in the Campbell 
laboratory on an Aria II flow cytometer (BD). Compensation (parallel controls using cells 
singly stained for each color) and data analysis will be performed using FlowJo flow 
cytometry analysis software (TreeStar). The percentage and/or mean fluorescence 
intensity (MFI) of cells staining for individual markers will be determined, and 
CD107A+ degranulating NK cells in functional assays, will be compared to isotype 
controls to establish baseline values. Pembrolizumab  will be used to stain for PD-1 
expression on leukocytes in pre-treatment samples and a secondary anti-human IgG4 will 
be used to assess the remaining Pembrolizumab  bound to PD-1 on treatment samples. 
Samples should be collected according to the institutional procedures for venipuncture.  
 
Archival tissue or biopsy - Tissue will be used for immunohistochemistry and next gene 
sequencing. If archival tissue is not available an optional biopsy may be performed. ” 
Label slides with patient study #, pathology accession #. Slides will be prepared by PSL 
stored at 4oC, batched and transferred to Qualtek  for immunohistochemistry analysis. 
 
PBMC preparation (green top tubes) –  
 
Remaining PBMC will be frozen in 10%DMSO + 90% FBS at a conc. of 5-10 x 106 
cells/vial and stored at –70oC and transferred to liquid nitrogen. 


 
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 Management of immune related adverse events from Pembrolizumab.  
PDF provided separately 
 
 Common Terminology Criteria for Adverse Events V4.0 (CTCAE) 
The descriptions and grading scales found in the revised NCI Common Terminology 
Criteria for Adverse Events (CTCAE) version 4.0 will be utilized for adverse event 
reporting. (http://ctep.cancer.gov/reporting/ctc.html)