Conditions: Metastatic Colon Cancer Solid Tumor
Keywords: Immunotherapy Anti-programmed death 1 (PD-1) inhibitor Immunostimulant monoclonal antibody TLR3 agonist Immunologic factors
Allocation: NON_RANDOMIZED | Intervention model: SINGLE_GROUP
Enrollment: 42
Healthy volunteers: no

Brief summary:
The main purpose of this study is to determine the dose of poly-ICLC that is safe and tolerable when it is combined with pembrolizumab in patients with colon cancer. This study will also evaluate how the combination of pembrolizumab and poly-ICLC activates the immune system in the patient's blood and inside the tumor; how it affects the size and number of tumor(s) in each patient; and how effective the combination is in patients with colon cancer that is unlikely to respond to pembrolizumab alone.

Detailed description:
Mismatch repair genes normally serve to fix the small glitches that occur when DNA is copied as cells divide. In 1993, researchers discovered that mutations in human mismatch repair genes play a key role in the development of certain forms of colorectal cancer; individuals who are deficient in these mismatch repair genes are at high risk for colorectal cancer. Accumulating evidence has shown that immunotherapy may be most effective against these cancers.

Programmed cell death protein 1, also known as PD-1, functions as an immune checkpoint, down-regulating the immune system by preventing the activation of T-cells, which in turn reduces autoimmunity and promotes self-tolerance. A new class of immunotherapy drugs that block PD-1, the PD-1 inhibitors, activate the immune system to attack tumors and are therefore used with varying success to treat some types of cancer.

Current clinical trials are showing that patients whose tumors are mismatch repair deficient are more likely to respond to immune-boosting anti-PD-1 drugs-such as pembrolizumab-than those with tumors proficient in mismatch repair. The idea is that the greater the number of DNA glitches in a tumor cell, the more abnormal proteins it will produce-and the more abnormal proteins that are generated, the greater the odds that the body's immune cells will regard the tumor cells as "foreign" and target them for destruction. Thus far, PD-1 inhibitors have shown great promise for mismatch repair deficient cancer patients, but not for mismatch repair proficient (MRP) cancer patients.

In this clinical trial, the investigators hypothesize that treating MRP colon cancer patients with immunostimulating agent poly-ICLC will generate an inflammatory response, increasing epitope recognition and development of tumor reactive T-cells at the tumor site. However, interferon alpha and gamma produced by the poly-ICLC will increase PD-L1 expression and limit new T-cell development. Thus, PD1 blockade will increase the effectiveness of treatment with pembrolizumab.

Arms:
arm 1: This "Run In" phase is aimed to determine if poly-ICLC can be safely combined with standard dosages of pembrolizumab:

i. Pembrolizumab will be administered 200 mg intravenously (IV) every 3 weeks (q3w)

ii. Poly-ICLC will be administered intramuscularly (IM) twice weekly at one of two dose levels: 1 mg or 2 mg

Each dose level will enroll 3-6 participants, up to 12 participants total, depending on the occurrence of dose limiting toxicities (DLT) at each dosing level.

Participants may receive treatment for 1 year (\~17 cycles). arm 2: In Phase 2, all participants will receive the standard pembrolizumab dose (200 mg IV q3w) in addition to the maximum tolerated dose of poly-ICLC (either 1 mg or 2 mg), as determined by the Phase 1 arm.

Up to 30 participants will be treated in Phase 2. Participants may receive treatment for 1 year (\~17 cycles).

Interventions: intervention 1: pembrolizumab intervention 2: Poly-ICLC
Intervention descriptions: intervention 1: 200mg pembrolizumab will be given intravenously on Day 1 of each 3-week cycle intervention 2: The maximum tolerated dose of Poly ICLC will be given twice weekly, in each 3-week cycle:

Week 1, Days 1 and 4

Week 2, Days 8 and 11

Week 3, Days 15 and 18

Protocol document:
Prot_SAP_ICF_001.pdf: 
Short title: Pembro + Poly-ICLC IM in MRP colon cancer 
Version date:   14Nov2022 
 
Page 1 of 77 
 
TITLE:  
A phase I/II trial of pembrolizumab (MK-3475) and poly-ICLC in patients 
with metastatic mismatch repair-proficient (MRP) colon cancer 
 
IND NUMBER:  
129974 
 
PROTOCOL #:   
CC-16047 
 
ClinicalTrials.gov #: NCT02834052 
 
PROTOCOL  
  
SPONSOR/PI:  
Asha Nayak-Kapoor, M.D. 
 
 
Clinical Site: 
Georgia Cancer Center  
 
Augusta University 
 
1411 Laney Walker Blvd. 
 
Augusta, GA 30912 
 
Phone:  706-721-6744 
 
http://www.augusta.edu/cancer/ 
 
 
Investigational Agent(s):     
 
 
 
 
 
 
 
 
 
 
Protocol History 
Original version: 
25May2016 (Approved by FDA 5/27/2016) 
Amendment 1: 
20Sept2016  
Amendment 2: 
27Sept2017 
Amendment 3: 
26Jan2018 
Amendment 4:           04Jan2019 
Amendment 5:           29Jan2019 
Amendment 6:           25Apr2019 
Amendment 7:           28Aug2020 
Amendment 8:           11Oct2021 
Amendment 9:           26Jul2022 
Amendment 10:         14Nov2022 
 
 
 
Drug Name: 
Pembrolizumab 
Poly-ICLC 
Other Identifier: 
MK-3475 
Polyinosinic-Polycytidylic 
acid – poly-L-lysine 
carboxymethylcellulose 
IND Number: 
123,482 
43984 
Manufacturer: 
Merck 
Oncovir 


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CONTACT INFORMATION 
Sponsor-PI  
Asha Nayak-Kapoor, MD 
 
Leader, Gastrointestinal Cancer Program 
Associate Professor.of Medicine (Hematology/Oncology) 
Director, Inpatient Oncology Service 
Address: Georgia Cancer Center, Augusta University 
1120 15th Street, BA-5516A 
Augusta, Georgia  30912 
Phone: 706-721-2505 
Email: ANKapoor@augusta.edu 
 
  
 
Lead Sub-I  
Sharad Ghamande, MD  
Associate Director, Clinical Research 
Section Chief, Section of Gynecologic Oncology 
Address: Georgia Cancer Center, Augusta University 
1120 15th Street, BA-7411A 
Augusta, Georgia  30912 
Phone: 706-721-3992 
Email: SGhamande@augusta.edu 
 
  
Biostatistician 
Ramses Sadek, PhD 
 
Director, Cancer Research Center Biostatistics Core 
Address: Georgia Cancer Center, Augusta University 
1120 15th Street, CN-4123 
Augusta, Georgia  30912 
Phone: 706-721-6930 
Email: RSadek@augusta.edu 
 
  
 
 
 
  
  
  
  
 
 
 
 


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CONTENTS 
 
TRIAL SUMMARY.................................................................................................... 6 
 
TRIAL DESIGN.......................................................................................................... 6 
2.1 
Trial Design ............................................................................................................. 6 
2.2 
Trial Diagrams ........................................................................................................ 6 
 
OBJECTIVES & HYPOTHESES ............................................................................. 8 
3.1 
Primary Objectives & Hypotheses ........................................................................ 8 
3.2 
Secondary Objectives ............................................................................................. 8 
3.3 
Exploratory Objectives ........................................................................................... 8 
 
BACKGROUND & RATIONALE ............................................................................ 8 
4.1 
Background ............................................................................................................. 8 
4.2 
Rationale ................................................................................................................ 14 
 
METHODOLOGY ................................................................................................... 17 
5.1 
Entry Criteria ........................................................................................................ 17 
5.2 
Subject Inclusion Criteria .................................................................................... 17 
5.3 
Trial Treatments ................................................................................................... 20 
5.4 
Dose Selection ........................................................................................................ 20 
5.5 
Treatment Allocation ............................................................................................ 26 
5.6 
Concomitant Medications/Vaccinations (allowed & prohibited) ..................... 26 
5.7 
Rescue Medications & Supportive Care ............................................................. 27 
5.8 
Diet/Activity/Other Considerations ..................................................................... 31 
5.9 
Subject Withdrawal/Discontinuation Criteria ................................................... 33 
5.10 
Subject Replacement Strategy ............................................................................. 34 
5.11 
Clinical Criteria for Early Trial Termination ................................................... 34 
 
TRIAL FLOW CHART ........................................................................................... 35 
 
TRIAL PROCEDURES ........................................................................................... 37 
7.1 
Administrative Procedures .................................................................................. 37 
7.2 
Clinical Procedures/Assessments ......................................................................... 38 


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7.3 
Assessing and Recording Adverse Events .......................................................... 44 
 
STATISTICAL ANALYSIS PLAN ........................................................................ 52 
8.1 
Introduction ........................................................................................................... 52 
8.2 
Study Objectives ................................................................................................... 52 
8.3 
Study Design/Endpoints ....................................................................................... 53 
8.4 
Sample Size/Accrual Rate .................................................................................... 53 
8.5 
Analysis of Endpoints ........................................................................................... 53 
8.6 
Analysis Datasets ................................................................................................... 54 
8.7 
Interim Analysis .................................................................................................... 54 
 
LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL 
SUPPLIES ................................................................................................................. 54 
9.1 
Investigational Products ....................................................................................... 54 
9.2 
Packaging and Labeling Information ................................................................. 55 
9.3 
Clinical Supplies Disclosure ................................................................................. 55 
9.4 
Storage and Handling Requirements .................................................................. 56 
9.5 
Returns and Reconciliation .................................................................................. 56 
 
ADMINISTRATIVE AND REGULATORY DETAILS ....................................... 56 
10.1 
Confidentiality ....................................................................................................... 56 
10.2 
Compliance with Financial Disclosure Requirements ....................................... 56 
10.3 
Compliance with Law, Audit and Debarment ................................................... 56 
10.4 
Compliance with Trial Registration and Results Posting Requirements ........ 56 
10.5 
Quality Management System ............................................................................... 57 
10.6 
Data Management ................................................................................................. 57 
10.7 
Data Export & Reporting..................................................................................... 58 
 
APPENDICES ........................................................................................................... 59 
11.1 
ECOG Performance Status .................................................................................. 59 
11.2 
Common Terminology Criteria for Adverse Events V4.03 (CTCAE) ............. 59 
11.3 
Immune Related Response Criteria (irRC) with Response Evaluation Criteria in 
Solid Tumors (RECIST) 1.1 ................................................................................. 59 


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11.4 
Guidelines for Evaluation of Objective Tumor Response Using RECIST 1.1 
Criteria ................................................................................................................... 62 
11.5 
Lab Specimens Summary ..................................................................................... 71 
11.6 
Laboratory Manual .............................................................................................. 73 
 
REFERENCES .......................................................................................................... 76 
TABLES  
Table 1.  Adequate Organ Function Laboratory Values................................................17 
Table 2.  Trial Treatment ..................................................................................................20 
Table 3. Dose Modification Guidelines for Drug-Related Adverse Events ..................21 
Table 4. Supportive Measures……………………………………………………….......28 
Table 5. Infusion Reaction Treatment Guidelines ..........................................................30 
Table 6. Laboratory Safety Evaluations (Hematology, Chemistry and Urinalysis) ....41 
Table 7. Evaluating Adverse Events.................................................................................49 
Table 8. Product Descriptions ...........................................................................................54 
 


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TRIAL SUMMARY 
Abbreviated Title 
Pembrolizumab and Poly-ICLC in MRP colon cancer 
Trial Phase 
1/2 
Clinical Indication 
Phase 1: All solid tumors;  
Phase 2: Metastatic Mismatch Repair Proficient (MRP) Colon 
Cancer, which includes disease that is microsatellite 
instability status low (MSI-low) and microsatellite stable 
(MSS). 
Trial Type 
Interventional 
Type of control 
Historical 
Route of administration 
Pembrolizumab IV, Poly-ICLC IM 
Trial Blinding 
None 
Treatment Groups  
1 
Number of trial subjects 
31 
Estimated enrollment 
period 
18 months 
Estimated duration of trial 30 months 
Duration of Participation 
2-3 years 
Estimated average length 
of treatment per patient 
6 months 
 
 
TRIAL DESIGN 
2.1 Trial Design 
This study will enroll its patients into two separate phases: 
1) Run In phase  
a. Aimed to determine if poly-ICLC can be safely combined with standard dosages of 
pembrolizumab. 
i. Poly-ICLC will be administered intramuscularly twice weekly at two dose 
levels: 1 mg or 2 mg 
ii. Pembrolizumab will be administered 200 mg IV q3w 
b. Each dose level enrolls 3-6 patients, with the potential for 12 patients if dose limiting 
toxicity (DLT) occurs at each dosing level. 
c. Patients with any solid tumor that is unresponsive to at least one line of therapy are 
eligible for the dose escalation phase unless curative options exist 
2) Phase II trial expansion 
a. The combination will then be administered at the recommended phase II dose in up to 
27 patients with metastatic MRP colon cancer  
2.2 Trial Diagrams 
 


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2.2.1 Trial Phases 
2.2.2 Trial Treatments 
 
 
 
  
Phase I  
(up to 12 patients) 
Pembrolizumab 200mg IV q3w 
+ 
Poly-ICLC 1mg or 2mg IM 
(twice weekly, 3 days apart)  
Phase II 
(up to 30 patients) 
Pembrolizumab 200mg IV q3w 
+ 
Poly-ICLC 1.8mg/mL IM (twice 
weekly, 3 days apart)  
Determine 
Poly-ICLC 
max tolerated 
dose 


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OBJECTIVES & HYPOTHESES 
3.1 
Primary Objectives & Hypotheses 
3.1.1 Objectives:  
a. Phase 1: Determine the maximum tolerated dose of poly-ICLC that can be combined 
with pembrolizumab 
b. Determine the response rate, as assessed by RECIST 1.1, of metastatic MRP colon cancer 
that has progressed following two lines of therapy in the metastatic setting to the 
combination of pembrolizumab and poly-ICLC 
3.1.2 Hypotheses:   
a. Poly-ICLC will generate an inflammatory response increasing epitope recognition and 
development of tumor reactive T cells at the tumor site.  However, interferon alpha and 
gamma produced by the poly-ICLC will increase PD-L1 expression and limit new T cell 
development.  Thus, PD1 blockade will increase the effectiveness of the therapy. 
b. Phase 1 – Combination of Poly-ICLC and Pembrolizumab is tolerable at the doses 
proposed for this intervention 
c. Phase 2 – Combination of poly-ICLC and pembrolizumab has increased efficacy 
compared to pembrolizumab alone in patients with colon cancer. The RR will increase 
to 20% for the combination treatment from an expected 5% response rate for 
pembrolizumab alone. 
3.2 
Secondary Objectives  
a. Phase I and II - Determine the adverse event profile and dose limiting toxicities of the 
combination of pembrolizumab and poly-ICLC 
b. Determine the progression free survival rate, overall survival rate and duration of 
response of recurrent metastatic MRP colon cancer to the combination of pembrolizumab 
and poly-ICLC 
3.3 
Exploratory Objectives  
a. Evaluation of inflammatory state in tumor biopsies with specific attention to definition 
of tumor infiltration with hematopoietic cells, cell surface signaling molecule expression  
b. Evaluation of pre-treatment and post-treatment microarray panels in tumor samples and 
peripheral blood   
c. Determine response rate by irRECIST 
 
BACKGROUND & RATIONALE 
4.1 Background 
Refer to the Investigator’s Brochure (IB)/approved labeling for detailed background information on 
Pembrolizumab (MK-3475).  Refer to the Investigator’s Brochure (IB) for detailed background 
information on Poly-ICLC 


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4.1.1 Pharmaceutical and Therapeutic Background for pembrolizumab 
The importance of intact immune surveillance in controlling outgrowth of neoplastic transformation 
has been known for decades.  Accumulating evidence shows a correlation between tumor-infiltrating 
lymphocytes (TILs) in cancer tissue and favorable prognosis in various malignancies.  In particular, 
the presence of CD8+ T-cells and the ratio of CD8+ effector T-cells / FoxP3+ regulatory T-cells 
seems to correlate with improved prognosis and long-term survival in many solid tumors. 
 
The PD-1 receptor-ligand interaction is a major pathway hijacked by tumors to suppress immune 
control.  The normal function of PD-1, expressed on the cell surface of activated T-cells under 
healthy conditions, is to down-modulate unwanted or excessive immune responses, including 
autoimmune reactions.  PD-1 (encoded by the gene Pdcd1) is an Ig superfamily member related to 
CD28 and CTLA-4 which has been shown to negatively regulate antigen receptor signaling upon 
engagement of its ligands (PD-L1 and/or PD-L2).  The structure of murine PD-1 has been resolved.  
PD-1 and family members are type I transmembrane glycoproteins containing an Ig Variable-type 
(V-type) domain responsible for ligand binding and a cytoplasmic tail which is responsible for the 
binding of signaling molecules.  The cytoplasmic tail of PD-1 contains 2 tyrosine-based signaling 
motifs, an immunoreceptor tyrosine-based inhibition motif (ITIM) and an immunoreceptor tyrosine-
based switch motif (ITSM).  Following T-cell stimulation, PD-1 recruits the tyrosine phosphatases 
SHP-1 and SHP-2 to the ITSM motif within its cytoplasmic tail, leading to the dephosphorylation 
of effector molecules such as CD3ζ, PKCθ and ZAP70 which are involved in the CD3 T-cell 
signaling cascade.  The mechanism by which PD-1 down modulates T-cell responses is similar to, 
but distinct from that of CTLA-4 as both molecules regulate an overlapping set of signaling proteins.  
PD-1 was shown to be expressed on activated lymphocytes including peripheral CD4+ and CD8+ 
T-cells, B-cells, T regs and Natural Killer cells.  Expression has also been shown during thymic 
development on CD4-CD8- (double negative) T-cells as well as subsets of macrophages and 
dendritic cells.  The ligands for PD-1 (PD-L1 and PD-L2) are constitutively expressed or can be 
induced in a variety of cell types, including non-hematopoietic tissues as well as in various tumors.  
Both ligands are type I transmembrane receptors containing both IgV- and IgC-like domains in the 
extracellular region and contain short cytoplasmic regions with no known signaling motifs.  Binding 
of either PD-1 ligand to PD-1 inhibits T-cell activation triggered through the T-cell receptor.  PD-
L1 is expressed at low levels on various non-hematopoietic tissues, most notably on vascular 
endothelium, whereas PD-L2 protein is only detectably expressed on antigen-presenting cells found 
in lymphoid tissue or chronic inflammatory environments.  PD-L2 is thought to control immune T-
cell activation in lymphoid organs, whereas PD-L1 serves to dampen unwarranted T-cell function in 
peripheral tissues.  Although healthy organs express little (if any) PD-L1, a variety of cancers were 
demonstrated to express abundant levels of this T-cell inhibitor.  PD-1 has been suggested to regulate 
tumor-specific T-cell expansion in subjects with melanoma (MEL).  This suggests that the PD-1/PD-
L1 pathway plays a critical role in tumor immune evasion and should be considered as an attractive 
target for therapeutic intervention. 
Pembrolizumab is a potent and highly selective humanized monoclonal antibody (mAb) of the 
IgG4/kappa isotype designed to directly block the interaction between PD-1 and its ligands, PD-L1 
and PD-L2.  KeytrudaTM (pembrolizumab) has recently been approved in the United Stated for the 
treatment of patients with unresectable or metastatic melanoma and disease progression following 
ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor. 


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4.1.2 Pharmaceutical and Therapeutic Background for poly-ICLC 
Polyinosinic-Polycytidylic acid stabilized with poly-L-lysine and carboxymethylcellulose (Poly-
ICLC, Hiltonol®) is a synthetic double-stranded ribonucleic acid (dsRNA) ‘host-targeted’ 
therapeutic viral-mimic and Pathogen-associated molecular pattern (PAMP) with broad innate and 
adaptive immune enhancing, vaccine adjuvant, antiviral and anti-proliferative effects. These effects 
are mediated partly by its induction of a ‘natural mix’ of interferons (IFNs), cytokines, and 
chemokines, activation of natural killer [NK] cells, myeloid dendritic cells via TLR3 and MDA5, 
T4 and T8 cells, and activation of several nuclear and cytoplasmic enzyme systems, including the 
oligoadenylate synthetase [OAS], the dsRNA dependent protein kinase [PKR], RIG-I Helicase, and 
MDA5 that are involved in antiviral and antitumor host defenses. It has been shown to have broad 
gene regulatory actions as well.  
 
Poly-ICLC was used intravenously as an IFN inducer some years ago in patients with various types 
of cancers, including leukemia, lymphoma, gliomas, myeloma, juvenile laryngeal papillomatosis, 
renal cell carcinoma, breast cancer, ovarian cancer, and melanoma.1-9 In most of these early trials, 
about 6 mg/m2 Poly-ICLC was generally used intravenously. Few objective responses were reported 
in these high dose clinical trials and Poly-ICLC was generally abandoned when recombinant IFN 
became available. It was subsequently determined that lower doses (10 to 50 μg/kg) of Poly-ICLC 
resulted in a broader host defense stimulation, a potent adjuvant and antiviral effects.10   
Consequently, Poly-ICLC is currently being developed for use only at doses up to about 30 μg/kg 
and the data presented in the following sections focus on studies using Poly-ICLC in this target dose 
range. 
 
Pharmacokinetics and Product Metabolism in Humans 
Poly-ICLC is not detectable in serum 24 hours after administration. However, the clinical half-life 
of the OAS response to 30 μg/kg IM Poly-ICLC in healthy human volunteers is about 2.5 days, 
suggesting an optimum dose schedule of two or three times per week. Twenty-four of 29 patients 
treated with 10 to 20 μg/kg Poly-ICLC by IM injection showed at least a 300% increase in serum 
OAS. A significant association of serum OAS with tumor response has been observed in patients 
with malignant glioma participating in an open pilot trial. 
 
Mechanism of Action 
Poly-ICLC stimulates at least 4 interrelated systems, any of which (alone or in combination) might 
be responsible for its possible antitumor and antiviral activity; induction of IFN and multiple other 
cytokines, chemokines and costimulatory factors, a broad immune-enhancing effect,5 direct 
antiviral/antineoplastic effect, and modulation of gene expression. 
 
Poly-ICLC induces a ‘natural mix’ of interferons, cytokines and chemokines, including IFN 
production. As expected, the amount of these measurable in serum is dose-dependent, although 
biologically significant induction likely occurs locally. In previous studies, the minimal serum IFN 
levels induced by the currently recommended low doses of Poly-ICLC have not been associated with 
antitumor or antiviral action. A study of the immunomodulatory effect of Poly-ICLC in cancer 
patients showed no detectable serum IFN in patients receiving 1 mg/m2 poly-ICLC by IM injection.1 
In contrast, IFN was detectable in the serum of patients receiving 4 mg/m2 IV poly-ICLC. 
 


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Low-dose Poly-ICLC directly stimulates the immune system through activation of NK cells, 
myeloid dendritic cells via TLR3 and MDA5, T-cells, macrophages and by inducing a ‘natural mix 
of interferons, cytokines and chemokines’. Some of these actions are related to the potent PAMP-
adjuvant actions of poly-ICLC with various vaccine platforms, as well as to the broad antiviral state 
induced by the drug. 
 
The third action of poly-ICLC is a more direct broad host-targeted antiviral and perhaps 
antineoplastic effect mediated by the two IFN-inducible nuclear enzyme systems, the 2’5’-
oligoadenylate synthase (OAS) and the double stranded RNA kinase P1/eIF2a kinase, also known 
as the PKR,3-5 as well as RIG-I helicase and MDA5. The concentration of the 2’5’-OAS was elevated 
in the peripheral blood mononuclear cells of all Poly-ICLC-treated patients. Intramuscular 
administration of low-dose Poly-ICLC increased NK cells and growth inhibitory activities and 2’5’-
OAS levels to a greater extent than high-dose IV infusion. Clinically, a maximal OAS response was 
observed at an IM dose of 30 μg/kg Poly-ICLC, and was greatly decreased at greater than 100 μg/kg 
in normal volunteers.11 The hypothesis that OAS and/or PKR may be involved in the antineoplastic 
effect of Poly-ICLC may thus explain the relative ineffectiveness of high dose Poly-ICLC in early 
cancer trials. However, further studies are needed to confirm this. 
 
A fourth aspect of the action of Poly-ICLC involves modulation of the expression of a broad range 
of innate immune and other genes in a pattern closely paralleling that of a live virus vaccine (YF).11,12 
Some of these genes play critical roles in the body’s natural defenses against a variety of neoplasms 
and microbial infections, and in controlling other cell functions, including protein synthesis, 
programmed (apoptotic) cell death, cell metabolism, cellular growth, the cytoskeleton and the 
extracellular matrix.  
 
Immune Effects of Poly-ICLC administration  
A randomized trial of poly-ICLC administration to normal volunteers was conducted to establish the 
signaling effects of the molecule and to establish its comparability to live viral vaccines.  Eight 
volunteers received poly-ICLC and four received placebo.  In addition, another group of volunteers 
received a live viral vaccine to yellow fever to allow a comparison with the poly-ICLC treated 
subjects.  Poly-ICLC was administered at a dose of 1.6 mg subcutaneously in this study.  RNA 
samples from peripheral blood were obtained at multiple time points (6 hr, 12 hr, and 1, 2, 3, 7, 14, 
and 28 days after treatment).  The peak response was observed at day 1 in five of the eight subjects 
and at 12 hours in the others.  There was no change in microarray expression patterns observed in 
the placebo group following injection whereas there were 31, 212 and 52 genes showing more than 
a 2 fold increase at 12 hr, day 1 and 2 respectively and the expression patterns were comparable.  An 
examination of the time course of the total number of differentially expressed genes following poly-
ICLC administration shows a peak effect at 24 hours with a return to pretreatment levels on day 
three.  Based on this and other observations a twice weekly dosing regimen would provide optimal 
results for enhancement of Poly-ICLC effects.   Poly-ICLC induced a broad array of interferon-
regulated genes (IRGs) associated both with viral control and enhancement of viral replication.  
Using pathway analysis the expression of other innate signaling pathways was stimulated including 
NF-κB, dendritic cell maturation, antigen presentation and inflammasome-associated genes.  Poly-
ICLC also induced expression of BAFF which triggers Ig class switching and increased the 
expression of components of the complement system (C1QB, C3AR1 and SERPING1).  A 
comparison with the effects of yellow fever vaccine on peripheral blood microarray showed that 


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poly-ICLC induced a similar pattern although the time course was different with peak activation at 
1 day for poly-ICLC and 7 days for yellow fever vaccine.   
Safety and Tolerance of Poly-ICLC 
The side effects of poly-ICLC depend on several factors including dose, route of injection, and 
health status of the patient.  Early Phase I trials in advanced cancer patients studies reported a 
maximum tolerated dose (MTD) of about 12 mg/m2 IV; at this dose, the mean serum type I IFN 
level was 2000 IU/mL, well above that attainable with exogenous IFN.  Patients typically showed 
fevers of 40ºC, myalgia, arthralgia, malaise, and some nausea and vomiting, similar to symptoms 
seen with high dose interferon (IFN).   While the dose in most of the early cancer trials, was 
about 6 mg/m2 poly-ICLC IV, it was subsequently found that a much lower IM dose (<1mg/ m2) 
was better for enhancing immune effects, with much milder side effects than IV administration 
13 14  More specific side effects of IM poly-ICLC are listed below.  Please note that these are 
generally at higher doses than that proposed for this trial. 
 
Discomfort at IM injection site: 
The most common adverse effect is mild, transient discomfort at the site of IM injection.  With 
subcutaneous (SC) injections there is a transient mild to moderate grade 1 or 2 erythematous skin 
reaction. 15.  However, when combined with peptide vaccine plus Montanide SC, it can produce 
a transient skin reaction with induration or sterile abscess. Biopsy of such lesions has 
demonstrated infiltration by T-cells sensitized to the peptide. Such responses have not been 
reported with poly-ICLC alone or mixed with other vaccines.  
 
In a recent pilot study of intratumoral Poly-ICLC in patients with large metastatic tumors, most  
patients showed tumor necrosis and or inflammation of the injected tumor.  Two of those patients 
had large facial lesions that became infected and were treated with antibiotics.  The necrosis 
resulted in a void where the tumor had been. In one patient, the inflammation was treated 
transiently with corticosteroids. 
 
Flu-like symptoms: 
Approximately 8 to 12 hours after doses of 10 to 50 mcg/kg IM, patients may develop a mild 
flu-like syndrome with fever of less than 38ºC, which may last for about 12 hours, but responds 
readily to acetaminophen or aspirin.  Mild myalgia, arthralgia, sometimes nausea, and malaise 
can be present during this period of time.  This flu-like syndrome typically diminishes markedly 
after the first few poly-ICLC treatments.  On very rare occasions in the course of treatment, 
patients who have been tolerating treatment uneventfully may develop an earlier, more 
pronounced fever with chills and malaise (typical of higher dose IV poly-ICLC) in response to 
an IM injection.  This will typically resolve over 12 to 24 hours, responds to acetaminophen, and 
does not typically recur on subsequent dosing.   
 
Hematologic abnormalities: 
Several cases of transient leukopenia have been reported.  Poly-ICLC was restarted after a drug 
holiday in most cases, but leukopenia recurred in only one patient, with rapid resolution within 
two days after discontinuation of drug for the second time. This was felt to represent transient 
migration and compartmental sequestration of WBC rather than myelotoxicity. High dose Poly-
ICLC has been associated with a coagulopathy in dogs, but not in other species including 
primates.  There has been no change in the expected incidence of deep venous thrombosis, 


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pulmonary embolus, or coagulopathy in multiple sclerosis, AIDS or malignant glioma patients 
on low dose IM poly-ICLC. One paralyzed multiple sclerosis patient treated with 100 mcg/kg 
IV suffered a fatal pulmonary embolus, which was not judged to be due to the drug. 
 
Hepatic enzyme elevation: 
Mild (grade 1), transient (<7 days) hepatic enzyme elevations were described in a trial of 100 
mcg/kg poly-ICLC given IV in multiple sclerosis patients.  In three patients, this was prolonged 
for >7 days, but in all patients the enzymes returned to normal after temporary discontinuation 
of the poly-ICLC. Enzyme elevation was not typically seen with doses of 10 to 50 mcg/kg three 
times weekly. However, one patient receiving 20 mcg/kg three times per week had to be dropped 
from study because of a transient enzyme elevation that persisted slightly longer than the 4-week 
protocol cutoff. In addition, preclinical studies have shown increased hepatic NK cells, as well 
as suppression of the P450 hepatic enzyme system by poly-ICLC, as well as by IFN, but the 
clinical implications of this finding are not clear.16 17  
 
Seizures: 
Three glioma patients with epilepsy had seizures during a high febrile episode, but recovered 
uneventfully.  
 
Transient peritumoral inflammation or edema: 
In a pilot brain tumor trial, a few patients showed an increase in their gadolinium enhancing 
lesions after 3-6 months of IM poly-ICLC, followed by an apparent tumor response at 6-12 
months and prolonged survival on continued treatment.18  Decadron was used as needed in first 
few months of treatment on that study.  In a more recent follow-up open study in patients with 
advanced recurrent gliomas, several patients have shown increased peritumoral edema after 
several weeks of poly-ICLC therapy.  This has resolved in all cases on continued poly-ICLC, 
with or without concomitant steroids. (Merchant, Young et al, 2000) Biopsy data in at least two 
patients treated with poly-ICLC also showed a peritumoral inflammatory response.  These 
findings support the possibility that poly-ICLC may at times be facilitating a relatively early 
immunologic response to the tumor, perhaps manifested by transient increased inflammation or 
gadolinium enhancement.  
Multicenter glioma Clinical trials 
In a recent multi-center study of glioblastoma patients, 21 of the 24 subjects (88%) receiving 20 
mcg/kg poly-ICLC alone three times weekly reported at least one adverse event. The incidence 
of adverse events was reported by the worst grade for an event for an individual subject. The 
majority of adverse events were classified as either grade 1 (71 of 104 or 68%) or grade 2 (28 of 
104 or 27%) toxicity. There were only 3 of 104 (3%) and 2 of 104 (2%) events reported as a 
grade 3 or grade 4 event, respectively. The most frequently reported events (toxicities) were 
fatigue (15 subjects), local ‘pain-other’ (10 subjects), and myalgia (9 subjects). Only 57 out of 
380 events were definitely or probably ascribed to Poly-ICLC. 19,20 
 
In a separate trial in patients with multiply recurrent anaplastic glioma receiving the same dose 
IM, all 24 subjects treated (100%) reported at least one adverse event. The majority of adverse 
events reported were classified as either grade 1 (41 of 63 or 65%) or grade 2 (14 of 63 or 22%). 
There were 7 of 63 (11%) grade 3 events and only 1 of 63 (2%) grade 4 event. The most 
frequently reported adverse events were fatigue (9 subjects), transient increases in SGOT, SGPT 


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and alkaline phosphatase (4 subjects each) and pain, type not specified (4 subjects). Only 19 out 
of 406 events were definitely or probably ascribed to the Poly-ICLC. 21 
 
SC Poly-ICLC in Normal volunteers 
In a trial of a single dose of 1.6mg SC Poly-ICLC in normal volunteers, no treatment-related, 
grade 4, or serious adverse events were reported. Nonetheless, volunteers receiving poly-ICLC 
developed erythema and induration at the site of injection.  Systemic reactogenicity included 
transient flu-like symptoms, such as malaise, headache, fever, and chills, which were generally 
mild to moderate in severity). In addition, there were no clinically significant changes in 
complete blood cell counts and serum chemistries, including liver function tests, 3 and 7 d after 
poly-ICLC administration.11 
4.1.3 Preclinical and Clinical Trial Data 
Refer to the Investigator’s Brochures for Preclinical and Clinical data. 
4.2 
Rationale 
4.2.1 Rationale for the Trial and Selected Subject Population 
A significant challenge to the development of effective immunotherapy of cancer is the induction 
and maintenance of T cells that recognize tumor antigens.  Vaccination to defined tumor antigens is 
being used in the treatment of many cancers including melanoma and cervical cancer but for many 
tumors no defined tumor antigens have been characterized.  Alternative vaccination strategies using 
whole cell vaccines, dendritic cells pulsed with peptides or RNAs derived from tumors are being 
investigated in this situation.  There is currently one FDA approved vaccine for the treatment of 
cancer, specifically Sipuleucel-T for the treatment of prostate cancer.  A strategy to induce a T cell 
response without the need for a specific vaccine for each type of cancer would provide a major 
advance in the immunotherapy of cancer. The combination of poly-ICLC and PD-1 blockade 
produced by antibodies directed at PD-1 or its ligand PD-L1 were recently shown to induce CD8 T 
cell responses in the absence of peptide vaccines or with irrelevant peptide vaccines.  In the B16 
melanoma and MC38 colon carcinoma models enhanced tumor regression compared to either agent 
alone was observed.  This effect was associated with long-term immunity that protected from 
subsequent tumor challenge. 
 
In a review of 97 patients treated with monoclonal antibodies directed at PD-1 or its ligand PD-L1 
only a single response was observed in patients with colorectal cancer.  The one response was also 
unusual as it was a complete response (CR) that has been maintained.   Subsequently it was found 
that the patient had a mismatch repair defect that would allow for production of multiple new 
antigens with potential for recognition by the immune system.  This led to a phase 2 clinical trial in 
patients with colorectal cancer stratified on the basis of microsatellite DNA stability.    
 
Microsatellite instability (MSI) is caused by the loss of DNA mismatch repair activity and is 
associated with increased numbers of mutations in the cellular genome (mean 1782 somatic 
mutations per tumor in MSI compared with 73 in MRP tumors).  MSI colon cancer represents 
approximately 15% of patients with most cases due to acquired hypermethylation of the promoter 
of the MLH1 gene.  It has been postulated that patients with microsatellite instability would possess 
more immunogenic tumors and these patients have a slightly better prognosis than microsatellite 
stable patients.  This has now been demonstrated in a phase 2 trial with 4 of 10 patients with MSI 
colon cancer responding, whereas no MRP patients responded, as had been observed in the earlier 


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trials.  In a follow up to this manuscript at ASCO2015 it was reported that the response rate was 
62% (Susan Topalian ASCO 2015 meeting, unpublished).  It will therefore require a large numbers 
of patients to demonstrate an improvement in outcome with MSI colon cancer whereas the lack of 
response in MRP (microsatellite stable) colon cancer will provide a means to evaluate the toxicity 
of the regimen and a preliminary evaluation of its ability to enhance immune responses and clinical 
benefit.  The use of chemotherapy has the potential to impair the development of immunity to tumor-
associated neoantigens in animal models and could potentially have a similar effect in humans.22,23 
We therefore selected patients with progressive disease following two lines of chemotherapy for 
metastatic cancer as the patient population for investigation.  The additional third line regimen of 
pembrolizumab with poly-ICLC could impair the activity of PD-1 blockade in reinvigorating 
exhausted T cell populations that are reactive to tumor neoantigens.   
4.2.2 Rationale for Dose Selection/Regimen/Modification 
Pembrolizumab (MK-3475) dosing 
An open-label Phase I trial (Protocol 001) is being conducted to evaluate the safety and clinical 
activity of single agent MK-3475.  The dose escalation portion of this trial evaluated three dose 
levels, 1 mg/kg, 3 mg/kg, and 10 mg/kg, administered every 2 weeks (Q2W) in subjects with 
advanced solid tumors.  All three dose levels were well tolerated and no dose-limiting toxicities 
were observed.  This first in human study of MK-3475 showed evidence of target engagement 
and objective evidence of tumor size reduction at all dose levels (1 mg/kg, 3 mg/kg and 10 mg/kg 
Q2W).  No MTD has been identified to date.  10.0 mg/kg Q2W, the highest dose tested in PN001, 
will be the dose and schedule utilized in Cohorts A, B, C and D of this protocol to test for initial 
tumor activity.  Recent data from other clinical studies within the MK-3475 program has shown 
that a lower dose of MK-3475 and a less frequent schedule may be sufficient for target 
engagement and clinical activity. 
 
PK data analysis of MK-3475 administered Q2W and Q3W showed slow systemic clearance, 
limited volume of distribution, and a long half-life (refer to IB).  Pharmacodynamics data (IL-2 
release assay) suggested that peripheral target engagement is durable (>21 days).  This early PK 
and pharmacodynamics data provides scientific rationale for testing a Q2W and Q3W dosing 
schedule.   
 
A population pharmacokinetic analysis has been performed using serum concentration time data 
from 476 patients. Within the resulting population PK model, clearance and volume parameters 
of MK-3475 were found to be dependent on body weight. The relationship between clearance 
and body weight, with an allometric exponent of 0.59, is within the range observed for other 
antibodies and would support both body weight normalized dosing or a fixed dose across all 
body weights.  MK-3475 has been found to have a wide therapeutic range based on the melanoma 
indication.  The differences in exposure for a 200 mg fixed dose regimen relative to a 2 mg/kg 
Q3W body weight based regimen are anticipated to remain well within the established exposure 
margins of 0.5 – 5.0 for MK-3475 in the melanoma indication. The exposure margins are based 
on the notion of similar efficacy and safety in melanoma at 10 mg/kg Q3W vs. the proposed dose 
regimen of 2 mg/kg Q3W (i.e. 5-fold higher dose and exposure). The population PK evaluation 
revealed that there was no significant impact of tumor burden on exposure. In addition, exposure 
was similar between the NSCLC and melanoma indications. Therefore, there are no anticipated 
changes in exposure between different indication settings. 
 


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The rationale for further exploration of 2 mg/kg and comparable doses of pembrolizumab in 
solid tumors is based on: 1) similar efficacy and safety of pembrolizumab when dosed at either 
2 mg/kg or 10 mg/kg Q3W in melanoma patients, 2) the flat exposure-response relationships of 
pembrolizumab for both efficacy and safety in the dose ranges of 2 mg/kg Q3W to 10 mg/kg 
Q3W, 3) the lack of effect of tumor burden or indication on distribution behavior of 
pembrolizumab (as assessed by the population PK model) and 4) the assumption that the 
dynamics of pembrolizumab target engagement will not vary meaningfully with tumor type. 
 
The choice of the 200 mg Q3W as an appropriate dose for the switch to fixed dosing is based on 
simulations performed using the population PK model of pembrolizumab showing that the fixed 
dose of 200 mg every 3 weeks will provide exposures that 1) are optimally consistent with those 
obtained with the 2 mg/kg dose every 3 weeks, 2) will maintain individual patient exposures in 
the exposure range established in melanoma as associated with maximal efficacy response and 
3) will maintain individual patients exposure in the exposure range established in melanoma that 
are well tolerated and safe.  
 
A fixed dose regimen will simplify the dosing regimen to be more convenient for physicians and 
to reduce potential for dosing errors.  A fixed dosing scheme will also reduce complexity in the 
logistical chain at treatment facilities and reduce wastage. 
Poly-ICLC dosing 
Poly-ICLC at high doses was ineffective in the therapy of cancer but at low doses produces 
activation of multiple pathways that are similar to those associated with viral vaccines.  Induction 
of these pathways was associated with protective tumor immunity in three mouse tumor models.  
The dosing studies in normal volunteers provides a rationale for selection of a low dose regimen 
of poly-ICLC to maximize its effects on the innate immune system.  In that study a dose of 1.5 
mg of poly-ICLC was used as a subcutaneous injection. The microarray studies of peripheral 
blood lymphocytes from normal volunteers showed that the maximal effect of poly-ICLC in 
terms of numbers of differentially expressed genes following administration is noted at 24 hours 
and returned to pretreatment levels by three days.  We will use an IM route of administration as 
it has a much greater safety profile and will use two doses bracketing that level, 1 or 2 mg.  Poly-
ICLC will be given IM and followed by infusion of pembrolizumab.  Patients will be instructed 
on self-administration of poly-ICLC. 
 
4.2.3 Rationale for Endpoints 
Efficacy Endpoints 
Clinical response is a standard endpoint for clinical trials of new cancer agents.  The immune 
RECIST and RECIST response criteria will be used in the study.  The immune RECIST 
response rate as determined by Dr. Nayak will be the primary endpoint.   Therapy will be 
continued until patients have confirmed disease progression unless there is clinical 
decompensation or alternative options are selected.  
Biomarker Research 
Expression of PD-L1 has been associated with response to PD-1 blockade in multiple tumor 
types and will be evaluated in this study.  Microarray analysis of peripheral blood 
lymphocytes will be used to characterize the response to poly-ICLC alone and in 
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METHODOLOGY 
5.1 Entry Criteria 
5.1.1 Diagnosis/Condition for Entry into the Trial 
5.1.1.1 Phase 1 – Presence of histologically confirmed malignancy that has progressed following at 
least one therapy and able to be visualized on imaging.  Measureable disease is not required.  
Patients with known targetable mutations must have progressive disease on the appropriated 
targeted drug therapy.  
5.1.1.2 Phase 2 – Diagnosis of mismatch repair proficient “MRP” (includes microsatellite stable 
[MSS] and MSI-low) colon cancer that has progressed following at least two lines of therapy. 
Tissue for microsatellite testing is required to document microsatellite status. Using MSI 
Analysis System (Promega) is preferred, but the assay may be performed by any accredited 
laboratory. Ten patients will be included who have disease that can be biopsied pre- and post- 
therapy (on treatment biopsies).  
 
5.2 Subject Inclusion Criteria 
In order to be eligible for participation in this trial, the subject must: 
1. Be willing and able to provide written informed consent/assent for the trial. 
2. Be ≥ 18 years of age on day of signing informed consent. 
3. Have measurable disease based on RECIST 1.1 (Phase 2 only).   For definition of 
measurable, non-measurable, target and non-target lesions, see Appendix 11.4, RECIST 1.1 
Guidelines. 
4. All subjects (Phase I and Phase II) will be consented for access of archival tissue (paraffin 
block or unstained slides) for immunohistochemistry analysis (Phase I patients will be 
reconsented for this). 
5. Be willing to provide tissue from a newly obtained core or excisional biopsy of a tumor 
lesion. (Phase 2 only) Newly-obtained is defined as a specimen obtained up to 6 weeks (42 
days) prior to initiation of treatment on Day 1.  Optional fresh tissue biopsies may be 
obtained before Cycle 4, end of treatment visit and follow-up period if relapse is 
encountered.  Subjects for whom newly-obtained samples cannot be provided (e.g. 
inaccessible or subject safety concern) may submit an archived specimen only upon 
agreement from the Sponsor. 
6. Have a performance status of 0 or 1 on the ECOG Performance Scale. 
7. Demonstrate adequate organ function as defined in Table 1; all screening labs should be 
performed within 10 days of treatment initiation.   
Table 1.  Adequate Organ Function Laboratory Values 
System 
Laboratory Value 
Hematological 
 
Absolute neutrophil count (ANC) 
≥1,500 /mcL 
Platelets 
≥100,000 / mcL 
Hemoglobin 
≥9 g/dL or ≥5.6 mmol/L without transfusion or EPO dependency 
(within 7 days of assessment) 
Renal 
 
Serum creatinine OR 
≤1.5 X upper limit of normal (ULN) OR 


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Measured or calculateda creatinine 
clearance 
(GFR can also be used in place of 
creatinine or CrCl) 
≥60 mL/min for subject with creatinine levels > 1.5 X institutional 
ULN 
Hepatic 
 
Serum total bilirubin 
≤ 1.5 X ULN OR 
 
Direct bilirubin ≤ ULN for subjects with total bilirubin levels > 1.5 
ULN 
AST (SGOT) and ALT (SGPT) 
≤ 2.5 X ULN  OR 
≤ 5 X ULN for subjects with liver metastases 
Albumin 
>2.5 mg/dL 
Coagulation 
International Normalized Ratio 
(INR) or Prothrombin Time (PT) 
 
Activated Partial Thromboplastin 
Time (aPTT) 
≤1.5 X ULN unless subject is receiving anticoagulant therapy 
as long as PT or PTT is within therapeutic range of intended use of 
anticoagulants 
≤1.5 X ULN unless subject is receiving anticoagulant therapy 
as long as PT or PTT is within therapeutic range of intended use of 
anticoagulants 
aCreatinine clearance should be calculated per institutional standard. 
 
8. Female subject of childbearing potential should have a negative urine or serum pregnancy 
within 72 hours prior to receiving the first dose of study medication.  If the urine test is 
positive or cannot be confirmed as negative, a serum pregnancy test will be required.   
9. Female subjects of childbearing potential must be willing to use an adequate method of 
contraception as outlined in Section 5.9.2 – Contraception,  for the course of the study 
through 120 days after the last dose of study medication. 
Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for 
the subject. 
10. Male subjects of childbearing potential must agree to use an adequate method of 
contraception as outlined in Section 5.9.2- Contraception, starting with the first dose of 
study therapy through 120 days after the last dose of study therapy. 
Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for 
the subject. 
5.2.1 Subject Exclusion Criteria 
The subject must be excluded from participating in the trial if the subject: 
1. Microsatellite instability-high (MSI-H) tumor status detected by Promega or an accredited 
laboratory per local procedures (Phase 2 only). 
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. 
3. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other 
form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment 
with the exceptions of intranasal and inhaled corticosteroids or systemic corticosteroids at 
physiological doses, which are not to exceed 10 mg/day of prednisone, or an equivalent 
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4. Has a known history of active TB  (Bacillus Tuberculosis) 
5. Hypersensitivity to pembrolizumab or any of its excipients. 
6. Has had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to study Day 
1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to agents 
administered more than 4 weeks earlier. 
7. Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy within 
2 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from 
adverse events due to a previously administered agent. 
• Note:  Subjects with ≤ Grade 2 neuropathy are an exception to this criterion and 
may qualify for the study. 
• Note:  If subject received major surgery, they must have recovered adequately from 
the toxicity and/or complications from the intervention prior to starting therapy.   
8. Has a known additional malignancy that is progressing or requires active treatment.  
Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the skin 
that has undergone potentially curative therapy or in situ cervical cancer. 
9. Has known active central nervous system (CNS) metastases and/or carcinomatous 
meningitis.  Subjects with previously treated brain metastases may participate provided 
they are stable (without evidence of progression by imaging for at least four weeks prior to 
the first dose of trial treatment and any neurologic symptoms have returned to baseline), 
have no evidence of new or enlarging brain metastases, and are not using steroids for at 
least 7 days prior to trial treatment.  This exception does not include carcinomatous 
meningitis which is excluded regardless of clinical stability.   
10. Has active autoimmune disease that has required systemic treatment in the past 2 years (i.e. 
with use of disease modifying agents, corticosteroids or immunosuppressive drugs). 
Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement 
therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic 
treatment.  
11. Has known history of non-infectious pneumonitis that required steroids, or any evidence 
of current pneumonitis. 
12. Has an active infection requiring systemic therapy. 
13. Has a history or current evidence of any condition, therapy, or laboratory abnormality that 
might confound the results of the trial, interfere with the subject’s participation for the full 
duration of the trial, or is not in the best interest of the subject to participate, in the opinion 
of the treating investigator.   
14. Has known psychiatric or substance abuse disorders that would interfere with cooperation 
with the requirements of the trial. 
15. Is pregnant or breastfeeding, or expecting to conceive or father children within the 
projected duration of the trial, starting with the pre-screening or screening visit through 
120 days after the last dose of trial treatment. 
16. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent. 
17. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies). 
18. Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA 
[qualitative] is detected). 


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19. Has received a live vaccine within 30 days of planned start of study therapy. 
Note:  Seasonal influenza vaccines for injection are generally inactivated flu vaccines and 
are allowed; however intranasal influenza vaccines (e.g., Flu-Mist®) are live attenuated 
vaccines, and are not allowed. 
5.3 
Trial Treatments 
The treatment to be used in this trial is outlined below in Table 2. 
Table 2.  Trial Treatment 
Drug 
Dose/ 
Potency 
Dose 
Frequency 
Route of 
Administration 
Regimen/ 
Treatment Period 
Use 
Pembrolizumab 
200 mg  
Q3W 
IV infusion 
Day 1 of each 3 
week cycle 
Experimental 
Poly-ICLC 
1.8mg/mL
* 
Twice 
weekly 
Intramuscular 
injection 
Day 0/1, 4, 8, 11, 
15, 18 of each 
cycle 
Experimental 
*Per manufacturer, drug product is now formulated at the original 1.8/mg/mL “dry” weight which 
is equivalent to 2.0mg/mL “wet” concentration of Poly-ICLC.  This is a label correction for residual 
water of hydration in the lyophilized components and represents no change in the product or 
formulation, but simply a calculation correction.  
 
The treatment to be used in this trial will follow the same regimen in both phases; all subjects will 
receive both poly-ICLC and pembrolizumab on Day 1of each cycle.  The Day 1dose of poly-ICLC 
should be administered in the clinic for all cycles, in both phases.  This will allow for assessment of 
AEs/SAEs and application of dose modifications, if needed, prior to dispensing drug for that cycle. 
 
Trial treatment will be given for 17 cycles.  If therapy is not interrupted this will be one year of 
therapy but therapy may extend for more than one year if interruptions are needed.  A subject who, 
after completing 17 cycles of study treatment and, at that time, has a radiologic disease status of SD, 
PR or CR, may continue to receive study treatment without interruption for an additional year (up 
to a total of 35 cycles) of study treatment (Second Course Phase/Retreatment Period, section 7.2.13).  
See section 5.4.2, Dose Administration, for details regarding drug administration.   
5.4 
Dose Selection 
The rationale for selection of doses to be used in this trial is provided in Section 4.0, Background 
and Rationale.   
 
5.4.1 Dose Modification (Escalation/Titration/Other) 
Adverse events (both non-serious and serious) associated with pembrolizumab exposure may 
represent an immunologic etiology.  These adverse events may occur shortly after the first dose or 
several months after the last dose of treatment. Pembrolizumab must be withheld for drug-related 
toxicities and severe or life-threatening AEs as per Table 3 below. See Section 5.8.1 for supportive 
care guidelines, including use of corticosteroids.  
 


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Table 3. Dose Modification Guidelines for Drug-Related Adverse Events 
Toxicity 
Hold 
Treatment 
For Grade 
Timing for Restarting 
Treatment 
Treatment Discontinuation 
Diarrhea/Colitis 
2-3 
 
Toxicity resolves to 
Grade 0-1 
Toxicity does not resolve within 12 
weeks of last dose or inability to reduce 
corticosteroid to 10 mg or less of 
prednisone or equivalent per day within 
12 weeks 
4 
Permanently discontinue 
Permanently discontinue 
AST, ALT, or 
Increased 
Bilirubin 
2 
Toxicity resolves to 
Grade 0-1 
Toxicity does not resolve within 12 
weeks of last dose 
3-4 
Permanently discontinue 
(see exception below)a 
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 
2-4 
Toxicity resolves to 
Grade 0-1. Therapy with 
pembrolizumab can be 
continued while 
endocrine replacement 
therapy is instituted 
Toxicity does not resolve within 12 
weeks of last dose or inability to reduce 
corticosteroid to 10 mg or less of 
prednisone or equivalent per day within 
12 weeks 
Hyperthyroidism  3 
Toxicity resolves to 
Grade 0-1 
Toxicity does not resolve within 12 
weeks of last dose or inability to reduce 
corticosteroid to 10 mg or less of 
prednisone or equivalent per day within 
12 weeks 
4 
Permanently discontinue 
Permanently discontinue 
Hypothyroidism 
 
Therapy with 
pembrolizumab can be 
continued while thyroid 
replacement therapy is 
instituted 
Therapy with pembrolizumab can be 
continued while thyroid replacement 
therapy is instituted 
Infusion 
Reaction 
2b 
Toxicity resolves to 
Grade 0-1  
Permanently discontinue if toxicity 
develops despite adequate premedication  
3-4 
Permanently discontinue 
Permanently discontinue 
Pneumonitis 
2 
Toxicity resolves to 
Grade 0-1 
Toxicity does not resolve within 12 
weeks of last dose or inability to reduce 
corticosteroid to 10 mg or less of 


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5.4.1.1 Determining the Recommended Phase 2 Dose (RP2D) of Poly-ICLC:   
For the Phase I component of the trial, classical 3+3 design will be employed and will include 
dose-escalation to determine the RP2D of Poly-ICLC to be combined with pembrolizumab.  
a. We will consider two dose levels, 1 and 2 mg of Poly-ICLC.   
b. A minimum of 3 patients will be treated depending on DLT.  Dose level 1 (1mg) will be 
administered to a cohort of 3 patients.  
c. If 0 out of 3 experience DLT, then dose escalation will proceed to the dose level 2 (2mg).  
d. If one out of three patients experience DLT, a cohort of additional three patients will be 
assigned to the same dose level (1mg).  
e. If two or more patients of three (or six) patients experience DLT at the first dose level, 
then enrollment of patients will be stopped.  
f. If a maximum one patient experiences DLT at dose level 2, then the dose will be declared 
the RP2D.  
g. If 2 or more out of 6 patients experience DLT at the second dose level, then the first dose 
level (1mg) will be declared the RP2D.  
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 resolve within 12 
weeks of last dose or inability to reduce 
corticosteroid to 10 mg or less of 
prednisone or equivalent per day within 
12 weeks 
3-4 
Permanently discontinue 
Permanently discontinue 
All Other Drug-
Related 
Toxicityc 
3 or Severe 
Toxicity resolves to 
Grade 0-1 
Toxicity does not resolve within 12 
weeks of last dose or inability to reduce 
corticosteroid to 10 mg or less of 
prednisone or equivalent per day within 
12 weeks 
4 
Permanently discontinue 
Permanently discontinue 
Note: Permanently discontinue for any severe or Grade 3 drug-related AE that recurs or any life-
threatening event. 
a For patients with liver metastasis who begin treatment with Grade 2 AST or ALT, if AST or ALT 
increases by greater than or equal to 50% relative to baseline and lasts for at least 1 week then patients 
should be discontinued. 
b 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 pre-medicated for the next scheduled dose; Refer to 
Infusion Treatment Guidelines for further management details. 
c Patients with intolerable or persistent Grade 2 drug-related AE may hold study medication at physician 
discretion.  Permanently discontinue study drug for persistent Grade 2 adverse reactions for which 
treatment with study drug has been held, that do not recover to Grade 0-1 within 12 weeks of the last 
dose. 


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h. The RP2D should have at least 6 patients enrolled at the dose level with a maximum of 
1 patient experiencing DLT.  Toxicities that occur during the phase II portion of the study 
will be taken into account in determining the RP2D.   
5.4.1.2 Dose Limiting Toxicity (DLT) Criteria for poly-ICLC escalation phase: 
A DLT will be defined as any Grade ≥ 3 or higher treatment-related toxicity that occurs during 
the DLT-evaluation period. Toxicity that is clearly and directly related to the primary disease or 
to another etiology is excluded from this definition. The following will be DLTs, regardless of 
relatedness: 
• Any Grade 4 irAE 
• Any Grade 4 non-hematologic toxicity 
• Any Grade ≥ 3 diarrhea or vomiting that does not resolve within 3 days 
• Any Grade 3 irAE, excluding colitis or pneumonitis, which does not downgrade to ≤ 
Grade 2 within 3 days after onset of the event despite maximal medical supportive care 
including systemic corticosteroids or does not downgrade to ≤ Grade 1 or baseline 
within 14 days.  
• Any ≥ Grade 3 colitis irrespective of duration 
• Any Grade ≥ 3 non-infectious pneumonitis irrespective of duration 
• Liver transaminase elevation ≥ 5 × but ≤ 8 × ULN that does not downgrade to Grade 2 
within 5 days after onset with optimal medical management, including systemic 
corticosteroids. Transaminase elevation > 8 × ULN or total bilirubin > 5 × ULN will 
be considered a DLT regardless of duration or reversibility 
• Any increase in AST or ALT > 3 × ULN and concurrent increase in total bilirubin > 2 
× ULN (Hy’s Law). 
  
The definition of DLT excludes the following conditions: 
• Grade 3 fatigue for ≤ 7 days 
• Grade 3 endocrine disorder (thyroid, pituitary, and/or adrenal insufficiency) that is 
managed with or without systemic corticosteroid therapy and/or hormone replacement 
therapy 
• Grade 3 inflammatory reaction attributed to a local antitumor response that resolved to 
≤ Grade 1 within 30 days 
• Concurrent vitiligo or alopecia of any AE grade 
• Grade 3 infusion-related reaction (IRR; first occurrence and in the absence of steroid 
prophylaxis) that resolves within 6 hours with appropriate clinical management. 
•  Grade 3 neutropenia that is not associated with fever or systemic infection that 
improves by at least 1 grade within 3 days. 
• Grade 3 or Grade 4 lymphopenia (unless clinically significant) 
• Grade 3 thrombocytopenia that is not associated with clinically significant bleeding 
that requires medical intervention, and improves by at least 1 grade within 7 days 
• Isolated Grade 3 electrolyte abnormalities that are not associated with clinical signs or 
symptoms and are reversed with appropriate maximal medical intervention within 3 
days 
• Grade 3 fever lasting ≤ 24 hours with or without medical therapy and is not considered 
a serious adverse event 


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The period for definition of DLT will be the first 3 weeks of treatment.  Dosing 
interruptions are permitted in the case of medical / surgical events or logistical reasons not 
related to study therapy (e.g., elective surgery, unrelated medical events, patient vacation, 
and/or holidays). Subjects should be placed back on study therapy within 3 weeks of the 
scheduled interruption, unless otherwise discussed with the Sponsor. The reason for 
interruption should be documented in the patient's study record. 
5.4.2 Dose Administration 
Trial treatment should be administered on Day 1 of each cycle after all procedures/assessments have 
been completed as detailed on the Trial Flow Chart (Section 6.0).  Trial treatment may be 
administered up to 3 days before or after the scheduled Day 1 of each cycle due to administrative 
reasons. 
5.4.2.1 Pembrolizumab Preparation, Storage and Administration 
Pembrolizumab 200 mg will be administered as a 30 minute IV infusion on an outpatient basis every 
3 weeks.  Sites should make every effort to target infusion timing to be as close to 30 minutes as 
possible.  However, given the variability of infusion pumps from site to site, a window of -5 minutes 
and +10 minutes is permitted (i.e., infusion time is 30 minutes: -5 min/+10 min).  Preparation and 
administration of the investigational agent, pembrolizumab, will follow the same guidelines as for 
the FDA-approved agent, pembrolizumab, known commercially as Keytruda. 
 
Preparation for Intravenous Infusion 
• Visually inspect the solution for particulate matter and discoloration prior to administration. 
The solution is clear to slightly opalescent, colorless to slightly yellow. Discard the vial if 
visible particles are observed. 
• Dilute pembrolizumab injection (solution) or reconstituted lyophilized powder prior to 
intravenous administration. 
• Withdraw the required volume from the vial(s) of pembrolizumab and transfer into an 
intravenous (IV) bag containing 0.9% Sodium Chloride Injection, USP or 5% Dextrose 
Injection, USP. Mix diluted solution by gentle inversion. The final concentration of the 
diluted solution should be between 1 mg/mL to 10 mg/mL. 
• Discard any unused portion left in the vial. 
Storage of Diluted Solutions 
The product does not contain a preservative. Store the diluted solution of pembrolizumab either: 
• At room temperature for no more than 6 hours from the time of dilution. This includes room 
temperature storage of the infusion solution in the IV bag, and the duration of infusion. 
• Under refrigeration at 2°C to 8°C (36°F to 46°F) for no more than 24 hours from the time of 
dilution. If refrigerated, allow the diluted solution to come to room temperature prior to 
administration. Do not freeze. 
Administration 
• Administer infusion solution intravenously over 30 minutes through an intravenous line 
containing a sterile, non-pyrogenic, low-protein binding 0.2 micron to 5 micron in-line or 
add-on filter. 
• Do not co-administer other drugs through the same infusion line. 


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• The first injection of Pembrolizumab will be administered in clinic one hour after the first 
IM injection of Poly ICLC in the concurrent treatment group under the supervision of study 
clinical staff. Pembrolizumab will be administered one day after Poly ICLC injection in the 
subsequent treatment group. These two groups apply to phase II, while phase I will follow 
similar schedule as concurrent treatment group.  
• The patient will be monitored for at least 30 minutes including a determination of blood 
pressure, heart rate, and respiratory rate before and after each injection. 
5.4.2.2 Poly-ICLC Preparation, Storage and Administration 
Poly-ICLC is provided in vials containing 1.8mg (1 ml).   Excess volume is expected for the first 
cohort of subjects (1 mg/ .5ml). Unless labeled otherwise, the poly-ICLC vials being provided for 
this trial are labeled as single-use; therefore excess volume will be discarded.  For doses that are 
administered at the clinical site, staff will dispose of the vials according to local protocol.  For doses 
that are administered at the subject’s home, used vials should be kept and returned to clinical staff 
at the following visit for reconciliation/compliance assessment.  
 
Study subjects will receive intramuscular (IM) injections of 1 or 2 mg poly-ICLC on Days 1, 4, 8, 
11, 15, 18 of each three-week cycle (twice weekly). The first injection of each cycle will be 
administered in clinic under the supervision of study clinical staff.  The subject will be monitored 
for at least 30 minutes after the first IM injection; blood pressure, heart rate, and respiratory rate 
should be assessed before and after injection.  Approximately one hour after the poly-ICLC injection 
is given, the subject will begin pembrolizumab IV infusion.   
 
Following the first treatment, subsequent poly-ICLC injections may be administered at home by the 
study subject or the study subjects’ person of choice (e.g., family member, friend). Study subjects 
will be given a set of written instructions to follow, and a diary sheet that they are required to 
maintain showing the dates and times when injections were given and the injection sites 
(extremities). At the investigator’s discretion, subsequent injections may be scheduled to be given 
in the outpatient clinic instead of at-home administration. 
 
IM injections will be performed using standard technique into the thighs or upper arms. Injection 
site may be rotated based on study subjects’ and investigator preference and will be recorded in the 
diary. The study nurse will train the study subjects or the study subjects’, person of choice on how 
to inject IM Poly-ICLC during the first treatment.   
 
The investigational pharmacy will follow its standard operating procedures (SOPs) when dispensing 
the study drug for distribution to the study subjects. Study subjects will be instructed to administer 
(or have their person of choice administer) the second IM injection 3 days following the first 
injection (Day 4). The clinical staff will provide study subjects with a sufficient supply of Poly-
ICLC, sterile syringes with needles and alcohol swabs for this purpose. Study subjects will be 
instructed to store the vials in the refrigerator, in a location that prevents the study drug from 
freezing, until it is time to administer the study drug. They will be told to exchange any vials of Poly-
ICLC that inadvertently becomes frozen.   
 
The study subjects will also be provided with a diary wherein the date, time and injection site of the 
study drug is to be noted as well as comments on any side effects. The diary will be reviewed by the 
clinic staff with the study subject at clinic visits and collected from the study subject at the following 


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study visit. Study subjects and/or their person of choice will be instructed to allow a 72-hour interval 
between each injection. Study subjects will be instructed to contact the study doctor with any 
concerns regarding injections. 
5.4.3 Trial Blinding/Masking 
This is an open-label trial; therefore, the Sponsor, investigator and subject will know the treatment 
administered. 
5.5 
Treatment Allocation 
5.6 
There will be no randomization utilized in this study.  Aside from the predetermined 
dose-escalation (and individual dose modifications, if needed, all subjects will receive 
the same treatment). Concomitant Medications/Vaccinations (allowed & prohibited) 
Medications or vaccinations accepted or prohibited to use in this trial are detailed in following 
paragraphs. If there is a clinical indication for one of these medications or vaccinations prohibited 
during the trial, discontinuation from trial therapy may be required.  The investigator should discuss 
any questions regarding this with the Merck Clinical team.  The final decision on any supportive 
therapy or vaccination rests with the investigator and/or the subject's primary physician.  
5.6.1 Acceptable Concomitant Medications 
All treatments that the investigator considers necessary for a subject’s welfare may be administered 
at the discretion of the investigator in keeping with the community standards of medical care.  All 
concomitant medication will be recorded on the electronic Case Report Form (eCRF) in OnCore 
including all prescription, over-the-counter (OTC), herbal supplements, and IV medications and 
fluids.  If changes occur during the trial period, documentation of drug dosage, frequency, route, and 
date may also be included on the eCRF. 
 
All concomitant medications received within 28 days before the first dose of trial treatment and 30 
days after the last dose of trial treatment should be recorded.  Concomitant medications administered 
after 30 days after the last dose of trial treatment should be recorded for SAEs and ECIs as defined 
in Section 7.3. 
5.6.2 Prohibited Concomitant Medications 
Subjects are prohibited from receiving the following therapies during the Screening and Treatment 
Phase (including retreatment for post-complete response relapse) of this trial: 
• Antineoplastic systemic chemotherapy or biological therapy  
• Immunotherapy not specified in this protocol 
• Chemotherapy not specified in this protocol 
• Investigational agents other than pembrolizumab and Poly-ICLC 
• Radiation therapy  
o Note:  Radiation therapy to a symptomatic solitary lesion or to the brain may be allowed at the 
investigator’s discretion.   
• Live vaccines within 30 days prior to the first dose of trial treatment and while participating in the 
trial.  Examples of live vaccines include, but are not limited to, the following: measles, mumps, 
rubella, varicella/zoster, yellow fever, 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. 


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Subjects who, in the assessment by the investigator, require the use of any of the aforementioned 
treatments for clinical management should be removed from the trial.  Subjects may receive other 
medications that the investigator deems to be medically necessary. 
 
The Exclusion Criteria describes other medications which are prohibited in this trial.  There are no 
prohibited therapies during the Post-Treatment Follow-up Phase. 
5.7 
Rescue Medications & Supportive Care 
5.7.1 Supportive Care Guidelines 
Subjects should receive appropriate supportive care measures as deemed necessary by the treating 
investigator.  Suggested supportive care measures for the management of adverse events with 
potential immunologic etiology are outlined below. Where appropriate, these guidelines include the 
use of oral or intravenous treatment with corticosteroids as well as additional anti-inflammatory 
agents if symptoms do not improve with administration of corticosteroids.   Note that several courses 
of steroid tapering may be necessary as symptoms may worsen when the steroid dose is decreased. 
For each disorder, attempts should be made to rule out other causes such as metastatic disease or 
bacterial or viral infection, which might require additional supportive care. The treatment guidelines 
are intended to be applied when the investigator determines the events to be related to 
pembrolizumab.  
 
Note: if after the evaluation the event is determined not to be related, the investigator does not need 
to follow the treatment guidance (as outlined below). Refer to the dose modification section.  
 
It may be necessary to perform conditional procedures such as bronchoscopy, endoscopy, or skin 
photography as part of evaluation of the event.  
• Pneumonitis:  
o For Grade 2 events, treat with systemic corticosteroids. When symptoms improve to 
Grade 1 or less, steroid taper should be started and continued over no less than 4 weeks. 
o For Grade 3-4 events, immediately treat with intravenous steroids.  Administer 
additional anti-inflammatory measures, as needed. 
o Add prophylactic antibiotics for opportunistic infections in the case of prolonged steroid 
administration. 
 
• Diarrhea/Colitis:  
Subjects should be carefully monitored for signs and symptoms of enterocolitis (such as 
diarrhea, abdominal pain, blood or mucus in stool, with or without fever) and of bowel 
perforation (such as peritoneal signs and ileus).   
o All subjects who experience diarrhea/colitis should be advised to drink liberal quantities 
of clear fluids.  If sufficient oral fluid intake is not feasible, fluid and electrolytes should 
be substituted via IV infusion.  For Grade 2 or higher diarrhea, consider GI consultation 
and endoscopy to confirm or rule out colitis. 
o For Grade 2 diarrhea/colitis, administer oral corticosteroids.  
o For Grade 3 or 4 diarrhea/colitis, treat with intravenous steroids followed by high dose 
oral steroids.   
o When symptoms improve to Grade 1 or less, steroid taper should be started and continued 
over no less than 4 weeks. 


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• Type 1 diabetes mellitus (if new onset, including diabetic ketoacidosis [DKA]) or ≥ Grade 
3 Hyperglycemia, if associated with ketosis (ketonuria) or metabolic acidosis (DKA) 
o For T1DM or Grade 3-4 Hyperglycemia 
 Insulin replacement therapy is recommended for Type I diabetes mellitus and for Grade 
3-4 hyperglycemia associated with metabolic acidosis or ketonuria.  
 Evaluate patients with serum glucose and a metabolic panel, urine ketones, 
glycosylated hemoglobin, and C-peptide.  
• Hypophysitis: 
o For Grade 2 events, treat with corticosteroids. When symptoms improve to Grade 1 or 
less, steroid taper should be started and continued over no less than 4 weeks. Replacement 
of appropriate hormones may be required as the steroid dose is tapered. 
o For Grade 3-4 events, treat with an initial dose of IV corticosteroids followed by oral 
corticosteroids. When symptoms improve to Grade 1 or less, steroid taper should be 
started and continued over no less than 4 weeks. Replacement of appropriate hormones 
may be required as the steroid dose is tapered. 
 
• Hyperthyroidism or Hypothyroidism:  
Thyroid disorders can occur at any time during treatment. Monitor patients for changes in 
thyroid function (at the start of treatment, periodically during treatment, and as indicated based 
on clinical evaluation) and for clinical signs and symptoms of thyroid disorders. 
o Grade 2 hyperthyroidism events (and Grade 2-4 hypothyroidism): 
 In hyperthyroidism, non-selective beta-blockers (e.g. propranolol) are suggested as 
initial therapy. 
 In hypothyroidism, thyroid hormone replacement therapy, with levothyroxine or 
liothyroinine, is indicated per standard of care. 
o Grade 3-4 hyperthyroidism  
 Treat with an initial dose of IV corticosteroid followed by oral corticosteroids. When 
symptoms improve to Grade 1 or less, steroid taper should be started and continued 
over no less than 4 weeks. Replacement of appropriate hormones may be required as 
the steroid dose is tapered. 
 
• Hepatic: 
o For Grade 2 events, monitor liver function tests more frequently until returned to 
baseline values (consider weekly). 
 Treat with IV or oral corticosteroids 
o For Grade 3-4 events, treat with intravenous corticosteroids for 24 to 48 hours.  
o When symptoms improve to Grade 1 or less, a steroid taper should be started and 
continued over no less than 4 weeks. 
 
• Renal Failure or Nephritis: 
o For Grade 2 events, treat with corticosteroids. 
o For Grade 3-4 events, treat with systemic corticosteroids. 
o When symptoms improve to Grade 1 or less, steroid taper should be started and 
continued over no less than 4 weeks.  
 Table 4. Supportive Measures 


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• Management of Infusion Reactions: Signs and symptoms usually develop during or shortly 
after drug infusion and generally resolve completely within 24 hours of completion of infusion.  
The table below shows treatment guidelines for subjects who experience an infusion reaction 
associated with administration of pembrolizumab (MK-3475). 
 
Toxicity 
Gra
de 
Supportive Treatment 
Pneumonitis¹ 
2 
 
Treat with systemic corticosteroids² 
3-4 
Immediately treat with intravenous steroids.  Administer additional 
anti-inflammatory measures, as needed 
Diarrhea/Colitis³’⁴ 
2 
Administer oral corticosteroids² 
3-4 
Treat with intravenous steroids followed by high dose oral steroids.   
Type 1 diabetes 
mellitus (if new onset) 
or Hyperglycemia⁵ 
T1D
M or  
3-4 
Insulin replacement therapy is recommended for Type I diabetes 
mellitus and for Grade 3-4 hyperglycemia associated with metabolic 
acidosis or ketonuria.  
Hypophysitis 
2 
Treat with oral corticosteroids²’⁶ 
3-4 
Treat with intravenous steroids followed by high dose oral steroids⁶  
Hyperthyroidism  
3 
Non-selective beta-blockers (e.g. propranolol) are suggested as initial 
therapy. 
4 
Treat with an initial dose of IV corticosteroid followed by oral 
corticosteroids 
Hypothyroidism 
2-4 
Thyroid hormone replacement therapy, with levothyroxine or 
liothyroinine, is indicated per standard of care² 
Hepatic Reaction 
2 
Monitor liver function tests more frequently until returned to baseline 
values (consider weekly) 
3-4 
Treat with intravenous corticosteroids for 24 to 48 hours² 
Renal Failure or 
Nephritis 
2 
Treat with oral corticosteroids² 
3-4 
Treat with intravenous steroids followed by high dose oral steroids²’⁶  
1) Add prophylactic antibiotics for opportunistic infections in the case of prolonged steroid 
administration. 
2) When symptoms improve to Grade 1 or less, steroid taper should be started and continued over no 
less than 4 weeks. 
3) 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.   
4) For Grade 2 or higher diarrhea, consider GI consultation and endoscopy to confirm or rule out 
colitis. 
5) Evaluate patients with serum glucose and a metabolic panel, urine ketones, glycosylated 
hemoglobin, and C-peptide. 
6) Replacement of appropriate hormones may be required as the steroid dose is tapered. 


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


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NCI CTCAE Grade 
Treatment 
Premedication at 
subsequent dosing 
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 
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. 
Appropriate resuscitation equipment should be available in the room and a physician readily 
available during the period of drug administration. 
 
5.8 
Diet/Activity/Other Considerations 
5.8.1 Diet 
Subjects should maintain a normal diet unless modifications are required to manage an AE such as 
diarrhea, nausea or vomiting. 
5.8.2 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. 
 


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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): 
o Intrauterine device (IUD) 
o Vasectomy of a female subject’s male partner  
o Contraceptive rod implanted into the skin 
  
• Combination method (requires use of two of the following): 
o Diaphragm with spermicide (cannot be used in conjunction with cervical cap/spermicide) 
o Cervical cap with spermicide (nulliparous women only)   
o Contraceptive sponge (nulliparous women only)  
o Male condom or female condom (cannot be used together) 
o 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. 
 
Subjects should be informed that taking the study medication may involve unknown risks to the 
fetus (unborn baby) if pregnancy were to occur during the study.  In order to participate in the study 
subjects of childbearing potential must adhere to the contraception requirement (described above) 
from the day of study medication initiation (or 14 days prior to the initiation of study medication for 
oral contraception) throughout the study period up to 120 days after the last dose of trial therapy.  If 
there is any question that a subject of childbearing potential will not reliably comply with the 
requirements for contraception, that subject should not be entered into the study. 
5.8.3 Use in Pregnancy 
If a subject inadvertently becomes pregnant while on treatment with pembrolizumab, the subject will 
immediately be removed from the study.  The site will contact the subject at least monthly and 
document the subject’s status until the pregnancy has been completed or terminated.  The outcome 
of the pregnancy will be reported to the Sponsor and to Merck without delay and within 24 hours to 
the Sponsor and within 2 working days to Merck if the outcome is a serious adverse experience (e.g., 
death, abortion, congenital anomaly, or other disabling or life-threatening complication to the mother 
or newborn).   
The study investigator will make every effort to obtain permission to follow the outcome of the 
pregnancy and report the condition of the fetus or newborn to the Sponsor.   If a male subject 


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impregnates his female partner the study personnel at the site must be informed immediately and the 
pregnancy reported to the Sponsor and to Merck and followed as described above and in Section 
7.3.2. 
5.8.4 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. 
5.9 
Subject Withdrawal/Discontinuation Criteria 
Subjects may withdraw consent at any time for any reason or be dropped from the trial at the 
discretion of the investigator should any untoward effect occur.  In addition, a subject may be 
withdrawn by the investigator or the Sponsor if enrollment into the trial is inappropriate, the trial 
plan is violated, or for administrative and/or other safety reasons.  Specific details regarding 
discontinuation or withdrawal are provided in Other Procedures section. 
 
A subject must be discontinued from the trial for any of the following reasons: 
• The subject withdraws consent. 
• Confirmed radiographic disease progression 
Note: For unconfirmed radiographic disease progression, please see Appendix 11.4, 
RECIST 1.1 Guidelines, Confirmation of Progression. 
Note: A subject may be granted an exception to continue on treatment with confirmed 
radiographic progression if clinically stable or clinically improved; please see Appendix 
11.4, RECIST 1.1 Guidelines, Confirmation of Progression. 
• Unacceptable adverse experiences such as dose-limiting toxicities 
• Intercurrent illness that prevents further administration of treatment 
• Investigator’s decision to withdraw the subject 
• The subject has a confirmed positive serum pregnancy test 
• Noncompliance with trial treatment or procedure requirements 
• The subject is lost to follow-up 
• Completed 12 months of uninterrupted treatment with pembrolizumab and poly-ICLC (17 
administrations of combination study treatment [study diagram 2.2.2]). 
Note: 12 months of study medication is calculated from the date of first dose. Subjects who 
stop combination study treatment after 12 months may be eligible for up to one year of 
additional study treatment if they progress after stopping study treatment, provided they meet 
the requirements detailed in Section 7.2.13, Second Course Phase (Retreatment Period). 
• Administrative reasons 
The End of Treatment and Follow-up visit procedures are listed in Section 6 (Protocol Flow Chart) 
and Section 7.2.12 (Visit Requirements).  After the end of treatment, each subject will be followed 
for 30 days for adverse event monitoring (serious adverse events will be collected for 90 days after 
the end of treatment as described in Section 7.3).  Subjects who discontinue for reasons other than 
progressive disease will have post-treatment follow-up for disease status until disease progression, 
initiating a non-study cancer treatment, withdrawing consent or becoming lost to follow-up.  After 
documented disease progression each subject will be followed by telephone for overall survival until 
death, withdrawal of consent, or the end of the study, whichever occurs first. 


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5.9.1 Discontinuation of Study Therapy after CR  
Discontinuation of treatment may be considered for subjects who have attained a confirmed CR that 
have been treated for at least 24 weeks with pembrolizumab and had at least two treatments with 
pembrolizumab beyond the date when the initial CR was declared.  Subjects who then experience 
radiographic disease progression may be eligible for up to one year of additional treatment with 
pembrolizumab and poly-ICLC via the Second Course Phase at the discretion of the investigator if 
no cancer treatment was administered since the last dose of pembrolizumab, the subject meets the 
safety parameters listed in the Inclusion/Exclusion criteria, and the trial is open.  Subjects will 
resume therapy at the same dose and schedule at the time of initial discontinuation.  Additional 
details are provided in Section 7.2.13, Second Course Phase (Retreatment Period). 
5.10 Subject Replacement Strategy 
Subjects who withdraw from therapy prior to completion of cycle 1 of therapy will be replaced 
during the phase I portion of the trial to allow for evaluation of at least 3 subjects at each dose level.  
Similarly, if patients withdraw before assessment of tumor response in the phase II portion of the 
trial, they will be replaced unless withdrawal is due to clinical disease progression. 
5.11 Clinical Criteria for Early Trial Termination 
Early trial termination will be the result of the criteria specified below: 
1. Quality or quantity of data recording is inaccurate or incomplete 
2. Poor adherence to protocol and regulatory requirements 
3. Incidence or severity of adverse drug reaction in this or other studies indicates a potential health 
hazard to subjects 
4. Plans to modify or discontinue the development of the study drug 
 
In the event of Merck decision to no longer supply study drug, ample notification will be provided 
so that appropriate adjustments to subject treatment can be made. 


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TRIAL FLOW CHART 
Trial Period: 
Screening  
Treatment Cycles1 
End of 
Treatment 
Post-Treatment 
Treatment Cycle/Title: 
Study 
Screening 
(Visit 1) 
1 
2 
3 
4 
To be repeated, cycles 
9-17 
Second 
Course Phase 
(Retreatment 
Period)¹³ 
Discon 
Safety 
Follow-
up2 
Follow 
UpVisits3  
Survival 
Follow 
Up4 
5 
6 
7 
8 
 
Scheduling Window (Days): 
-28 to -1 
 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
 
 
± 3 
At time of 
Discon 
30 days 
post 
discon 
Every 12 
wks post 
discon 
Every 12 
wks post 
discon 
 
Administrative Procedures 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics and Medical History 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Prior and Concomitant Medication Review 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
Trial Treatment Administration 
Pembrolizumab5 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
Poly-ICLC6 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
Clinical Procedures/Assessments 
Review Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Full Physical Examination 
X 
 
 
 
 
 
 
 
 
 
X 
X 
 
 
Directed Physical Examination 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
 
Vital Signs and Weight 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
ECOG Performance Status 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
ECG7 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Post-study anticancer therapy/Survival Status 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
 
Laboratory Procedures/Assessments (analysis performed by LOCAL laboratory) 
Pregnancy Test – Urine or Serum β-HCG 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
PT/INR and aPTT 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
CBC with Differential 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Comprehensive Serum Chemistry Panel 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Urinalysis 
X 
 
 
 
X 
 
 
 
X 
X 
 
 
 
 
Infections work up: Hepatitis B, Hepatitis C, HIV 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
FreeT3, FreeT4 and TSH8 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
 
 
Correlative Studies Blood Collection (CENTRAL labs, analysis performed by Cancer Research Center)9 
1 ABI TEMPUS tube (~3ml blood) for RNA 
microarray analysis 
X 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
1 DNA PAXgene tube (~8.5 ml blood) for DNA 
analysis 
X 
X 
 
X 
 
 
 
 
 
 
 
 
 
 


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Trial Period: 
Screening  
Treatment Cycles1 
End of 
Treatment 
Post-Treatment 
Treatment Cycle/Title: 
Study 
Screening 
(Visit 1) 
1 
2 
3 
4 
To be repeated, cycles 
9-17 
Second 
Course Phase 
(Retreatment 
Period)¹³ 
Discon 
Safety 
Follow-
up2 
Follow 
UpVisits3  
Survival 
Follow 
Up4 
5 
6 
7 
8 
 
Scheduling Window (Days): 
-28 to -1 
 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
 
 
± 3 
At time of 
Discon 
30 days 
post 
discon 
Every 12 
wks post 
discon 
Every 12 
wks post 
discon 
1-2 EDTA BD Vacutainer tubes (at least 10 ml, 
ideally up to 20 ml) for PBMC, plasma 
collection/separation 
X 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Efficacy Measurements10 
Tumor Imaging (CT/MRI of Chest, Abdomen, 
Pelvis; bone scan if clinically indicated)  
X 
 
 
 
 
 
 
 
 
 
X 
X 
 
 
 
 
Tumor Biopsies/Archival Tissue Collection 
Archival or Newly Obtained Tissue 
Collection11,12 for microsatellite testing and 
immune evaluation; any sequence-based CLIA 
certified analysis system may be used.  PD-L1, 
IDO, CD3, CD4. CD8, and FOXp3 will be 
evaluated.  Other markers may also be analyzed. 
X 
 
 
 
X¹¹  
 
 
 
 
If disease 
progression 
(optional) 
 
If disease 
progression 
(optional) 
 
 1 Cycles should be scheduled continuously; however, initiation of subsequent cycles may be extended up to 3 days. 
  2 All subjects should have a Safety Follow Up visit, approximately 30 days after the last dose of trial treatment, or before the initiation of a new anti-cancer treatment, whichever comes 
first.   
 3 Subjects who discontinue treatment for a reason other than disease progression will move into the Follow Up phase and should be assessed every 12 weeks to monitor disease status.   
 4 Subjects with confirmed disease progression will move into the Survival Follow Up phase and should be contacted by telephone every 12 weeks to assess survival status until death, 
withdrawal of consent, or the end of the study, whichever occurs first. 
 5 Pembrolizumab is only administered on Day 1 of each 3-week cycle 
 6 Poly-ICLC is to be administered IM on Days 1, 4, 8, 11, 15, 18 of each cycle. Subjects will be instructed on self-administration. 
 7 Collect at baseline, and as clinically indicated. 
 8 Thyroid labs to be drawn every other cycle. 
 9 Blood for correlative studies to be collected at Screening, Cycle 1 Day 1 at 4-6 hours post-treatment, and Cycle 3 Day 1 at 4-6 hours post-treatment.  Preferably, blood should be drawn 6 
hours post-dose, but between 4-6 hours is acceptable, depending on individual patient’s circumstances. See Lab Manual (Appendix 11.6) for details. 
10 Baseline scans must be obtained within 28 days prior to the first dose of trial treatment.  The first on-study scan should be performed after Cycle 3, before beginning Cycle 4 treatment.  
Subsequent scans should be performed every 3 cycles (approximately every 9 weeks). The same method should be used for tumor measurement throughout therapy. After discontinuation 
of therapy scans will be performed every 12 weeks.  
11 Archival tissue may be used for MSI testing; all other testing should be done on fresh tissue, if available.  Fresh tissue biopsy at cycle 4, at end of treatment visit and during follow-up is 
optional for subject. 
12 Beginning with Amendment 4, tissue collection was expanded to include Phase 1 subjects; in previous protocol versions, tissue was only to be collected for Phase 2 subjects.  
¹³ Subjects who have a radiologic status of SD, PR or CR after completing 17 cycles of study therapy may continue without interruption for an additional year (up to a total of 35 cycles of 
trial treatment). 
 


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TRIAL PROCEDURES 
The Trial Flow Chart - Section 6.0 summarizes the trial procedures to be performed at each visit.  
Individual trial procedures are described in detail below.  It may be necessary to perform these 
procedures at unscheduled time points if deemed clinically necessary by the investigator. 
 
Furthermore, additional evaluations/testing may be deemed necessary by the Sponsor and/or Merck 
for reasons related to subject safety. In some cases, such evaluation/testing may be potentially 
sensitive in nature (e.g., HIV, Hepatitis C, etc.), and thus local regulations may require that additional 
informed consent be obtained from the subject.  In these cases, such evaluations/testing will be 
performed in accordance with those regulations. 
7.1 Administrative Procedures 
7.1.1 Informed Consent 
The Investigator must obtain documented consent from each potential subject prior to 
participating in a clinical trial. 
Consent must be documented by the subject’s dated signature on a consent form along with the 
dated signature of the person conducting the consent discussion. A copy of the signed and dated 
consent form should be given to the subject before participation in the trial. 
 
The initial informed consent form, any subsequent revised written informed consent form and 
any written information provided to the subject must receive the IRB/ERC’s approval/favorable 
opinion in advance of use.  The subject should be informed in a timely manner if new information 
becomes available that may be relevant to the subject’s willingness to continue participation in 
the trial.  The communication of this information will be provided and documented via a revised 
consent form or addendum to the original consent form that captures the subject’s dated 
signature. 
 
Specifics about a trial and the trial population will be added to the consent form template at the 
protocol level. The informed consent will adhere to IRB/ERC requirements, applicable laws and 
regulations and Sponsor requirements. 
7.1.2 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.  
7.1.3 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.   
7.1.4 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 


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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 in the 
Concomitant Medications eCRF, and as defined in Section 7.2. 
7.1.5 Disease Details and Treatments 
Disease Details  
The investigator or qualified designee will obtain prior and current details regarding disease 
status.  These details should be captured in the Disease History eCRF in OnCore. 
Prior Treatment Details 
The investigator or qualified designee review all prior cancer treatments including systemic 
treatments, radiation and surgeries.  These details should be captured in the Prior Therapies 
eCRF in OnCore. 
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.  
7.1.6 Assignment of Study Subject Number 
After the study subject has been consented and has met all eligibility criteria, the subject must 
be registered for active study treatment. The following should be provided to the Augusta 
University Cancer Clinical Research Unit (CCRU) multi-center coordinator, either in hard copy, 
or emailed to Cancer_Center_Trials@augusta.edu:   
• A copy of the signed consent form  
• A completed registration Eligibility Checklist, with investigator signature 
After confirmation of eligibility, the CCRU multi-center coordinator will email the study staff 
to confirm enrollment, including the assigned Study Subject number that will be associated with 
the subject for all study activities. The study staff may forward this correspondence to their on-
site pharmacy for release of investigational agents. 
7.2 
Clinical Procedures/Assessments 
7.2.1 Adverse Event (AE) Monitoring 
The investigator or qualified designee will assess each subject to evaluate for potential new or 
worsening AEs as specified in the Trial Flow Chart and more frequently if clinically indicated.  
Adverse experiences will be graded and recorded throughout the study and during the follow-
up period according to NCI CTCAE Version 4.03 (see Section 11.2).  Toxicities will be 
characterized in terms regarding seriousness, causality, toxicity grading, and action taken with 
regard to trial treatment.  
For subjects receiving treatment with pembrolizumab all AEs of unknown etiology associated 
with pembrolizumab exposure should be evaluated to determine if it is possibly an event of 
clinical interest (ECI) of a potentially immunologic etiology (termed immune-related adverse 


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Page 39 of 77 
events, or irAEs); see the separate ECI guidance document in Appendix 4 regarding the 
identification, evaluation and management of potential irAEs.   
Please refer to section 7.3 for detailed information regarding the assessment and recording of 
AEs.   
7.2.2 Full Physical Exam 
The investigator or qualified designee will perform a complete physical exam during the 
screening period.  Clinically significant abnormal findings should be recorded as medical 
history.   
7.2.3 Directed Physical Exam 
For cycles that do not require a full physical exam per the Trial Flow Chart, the investigator or 
qualified designee will perform a directed physical exam as clinically indicated prior to trial 
treatment administration.  
7.2.4 Electrocardiograms 
Resting 12-lead ECGs will be recorded at screening and as clinically indicated throughout the 
study. ECGs should be obtained after the patient has been in a supine position for 5 minutes 
and recorded while the patient remains in that position.  
At Screening, a single ECG will be obtained on which QTcF must be <470 ms.  In case of 
clinically significant ECG abnormalities, including a QTcF value >470 ms, two additional 12-
lead ECGs should be obtained over a brief period (eg, 30 minutes) to confirm the finding. A 
physician should be available to read these ECGs and make a decision if they are found to be 
abnormal.    
Situations in which ECG results should be reported as AEs are described in Section 7.3.   
7.2.5 Vital Signs 
The investigator or qualified designee will take vital signs at screening, prior to the 
administration of each dose of trial treatment and at treatment discontinuation as specified in 
the Trial Flow Chart (Section 6.0).  Vital signs should include temperature, pulse, respiratory 
rate, weight and blood pressure.  Height will be measured at screening only. 
7.2.6 Eastern Cooperative Oncology Group (ECOG) Performance Scale 
The investigator or qualified designee will assess ECOG status (see Section 11.1) at screening, 
prior to the administration of each dose of trial treatment and discontinuation of trial treatment 
as specified in the Trial Flow Chart.   
7.2.7 Tumor Imaging and Assessment of Disease 
CT, MRI, PET, ultrasound and bone scan may be used for evaluation of disease.  Tumor 
measurements should be performed on the same type of scan throughout treatment and it is 
preferred that CT or MRI be used.    
7.2.8 Tumor Tissue Collection and Correlative Studies Blood Sampling 
Blood sample volumes for the purposes of this study are restricted.  The amount of blood drawn 
from adults (those 18 years of age or older) for research purposes shall not exceed 10.5 mL/kg 
or 550 mL; whichever is smaller, in an 8-week period.  Blood will be drawn into TEMPUS 
blood collection tubes from Applied Biosystems for extracting RNA for flow cytometry 
evaluation.  See Appendix 11.6 for details regarding specimen processing.  


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Archival tumor tissue will be obtained on all patients (Phase I and Phase II) if possible.  
Formalin fixed paraffin embedded (FFPE) tumor sample or unstained slides will be accepted.  
All patients with tumors that are accessible utilizing reasonable clinical interventions will be 
requested to consent to tumor biopsy.  Approaches which may be utilized include but are not 
necessarily limited to needle aspiration, true-cut biopsy or incisional biopsy of superficial 
lesions or lesions accessible by interventional radiology.  Patients will be requested to undergo 
biopsy prior to/beginning of cycle 4 therapy.  Patients may be asked again for tissue biopsy at 
attainment of disease stabilization and at the time of disease progression, or toxicity leading to 
discontinuation of treatment.  Specimens will be processed as outlined below. 
7.2.9 Archival Tumor Sample/Tumor Biopsy Specimens  
Archival tumor tissue samples (paraffin block or unstained slides) will be obtained, if possible, 
on all subjects (Phase I and Phase II) for immunohistochemistry analysis. 
 
Tumor Biopsy Specimens (Phase II Only) 
Tumor biopsies are required prior to the beginning of treatment.  Optional, repeated biopsies 
at cycle 4 (±3 days), end of treatment visit and during the follow-up period are performed if 
relapse is encountered.  Where possible, 4 samples should be obtained at each biopsy.   
• The first will be preserved in standard formalin fixative.  This specimen should be 
accessioned and submitted to the Pathology Department for routine staining with 
hematoxylin and eosin.  After processing, the remaining block should be sent to tumor 
repository bank led by Dr. Roni Bollag.   
• The second will be preserved in a specialized fixative for analysis of fresh frozen tissue.  
• The third specimen will be snap frozen in liquid nitrogen for later protein and/or RNA 
analysis.  
• The 4th should be complimentary and hence either frozen or fixed with formalin based on 
size of tissue 
When needle aspiration is the only mechanism for acquisition of neoplastic tissue, cytospins 
will be collected and immediately processed to optimize protection of protein and/or RNA 
integrity.  
All biopsy specimens must include the study name, patients name, hospital number, date and 
time of collection and site of biopsy.  Questions regarding specimen collected may be directed 
to Drs. Roni Bollag or Asha Nayak-Kapoor.   
7.2.10 Laboratory Procedures/Assessments 
Details regarding specific laboratory procedures/assessments to be performed in this trial are 
provided below.  
   
 


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Table 6. Laboratory Safety Evaluations (Hematology, Chemistry and Urinalysis) 
Hematology 
Chemistry 
Urinalysis 
Other 
Hematocrit 
Albumin 
Blood 
Serum 
β-human 
chorionic 
gonadotropin† 
Hemoglobin 
Alkaline phosphatase 
Glucose 
  (β-hCG)† 
Platelet count 
Alanine 
aminotransferase 
(ALT) 
Protein 
PT (INR) 
WBC (total and differential) Aspartate 
aminotransferase 
(AST) 
Specific gravity  
aPTT 
Red Blood Cell Count 
Lactate dehydrogenase (LDH) 
Microscopic 
exam 
(If 
abnormal)  
Free Total triiodothyronine 
(FreeT3) 
Absolute Neutrophil Count 
Carbon Dioxide  
results are noted 
Free thyroxine (FreeT4) 
Absolute Lymphocyte Count   (CO2 or bicarbonate) 
Urine pregnancy test † 
Thyroid stimulating hormone (TSH) 
 
Uric Acid 
 
Hepatitis A, B, C antibody‡ 
 
Calcium 
 
HIV 1/2 antibody 
 
Chloride 
 
 
 
Glucose 
 
  
 
Phosphorus 
 
  
 
Potassium   
 
  
 
Sodium 
 
 Blood for correlative studies 
 
Magnesium 
 
  
 
Total Bilirubin 
 
  
 
Direct Bilirubin (If total 
bilirubin is elevated above the 
upper limit of normal) 
 
 
 
Total protein 
 
 
 
Blood Urea Nitrogen 
 
 
† Perform on women of childbearing potential only. If urine pregnancy results cannot be confirmed as negative, a serum pregnancy 
test will be required.   
‡ If any antibody test is reactive, follow up with PCR testing. 


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Laboratory tests for screening or entry into the Second Phase should be performed within 10 days 
prior to the first dose of treatment.  After Cycle 1, pre-dose laboratory procedures can be conducted 
up to 72 hours prior to dosing. Results must be reviewed by the investigator or qualified designee 
and found to be acceptable prior to each dose of trial treatment.  
7.2.11 Other Procedures 
Withdrawal/Discontinuation 
When a subject discontinues/withdraws prior to trial completion, all applicable activities 
scheduled for the final trial visit should be performed at the time of discontinuation.  Any 
adverse events which are present at the time of discontinuation/withdrawal should be followed 
in accordance with the safety requirements outlined in Section 7.3, Assessing and Recording 
Adverse Events.  Subjects who a) attain a CR or b) complete 12 months of treatment with 
pembrolizumab and poly-ICLC may discontinue treatment with the option of restarting 
treatment if they meet the criteria specified in Section 7.2.13, Second Course Phase 
(Retreatment Period).  After discontinuing treatment following assessment of CR, these 
subjects should return to the site for a Safety Follow-up Visit and then proceed to the Follow-
Up Period of the study. 
Blinding/Unblinding 
Not applicable. 
7.2.12 Visit Requirements 
Visit requirements for screening and the treatment periods are outlined in Section 6.0 - Trial Flow 
Chart.   Specific procedure-related details are provided above in Section 7.1 - Trial Procedures. 
Safety Follow-Up Visit 
The mandatory Safety Follow-Up Visit should be conducted approximately 30 days after the 
last dose of trial treatment or before the initiation of a new anti-cancer treatment, whichever 
comes first.  All AEs that occur prior to the Safety Follow-Up Visit should be recorded.  
Subjects with an AE of Grade > 1 will be followed until the resolution of the AE to Grade 0-1 
or until the beginning of a new anti-neoplastic therapy, whichever occurs first.  SAEs that occur 
within 90 days of the end of treatment or before initiation of a new anti-cancer treatment should 
also be followed and recorded.  Subjects who are eligible for retreatment with pembrolizumab 
(as described in Section 7.2.13, Second Course Phase (Retreatment Period) 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 6 weeks (42 ± 7 days) by radiologic 
imaging to monitor disease status.  After 1 year, the imaging time point will occur every 9 weeks 
(± 7 days). Every effort should be made to collect information regarding disease status until the 
start of new anti-neoplastic therapy, disease progression, death, end of the study or if the subject 
begins retreatment with pembrolizumab as detailed in Section 7.2.13, Second Course Phase 
(Retreatment Period). Information regarding post-study anti-neoplastic treatment will be 
collected if new treatment is initiated. 
 


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Subjects who are eligible to receive retreatment with pembrolizumab and poly-ICLC according 
to the criteria in Section 7.2.13, Second Course Phase (Retreatment Period) will move from the 
follow-up phase to the Second Course Phase when they experience disease progression.      
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.  
7.2.13 Second Course Phase (Retreatment Period) 
Subjects who stop the combination pembrolizumab and poly-ICLC treatment with SD or better 
may be eligible for up to one year of additional 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  
• Stopped initial treatment with study drugs 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 
• Had SD, PR or CR and stopped pembrolizumab treatment after 12 months of study therapy 
for reasons other than disease progression or intolerability 
• A subject who, after completing 17 cycles of study treatment and, at that time, has a 
radiologic disease status of CR, PR or SD may continue to receive study treatment without 
interruption for an additional year (up to a total of 35 cycles of study treatment). 
AND 
• Experienced an investigator-determined confirmed radiographic disease progression after 
stopping their initial treatment with pembrolizumab and poly-ICLC 
• Did not receive any anti-cancer treatment since the last dose of pembrolizumab and poly-
ICLC 
• Has a performance status of 0 or 1 on the ECOG Performance Scale 
• Demonstrates adequate organ function as detailed in Section 5.1.2 
• Female subject of childbearing potential should have a negative serum or urine pregnancy 
test within 72 hours prior to receiving retreatment with study medication.   
• Female subject of childbearing potential should be willing to use 2 methods of birth control 
or be surgically sterile, or abstain from heterosexual activity for the course of the study 
through 120 days after the last dose of study medication (Reference Section 5.9.2).  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.   


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• Does not have a history or current evidence of any condition, therapy, or laboratory 
abnormality that might interfere with the subject’s participation for the full duration of the 
trial or is not in the best interest of the subject to participate, in the opinion of the treating 
investigator. 
Subjects who are eligible to restart treatment will be retreated at the same dose levels of poly-ICLC 
(to be determined) and pembrolizumab (standard 200mg) that were initiated for their treatment.  
Additionally, subjects who have received study treatment with a radiologic response of CR, PR or 
SD may continue study treatment without interruption for an additional year (for up to 35 cycles of 
study treatment).  Visit requirements are outlined in Section 6.0 – Trial Flow Chart. 
7.3 
 Assessing and Recording Adverse Events 
An adverse event is defined as any untoward medical occurrence in a patient or clinical investigation 
subject administered a pharmaceutical product and which does not necessarily have to have a causal 
relationship with this treatment. An adverse event can therefore be any unfavorable and unintended 
sign (including an abnormal laboratory finding, for example), symptom, or disease temporally 
associated with the use of a medicinal product or protocol-specified procedure, whether or not 
considered related to the medicinal product or protocol-specified procedure.  Any worsening (i.e., 
any clinically significant adverse change in frequency and/or intensity) of a preexisting condition 
that is temporally associated with the use of the Merck’s product, is also an adverse event. 
 
Changes resulting from normal growth and development that do not vary significantly in frequency 
or severity from expected levels are not to be considered adverse events.  Examples of this may 
include, but are not limited to, teething, typical crying in infants and children and onset of menses 
or menopause occurring at a physiologically appropriate time.  Merck product includes any 
pharmaceutical product, biological product, device, diagnostic agent or protocol-specified 
procedure, whether investigational (including placebo or active comparator medication) or 
marketed, manufactured by, licensed by, provided by or distributed by Merck for human use. 
 
Adverse events may occur during the course of the use of Merck product in clinical trials, or as 
prescribed in clinical practice, from overdose (whether accidental or intentional), from abuse and 
from withdrawal. 
 
Progression of the cancer under study is not considered an adverse event.  
 
All adverse events that occur after the consent form is signed but before treatment allocation must 
be reported by the investigator if they cause the subject to be excluded from the trial, or are the result 
of a protocol-specified intervention, including but not limited to washout or discontinuation of usual 
therapy, diet, placebo treatment or a procedure. 
 
From the time of treatment allocation through 30 days following cessation of treatment, all adverse 
events must be reported by the investigator. Such events will be recorded at each examination on the 
Adverse Event case report forms/worksheets.  The reporting timeframe for adverse events meeting 
any serious criteria is described in section 7.3.3.1. The investigator will make every attempt to follow 
all subjects with non-serious adverse events for outcome. 
 


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Adverse events will not be collected for subjects during the pre-screening period (for determination 
of archival tissue status) as long as that subject has not undergone any protocol-specified procedure 
or intervention.  If the subject requires a blood draw, fresh tumor biopsy etc., the subject is first 
required to provide consent to the main study and AEs will be captured according to guidelines for 
standard AE reporting.  
 
7.3.1 Definition of an Overdose for This Protocol and Reporting of Overdose to the Sponsor 
and to Merck 
For purposes of this trial, an overdose of pembrolizumab will be defined as any dose of 1,000 mg 
or greater (≥5 times the indicated dose).  No specific information is available on the treatment of 
overdose of pembrolizumab. Appropriate supportive treatment should be provided if clinically 
indicated. In the event of overdose, the subject should be observed closely for signs of toxicity.  
Appropriate supportive treatment should be provided if clinically indicated. 
 
If an adverse event(s) is associated with (“results from”) the overdose of a Merck product, the 
adverse event(s) is reported as a serious adverse event, even if no other seriousness criteria are 
met. 
 
If a dose of Merck’s product meeting the protocol definition of overdose is taken without any 
associated clinical symptoms or abnormal laboratory results, the overdose is reported as a non-
serious Event of Clinical Interest (ECI), using the terminology “accidental or intentional overdose 
without adverse effect.” 
 
All reports of overdose with and without an adverse event must be reported within 24 hours 
to the Sponsor and within 2 working days hours to Merck Global Safety. (Attn: Worldwide 
Product Safety; FAX 215 993-1220) 
7.3.2  Reporting of Pregnancy and Lactation to the Sponsor and to Merck 
Although pregnancy and lactation are not considered adverse events, it is the responsibility of 
investigators or their designees to report any pregnancy or lactation in a subject (spontaneously 
reported to them) that occurs during the trial. 
 
Pregnancies and lactations that occur after the consent form is signed but before treatment 
allocation must be reported by the investigator if they cause the subject to be excluded from the 
trial, or are the result of a protocol-specified intervention, including but not limited to washout or 
discontinuation of usual therapy, diet, placebo treatment or a procedure.   
 
Pregnancies and lactations that occur from the time of treatment allocation through 120 days 
following cessation of Sponsor’s product, or 30 days following cessation of treatment if the subject 
initiates new anticancer therapy, whichever is earlier, must be reported by the investigator.  All 
reported pregnancies must be followed to the completion/termination of the pregnancy. Pregnancy 
outcomes of spontaneous abortion, missed abortion, benign hydatid form 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. 
 


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Such events must be reported within 24 hours to the Sponsor and within 2 working days to Merck 
Global Safety. (Attn: Worldwide Product Safety; FAX 215 993-1220) 
7.3.3  Immediate Reporting of Adverse Events to the Sponsor and to Merck 
7.3.3.1 Serious Adverse Events 
A serious adverse event is any adverse event occurring at any dose or during any use of Merck’s 
product that: 
• Results in death; 
• Is life threatening; 
• Results in persistent or significant disability/incapacity; 
• Results in or prolongs an existing inpatient hospitalization; 
• Is a congenital anomaly/birth defect; 
• Is another important medical event  
Note: In addition to the above criteria, adverse events meeting either of the below criteria, 
although not serious per ICH definition, are reportable to the Merck in the same timeframe as 
SAEs to meet certain local requirements. Therefore, these events are considered serious by 
Merck for collection purposes. 
● Is a new cancer (that is not a condition of the study); 
● Is associated with an overdose. 
Refer to Table 6 for additional details regarding each of the above criteria. 
 
For the time period beginning when the consent form is signed until treatment allocation, 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 (reference Section 7.3.3.3 for additional details 
that occurs to any subject must be reported within 24 hours to the Sponsor and within 2 working 
days to Merck Global Safety if it causes the subject to be excluded from the trial, or is the result 
of a protocol-specified intervention, including but not limited to washout or discontinuation of 
usual therapy, diet, placebo treatment or a procedure. 
 
For the time period beginning at treatment allocation through 90 days following cessation of 
treatment, or 30 days following cessation of treatment if the subject initiates new anticancer 
therapy, whichever is earlier, any 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 (reference 
Section 7.3.3.3 for additional details), whether or not related to the Merck product, must be 
reported within 24 hours to the Sponsor and within 2 working days to Merck Global Safety. 
 
Additionally, any serious adverse event, considered by an investigator who is a qualified 
physician to be related to Merck product that is brought to the attention of the investigator at any 
time following consent through the end of the specified safety follow-up period specified in the 
paragraph above, or at any time outside of the time period specified in the previous paragraph 
also must be reported immediately to the Sponsor and to Merck Global Safety. 
All subjects with serious adverse events must be followed up for outcome. 
 
SAE reports and any other relevant safety information are to be forwarded to the Merck 
Global Safety facsimile number:  +1-215-993-1220 


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A copy of all 15 Day Reports and Annual Progress Reports is submitted as required by FDA, 
European Union (EU), Pharmaceutical and Medical Devices agency (PMDA) or other local 
regulators. Investigators will cross-reference this submission according to local regulations to 
the Merck Investigational Compound Number (IND, CSA, etc.) at the time of submission.  
Additionally investigators will submit a copy of these reports to Merck & Co., Inc. (Attn: 
Worldwide Product Safety; FAX 215 993-1220) at the time of submission to FDA. 
7.3.3.2 Events of Clinical Interest 
Selected non-serious and serious adverse events are also known as Events of Clinical Interest 
(ECI) and must be reported within 24 hours to the Sponsor and within 2 working days to Merck 
Global Safety. (Attn: Worldwide Product Safety; FAX 215 993-1220). 
 
For the time period beginning when the consent form is signed until treatment allocation, any 
ECI, or follow up to an ECI, that occurs to any subject must be reported within 24 hours to the 
Sponsor and within 2 working days to Merck Global Safety if it causes the subject to be excluded 
from the trial, or is the result of a protocol-specified intervention, including but not limited to 
washout or discontinuation of usual therapy, diet, placebo treatment or a procedure. 
 
For the time period beginning at treatment allocation through 90 days following cessation of 
treatment, or 30 days following cessation of treatment if the subject initiates new anticancer 
therapy, whichever is earlier, any ECI, or follow up to an ECI, whether or not related to Merck 
product, must be reported within 24 hours to the Sponsor and within 24 hours to Merck Global 
Safety. 
 
Events of clinical interest for this trial include: 
1.  an overdose of Merck product, as defined in Section 7.3.1 - Definition of an Overdose for 
This Protocol and Reporting of Overdose to the Sponsor, that is not associated with clinical 
symptoms or abnormal laboratory results.  
2.  an elevated AST or ALT lab value that is greater than or equal to 3X the upper limit of 
normal and an elevated total bilirubin lab value that is greater than or equal to 2X the upper 
limit of normal and, at the same time, an alkaline phosphatase lab value that is less than 2X the 
upper limit of normal, as determined by way of protocol-specified laboratory testing or 
unscheduled laboratory testing.* 
*Note:  These criteria are based upon available regulatory guidance documents. The purpose 
of the criteria is to specify a threshold of abnormal hepatic tests that may require an additional 
evaluation for an underlying etiology.  
7.3.3.3 Protocol-Specific Exceptions to Serious Adverse Event Reporting  
Efficacy endpoints as outlined in this section will not be reported to Merck as described in 
Section 7.3.3, Immediate Reporting of Adverse Events to the Sponsor and to Merck, unless there 
is evidence suggesting a causal relationship between the drug and the event. Any such event will 
be submitted to the Sponsor within 24 hours and to Merck Global Safety within 2 working days 
either by electronic or paper media. 
 
Specifically, the suspected/actual events covered in this exception include any event that is 
disease progression of the cancer under study. 
 


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The Sponsor will monitor unblinded aggregated efficacy endpoint events and safety data to 
ensure the safety of the subjects in the trial. Any suspected endpoint which upon review is not 
progression of the cancer under study will be forwarded to Merck Global Safety as a SAE within 
2 working days of determination that the event is not progression of the cancer under study.  
Hospitalization related to convenience (e.g. transportation issues etc.) will not be considered a 
SAE. 
 
7.3.4 Evaluating Adverse Events 
An investigator who is a qualified physician will evaluate all adverse events according to the 
NCI Common Terminology for Adverse Events (CTCAE), version 4.03. Any adverse event 
which changes CTCAE grade over the course of a given episode will have each change of grade 
recorded on the adverse event case report forms/worksheets. All adverse events regardless of 
CTCAE grade must also be evaluated for seriousness. 


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Table 7. Evaluating Adverse Events 
An investigator who is a qualified physician, will evaluate all adverse events as to: 
V4.03 
CTCAE 
Grading 
Grade 1 
Mild; asymptomatic or mid symptoms; clinical or diagnostic observations only; intervention not 
indicated. 
Grade 2 
Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate 
instrumental ADL. 
 
Grade 3 
Severe or medically significant but not immediately life-threatening; hospitalization or 
prolongation or hospitalization indicated; disabling; limiting self-care ADL. 
 
Grade 4 
Life threatening consequences; urgent intervention indicated. 
 
Grade 5 
Death related to AE 
Seriousness 
A serious adverse event is any adverse event occurring at any dose or during any use of Merck product that: 
 
†Results in death; or 
 
†Is life threatening; or places the subject, in the view of the investigator, at immediate risk of death from the event 
as it occurred (Note: This does not include an adverse event that, had it occurred in a more severe form, might have 
caused death.); or 
 
†Results in a persistent or significant disability/incapacity (substantial disruption of one’s ability to conduct 
normal life functions); or 
 
†Results in or prolongs an existing inpatient hospitalization (hospitalization is defined as an inpatient 
admission, regardless of length of stay, even if the hospitalization is a precautionary measure for continued 
observation. (Note: Hospitalization for an elective procedure to treat a pre-existing condition that has not worsened 
is not a serious adverse event.  A pre-existing condition is a clinical condition that is diagnosed prior to the use of a 
Merck product and is documented in the patient’s medical history.); or 
 
†Is a congenital anomaly/birth defect (in offspring of subject taking the product regardless of time to 
diagnosis);or 
 
Is a new cancer (that is not a condition of the study) (although not serious per ICH definition, is reportable to the 
Sponsor within 24 hours and to Merck within 2 working days to meet certain local requirements); or 
 
Is an overdose (whether accidental or intentional).  Any adverse event associated with an overdose is considered a 
serious adverse event for collection purposes. An overdose that is not associated with an adverse event is 
considered a non-serious event of clinical interest and must be reported within 24 hours to the Sponsor and to 
Merck within 2 working days. 


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Other important medical events that may not result in death, not be life threatening, or not require hospitalization 
may be considered a serious adverse event when, based upon appropriate medical judgment, the event may 
jeopardize the subject and may require medical or surgical intervention to prevent one of the outcomes listed 
previously (designated above by a †). 
Duration 
Record the start and stop dates of the adverse event. If less than 1 day, indicate the appropriate length of time and 
units 
Action 
taken  
Did the adverse event cause Merck product to be discontinued? 
Relationship 
to 
Merck 
Product  
Did Merck product cause the adverse event? The determination of the likelihood that Merck product caused the 
adverse event will be provided by an investigator who is a qualified physician. The investigator’s signed/dated 
initials on the source document or worksheet that supports the causality noted on the AE form, ensures that a 
medically qualified assessment of causality was done. This initialed document must be retained for the required 
regulatory time frame. The criteria below are intended as reference guidelines to assist the investigator in assessing 
the likelihood of a relationship between the test drug and the adverse event based upon the available information. 
The following components are to be used to assess the relationship between Merck product and the AE; the 
greater the correlation with the components and their respective elements (in number and/or intensity), the more 
likely Merck product caused the adverse event (AE): 
 
Exposure 
Is there evidence that the subject was actually exposed to Merck product such as: reliable history, 
acceptable compliance assessment (pill count, diary, etc.), expected pharmacologic effect, or 
measurement of drug/metabolite in bodily specimen? 
 
Time 
Course 
Did the AE follow in a reasonable temporal sequence from administration of Merck product?  
Is the time of onset of the AE compatible with a drug-induced effect (applies to trials with 
investigational medicinal product)? 
 
Likely 
Cause 
Is the AE not reasonably explained by another etiology such as underlying disease, other 
drug(s)/vaccine(s), or other host or environmental factors 
 


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


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7.3.5 Sponsor Responsibility for Reporting Adverse Events 
All Adverse Events will be reported to regulatory authorities, IRB/IECs and investigators in 
accordance with all applicable global laws and regulations.  
 
STATISTICAL ANALYSIS PLAN 
8.1 
  Introduction 
This study has two parts: 
a. Phase I dose-escalation to determine the recommended phase II dose of Poly-ICLC to 
be combined with the standard dose of pembrolizumab. Patients with any solid tumor 
that is unresponsive to at least two lines of therapy is eligible for the dose escalation 
phase unless curative options exist.  
b. The combination will then be administered at the recommended phase II dose to in up 
to 27 patients with relapsed metastatic colon cancer.  MSI-high patients will be 
excluded. 
Descriptive statistics will be presented for primary and secondary endpoints. Summary 
statistics for continuous variables will include the mean, standard deviation, median, and 
range (minimum/maximum). Categorical variables will be presented as frequency counts and 
percentages; and time-to-event variables will be summarized by Kaplan-Meier medians and 
survival plots. Data listings will be created to support each table and to present all data. The 
data will be tabulated and analyzed with respect to patient enrollment and disposition, 
demographic and baseline characteristics, for primary efficacy and safety measures per study 
part (Phase I, II), and on a per dose level for phase I part. The primary efficacy analysis will 
be conducted on the efficacy evaluable population and safety analysis will be performed on 
the safety evaluable population. Maximum tolerated dose for of Poly-ICLC to be combined 
with pembrolizumab will be estimated based on the data from the 3+3 dose escalation. RP2D 
will then be determined based on the estimated MTD, which should not exceed 1/6 of RLT.  
SAS 9.3 software, or higher will be used for data analysis.   
8.2 
 Study Objectives 
8.2.1   Primary Objectives    
a. Phase 1: Determine the maximum tolerated dose of poly-ICLC that can be combined 
with pembrolizumab 
b. Phase II: Determine the response rate of metastatic MRP colon cancer that has 
progressed following two lines of therapy in the metastatic setting to the combination 
of pembrolizumab and poly-ICLC by RECIST 1.1. 
8.2.2   Secondary Objectives  
a. Phase I and II - Determine the adverse event profile and dose limiting toxicities of the 
combination of pembrolizumab and poly-ICLC 
b. Determine the progression free survival rate, overall survival rate and duration of 
response of recurrent metastatic MRP colon cancer to the combination of 
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8.2.3   Exploratory Objectives 
a. Evaluation of inflammatory state in tumor biopsies with specific attention to definition of 
tumor infiltration with hematopoietic cells, cell surface signaling molecule expression. 
b. Evaluation of pre-treatment and post-treatment microarray panels in tumor samples and 
peripheral blood.   
8.3 
Study Design/Endpoints 
Phase I: Classical 3+3 design will be employed and will include dose-escalation to 
determine the RP2D of Poly-ICLC to be combined with pembrolizumab. We will consider 
two dose levels, 1 and 2 mg of Poly-ICLC. 
Phase II: Primary endpoint is the response rate defined according to RECIST 1.1 criteria.  
irRECIST response will be assessed as an exploratory endpoint. 
8.4 
 Sample Size/Accrual Rate 
For part 1:  3 to 12 patients will be used for the dose escalation part. The actual number of 
patients will depend on the DLT and MTD. We are expecting 3 patients per month to be 
enrolled in the study.  
For Part 2:  With the assumption that the RR rate for pembrolizumab alone is about H0=5%, 
27 patients are needed to detect an increase in RR to H1=20% for the treatment 
combination to achieve 80% power and keep the probability of type I error (α) at 0.05. We 
are expecting accrual rate of 5 patients per month during the phase II portion of the study. 
8.5 
Analysis of Endpoints 
8.5.1 Analysis of Primary Endpoints 
a. A minimum of 3 patients will be treated depending on DLT.  Dose level 1 (1mg) will 
be administered to a cohort of 3 patients. If 0 out of 3 experience DLT, then dose 
escalation will proceed to the dose level 2 (2mg). If one out of three patients experience 
DLT, a cohort of additional three patients will be assigned to the same dose level (1mg). 
If two or more patients of three (or six) patients experience DLT at the first dose level, 
the trial, then enrollment of patients will be stopped. If a maximum one patient 
experience DLT at dose level 2, then the dose will be declared the RP2D. If 2 or more 
out of 6 patients experience DLT at the second dose level, then the first dose level 
(1mg) will be declared the RD2D. The RP2D should have at least 6 patients enrolled 
at the dose level with a maximum of 1 patient experiencing DLT. 
b. To assess preliminary evidence of antitumor activity, in terms of Objective Response 
Rate (ORR).  ORR will be calculated as the number of participants with complete 
response (CR) or partial response (PR) by RECIST criteria, divided by the total number 
of participant in the dataset. The ORR will be estimated for every estimated and the 
associated exact 95% CI will be provided. 
 
8.5.2 Analysis of Secondary Endpoints 
a. The adverse event profile will be presented by dose level of the combination treatment 
for the phase I portion. 
b. The progression free survival rate, overall survival rate and duration of response of 
recurrent metastatic MRP colon cancer to the combination of pembrolizumab and poly-
ICLC administered at RP2D will be estimated along with the correspondent 95% 


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confidence interval. In addition, the 20-week PFS rate along with its 95% CI will be 
estimated and presented. 
8.6 
Analysis Datasets 
Analysis will be conducted on the modified intent-to-treat set (mITT), which Includes all 
enrolled subjects treated with at least 1 dose (or partial dose) of the study medications. The 
mITT set will be used for all safety and preliminary efficacy analysis. 
8.7 
  Interim Analysis 
 
No interim analysis is applicable for the proposed study. 
 
LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL SUPPLIES 
Table 8. Product Descriptions  
Product Name & Potency 
Dosage Form 
Poly-ICLC 2mg/vial 
Suspension for injection (IM) 
Pembrolizumab 100 mg/ 4mL 
Solution for injection (IV) 
 
9.1 
Investigational Products  
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. 
 
The use of both pembrolizumab and poly-ICLC are considered investigational in this clinical 
trial, which is conducted under IND#129974, held by Dr. Asha Nayak-Kapoor. 
 
9.1.1 Pembrolizumab (MK-3475, Keytruda®) 
Pembrolizumab will be provided by Merck for use in this investigational setting. Pembrolizumab 
is provided as a white to off white lyophilized powder (50 mg/vial) or as a liquid solution (100 
mg/vial) in Type I glass vials intended for single use only. Pembrolizumab Powder for Solution 
for Infusion, 50 mg/vial, is reconstituted with sterile water for injection prior to use. The drug 
product is stored as a stable lyophilized powder or liquid solution under refrigerated conditions 
(2 to 8°C). 
 
The lyophilized drug product after reconstitution with sterile water for injection, and the liquid 
drug product are a clear to opalescent solutions, essentially free of visible particles. The 
reconstituted lyophilized product and the liquid product are intended for IV administration. The 
reconstituted drug product solution or the liquid drug product can be further diluted with normal 
saline or 5% dextrose in the concentration range of 1 to 10 mg/mL in intravenous (IV) containers 
made of polyvinyl chloride (PVC) or non-PVC material. Reconstituted vials should be 
immediately used to prepare the infusion solution in the IV bag and the infusion solution should 
be immediately administered. Diluted pembrolizumab solutions may be stored at room 
temperature for a cumulative time of up to 4 hours. This includes room temperature storage of 
admixture solutions in the IV bags and the duration of infusion. In addition, IV bags can be 
stored at 2 to 8°C for up to a cumulative time of 20 hours. This recommendation is based on up 
to 24 hours of room temperature and up to 24 hours of refrigerated stability data of diluted MK-


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3475 solutions in the IV bags.  For each individual trial, clinical supplies are to be stored in 
accordance with specific instructions on the label. 
9.1.2 POLY-ICLC (Hiltonol®) 
Poly-ICLC is classified as an investigational new drug.  It is a synthetic complex of polyinosinic 
and polycytidylic acid, stabilized with polylysine and carboxymethyl cellulose.  
 
How supplied 
Poly-ICLC is supplied by the manufacturer (Oncovir) in vials containing 1.8mg/mL opalescent 
solution. Drug supply for “at home” study drug administrations will follow local investigational 
pharmacy procedures.  
Each vial poly-ICLC supplied by the manufacturer will be labeled with the following 
information: 
Drug Name 
Concentration 
Storage Conditions 
Lot Number 
Date of Manufacture, Manufacturer 
Investigational Use Statement 
 
Storage and stability 
Poly-ICLC is stable at room temperature for at least 4 weeks.  Treatment sites are asked to store 
the drug at approximately 2-8 °C.  Study subjects will have Poly-ICLC administered at home, 
and will be advised to store their doses in a standard refrigerator.  The vials should not be frozen.  
 
Supplier 
The drug to be used in this study is prepared and packaged using GMP conditions, under contract 
to Oncovir, Inc.  It is then tested for quality, activity, sterility and pyrogenicity before release to 
the site pharmacy for clinical use. 
 
Drug ordering information 
Order Poly-ICLC supplies by contacting: 
 
 
 
Andres M. Salazar, MD 
 
 
CEO & CSO, Oncovir, Inc  
 
 
 
529 Jefferson Street 
Winchester, VA 22601 
asalazar@oncovir.com 
 
9.2 
Packaging and Labeling Information 
Clinical supplies will be affixed with a clinical label in accordance with regulatory requirements. 
9.3 
Clinical Supplies Disclosure 
This trial is open-label; therefore, the subject, the trial site personnel, the Sponsor and/or 
designee are not blinded to treatment. Drug identity (name, strength) is included in the label text; 
random code/disclosure envelopes or lists are not provided. 


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9.4 
Storage and Handling Requirements 
Clinical supplies must be stored in a secure, limited-access location under the storage conditions 
specified on the label.   
Receipt and dispensing of trial medication must be recorded by an authorized person at the trial 
site. 
Clinical supplies may not be used for any purpose other than that stated in the protocol. 
9.5 
Returns and Reconciliation 
The investigator is responsible for keeping accurate records of the clinical supplies received from 
Merck or designee, the amount dispensed to and returned by the subjects and the amount 
remaining at the conclusion of the trial.  
 
Upon completion or termination of the study, all unused and/or partially used pembrolizumab 
will be destroyed at the site per institutional policy. All unused and/or partially used poly-ICLC 
will be returned to Oncovir for destruction. 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. 
 ADMINISTRATIVE AND REGULATORY DETAILS 
10.1 Confidentiality 
Only the investigator, the members of the research team, the sponsor, authorized officials from 
state and federal governments such as the Food and Drug Administration (FDA) or the Office of 
Human Research Protections (OHRP), and authorized representatives of the Western 
Institutional Review Board (WIRB) and Augusta University will have access to confidential data 
which would identify participants, unless specifically required to be disclosed by state or federal 
law.  Because of the need to release information to these parties, absolute confidentiality cannot 
be guaranteed. The results of this study may be presented at meetings or in publications. 
However, participants will not be identified in any reports or publications resulting from the 
study.  All reasonable steps will be taken to ensure confidentiality. 
10.2 Compliance with Financial Disclosure Requirements 
Investigators participating in the study will comply with federal and Augusta University financial 
disclosure requirements. 
10.3 Compliance with Law, Audit and Debarment 
Investigators will comply with federal and state laws.  This study will be audited by the Georgia 
Cancer Center’s auditing team. Investigators who have been debarred from clinical trial 
participation by the FDA may not participate in this trial.   
10.4 Compliance with Trial Registration and Results Posting Requirements 
Under the terms of the Food and Drug Administration Modernization Act (FDAMA) and the 
Food and Drug Administration Amendments Act (FDAAA), the Sponsor of the trial is solely 
responsible for determining whether the trial and its results are subject to the requirements for 
submission to the Clinical Trials Data Bank, http://www.clinicaltrials.gov.  Information posted 
will allow subjects to identify potentially appropriate trials for their disease conditions and 
pursue participation by calling a central contact number for further information on appropriate 
trial locations and trial site contact information.     


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10.5 Quality Management System 
10.6 Data Management 
The DM (Data Monitor) Console is OnCore’s data management tool and is the validation and 
management workspace for online forms in OnCore. 
 
Electronic case report forms (eCRFs) are created in the eCRFs Console, and attached to specific 
protocol calendar visits for completion by the coordinator. 
10.6.1 Data Entry 
Recording and handling data 
In OnCore, when a subject visit as occurred, forms that need to be completed are listed on 
the Forms by Status > To Do Forms tab.  Data is recorded specific to each form/visit.  By 
opening the form, it becomes “Active,” and the coordinator can continue to work on the 
form until the “Complete” button is selected.  In declaring a form as complete, coordinators 
are in effect stating that the form is completely filled-out and is ready for a data monitor 
(DM) to validate the data. 
 
Subject documents (questionnaires, diaries) 
Subject documents, such as questionnaires and diaries, completed by the subject on paper, 
is then manually transcribed and entered into OnCore by the research staff. 
10.6.2 Query Management 
In the DM Console, forms are categorized by the following statuses: 
 
To Do 
Assigned to forms for a subject visit marked as Occurred. This status will remain until form 
data entry begins.  
 
Started 
Assigned to a form when the data entry process is started. This status is set the first time 
the form is accessed.  
 
Completed 
Assigned when the form is declared as Completed.  
 
Queried 
Assigned when the Data Monitor adds a note questioning the form data. The CRA is 
expected to respond.  
 
Amended 
Assigned when the CRA responds to a Queried form. The response is sent to the Data 
Monitor.  
 
Missed 
Assigned to a form that has been marked as Missed or occurs on a visit or procedure that 
was marked as Missed.  
 


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Additional 
Assigned to an additional form instance created for a subject’s visit.  
 
Validated 
Assigned when a Data Monitor declares the form data is valid. Validated forms are not 
editable.  
 
Locked 
Assigned when a Data Monitor locks the form, declaring the form data as unchangeable. 
A special security privilege is required to undo this status.  
 
N/A 
Assigned to a form that has been marked as Not Applicable or occurs on a visit or procedure 
that was marked as Not Applicable. 
10.6.3 Study Data Flow 
 
Validation 
As online forms are declared as Completed, the data monitor validates the data and either 
raise a query or locks the form. If the data is accurate and the monitor has no questions, the 
form can be validated by clicking the Validate button (shown for Completed and Amended 
forms) in the DM Console. After all queries have been resolved, the form can be Locked. 
 
 
Queries 
Raising a query sends the form and a question back to the person who entered the data 
within OnCore.   A queried form can be amended and then validated and locked. The 
process of querying and amending a form may have multiple iterations. 
 
 
Database lock 
In OnCore, individual validated forms are locked, preventing further edits.  After all forms 
are validated, the database is essentially locked. 
10.7 Data Export & Reporting 
 
Data export formats 
OnCore’s Biostat Console is used to extract data from OnCore for use in statistical analysis 
tools.  The subject’s full name is never included in the export. The Biostat Console can 
also be used to view the current progress of protocols related to accruals, forms, and 
adverse events.  From the Data Export page, selected data can be exported into Excel 
spreadsheets or files formatted for easier import into SAS. 
 
 
 


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 APPENDICES 
11.1 ECOG Performance Status 
Grade 
Description 
0 
Normal activity. Fully active, able to carry on all pre-disease performance 
without restriction. 
1 
Symptoms, but ambulatory. Restricted in physically strenuous activity, but 
ambulatory and able to carry out work of a light or sedentary nature (e.g., light 
housework, office work). 
2 
In bed <50% of the time. Ambulatory and capable of all self-care, but unable 
to carry out any work activities. Up and about more than 50% of waking hours. 
3 
In bed >50% of the time. Capable of only limited self-care, confined to bed or 
chair more than 50% of waking hours. 
4 
100% bedridden. Completely disabled. Cannot carry on any self-care. Totally 
confined to bed or chair. 
5 
Dead. 
* As published in Am. J. Clin. Oncol.:  Oken, M.M., Creech, R.H., Tormey, D.C., Horton, 
J., Davis, T.E., McFadden, E.T., Carbone, P.P.: Toxicity And Response Criteria Of The 
Eastern Cooperative Oncology Group. Am J Clin Oncol 5:649-655, 1982. The Eastern 
Cooperative Oncology Group, Robert Comis M.D., Group Chair. 
 
11.2 Common Terminology Criteria for Adverse Events V4.03 (CTCAE) 
The descriptions and grading scales found in the revised NCI Common Terminology Criteria for 
Adverse Events (CTCAE) version 4.03 will be utilized for adverse event reporting. 
(http://ctep.cancer.gov/reporting/ctc.html) 
 
11.3 Immune Related Response Criteria (irRC) with Response Evaluation Criteria in 
Solid Tumors (RECIST) 1.1  
Responses will be evaluated in all subjects.  Because of direct clinical observations of immune 
cell influx into tumor causing enlargement in some patients prior to sustained response, recently 
it has been suggested that clinical trials involving the use of immunotherapy use alternative 
guidelines, called immune related response criteria (irRC) to determine radiographic response or 
progression after therapy.  The criteria for evaluation of response are those defined in Wolchok 
JD, Hoos A, O’Day S, et al. Guidelines for the evaluation of immune therapy activity in solid 
tumors: Immune-related response criteria. Clin Cancer Res 2009; 15:7412-7420.   
 
These recommendations have been used in recent clinical trials.  One study of 227 subjects with 
metastatic melanoma showed that the approximately 10% of patients who had PD by modified 
WHO criteria but either CR, PR or SD by irRC had a similar overall survival as those patients 
who had SD, PR or CR by both criteria. The irRC was created using bidimensional measurements 
(as previously widely used in the WHO criteria).  We have taken the concepts of the irRC and 
combined them with the recently revised RECIST 1.1 to come up with the modified irRC used 
in this protocol.  Consistent with the irRC, the main changes from RECIST 1.1 are (a) a 
requirement for confirmation of both progression and response by imagining at least 4 weeks 


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after initial imaging and (b) not automatically calling the appearance of new lesions progressive 
disease if the total measurable tumor burden has not met criteria for progressive disease.   
 
For immune-related response criteria (irRC), only index and measurable new lesions are taken 
into account.  At baseline tumor assessment on this trial, target lesions will be measured along 
the longest axis and the measurements will be summed, called sum of largest diameter 
(SLD).  These lesions must be a minimum of 10mm per lesion, maximum of 5 target lesions, 
maximum of 2 per organ system.  At each subsequent tumor assessment, the unidimensional 
measurement of target lesions and of new measureable lesions are added together to provide the 
total tumor burden:  As per the modified definitions below, all responses and progression except 
stable disease (SD) required confirmation on a consecutive scan at least 4 weeks from the initial 
observation).  
 
Definitions of irRC: 
Response 
irRC 
New measurable 
lesions  
Incorporated into tumor burden 
New non-measurable 
lesions  
Do not define progression (but precludes irCR) 
Non-index lesions 
Contributes to defining irCR (complete disappearance required) 
Overall irCR 
100% disappearance of all lesions, whether measurable or not, and no 
new lesions, in two consecutive observations not less than 4 wks 
from the date first documented.  All measurable lymph nodes also 
must have reduction in short axis to <10mm. 
Overall irPR 
≥ 30% decrease in SLD compared with baseline confirmed by a 
consecutive assessment at least 4 wk after first documentation 
Overall irSD 
Not meeting criteria for irCR or irPR, in absence of irPD:  30% 
decrease in SLD compared with baseline cannot be established nor 
20% increase compared with nadir. 
Overall irPD 
At least 20% increase in SLD compared with nadir (minimum 
recorded tumor burden) and an increase of at least 5mm over the 
nadir, confirmed by a repeat, consecutive observation at least 4 wk 
from the date first documented. 
 
 
 
 
 
 
 
 
 
 
 
 


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Overall responses derived from changes in index, non-index and new lesions as demonstrated in 
the following table: 
Measurable response 
Non-measurable response 
Overall response 
using irRC 
Index and new, 
measurable lesions 
(tumor burden)* % 
Non-index 
lesions 
New, non-
measurable lesions  
Decrease 100% 
Absent 
Absent 
irCR& 
Decrease 100% 
Stable 
Any 
irPR& 
Decrease 100% 
Unequivocal 
progression 
Any 
irPR& 
Decrease ≥ 30% 
Absent / Stable 
Any 
irPR& 
Decrease ≥ 30% 
Unequivocal 
progression 
Any 
irPR& 
Decrease < 30% to 
increase < 20% 
Absent / Stable 
Any 
irSD 
Decrease < 30% to 
increase < 20% 
Unequivocal 
progression 
Any 
irSD 
Decrease ≥ 20% 
Any 
Any 
irPD 
* Decreases assessed relative to baseline 
& Assuming response (irCR) and progression (irPD) are confirmed by a second, 
consecutive assessment at least 4 weeks apart.


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11.4 Guidelines for Evaluation of Objective Tumor Response Using RECIST 1.1 Criteria  
RECIST 1.1 TABLE OF CONTENTS 
 
 
 
 
 
 
 
         
1. 
INTRODUCTION .....................................................................................................  
2. 
DEFINITION OF MEASURABLE, NON-MEASURABLE, TARGET 
AND NON-TARGET LESIONS .................................................................................. 
3. 
METHODS OF ASSESSMENT ...............................................................................  
3.1 
CT and MRI ..............................................................................................................  
3.2 
Clinical examination .................................................................................................  
3.3 
X-ray ..........................................................................................................................  
3.3.1 
Plain X-ray ................................................................................................................  
3.4 
Ultrasound .................................................................................................................  
3.5 
Endoscopy and laparoscopy ......................................................................................  
3.6 
Tumor markers ..........................................................................................................  
3.7 
Cytology and histology .............................................................................................  
3.8 
Isotopic bone scan .....................................................................................................  
3.9 
FDG-PET scan ..........................................................................................................  
4. 
TUMOR RESPONSE EVALUATION .....................................................................  
4.1 
Schedule of evaluation ...............................................................................................  
4.2 
Target lesions .............................................................................................................  
4.2.1 
Documentation of target lesions ................................................................................  
4.2.2 
Evaluation of target lesions .......................................................................................  
4.3 
Non-target lesions ......................................................................................................  
4.3.1 
Evaluation of non-target lesions ................................................................................  
4.4 
New lesions ...............................................................................................................  
4.5 
Symptomatic deterioration ........................................................................................  
4.6 
Evaluation of overall visit response ..........................................................................  
5. 
CONFIRMATION OF PROGRESSION ..................................................................  
6. 
REFERENCES ..........................................................................................................  
LIST OF TABLES 
Table 1 
Summary of methods of assessment ........................................................... 
Table 2 
Evaluation of target lesions ...................................................................... 
Table 3 
Evaluation of non-target lesions ............................................................... 
Table 4 
Overall visit response ................................................................................ 


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1. INTRODUCTION 
This appendix details the implementation of Response Evaluation Criteria in Solid Tumors 
(RECIST) 1.1 guidelines (Eisenhauer et al 2009) for the CC-16047 study with regards to 
Investigator assessment of tumor burden including protocol-specific requirements for this 
study. 
2. DEFINITION OF MEASURABLE, NON-MEASURABLE, TARGET AND NON-
TARGET LESIONS 
Only patients with measurable disease at baseline should be included in the study. 
Measurable disease is defined by the presence of at least 1 measurable (by RECIST 1.1) 
lesion which has not been previously irradiated.  A tumor lesion in a previously irradiated 
field can be assessed as measurable disease provided the lesion has been deemed to 
demonstrate progression. 
Measurable: 
A lesion, not previously irradiated per the protocol prior to enrollment, that can be 
accurately measured at baseline as ≥10 mm in the longest diameter (except lymph nodes 
which must have short axis ≥15 mm) with computed tomography (CT) or magnetic 
resonance imaging (MRI) and that is suitable for accurate repeated measurements.  A tumor 
lesion in a previously irradiated field can be assessed as measurable disease provided the 
lesion has been deemed to demonstrate progression. 
Non-measurable: 
o All other lesions, including small lesions (longest diameter <10 mm or pathological 
lymph nodes with ≥10 mm to <15 mm short axis at baseline.   
o Truly non-measurable lesions include the following: bone lesions, leptomeningeal 
disease, ascites, pleural/pericardial effusion, inflammatory breast disease, 
lymphangitic involvement of skin or lung, or abdominal masses/abdominal 
organomegaly identified by physical examination that is not measurable by CT or 
MRI. 
o Lesions <2 cm biopsied within the screening period (newly acquired tumor biopsy) 
o Previously irradiated lesions that have not demonstrated progression12 
o Brain metastasis 
 
Special cases: 
o Lytic bone lesions or mixed lytic–blastic lesions, with identifiable soft tissue 
components, can be considered measurable if the soft tissue component meets the 
definition of measurability.  Blastic lesions are considered non-measurable. 
o Cystic metastases can be considered measurable lesions if they meet the criteria for 
measurability from a radiological point of view, but if non-cystic lesions are present in 
the same patient, these should be selected as target lesions (TLs).  
Target lesions: 
A maximum of 5 measurable lesions (with a maximum of 2 lesions per organ), 
representative of all lesions involved suitable for accurate repeated measurement, should be 
identified as TLs at baseline. 
Non-target lesions: 


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All other lesions (or sites of disease) not recorded as TL should be identified as NTL at 
baseline.  
1. METHODS OF ASSESSMENT   
The same method of assessment and the same technique should be used to characterize each 
identified and recorded lesion at baseline and during follow-up visits.  A summary of the 
methods to be used for RECIST assessment is provided in Table 1, and those excluded from 
tumor assessments for this study are highlighted with the rationale provided. 
Table 1 
Summary of methods of assessment 
 
 
Target lesions 
Non-target lesions 
New lesions 
CT (preferred) 
CT (preferred) 
CT (preferred) 
MRI 
MRI 
MRI 
 
Clinical examination 
Clinical examination 
 
X-ray, Chest X-ray 
X-ray, Chest X-ray 
 
 
Ultrasound 
 
 
Bone scan 
 
 
FDG-PET 
CT: Computed tomography; FDG-PET: 18-Fluoro-deoxyglucose positron 
emission tomography; MRI: Magnetic resonance imaging. 
 
3.1 CT and MRI 
CT and MRI are generally considered to be the best currently available and reproducible 
methods to measure TL selected for response assessment and to assess NTL and 
identification of any new lesions. 
 
In the CC-16047 study, the methods of assessment of tumor burden used at baseline and 
follow-up visits are contrast-enhanced CT/MRI of the neck, chest, and abdomen (including 
liver and adrenal glands).  Any other areas of disease involvement should be additionally 
imaged based on the signs and symptoms of individual patients.  CT examination with 
intravenous contrast media administration is the preferred method. MRI should be used 
where CT is not feasible or it is medically contra-indicated.  For brain lesion assessment, 
MRI is the preferred method. 
 
3.2 Clinical examination 
In the CC-16047 study, clinical examination will not be used for assessment of TL. 
Clinically detected lesions can be selected as TLs if they are assessed by CT or MRI 
scans. Clinical examination can be used to assess NTL and to identify the presence of 
new lesions. 
 
 
3.3 X-ray 
In the CC-16047 study plain X-ray may be used as a method of assessment for bone NTL and 
to identify the presence of new bone lesions. 
 
 


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3.4 Ultrasound 
In the CC-16047 study, ultrasound examination will not be used for assessment of TL and NTL 
as it is not a reproducible method, does not provide an accurate assessment of tumor size and it 
is subjective and operator dependent. Ultrasound examination can, however, be used to identify 
the presence of new lesions.  If new clinical symptoms occur and an ultrasound is performed 
then new lesions should be confirmed by CT or MRI examination. 
 
3.5 Endoscopy and laparoscopy 
In the CC-16047 study, endoscopy and laparoscopy will not be used for tumor assessments as 
they are not validated in the context of tumor assessment. 
 
3.6 Tumor markers 
In the CC-16047 study, tumor markers will not be used for tumor response assessments as per 
RECIST 1.1. 
 
3.7 Cytology and histology 
In the CC-16047 study histology will not be used as part of the tumor response assessment as 
per RECIST 1.1. 
 
3.8 Isotopic bone scan 
Bone lesions identified on an isotopic bone scan at baseline and confirmed by CT, MRI, or 
X-ray at baseline should be recorded as NTL and followed by the same method as per baseline 
assessment. 
 
In the CC-16047 study, isotopic bone scans may be used as a method of assessment to identify 
the presence of new bone lesions at follow-up visits.  New lesions will be recorded where a 
positive hot-spot that was not present on the baseline bone scan assessment is identified on a 
bone scan performed at any time during the study. The Investigator should consider the positive 
hot-spot to be a significant new site of malignant disease and represent true disease progression 
in order to record the new lesion.  Confirmation by CT, MRI and X-ray is recommended where 
bone scan findings are equivocal. 
 
3.9 FDG-PET scan 
In the CC-16047 study, 18-Fluoro-deoxyglucose positron emission tomography (FDG-PET) scans 
may be used as a method for identifying new lesions, according with the following algorithm:  
New lesions will be recorded where there is positive 18-Fluoro-deoxyglucose uptake3 not present 
on baseline FDG-PET scan or in a location corresponding to a new lesion on CT/MRI at the same 
follow-up visit.  If there is no baseline FDG-PET scan available, and no evidence of new lesions 
on CT/MRI scans then follow-up CT/MRI assessments should be continued, scheduled as per 
protocol or clinical indicated, in order to confirm new lesions. 
 
 
 
3 A positive FDG-PET scan lesion should be reported only when an uptake greater than twice 
that of the surrounding tissue is observed. 
 


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2. TUMOR RESPONSE EVALUATION 
4.1 Schedule of evaluation 
RECIST assessments will be performed using contrast-enhanced CT/MRI assessments of 
chest, abdomen, and pelvis.  Additional anatomy should be imaged based on signs and 
symptoms of individual patients at baseline and follow-up.  Baseline assessments should be 
performed no more than 28 days before start of study treatment, and ideally should be 
performed as close as possible to the start of study treatment.  The first on-study scan should 
be performed after Cycle 3, before beginning Cycle 4 treatment.  Subsequent scans should 
be performed every 3 cycles (approximately every 9 weeks) thereafter until confirmed 
objective disease progression as defined by RECIST 1.1 (irrespective of the reason for 
stopping treatment or subsequent therapy).  The same method should be used for tumor 
measurement throughout therapy. After discontinuation of therapy scans will be performed 
every 12 weeks.  
 
Additional assessments will be performed post confirmed objective disease progression for 
patients remaining on assigned treatment, re-treatment, or until subsequent cancer therapy 
according to the clinical study protocol.  Any other sites at which new disease is suspected 
should also be adequately imaged at follow-up. 
 
If an unscheduled assessment was performed and the patient has not progressed, every attempt 
should be made to perform the subsequent assessments at their scheduled visits.  This schedule 
is to be followed in order to minimize any unintentional bias caused by some patients being 
assessed at a different frequency than other patients. 
4.2 Target lesions 
4.2.1 Documentation of target lesions 
A maximum of 5 measurable lesions, with a maximum of 2 lesions per organ (including lymph 
nodes), representative of all lesions involved should be identified as TL at baseline. Target 
lesions should be selected on the basis of their size (longest diameter for non-nodal lesions or 
short axis for nodal lesions), 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. 
 
The site and location of each TL should be documented as well as the longest diameter for 
non-nodal lesions (or short axis for lymph nodes).  All measurements should be recorded in 
millimeters.  At baseline the sum of the diameters for all TL will be calculated and reported as 
the baseline sum of diameters.  At follow-up visits the sum of diameters for all TL will be 
calculated and reported as the follow-up sum of diameters.  
 
Special cases: 
• For TL measurable in 2 or 3 dimensions, always report the longest diameter.  For 
pathological lymph nodes measurable in 2 or 3 dimensions, always report the short axis. 
• If the CT/MRI slice thickness used is >5 mm, the minimum size of measurable disease at 
baseline should be twice the slice thickness of the baseline scan. 
• If a lesion has completely disappeared, the longest diameter should be recorded as 0 mm. 


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• If a TL splits into two or more parts, then record the sum of the diameters of those parts. 
• If two or more TLs merge then the sum of the diameters of the combined lesion should be 
recorded for one of the lesions and 0 mm recorded for the other lesion(s). 
• If a TL is believed to be present and is faintly seen but too small to measure, a default value 
of 5 mm should be assigned.  If an accurate measure can be given, this should be recorded, 
even if it is below 5 mm. 
• If a TL cannot be measured accurately due to it being too large, provide an estimate of the 
size of the lesion.  Although a visit response of PD will be assigned in the vast majority of 
these cases, a case should be flagged and reviewed by the Study Physician in a blinded 
fashion if use of the estimated size in the calculation of TL would not give an overall visit 
response of PD. 
• When a TL has had any intervention eg, radiotherapy, embolization, surgery, during the 
study, the size of the TL should still be provided where possible. 
 
4.2.2 Evaluation of target lesions 
This section provides the definitions of the criteria used to determine objective tumor visit 
response for TL (see Table 2). 
 
Table 2 
 
 
 
Evaluation of target lesions 
 
Complete Response (CR) 
Disappearance of all TLs since baseline. Any pathological 
lymph 
nodes selected as TLs must have a reduction in short axis to <10 
mm. 
 
Partial Response (PR) 
At least a 30% decrease in the sum of the diameters of TLs, 
taking 
as reference the baseline sum of diameters. 
 
Stable Disease (SD) 
Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for 
PD. 
 
Progression of disease (PD) 
At least a 20% increase in the sum of diameters of TLs and an 
absolute increase of at least 5 mm, taking as reference the 
smallest sum on study (this includes the baseline sum if that 
is the smallest on study). 
 
Not Evaluable (NE) 
Only relevant if any of the TLs were not assessed or not 
evaluable 
or had a lesion intervention at this visit. Note: if the sum 
of diameters meets the progressive disease criteria, 
progressive disease overrides not evaluable as a TL 
response. 
 
 
CR Complete response; PR Partial response; PD Progression of disease; NE Not evaluable; 
SD Stable disease; TL Target lesion. 
 


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4.3 Non-target lesions 
4.3.1 Evaluation of non-target lesions 
All other lesions (or sites of disease) not recorded as TL should be identified as NTL at 
baseline.  Measurements are not required for these lesions, but their status should be followed 
at subsequent visits.  At each visit an overall assessment of the NTL response should be 
recorded by the Investigator.  This section provides the definitions of the criteria used to 
determine and record overall response for NTL at the investigational site at each visit (see Table 
3). 
Table 3 
Evaluation of non-target lesions 
 
Complete response (CR) 
Disappearance of all NTLs since baseline. All lymph nodes 
must 
be non-pathological in size (<10 mm short axis). 
 
Non CR/Non PD 
Persistence of one or more NTL with no evidence of 
progression. 
 
Progression (PD) 
Unequivocal progression of existing NTLs. Unequivocal 
progression may be due to an important progression in one 
lesion only or in several lesions.  In all cases the progression 
MUST be clinically significant for the physician to consider 
changing (or stopping) therapy. 
 
Not evaluable (NE) 
Only relevant when one or some of the NTLs were not assessed 
and, in the Investigator’s opinion, they are not able to provide 
an evaluable overall NTL assessment at this visit. 
Note: for patients without TLs at baseline, this is relevant if 
any of the NTLs were not assessed at this visit and the 
progression criteria have not been met. 
 
 
CR Complete response; PR Partial response; PD Progression of disease; NE Not evaluable; 
NTL Non-target lesion; TL Target lesion. 
 
To achieve “unequivocal progression” on the basis of NTLs, there must be an overall level of 
substantial worsening in non-target disease such that, even in presence of stable disease or 
partial response in TLs, the overall tumor burden has increased sufficiently to merit 
discontinuation of therapy.  A modest “increase” in the size of 1 or more NTLs is usually not 
sufficient to qualify for unequivocal progression status. 
 
4.4 New lesions 
Details of any new lesions will also be recorded with the date of assessment. The presence of 
one or more new lesions is assessed as progression. 
 
A lesion identified at a follow up assessment in an anatomical location that was not scanned 
at baseline is considered a new lesion and will indicate disease progression. 


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The finding of a new lesion should be unequivocal: ie, not attributable to differences in 
scanning technique, change in imaging modality, or findings thought to represent something 
other than tumor. 
 
If a new lesion is equivocal, for example because of its small size, the treatment and tumor 
assessments should be continued until the new lesion has been confirmed.  If repeat scans 
confirm there is a new lesion, then the progression date should be declared using the date of 
the initial scan. 
 
4.5 Symptomatic deterioration 
Symptomatic deterioration is not a descriptor of an objective response: it is a reason for 
stopping study therapy. 
 
Patients with “symptomatic deterioration” requiring discontinuation of treatment without 
objective evidence of disease progression at that time should continue to undergo tumor 
assessments where possible until objective disease progression is observed. 
 
4.6 Evaluation of overall visit response 
The overall visit response will be derived using the algorithm shown in Table 4. 
 
Table 4 
Overall visit response 
Target lesions 
Non-target lesions 
New lesions 
Overall response 
CR 
CR 
No or NE 
CR 
CR 
NA 
No or NE 
CR 
CR 
Non CR/Non PD 
No or NE 
PR 
CR 
NE 
No or NE 
PR 
PR 
Non PD or NE or NA 
No or NE 
PR 
SD 
Non PD or NE or NA 
No or NE 
SD 
NE 
Non PD or NE or NA 
No or NE 
NE 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
CR Complete response, PR Partial response, SD Stable disease, PD Progression of disease, NE 
Not evaluable, 
NA Not applicable (only relevant if there were no non-target lesions at baseline). 
 
 


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3. CONFIRMATION OF PROGRESSION 
In the CC-16047 study, imaging for confirmation of response (complete response or partial 
response) should be performed at next scheduled visit (and no less than 4 weeks) following the 
date the criteria for response were first met. 
 
Disease progression in this immunomodulatory therapy requires confirmation. The confirmatory 
scan should occur preferably at the next scheduled visit and no earlier than 4 weeks after the initial 
assessment of progression of disease (PD) in the absence of clinical deterioration.   
 
Progression would be considered confirmed if the following criteria are met: 
 
• 
≥20% increase in the sum diameters of TLs compared with the nadir at 2 
consecutive visits with an absolute increase of 5mm (3) 
 
• 
And/or significant progression (worsening) of NTLs or new lesions at the 
confirmatory PD time-point compared with the first time point where 
progression of NTLs or new lesions identified 
 
• 
And/or additional new unequivocal lesions at the confirmatory PD time-
point compared with the first time point new lesions identified 
 
(3) The assessment of progression requires a ≥20% increase in the sum diameters of target 
lesions at the first progression timepoint relative to the nadir.  The nadir is the smallest sum of 
diameters, and this may be at baseline or subsequent follow-up assessments.  The confirmatory 
scan confirms the persistence of the ≥20% increase relative to the nadir. The minimum absolute 
increase in the sum of diameters of target lesions is at least 5 mm at both assessments. 
 
In the absence of significant clinical deterioration the Investigator should continue assigned 
treatment until progression is confirmed.  If progression is not confirmed, then the patient should 
continue on assigned treatment and on treatment assessments. 
 
If a patient discontinues treatment (and/or receives a subsequent cancer therapy) prior to 
progression, then the patient should still continue to be followed until confirmed objective disease 
progression. 
 
4. RECIST GUIDELINE REFERENCES 
Eisenhauer et al 2009 
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al.  New response evaluation 
criteria in solid tumors: revised RECIST guideline (version 1.1).  Eur J Cancer 2009;45(2):228-47. 
 
Nishino et al 2013 
Nishino M Giobbie-Hurder A, Gargano M, Suda M, Ramaiya NH, Hodi FS. Developing a common 
language for tumor response to immunotherapy: Immune-related response criteria using unidimensional 
measurements. Clin Cancer Res, 2013;19(14):3936-43. 
 


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11.5 Lab Specimens Summary 
Sample Type 
Collection Tube 
Screen
ing 
 
Collection 
Cycle(s) 
 
D1 
 
Amount 
of Blood 
(approx.) 
Teaspoon 
Equivalent 
Blood 
Hematology 
Lavender top (EDTA) 
X 
All cycles 
(Q3W) 
X 
5 mL 
1 tsp per 
draw 
Chemistry 
light green top tube 
(lithium heparin) 
X 
All Cycles 
(Q3W) 
X 
5 mL 
1 tsp per 
draw 
Other:  
b-HCG,TSH, 
PT/PTT, etc 
light green top tube 
(lithium heparin) or as 
indicated by Path 
manual¹ 
X 
Only Screening 
or as needed 
 
 
 
Correlative Blood Studies  
RNA Microarray 
Sampling 
TEMPUS tube 
X 
Cycle 1, 6-hr 
post-infusion 
X 
 
2.5 mL 
½ tsp 
 
 
Cycle 3, 6-hr 
post-infusion 
X 
2.5 mL 
½ tsp 
DNA Analysis 
PAXgene tube 
X 
Cycle 1, 6-hr 
post-infusion 
X 
8.5 mL 
1 ½ tsp 
 
 
 
Cycle 3, 6-hr 
post-infusion 
X 
8.5 mL 
1 ½ tsp 
PBMC, Plasma 
Collection/ 
Separation Analysis 
1-2 10 ml Lavender top 
EDTA tubes (at least 10 
ml, ideally up to 20 ml) 
X 
Cycle 1, 6-hr 
post-infusion 
X 
10-20 mL  
2-4 tsp 
 
Cycle 3, 6-hr 
post-infusion 
X 
10-20 mL 
2-4 tsp 
Experimental Biopsies (Phase II only) 
Pre-therapy tumor 
biopsy sample 
Formalin + Fresh 
Frozen 
X 
Only screening 
N/A 
 
 
N/A 
N/A 
Post-therapy tumor 
biopsy sample (5-10) 
(optional) 
Formalin + Fresh 
Frozen 
 
C4 
N/A 
 
 
N/A 
N/A 
Post-therapy tumor 
biopsy sample (5-10) 
(optional) 
Formalin + Fresh 
Frozen 
 
End of 
treatment visit 
and follow-up 
period 
N/A 
 
 
N/A 
N/A 
Diagnostic Biopsy 
Historical Biopsy 
or repeat biopsy  
if no historic 
biopsy 
Formalin + Fresh 
Frozen 
X 
Only 
Screening or 
as needed 
N/A 
 
 
N/A 
N/A 
Archival tumor tissue 
on all subjects 
Paraffin-embedded block 
or unstained slides 
X 
 
 
 
 


Short title: Pembro + Poly-ICLC IM in MRP colon cancer 
Version date:   14Nov2022 
 
Page 72 of 77 
¹https://paws.gru.edu/pub/pathology/Pages/Pathology-Lab-Manual.aspx# 


Short title: Pembro + Poly-ICLC IM in MRP colon cancer 
Version date:   14Nov2022 
 
Page 73 of 77 
11.6 Laboratory Manual 
11.6.1 Patient Guide (for at-home administration of poly-ICLC)  
A folder containing printed documents that describe how to handle, prepare, and administer the poly-
ICLC intramuscular injections will be provided to each enrolled subject.  The study coordinator 
should review the guide with the patient and caregiver to ensure understanding, and to answer any 
questions.  The subject may also use the folder to keep up with their injection diary sheets.    
 
11.6.2 Patient Injection Kits 
When poly-ICLC vials are dispensed to the subject for at-home injection, the study subject  should 
be given a patient injection kit (pictured below).  The GCC CTO has assembled injection kits with 
supplies from  the AU Health/AU Medical Center Central Distribution office.  Supply refills will be 
managed by the Multi-Center Research Coordinator. 
 
Standard kits (for a full cycle with 
six injections of poly-ICLC) should 
include the following:  
• Six 3ml syringes (single-use, 
sterile) 
• Six 23 gauge needles with safety 
(single-use, sterile) 
• Six double alcohol preps (one for 
cleaning the skin, one for 
cleaning the medicine vial) 
• Six gauze pads 
• Six non-latex bandages 
 
If sharps containers are available 
from other sources within the clinic, 
they may be provided to the patient.  
Otherwise, patients and caregivers 
should be instructed to identify a 
puncture-proof container (with lid) 
to throw out their used needles and 
syringes.  Sharps containers may be 
purchased at a drugstore or medical 
supply 
store, 
or 
a 
common 
household container such as an 
empty laundry detergent bottle or 
similar container may be used.   
 
Patients and caregivers should also be instructed to return full sharps containers to the clinic to be 
disposed of properly. 
 


Short title: Pembro + Poly-ICLC IM in MRP colon cancer 
Version date:   14Nov2022 
 
Page 74 of 77 
Correlative Study Sample Collection, Processing, and Storage  
Tempus Blood Collection Tubes from Applied Biosystems have been selected for extracting RNA 
from whole blood to be used for the research in this protocol.   
 
When collecting whole blood into a TEMPUS 
tube for RNA extraction please follow these steps; 
failure to follow all of these steps can significantly 
affect the RNA yield of the sample: 
 
1. Draw the 3 ml whole blood sample either 
directly into the TEMPUS tube with a 
straight needle or butterfly collection system 
or by drawing blood into a syringe and then 
transferring it into the TEMPUS tube.  Be 
sure to position the TEMPUS tube below the 
butterfly tubing or below the patient’s arm to 
ensure that the buffer in the TEMPUS tube 
does not flow toward the patient. 
 
2. Immediately cover the filled TEMPUS tube 
with a gloved thumb or gauze square and 
shake the tube extremely vigorously for a 
full 15 seconds. The shaking should be 
vigorous enough to cause some foaming of 
the sample.   It is important to shake the tube 
hard enough to break up any small clots that 
have begun to form during drawing, and the 
break the cells themselves, allowing the 
buffer to protect the RNA inside. 
 
3. Leave the tube upright at room temperature 
for 2-4 hours, then store in refrigerator for 
up to 24 hours or transfer to Tumor Bank. 
 
4. Transfer the sample, with a refrigerated 
cool-pack, to Tumor Bank for storage at    -
80 °C.   
5. Samples may be stored for up to 6 years.  
(Duale et al. BMC Research Notes 2014, 
7:633) 
 


Short title: Pembro + Poly-ICLC IM in MRP colon cancer 
Version date:   14Nov2022 
 
Page 75 of 77 
Contact for RNA sequencing, microarray analysis, flow analysis: 
Michiko Shimoda, Ph.D 
Co-Director, Immune Monitoring  
Shared Resources Laboratory 
Georgia Cancer Center 
Augusta University 
Room: CN-2149 
Phone: 706-446-4948 
Email:  mshimoda@augusta.edu 
 
Rafal Pacholczyk, Ph.D. 
Senior Research Scientist 
Biochemistry and Molecular Biology 
Co-Director, Immune Monitoring  
Shared Resources Laboratory 
Georgia Cancer Center 
Augusta University 
Room:  CN-4135A 
Phone:  706-721-3528 
Email:  rpacholczyk@augusta.edu 
 
Contacts for Georgia Cancer Center Tumor Tissue and Serum Repository (Tumor Bank): 
Sameera Qureshi 
Senior Research Associate,  
GCC Tumor Bank 
Cancer Research Center 
Room: CN-1191 
Phone: (Lab) 706-721-4689   
Email:  SQURESHI@augusta.edu   
 
Roni Bollag, MD, PhD  
Director, Biorepository 
Associate Professor, Clinical Pathology 
Distinguished Chair in Oncologic Pathology 
Cancer Research Center 
Room: CN-2174 
Phone: 706-721-0923 
Email:  rbollag@augusta.edu 


Short title: Pembro + Poly-ICLC IM in MRP colon cancer 
Version date:   14Nov2022 
 
Page 76 of 77 
 REFERENCES 
 
1. Droller MJ: Immunotherapy of metastatic renal cell carcinoma with polyinosinic-
polycytidylic acid. J Urol 137:202-6, 1987 
 
2. Hawkins MJ, Levin M, Borden EC: An Eastern Cooperative Oncology Group phase I-II 
pilot study of polyriboinosinic-polyribocytidylic acid poly-L-lysine complex in patients with 
metastatic malignant melanoma. J Biol Response Mod 4:664-8, 1985 
 
3. Krown SE, Kerr D, Stewart WE, 2nd, et al: Phase I trials of poly(I,C) complexes in 
advanced cancer. J Biol Response Mod 4:640-9, 1985 
 
4. Lampkin BC, Levine AS, Levy H, et al: Phase II trial of a complex polyriboinosinic-
polyribocytidylic acid with poly-L-lysine and carboxymethyl cellulose in the treatment of 
children with acute leukemia and neuroblastoma: a report from the Children's Cancer Study 
Group. Cancer Res 45:5904-9, 1985 
 
5. Levine AS, Levy HB: Phase I-II trials of poly IC stabilized with poly-L-lysine. Cancer 
Treat Rep 62:1907-12, 1978 
 
6. Nakamura O, Shitara N, Matsutani M, et al: Phase I-II trials of poly(ICLC) in malignant 
brain tumor patients. J Interferon Res 2:1-4, 1982 
 
7. Rettenmaier MA, Berman ML, DiSaia PJ: Treatment of advanced ovarian cancer with 
polyinosinic-polycytidylic lysine carboxymethylcellulose (poly(ICLC)). Gynecol Oncol 
24:359-61, 1986 
 
8. Stevenson HC, Lacerna LV, Jr., Sugarbaker PH: Ex vivo activation of killer monocytes 
(AKM) and their application to the treatment of human cancer. J Clin Apher 4:118-21, 1988 
 
9. Theriault RL, Hortobagyi GN, Buzdar AU, et al: Evaluation of polyinosinic-polycytidylic 
and poly-L-lysine in metastatic breast cancer. Cancer Treat Rep 70:1341-2, 1986 
 
10. Ewel CH, Urba WJ, Kopp WC, et al: Polyinosinic-polycytidylic acid complexed with poly-
L-lysine and carboxymethylcellulose in combination with interleukin 2 in patients with cancer: 
clinical and immunological effects. Cancer Res 52:3005-10, 1992 
 
11. Caskey M, Lefebvre F, Filali-Mouhim A, et al: Synthetic double-stranded RNA induces 
innate immune responses similar to a live viral vaccine in humans. J Exp Med 208:2357-66, 
2011 
 
12. Geiss G, Jin G, Guo J, et al: A comprehensive view of regulation of gene expression by 
double-stranded RNA-mediated cell signaling. J Biol Chem 276:30178-82, 2001 
 
13. Salazar A, Levy H, Ondra S, et al: Long-term IM Poly-ICLC treatment of malignant 
glioma: an open pilot study. Neurosurgery 38:1096-1104, 1996 
 
14. Maluish A, Reid J, Crisp E, et al: Immunomodulatory effect of Poly-ICLC in cancer 
patients. J Biol Resp Modif 4:656-663, 1985 
 
15. Caskey M, Lefebvre F, Filali-Mouhim A, et al: Synthetic double stranded RNA reliably 
induces innate immunity similar to a live viral vaccine in humans J Exp Med 208, 2011 
 
16. Pilaro A, Taub D, McCormick K, et al: TNF-alpha is a principal cytokine involved in the 
recruitment of NK cells to liver parenchyma. J Immunol 153:333-42, 1994 
 
17. Morgan E, Norman C: Pretranslational suppression of cytochrome p450h (IIC11) gene 
expression in rat liver after administration of interfero inducers. Drug Metab Dispos 18:649-
53, 1990 
 
18. Salazar AM, Levy HB, Ondra S, et al: Long-term treatment of malignant gliomas with 
intramuscularly administered polyinosinic-polycytidylic acid stabilized with polylysine and 


Short title: Pembro + Poly-ICLC IM in MRP colon cancer 
Version date:   14Nov2022 
 
Page 77 of 77 
carboxymethylcellulose: an open pilot study. Neurosurgery 38:1096-103; discussion 1103-4, 
1996 
 
19. Butowski N, Chang S, Junck L, et al: A phase II clinical trial of poly-ICLC with radiation 
for adult patients with newly idagnosed supratentorial glioblastoma: a North American Brain 
Tumor Consortium (NABTC01-05). J Neurooncology 10, 2009 
 
20. Rosenfeld MR, Chamberlain MC, Grossman SA, et al: A multi-institution phase II study 
of poly-ICLC and radiotherapy with concurrent and adjuvant temozolomide in adults with 
newly diagnosed glioblastoma. Neuro Oncol 12:1071-7, 2010 
 
21. Butowski N, Lamborn K, Lee B, et al: A North American Brain Tumor Consortium phase 
II study of poly-ICLC for adult patients with recurrent anaplastic gliomas. J Neurooncol 
91:183-189, 2009 
 
22. Litterman AJ, Zellmer DM, Grinnen KL, et al: Profound impairment of adaptive immune 
responses by alkylating chemotherapy. J Immunol 190:6259-68, 2013 
 
23. Litterman AJ, Dudek AZ, Largaespada DA: Alkylating chemotherapy may exert a uniquely 
deleterious effect upon neo-antigen-targeting anticancer vaccination. Oncoimmunology 
2:e26294, 2013 
 
24. Boland CR, Goel A: Microsatellite instability in colorectal cancer. Gastroenterology 
138:2073-2087 e3, 2010 
 
25. Lynch HT, de la Chapelle A: Hereditary colorectal cancer. N Engl J Med 348:919-32, 2003 
 
26. Yamamoto H, Imai K, Perucho M: Gastrointestinal cancer of the microsatellite mutator 
phenotype pathway. J Gastroenterol 37:153-63, 2002 


Page 1 of 20 
CC-16047 
Participant’s Name: ______________________________ 
Pembrolizumab + Poly-ICLC 
Participant’s Medical Record Number: _______________ 
 
 
GCC Version Date:  8/28/20; 3/30/21, 11/15/21, 07/26/22, 11/15/22 
 
 
 
 
AUGUSTA UNIVERSITY 
 
RESEARCH INFORMED CONSENT DOCUMENT 
 
TITLE: 
A phase I/II trial of pembrolizumab (MK-3475) and poly-ICLC in 
patients with metastatic mismatch repair-proficient (MRP) colon 
cancer 
 
PROTOCOL NO.: 
CC-16047 
 
WCG IRB Protocol #20161318 
 
917962 
 
SPONSOR: 
Asha Nayak-Kapoor, MD  
 
INVESTIGATOR: 
Asha Nayak-Kapoor, MD 
 
1120 15th Street, CN-2101 
 
Augusta, GA 30912 
 
United States 
 
STUDY-RELATED 
PHONE NUMBER: 
Asha Nayak-Kapoor, MD 
 
706-721-2505 (24-hours) 
 
Invitation To Take Part In Research 
You are invited to take part in a research study of pembrolizumab (MK-3475) and poly-ICLC in 
patients with solid tumors and metastatic mismatch repair-proficient (MRP) colon cancer.  
Patients with colon cancer that have a defect in repair of damaged DNA will not be eligible for 
this study because of the high response rate observed with pembrolizumab alone.  This document 
will tell you about: 
• important information about the study 
• what will happen if you decide to take part in the study 
• the purpose of the study 
• and the potential risks and benefits of taking part in the study. 
 
The study doctor and/or study staff will: 
• discuss the study with you and  
• answer all of your questions. 
 
Taking part in this study is voluntary.  Please take the time to read this form carefully.  You can 
take home an unsigned copy of the consent form to discuss with friends and family while you 
make your decision.  Please ask any questions you may have before you agree to take part in the 
study.  If you decide to take part in this study you will be asked to: 
• sign this form 
 


Page 2 of 20 
CC-16047 
Participant’s Name: ______________________________ 
Pembrolizumab + Poly-ICLC 
Participant’s Medical Record Number: _______________ 
 
 
GCC Version Date:  8/28/20; 3/30/21, 11/15/21, 07/26/22, 11/15/22 
 
 
 
 
Why am I being asked to take part in this study? 
You are being asked to take part in this study because you have a cancer that is no longer 
responsive to at least one standard therapy.  For the first part of the study patients with any type 
of cancer will be eligible.  For the second part of the study you must have a cancer of the large 
bowel without a defect in DNA repair and that did not respond to two standard treatments. Your 
type of cancer shows specific genetic patterns that make it more resistant to immunologic 
treatments. Two drugs are being used in this study, pembrolizumab and Poly-ICLC. 
 
Pembrolizumab is an antibody that is made in the laboratory. An antibody is a natural protein 
made by our immune system that binds other proteins or molecules to fight infection and its ill 
effects. Pembrolizumab has been approved by the Food and Drug Association (FDA) for 
melanoma skin cancer and specific types of lung cancer.  Pembrolizumab is an experimental 
drug therapy for many other types of cancer and has shown outstanding effects in certain tumor 
types like Hodgkin lymphoma and microsatellite repair insufficient tumors particularly of the 
large bowel.  Pembrolizumab binds to another protein in the body and may prevent cancer 
growth by helping certain blood cells of the immune system eliminate the tumor. 
 
Poly-ICLC is an immunostimulating agent.  This means that it activates your immune system 
against infections and tumor cells.  It is an experimental drug that has not yet been approved by 
the FDA. 
 
Both Pembrolizumab and Poly-ICLC are investigational as used in this study. 
 
What Is the Purpose of This Study? 
The main purpose of this study is to determine the dose of poly-ICLC that is safe and tolerable 
when it is combined with pembrolizumab in subjects with cancer. This study will also evaluate 
how the combination of pembrolizumab and poly-ICLC activates your immune system in your 
blood and inside the tumor and how it affects the size and number of tumor(s) in your body and 
how effective the combination is in patients with colon cancer that is unlikely to respond to 
pembrolizumab alone. 
 
The study also determines how you benefit from the treatment by evaluating the tumor response 
to the treatment, prolonging your survival and duration of the response to the treatment. 
 
The combination of poly-ICLC and pembrolizumab is in a very early stage of development for 
use in humans.  Please carefully read the sections on risk and benefits below. 
 
The information learned in this study may be helpful in the further development of combining 
immune stimulating agents such as poly-ICLC and pembrolizumab in patients with specific types 
of tumor that benefit from immunological treatments. 
 
How many people are expected to take part in this study? 
This study is exclusively for adult patients over the age of 18. If you choose to take part in the 
study, you will be one of 31 people at Augusta University who are participating in this clinical 
trial. Approximately 12 people will take part in the first part of this study. The second phase of 
the study will enroll up to 27 patients. Both groups will receive pembrolizumab as an infusion 


Page 3 of 20 
CC-16047 
Participant’s Name: ______________________________ 
Pembrolizumab + Poly-ICLC 
Participant’s Medical Record Number: _______________ 
 
 
GCC Version Date:  8/28/20; 3/30/21, 11/15/21, 07/26/22, 11/15/22 
 
 
 
 
into the vein every three weeks at the outpatient clinic, combined with biweekly intramuscular 
injections of poly-ICLC. In order to participate in this trial, you must be able to either inject 
yourself with the poly-ICLC, or identify another person who can be trained to give you the 
injections.  This regimen will be given for 17 cycles. Each cycle is 21 days with pembrolizumab 
given on day 1 and poly-ICLC injections on days 1, 4, 8, 11, 15, 18. 
 
Study Procedures 
This study will enroll its patients into two separate phases: 
1) Phase I 
a. Aimed to determine if poly-ICLC can be safely combined with standard dosages of 
pembrolizumab. 
i. Poly-ICLC will be administered intramuscularly twice weekly at 1.8 mg. 
ii. Pembrolizumab will be administered 200 mg intravenously every three weeks. 
b. Each dose level enrolls 3-6 patients, with the potential for 12 patients. These patients 
are closely monitored for any possible drug reaction. 
c. Patients with any solid tumor that is unresponsive to at least one line of therapy are 
eligible for the dose escalation phase unless curative options exist. 
2) Phase II trial expansion 
a. Patients with any colon tumor that is unresponsive to at least two lines of therapy 
are eligible for the dose expansion phase unless curative options exist. 
b. The combination from Phase I with the highest tolerated dose of Poly-ICLC will 
then be administered at the recommended phase II dose in up to 27 patients with 
MRP colon tumor. 
 
The total duration of treatment for each phase is one year with total 17 cycles of combination 
treatment. If your cancer is responding to treatment, you may be able to continue with the study 
treatment for up to an additional year (or up to 35 cycles of study treatment). 
 
What will happen to me in the study? 
Your participation in this research study is expected to last approximately 52 weeks. After you 
are done participating in the study you need to attend follow up visits with your treating 
physician at day 30 and every 12 weeks thereafter, for up to 36 months. They will ask if you are 
in remission (cancer free), whether your cancer has returned, and if so, whether you are on a new 
form of cancer treatment. 
 
Screening Visit: 
The screening visit is done to see if you are eligible (qualify) for and can safely participate in this 
study. You will be given detailed information about the study and will have an opportunity to ask 
our doctors any questions. If you are still interested in taking part in the study, we will ask you to 
sign this consent form. This is not a contract binding you to the study. It is simply to show that 
you understand what the study is about and that you are willing to participate in the study, if 
eligible. You are free to withdraw from the study any time. 
 
We will conduct several routine screening procedures that include a physical examination and 
recording your medical history. In addition, you will have one blood draw of approximately 11.5 


Page 4 of 20 
CC-16047 
Participant’s Name: ______________________________ 
Pembrolizumab + Poly-ICLC 
Participant’s Medical Record Number: _______________ 
 
 
GCC Version Date:  8/28/20; 3/30/21, 11/15/21, 07/26/22, 11/15/22 
 
 
 
 
tablespoons of which two and a half tablespoons will be used to measure your blood chemistry, 
kidney/liver function and blood counts. The remaining 9 tablespoons of blood will be used to 
evaluate your immune responses (how your body recognizes and defends itself against bacteria, 
viruses, and substances that appear foreign and harmful to the body such as tumors). You will 
also have urine tests (approximately 4 oz or half a cup), and an electrocardiogram (ECG) to 
measure and record the electrical activity (heart beat) of your heart. Your doctor may review a 
tissue sample from the original biopsy that was done to confirm your cancer diagnosis. 
 
You will have a CT-scan of the chest/abdomen/pelvis and a CT scan of any extremity affected by 
your tumor, and a brain MRI or CT scan of the brain. In some cases you may have a PET/CT 
scan performed. You may have an ultrasound performed of the lesions to determine whether they 
can be biopsied under ultrasound guidance. The scanning imaging tests have to be done within 4 
weeks of your 1st study treatment. 
 
If you are a female who is able to become pregnant, you will have a pregnancy test taken to 
determine if you are pregnant. Pregnant women are not allowed to participate in this study 
because the risks of the study for an unborn fetus are unknown. If you are not pregnant and could 
become pregnant you must use contraceptives during the course of this study, and for 120 days 
after going off study (completion or involuntary). If you are a male you must use contraceptives 
(abstinence, condoms, outercourse) while on study and for 120 days after going off study 
(completion or involuntary). 
 
After we receive your test results we will contact you to let you know the outcome. If you 
qualify for enrollment onto the study and you still want to take part in it, you will be asked to 
return to the study doctor to begin your study treatment as described in the following pages.  
• In Phase 1, study medication poly-ICLC will be given via intramuscular injections twice 
weekly combined with the standard dose of pembrolizumab as a single intravenous 
infusion on Day 1 of each cycle. The lower dose will be given to a small number of 
subjects. If they can tolerate it, the higher dose will be given to another small group. 
Every week, two intramuscular injections of poly-ICLC will be given three days apart: on 
days 1, 4, 8, 11, 15, and 18. 
• Phase II: Combination treatment with the highest tolerated poly-ICLC dose and standard 
intravenous pembrolizumab will be continued in up to 27 patients with the proposed 
schema mentioned above. Treatment cycles are continued for total duration of one year 
(17 cycles) unless you or your study physician decide not to continue the study protocol. 
• Blood tests are done before every cycle. Urine tests are done every 4 cycles and specific 
thyroid tests will be checked every 2 cycles during both phase I and II of treatment. For 
each blood sampling, a single blood draw will be performed of approximately 6.5 
tablespoons. Half a tablespoon will be used to measure your blood chemistries, assess 
kidney/liver function and to count your red and white blood cells and platelets, and 6 
tablespoons will be taken to evaluate how your immune system is functioning. Urine tests 
(approximately 4 oz or half a cup) will also be performed. Immune response will be re-
evaluated based on the blood test samples provided on cycle 1, 3 and 7 of treatment 
protocol. 


Page 5 of 20 
CC-16047 
Participant’s Name: ______________________________ 
Pembrolizumab + Poly-ICLC 
Participant’s Medical Record Number: _______________ 
 
 
GCC Version Date:  8/28/20; 3/30/21, 11/15/21, 07/26/22, 11/15/22 
 
 
 
 
• All patients in Phase II of the study will have a biopsy taken from the tumor at the 
beginning/during cycle 4 of poly-ICLC. There may also be optional repeated biopsies at 
the beginning of cycle 4, during the end of study visit and follow-up period if relapse is 
encountered. The biopsy is provided by local anesthesia with the guide of CT scan or 
ultrasound. During the follow up, tumors might need a repeated biopsy if they show 
progression or appearance of new lesions. Biopsy samples are taken by special needles 
that may leave a minimal scar of few millimeters.  These studies are optional but are 
important to learn how the therapy works and what happens in the tumor when it stops 
working. 
 
If you decide to take part in this research study you will be responsible for the following things: 
• Being able to give yourself, or having your person of choice (e.g., family member, friend) 
give you the poly-ICLC injections at home.  The first injection will be administered in the 
clinic under the supervision of study clinical staff.  The study nurse will provide training 
on how to give yourself the injection.  You will be monitored for at least 30 minutes after 
the first injection to watch for any adverse reactions.  Following the first injection, 
subsequent injections will be administered at home. You will be given a set of written 
instructions to follow, and a diary sheet to show the dates and times of your injections, as 
well as where you received the injection (injection site).  
• Tell the study doctor how you feel and about any side effects. 
• Tell the study doctor about any medication, over-the-counter products, herbal remedies, 
or alternative therapies that you use while you are in this study. Certain medications 
cannot be taken while you are in this study. The study doctor will explain what these 
medications are. If you need treatment with any medications that are not allowed during 
this study, you must tell the study doctor or the study staff. You will not be denied 
medications required to treat an illness you may have, but you may be required to stop 
taking the study medication. This is for your safety, since some medications may not 
work well with Poly-ICLC, and you might have physical problems. You must check with 
the study doctor first if you need to take any new over-the- counter medications or herbal 
supplements, or if you need to change your usual prescription medications during this 
study. 
• You should not have any immunizations (vaccinations) without the study doctor’s 
approval. 
• Tell the study doctor about any medical treatments that you will have to get during the 
study (such as elective surgery). 
• If you decide to take part in the study, it is important that you follow the instructions and 
advice given to you by the study doctor. 
• You should not donate blood for 3 months following the last dose of study treatment. 
• You may be able to return to work or stay home at the time you receive your study drug. 
Normal daily activities need not to be changed unless you experience drug related serious 
adverse events or your study physician recommends you limited activities or special 
considerations. 
 
What Research Procedures Will Be Done Only Because I Am Taking Part In This Study? 


Page 6 of 20 
CC-16047 
Participant’s Name: ______________________________ 
Pembrolizumab + Poly-ICLC 
Participant’s Medical Record Number: _______________ 
 
 
GCC Version Date:  8/28/20; 3/30/21, 11/15/21, 07/26/22, 11/15/22 
 
 
 
 
Based on the information provided before, your blood samples will be withdrawn for further 
evaluation of kidney, liver and thyroid function as well as hematology and immune response 
assays. Urine samples are taken and tumor biopsies will be taken. Imaging studies for evaluation 
of the tumor size will be done within 4 weeks before enrollment as well as every 4 cycles during 
the study protocol and every 12 weeks during the follow up. 
 
What procedures will be done as part of my normal clinical care? 
• History and physical examinations, review of current medicinal products taken by the 
patient. You will be asked about any adverse events you experience in every visit and 
each post treatment follow up visit. 
• Blood samples will be taken every cycle during the treatment and every 3 weeks for the 
whole duration of follow up. 
• Imaging studies by CT scan with contrast media will be done before enrollment and 
every 3 cycles during the study and every 12 weeks thereafter. 
• Electrocardiogram (ECG) will be performed during screening, and thereafter as needed. 
 
Archival Tumor Samples 
Your tumor sample from tissue that was already collected from you through a previous surgery 
will be obtained for the study.  In such cases, the tumor sample (also called a “paraffin 
block”) is already stored in a pathology lab. 
 
RISKS 
What are the possible risks or discomforts? 
Possible adverse events include those associated with venipuncture, study drug administrations, 
and tumor biopsies. Imaging studies with CT scan as well as electrocardiography (ECG) may 
also show their own adverse reactions. Certain of the expected events listed below are also due to 
activation of the patient’s own immune system against the tumor, with potentially beneficial 
inflammation and tumor necrosis. 
 
There may be more risks that are not known or not expected as this is the first time this 
combination of drugs is being administered. 
 
Possible Risks Associated with Poly-ICLC: 
Following are risks and discomforts that you may experience during your participation in this 
research study. 
 
1) Discomfort at the injection site: You will likely experience discomfort, soreness and 
redness at the injection site, both during and afterwards. 
2)  You may also develop pain and swelling at the tumor sites that could cause symptoms, 
which would vary depending on the location of the tumor. Inflammation at other tumor 
sites could also be an indication that your body is fighting the tumor. 
3) Flu- like symptoms: You may develop flu like symptoms several hours after injection, 
which may last up to several days. These include muscle aches, fevers, headaches, chills, 
fatigue and general symptoms of having a viral infection. These symptoms should be 


Page 7 of 20 
CC-16047 
Participant’s Name: ______________________________ 
Pembrolizumab + Poly-ICLC 
Participant’s Medical Record Number: _______________ 
 
 
GCC Version Date:  8/28/20; 3/30/21, 11/15/21, 07/26/22, 11/15/22 
 
 
 
 
better with acetaminophen (Tylenol). 
4) Low white blood cell counts: While on study treatment it is possible that you could 
develop low white blood cell counts. Low white cell counts put you at risk for serious 
infection so if this were to happen, the dose of Poly-ICLC may have to be adjusted. If 
you get an infection while your white count is low you may have to be hospitalized and 
receive antibiotics. 
5) Liver abnormalities: While you are on study we will be checking your liver function by 
monitoring your blood work results. You may develop a temporary elevation in your liver 
function tests. There are no reported cases of this causing any clinical symptoms. 
6) Clotting abnormalities: This was reported in animal studies in non-human primates but 
never in humans, so is possible but unlikely. 
7) Anemia (low red blood cell counts): Due to repeated blood draws it is possible that you could 
develop anemia. Anemia causes people to feel week and have low energy. If anemia causes 
you symptoms or reaches levels of concern, no further blood draws will be obtained except 
as medically necessary until your levels return to the range that is normal for you. 
8) Seizures: Have been reported, but are extremely unlikely. Three patients who 
experienced seizures had brain tumors and were highly susceptible to seizures and may 
have had a history of such. They all recovered without a problem.  
 
Possible Risks Associated with pembrolizumab: 
Most of the possible side effects listed below are mild to moderate. However, some side 
effects can be very serious and life-threatening and may even result in death. Some side 
effects do not need treatment while others generally get better with treatment.  Some patients 
may need to delay doses of pembrolizumab to allow the side effects to get better.  The most 
important possible side effects, which are listed below, may occur because of the way 
pembrolizumab works on the immune system and they have been seen in patients treated 
with pembrolizumab in clinical studies. Side effects like these have also been seen in clinical 
studies with other drugs that are very similar to pembrolizumab. 
 
Very Common Side Effects (Out of 100 people who receive prembrolizumab, 20 or 
more people may have the following): 
• Diarrhea (loose or watery stools) 
• Rash/dry itchy skin 
• Cough 
 
Common Side Effects (Out of 100 people who receive pembrolizumab, at least 5 but less 
than 20 people may have the following): 
• Joint pain 
• Rash 
• Fever 
• Back pain 
• Pain in your belly 
• Loss of skin color 
• Not enough thyroid hormone, so you may feel tired, gain weight, feel cold or have 


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Participant’s Name: ______________________________ 
Pembrolizumab + Poly-ICLC 
Participant’s Medical Record Number: _______________ 
 
 
GCC Version Date:  8/28/20; 3/30/21, 11/15/21, 07/26/22, 11/15/22 
 
 
 
 
infrequent or hard stools (hypothyroidism) 
• Low levels of salt in the blood that may cause you to feel tired, feel confused, have a 
headache, have muscle cramps, and/or feel sick to your stomach (hyponatremia) 
 
Uncommon Side Effects (Out of 100 people who receive pembrolizumab, at least 1 but 
less than 5 people may have the following): 
• Inflammation of the lungs, so you may feel short of breath and cough (pneumonitis) 
• Too much thyroid hormone, so you may feel anxious, feel angry, have trouble sleeping, feel 
weak, tremble, sweat, feel tired, have loose and watery stools (hyperthyroidism) 
• Infusion reaction, where you may feel dizzy or faint, feel flushed, get a rash, have a fever, feel 
short of breath, experience a decrease in your blood pressure at the time of receiving your 
infusion (IV) or just after, or have pain at the site of infusion 
• Inflammation of the bowels/gut, which may cause severe pain in your belly with loose or watery 
stools, and black, tarry, sticky stools or stools with blood or mucus (colitis) 
• Inflammation of the skin so you may have peeling of the skin, itchiness, and/or skin redness. 
The skin inflammation (i.e., peeling, itching and redness) could also be widespread throughout 
your body.  More severe skin reactions may involve the inside of your mouth, the surface of 
your eye and genital areas, and/or may cause the top layer of your skin to peel from all over 
your body which can cause severe infection (Severe skin reactions, including Stevens-Johnson 
syndrome or toxic epidermal necrolysis) 
 
Rare (Out of 100 people who receive pembrolizumab, less than 1 person may have the following): 
• Inflammation of the nerves that may cause pain, weakness, or tingling in your hands and feet, 
and may spread to your legs, arms, and upper body, leading to severe muscle weakness and 
possible temporary paralysis (Guillain-Barré syndrome) 
• Inflammation of the muscles, so you may feel weak or have pain in your muscles (myositis) 
• Inflammation of the pancreas (a gland in your abdomen that controls sugar levels), so you may 
have severe pain in the top part of your belly that may move to your back, feel sick to your 
stomach, and have vomiting that gets worse when you eat (pancreatitis) 
• Inflammation of the eye, so you may have eye redness, blurred vision, sensitivity to light, eye 
pain, see floaters, or have headaches (uveitis) 
• Inflammation of the liver that may make you feel sick to your stomach and vomit, feel like not 
eating, feel tired, have a mild fever, a pain in the right side of your belly, yellow eyes and skin, 
and dark urine (hepatitis) 
• Inflammation of the pituitary gland (a gland in the head), which may cause you to feel sick to 
your stomach or have headaches, changes in your behavior, double vision, few to no menstrual 
cycles, weakness, vomiting and dizziness, or fainting (hypophysitis) 
• Adrenal glands (glands on top of the kidneys) that may not make enough hormone, which could 
cause tiredness, weight loss, muscle weakness, feeling faint, having joint, muscle, and 
bellyaches, nausea, vomiting, loose or watery stools, fever, salt craving, and sometimes 
darkening of the skin like a suntan (adrenal insufficiency) 
• Type 1 diabetes, a condition that can cause too much sugar in your blood, feeling thirstier than 
usual, frequent urination, and weight loss. You are likely to need regular insulin shots 
• Inflammation of the kidney, so you may pass less urine or have cloudy or bloody urine, 


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Participant’s Name: ______________________________ 
Pembrolizumab + Poly-ICLC 
Participant’s Medical Record Number: _______________ 
 
 
GCC Version Date:  8/28/20; 3/30/21, 11/15/21, 07/26/22, 11/15/22 
 
 
 
 
swelling, and low back pain (nephritis) 
• Inflammation of the middle layer of your heart wall that may cause your heart to have difficulty 
pumping blood throughout your body, which can cause chest pain, shortness of breath, and 
swelling of the legs. You may experience a fast or irregular heartbeat that may cause dizziness 
or fainting (myocarditis) 
• Inflammation of the thyroid gland, an organ that makes and stores thyroid hormones. This 
condition may lead to change in your heart rate, blood pressure, body temperature, and the rate 
at which food is converted into energy (thyroiditis) 
• A condition that may make you feel weak and tired and may cause drooping of the eyelids, 
blurred or double vision, difficulty swallowing, slurred speech, weakness in your arms and legs, 
or difficulty breathing (myasthenic syndrome/myasthenia gravis including exacerbation) 
• The formation of small clusters of immune cells (called granulomas) in parts of your body such 
as your lymph nodes, eyes, skin, or lungs (sarcoidosis) 
• Inflammation of the brain with confusion and fever. This may also include: disorientation, 
memory problems, seizures (fits), changes in personality and behavior, difficulty speaking, 
weakness or loss of movement in some parts of your body, and loss of consciousness 
(encephalitis) 
• Hypoparathyroidism which is a rare condition where the parathyroid glands, located in the neck 
near the thyroid gland, produce too little parathyroid hormone (causing low calcium level and 
high level of phosphorus in the blood) 
• Inflammation of the spinal cord with pain, numbness, tingling, or weakness in the arms or legs, 
bladder or bowel problems including needing to urinate more frequently, urinary incontinence, 
difficulty urinating, and constipation (myelitis) 
• Inflammation of the blood vessels (vasculitis). Symptoms will depend on the particular blood 
vessels that are involved in the inflammatory process, for example: if it is your skin, you may 
get a rash. If your nerves are not getting enough blood, you could have numbness and weakness. 
You may also experience fever, weight loss, and fatigue. 
 
Additionally, since pembrolizumab was approved in September 2014, the following side effects have 
been reported by people receiving pembrolizumab. These side effects were voluntarily reported from a 
group of people of unknown size. It is not possible to estimate the frequency of these side effect: 
• Inflammation of the joints which may include joint pain, stiffness and/or swelling (arthritis) 
• Severe responses of the immune system that cause the body to attack its own blood cells, 
spleen, liver, lymph nodes, skin and brain.  This may include fever, rash, inflammation of the 
liver, yellowing of the skin, an enlarged liver and spleen, low blood counts, and enlarged lymph 
nodes. The nervous system may also be affected and cause confusion, seizures, and even coma 
(hemophagocytic lymphohistiocytosis) 
• Changes in eyesight, eye pain, whitish patches on the skin and hearing loss (Vogt-Koyanagi-
Harada syndrome) 
• Inflammation and scarring of the bile ducts (tubes that carry digestive fluid that is made in the 
liver). This can cause symptoms similar to those seen with inflammation of the liver (hepatitis) 
such as pain in right side of your belly, yellow eyes and skin, feeling tired, and itching 
(sclerosing cholangitis). 
 


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CC-16047 
Participant’s Name: ______________________________ 
Pembrolizumab + Poly-ICLC 
Participant’s Medical Record Number: _______________ 
 
 
GCC Version Date:  8/28/20; 3/30/21, 11/15/21, 07/26/22, 11/15/22 
 
 
 
 
As well as the important possible risks described above patients with different types of cancer 
who have been treated with pembrolizumab in clinical trials have very commonly (i.e., more 
than 10% of patients) reported: feeling tired, nausea, vomiting, decreased appetite, shortness of 
breath, cough, fever and pain in muscles and joints. 
 
Biopsy: If you have easily accessible tumors, you will have a biopsy sample taken before 
beginning treatment and before receiving the fourth cycle of the treatment. There may also be 
optional repeated biopsies of the tumor at the end of study visit and follow-up period if relapse is 
encountered. The biopsies are done under the guidance of either ultrasound or CT scan and up to 
3 core needle biopsies less than 1mm in width will be taken of each lesion. These procedures are 
done to evaluate how your body recognizes and defends itself against cancer. A biopsy is a 
relatively safe surgical procedure. As with any surgical procedure, you may experience side 
effects that include pain, infection, temporary swelling/bleeding, tenderness, scarring at the 
surgical site and allergic reaction to the drugs. The study doctor will give you specific 
instructions on how to care for your biopsy site and contact information in case of an emergency. 
 
Blood Draw: Symptoms may include bleeding, fainting, injection site infection and/or anemia 
(low red blood cell levels that could result in tiredness, dizziness, sleeplessness, shortness of 
breath, leg cramps). Fainting can occur during or after a blood draw in some individuals. Your 
red blood cell level will be monitored periodically during the study. You may be asked to take 
iron supplements if your level decreases. 
 
Radiation Exposure: If you take part in this research, you will have a number of radiation 
procedures or examinations that are part of the regular medical care for your condition and you 
would have them whether or not you participate in this research. You will not be exposed to any 
additional radiation because you are participating in this research. 
 
These tests include X-rays, CT scans, and or PET scans, all of which are used routinely to follow 
up on your condition. The study doctor will decide which test you have, and when you have it, 
based upon your disease, where it is located, and your progress. You may also have MRI scans, 
but these do not involve radiation exposure. 
 
Some of the scans could involve “contrast”, which is like a dye injected into the bloodstream, 
which makes things appear more clearly on the test. Since some of the contrast dyes contain 
iodine, it is important that you tell the study doctor if you are allergic to iodine. 
 
The study doctors will always try to keep radiation exposure as low as reasonably achievable by 
choosing tests and procedures that involve the lowest possible exposure while providing the 
necessary information about your condition. 
 
Women of Childbearing Potential  
You cannot participate in this study if you are or plan to become pregnant, or if you are 
breastfeeding. There may be unknown risks to you, the embryo/fetus or nursing infant if you 
become pregnant during the study. 
 


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CC-16047 
Participant’s Name: ______________________________ 
Pembrolizumab + Poly-ICLC 
Participant’s Medical Record Number: _______________ 
 
 
GCC Version Date:  8/28/20; 3/30/21, 11/15/21, 07/26/22, 11/15/22 
 
 
 
 
You must be using adequate contraception for the duration of the study and for 120 days 
following your participation. If you become pregnant, suspect pregnancy, if you have a change in 
your menstrual cycle, or in your contraception method you should immediately contact the study 
doctor. Should you become pregnant during the study, you will be withdrawn from the study 
immediately and should seek care from a doctor who specializes in pregnant women (an 
OB/GYN, or obstetrics and gynecologist physician). The study doctor or any investigator on this 
study, or Merck and Oncovir, the manufacturers of the drugs are not responsible for any 
financial aspects of obstetrical, child or related care. 
 
Psycho/Social/Economic Risks: Risks and discomforts not only include physical injury, but also 
possible psychological, social or economic harm, discomfort or inconvenience, or breach of 
confidentiality. 
 
Privacy Risk: There always exists the potential for loss of private information; however, there 
are procedures in place to minimize this risk. 
 
Unknown Risks: It is possible that the study treatment or procedures may involve risks to you 
that are not currently known or foreseeable. It is important that you should consult with the 
treating physician regarding any questions or concerns you may have about the study treatments. 
 
If I take part in this study, can I take part in other studies? 
You are not allowed to enter any clinical study while you are enrolled in this study and during 
the follow up unless your study physician or you decide to withdraw/be withdrawn from the 
study. 
 
Can I take other medication while I am taking part in the study? 
You must tell the study team about any medicines (prescription or over-the-counter), and herbal, 
vitamins, or mineral supplements: 
• That you take now. 
• That you or your doctors add or take away. 
 
The combination of these medicines and the research study medicine is not known at this time.  
The combination may result in increased risk to you.  You must contact the research team at 706-
721-2505 if any changes are made to your current medicines and supplements. 
 
You agree not to drink alcohol while you are taking poly-ICLC and pembrolizumab since the 
combination of either experimental medication and alcohol may be harmful to you. 
 
Reproductive Risks 
Women who can get pregnant or are breastfeeding 
The effects of (name of study drug) on an embryo or fetus are not known.  You may not take part 
in this study if you are: 
• breastfeeding 
• pregnant 


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Participant’s Name: ______________________________ 
Pembrolizumab + Poly-ICLC 
Participant’s Medical Record Number: _______________ 
 
 
GCC Version Date:  8/28/20; 3/30/21, 11/15/21, 07/26/22, 11/15/22 
 
 
 
 
• think that you may be pregnant 
• Or are trying to get pregnant.  The risks to an unborn child are not known.  Your study 
doctor does not want you to become pregnant while you are taking part in this study. 
 
If you are female, from the time of informed consent through 120 days following the last dose of 
study medication, you must agree to the following: 
• Avoid pregnancy unless you are unable to become pregnant (e.g. have had your “tubes 
tied”, had a hysterectomy or are at least 1-year post-menopausal). If sexually active and 
able to become pregnant, you must agree to use 2 effective methods of birth control as 
noted in the table below.  Not engaging in sexual activity is an acceptable practice; 
however, occasional abstinence, the rhythm method and the withdrawal method are not 
acceptable methods of contraception. 
• Refrain from breastfeeding and egg cell donation. 
 
Effective Methods of Contraception (Two Methods Must be Used) 
 
Barrier Methods 
Intrauterine Device Methods 
Hormonal Methods 
• 
Male 
condom 
plus 
spermicide 
• 
Cap plus spermicide 
• 
Diaphragm 
plus 
spermicide 
• 
Copper T 
• 
Levonorgestrel-releasing 
intrauterine 
system 
(e.g. 
Mirena®) a 
• 
Implants 
• 
Hormone shot or 
injection 
• 
Combined pill 
• 
Minipill 
• 
Patch 
a 
This is also considered a hormonal method. 
 
Men 
If you are a male who is sexually active with a female partner who may become pregnant, from 
the time of informed consent through 120 days following the last dose of study medication, you 
must agree to the following: 
• Be unable to get a female partner pregnant (eg, had a vasectomy). 
• If sexually active you must agree to use 2 effective methods of birth control as noted in 
the table below.  Not engaging in sexual activity is an acceptable practice; however, 
occasional abstinence, the rhythm method and the withdrawal method are not acceptable 
methods of contraception. 
• Refrain from sperm donation. 
 
If during the study and through 120 days after your last dose of study medication, you learn that 
you are pregnant (female subject) or your female partner becomes pregnant (male subject), you 
must contact the Study Doctor immediately for further instructions about follow-up.  The study 
team will ask you about any pregnancy during the study visits and may continue to follow-up 
with female subjects for 120 days after your last dose of study medication.  If at any time you 
report a pregnancy of either you or your partner, the study team will collect information about 
the results of the pregnancy and/or birth and will schedule any follow-up visits that may be 
necessary.  The study doctor will ask the pregnant partner of a male subject to sign a separate 


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CC-16047 
Participant’s Name: ______________________________ 
Pembrolizumab + Poly-ICLC 
Participant’s Medical Record Number: _______________ 
 
 
GCC Version Date:  8/28/20; 3/30/21, 11/15/21, 07/26/22, 11/15/22 
 
 
 
 
consent form to allow the collection of this information.  This health information will become 
part of the clinical trial records and will be shared with the Sponsor so that the Sponsor may 
determine if there are any effects of the study medication on unborn children. 
 
If I get sick or become hurt because of the study, what will happen? 
Augusta University: 
If you think that you have suffered a research related injury, seek medical care right away and 
contact the study team as soon as possible at 706-721-2505. In the event that this research related 
activity results in an injury, treatment will be made available including first aid, emergency 
treatment, and follow-up care as needed. Cost for such care will be billed in the ordinary manner 
to you or your insurance company. No reimbursement, compensation, or free medical care is 
offered by Augusta University (AU), AU Medical Center, AU Medical Associates, AU Dental 
Associates, AU Nursing Associates, Inc., AU Health Professions Associates, Inc. collectively 
designated AU Affiliates [or any other facility involved with this study].  You do not give up 
your legal rights by participating in this study. 
 
COSTS 
The study drugs, pembrolizumab and poly-ICLC, will be provided for this study by Merck and 
Oncovir respectively.  There will be no charges for the laboratory tests related to the research 
part of the study. 
 
If you agree to participate in this study, you and/or your insurance will not be billed for the tests 
and treatments that are being done only for research. However, you are still responsible for 
paying for the usual care you would normally receive for the treatment of your illness. You will 
be responsible for all co-pays, deductibles, and denied claims. 
 
You have the right to ask specifically what it will cost you to take part in this study. You have 
the right to contact your insurance company to discuss the costs of your routine care and whether 
these will be covered if you participate in this study. You may choose not to be in this study if 
your insurance does not pay for your routine care. In that case, your doctor will discuss other 
treatment plans with you. 
 
No other compensation, such as lost wages or other damages, will be offered. 
 
BENEFITS 
How could I benefit from being in this study? 
Since this study is the first time poly-ICLC is administered in combination with pembrolizumab 
in patients with colon tumor, there is no way to know if there will be any benefit from this 
treatment. The combination of poly-ICLC and pembrolizumab is experimental. It is possible that 
the combination will have no direct benefit to you. Even in the future if it is found that either 
pembrolizumab or poly-ICLC can benefit cancer patients, a few patients on this study may 
receive a low dose of any of them for safety reasons; a low dose is given in this study to make 
sure that the drug does not have serious side effects and you do not have a choice what dose of 
pembrolizumab or poly-ICLC you will receive. The likelihood of you benefiting from this study 
is low.  Other people, including those with cancer, may benefit from what is learned in this 


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CC-16047 
Participant’s Name: ______________________________ 
Pembrolizumab + Poly-ICLC 
Participant’s Medical Record Number: _______________ 
 
 
GCC Version Date:  8/28/20; 3/30/21, 11/15/21, 07/26/22, 11/15/22 
 
 
 
 
study. 
 
Will the researchers tell me if they learn something new that may change my decision to 
continue in the study? 
You will be told of any new information about the study.  This new information may change 
your mind about being in the study. 
 
ALTERNATIVES/OTHER OPTIONS 
What other options do I have if I decide not to take part in the study? 
You are not required to take part in this study.  There are no curative options for your cancer.  
There are additional therapies available that have been shown to prolong the life of patients on 
average by 1-2 months such as regorafenib, trifluridine/tipiracil, or EGFR-directed antibodies if 
your tumor is RAS wild type.  You may still receive these therapies if the therapy given during 
this study is not effective.  If you do not want to take part in the study, your Study Doctor will 
discuss different options that are available to you. These options may include: 
• Treatment with other chemotherapy drugs; 
• Treatment with medications that will make you feel more comfortable, but have no effect 
on your cancer; 
• Other experimental treatments; 
• No treatment but palliative care to relieve your symptoms 
 
If you decide that you don’t want any more active treatment, one of your options is called 
“comfort care.”  Comfort care includes pain medication and other support.  It aims to maintain 
your comfort and dignity rather than cure disease.  Usually this care can be provided at home. 
 
The study staff will discuss these other options with you. 
 
ENDING THE STUDY 
Can I stop taking part in the study? 
Joining this study is voluntary.  You can decide not to take part or at any time after joining the 
study and for any reason, you can withdraw from the study without any penalty or loss of 
benefits to which you are otherwise entitled.  Your decision to leave the study will have no effect 
on your future care or treatment by physicians or by this institution. 
 
If you leave the study early, you are recommended to go through such study exit procedures as 
may be considered necessary by the doctor doing this study.  Your study doctor may ask if 
he/she can continue to collect relevant information for the study during your normal clinic visits. 
 
Can the study doctor remove me from the study? 
Yes, the study doctor may stop your taking part in the research study for many reasons.  Some 
examples are: 
• The sponsor or study doctor decides to stop the study. 
• The study doctor stops your taking part in the study for your safety. 
• You are not eligible to take part in the study. 


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CC-16047 
Participant’s Name: ______________________________ 
Pembrolizumab + Poly-ICLC 
Participant’s Medical Record Number: _______________ 
 
 
GCC Version Date:  8/28/20; 3/30/21, 11/15/21, 07/26/22, 11/15/22 
 
 
 
 
• Your condition changes and you need treatment that is not allowed while you are taking 
part in the study. 
• You do not follow the instructions from the study staff. 
• Failure to keep appointments, follow directions or take medications as instructed. 
• A serious adverse reaction to study treatment. 
• The need for treatment that is not allowed in the study. 
• Worsening of your disease. 
 
If you decide to stop taking part in the study for any reason, you must contact the study staff 
immediately at 706-721-2505 (24 hours/day, 7 days/week). 
 
What’s the best way to stop taking part in the study? 
Before you stop taking part in the study, contact the study staff.  You should follow the 
instructions they give you to safely stop the study. 
 
Could there be any harm to me if I decide to stop participating in the study before it’s 
finished? 
If you decide to stop taking part in the study, the study staff will discuss ways to safely remove 
you from the study.  You should follow the instructions the study staff gives you. 
 
If I withdraw from the study, can information about me still be used and/ or collected? 
If you stop taking part in the study the study staff will not collect any more information from 
you. The information that the study staff had about you before you decided to stop being in the 
study can be used. 
 
Will I be paid for taking part in the study? 
You will not be paid for taking part in this study. You will be responsible for the costs of 
transportation to participate in the study. 
 
CONFIDENTIALITY 
By signing this form you consent to the Study Doctor and his or her staff (“Study Team”) 
collecting and using personal data about you for the study (“Study Data”). This includes: your 
date of birth/age as permitted by local laws, your sex, your ethnic origin, and personal data on 
your physical or mental health or condition. 
 
Your consent to the use of Study Data does not have a specific expiration date, but you may 
withdraw your consent at any time by notifying the Study Doctor. If you withdraw your consent, 
any Study Data collected prior to that time may still be given to and used by the Sponsor but 
your Study Doctor will not collect any new Study Data. 
 
The Study Data given to and used by the Sponsor is protected by the use of a subject 
identification number (SID), which is a number specific to you. The Study Data given to the 
Sponsor does not include identifying information such as your name. The Study Doctor 
maintains a confidential list that links the SID to you. A person appointed by the Sponsor, 


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CC-16047 
Participant’s Name: ______________________________ 
Pembrolizumab + Poly-ICLC 
Participant’s Medical Record Number: _______________ 
 
 
GCC Version Date:  8/28/20; 3/30/21, 11/15/21, 07/26/22, 11/15/22 
 
 
 
 
regulatory authorities, or other supervisory bodies may review any Study Data held by the Study 
Doctor and the Study Doctor’s institution. The reason these people may look at your health 
information is to make sure the study has been done the right way and that the Study Data are 
accurate. 
 
The Study Doctor and his/her Study Team will use Study Data to conduct the Study. The 
Sponsor may use Study Data to conduct the Study and to support research and development of 
pharmaceutical products, diagnostics, or medical aids. The Sponsor may use the Study Data to 
apply for approval to market pembrolizumab as well as poly-ICLC. The Study Doctor’s 
institution and the Sponsor are each responsible for their handling of Study Data in accordance 
with applicable Data Protection law(s) and each act as a data controller of the Study Data for this 
purpose. 
 
The Sponsor may share Study Data with other companies within its group, with its service 
providers, its contractors, and with research institutions and research-based commercial 
organizations who will use Study Data only for the purposes described above. The Sponsor may 
transfer Study Data to countries outside of the United States for the purposes described in this 
document. Please be aware that the laws in such countries may not provide the same level of data 
protection as in the United States and may not stop Study Data from being shared with others. 
The Sponsor will take all steps reasonably necessary to ensure that any Study Data transferred is 
treated securely and in accordance with this form to the extent permitted by law. 
 
Although information about this study, including the results, may be published for scientific 
purposes or posted electronically (for example, in a clinical trials registry database) or presented 
to scientific groups, your identity will not be revealed. 
 
You have the right to request to see your Study Data held by the Study Doctor and the Sponsor. 
You also have the right to request that any inaccuracies in your data be corrected. If you wish to 
make a request, then please contact the Study Doctor, who can help you contact the Sponsor if 
necessary. 
 
How will the researchers protect my privacy and keep information about me confidential 
(private)? 
Any study information about you will be kept private and will only be given out with your 
permission. If the results of this study are published, your name will not be used. Your research 
records will be private to the extent allowed by law. In order to make sure the research is done 
properly, the Institutional Review Board may need access to information about your participation 
in this study. If you sign this consent form, you are giving us permission to collect, use and share 
your health information. 
 
Research records that identify you will be kept private. You will not be identified in study 
records or publications disclosed outside Augusta University and except as detailed in the 
following sections, if applicable. 
 
Authorization to Use or Disclose (Release) Health Information that Identifies You for a 


Page 17 of 20 
CC-16047 
Participant’s Name: ______________________________ 
Pembrolizumab + Poly-ICLC 
Participant’s Medical Record Number: _______________ 
 
 
GCC Version Date:  8/28/20; 3/30/21, 11/15/21, 07/26/22, 11/15/22 
 
 
 
 
Research Study 
 
If you sign this document, you give permission to Augusta University and AU Affiliates to use 
or disclose your health information that identifies you for the study described earlier in this 
document. 
 
The health information Augusta University and AU Affiliates may use or disclose for this study 
includes information in your medical or dental record, results of physical exams, medical or 
dental history, lab tests or certain health information indicating or relating to your condition.   
 
The health information listed above may be used by and/or disclosed to the following, as 
applicable: 
• Researchers and their staff; 
• The sponsor of the study including its agents such as data storage banks or contract 
research organizations monitoring the study; 
• Other institutions and investigators participating in the study; 
• Data Safety Monitoring Boards; 
• Accrediting agencies; 
• Clinical staff not involved in the study whom may become involved if it is relevant; 
• Health insurers or payers in order to secure payment for covered treatment; 
• Parents/Guardians of children younger than 18 years 
• Vendors to facilitate payment or reimbursement for your participation in this study; 
• Federal/state agencies and Augusta University and AU Affiliates committees having 
authority over the study. These may include, but are not limited to: 
o The Institutional Review Board (IRB) overseeing this study; 
o Committees with quality improvement responsibilities; 
o Office of Human Research Protections; 
o Privacy and security staff for oversight and investigations; 
o Food and Drug Administration; 
o National Institutes of Health; 
o Other governmental offices as required by law. 
 
Augusta University and AU Affiliates are required by law to protect your health information.  By 
signing this document, you authorize Augusta University and AU Affiliates to use and/or 
disclose your health information for this research.   
 
Once your information has been disclosed outside Augusta University and AU Affiliates, it may 
no longer be protected by federal laws and regulations and might be further disclosed by the 
persons or institutions receiving the information. 
 
Please note that: 
 
You cannot receive research-related treatment if you do not sign this Authorization. 
 


Page 18 of 20 
CC-16047 
Participant’s Name: ______________________________ 
Pembrolizumab + Poly-ICLC 
Participant’s Medical Record Number: _______________ 
 
 
GCC Version Date:  8/28/20; 3/30/21, 11/15/21, 07/26/22, 11/15/22 
 
 
 
 
Augusta University and AU Affiliates may not withhold treatment whether or not you sign this 
Authorization. 
 
You may change your mind and take back (revoke) this Authorization at any time.  If you revoke 
this Authorization, Augusta University and AU Affiliates may still use or release health 
information and any data and/or specimens they already have obtained about you as necessary 
for this study. If you revoke this Authorization, you cannot continue to participate in this study.  
To revoke this Authorization, you must write to the Principal Investigator listed at the top of this 
document.   
 
You may not be allowed to see or copy the study information described on this Authorization as 
long as the study is in progress.  Feel free to ask the study staff if this applies to this study. When 
the study is complete, you have a right to request a copy of your personal health information 
collected for the study.  
 
Your health information will be used or disclosed when required by law.  Your health 
information may be shared with a public health authority that is authorized by law to collect or 
receive such information for the purpose of preventing or controlling disease, injury or disability 
and for conducting public health surveillance, investigations or interventions.  No publication or 
public presentation about the study will reveal your identity without another signed authorization 
from you.   
 
You will be given a copy of this Authorization.  This Authorization does not have an expiration 
date.  If you have questions or concerns about this Authorization or your privacy rights, please 
contact the Augusta University and AU Affiliates Privacy Officer at 706-721-0900. 
 
Regulations require that you be given a copy of the Augusta University and AU Affiliates Notice 
of Privacy Practices describing the practices of Augusta University and AU Affiliates regarding 
your health information. 
 
Contact Information for Answers to Your Questions: 
You have read this form that serves as an informed consent document.  This form also serves as 
your authorization for Augusta University and/or to use and release (disclose) your PHI in the 
manner described as a study subject.  You have been given the opportunity to ask questions 
about the information on this form.  You will be given a signed copy of this form for your 
records. 
 
You can ask questions about the study at any time.  Please contact Asha Nayak-Kapoor, MD or 
the study staff at 706-721-2505 (24 hrs/day) if you have questions about: 
• More information of the study 
• Study procedures or treatments 
• Report an illness, injury, or other problem  
• Leaving the study before it is finished 
• Expressing a complaint or concern about the study 


Page 19 of 20 
CC-16047 
Participant’s Name: ______________________________ 
Pembrolizumab + Poly-ICLC 
Participant’s Medical Record Number: _______________ 
 
 
GCC Version Date:  8/28/20; 3/30/21, 11/15/21, 07/26/22, 11/15/22 
 
 
 
 
• Any other questions you may have about the study 
 
If you have questions about your rights as a research subject, or if you have questions, concerns, 
or complaints about the research you may contact: 
 
 
WCG IRB 
 
1019 39th Avenue SE Suite 120 
 
Puyallup, Washington  98374-2115 
 
Telephone:  855-818-2289 
 
E-mail:  researchquestions@wcgirb.com 
 
WCG IRB is a group of people who perform independent review of research. 
 
WCG IRB will not be able to answer some study-specific questions, such as questions about 
appointment times.  However, you may contact WCG IRB if the research staff cannot be reached 
or if you wish to talk to someone other than the research staff. 
 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required 
by U.S. Law.  This Web site will not include information that can identify you.  At most, the 
Web site will include a summary of the results.  You can search this Web site at any time. 
 
Voluntary Participation: 
Taking part in this research study is voluntary and your choice.  You may say no if you do not 
want to take part in the study.  If you take part in the study, you may stop at any time. 
 
You do not need to give a reason.  You will not be treated differently if you choose not to take 
part in the study now.  You will not be treated differently if you later decide to stop taking part in 
the study.  If you stop, contact the study staff immediately and follow instructions that they may 
give you. 
 
What documents will be given to me if I decide to be in the study? 
 
This “Research Informed Consent Document” 
 
STATEMENT OF CONSENT 
 
I have read this form and the information in it was explained to me.  I agree to take part in this 
research study.  All of my questions were answered. My taking part in the study is voluntary.  I 
will receive a copy of this form for my records.  I am not giving up my legal rights by signing 
this form. 
 
 
________________________________ 
Subject’s Name (print) 
 


Page 20 of 20 
CC-16047 
Participant’s Name: ______________________________ 
Pembrolizumab + Poly-ICLC 
Participant’s Medical Record Number: _______________ 
 
 
GCC Version Date:  8/28/20; 3/30/21, 11/15/21, 07/26/22, 11/15/22 
 
 
 
 
 
________________________________ 
 
/ 
 
Subject’s Signature 
Date 
Time (00:00) 
 
 
________________________________ 
 
/ 
 
Witness’ name (print)  
Date 
Time (00:00) 
 
 
________________________________ 
My signature indicates that I was present during the 
informed consent process and that informed consent 
was given freely by the subject.  My signature also indicates 
that I was present when the subject signed the form. 
 
INVESTIGATOR STATEMENT 
I acknowledge that I have discussed the above study with this subject and answered all of his/her 
questions. They have voluntarily agreed to participate.  I have documented this action in the 
subject’s medical record source documents or research chart source documents, as applicable.  A 
copy of this signed document will be placed in the subject’s medical record or research chart, as 
applicable. A copy of this document will be given to the subject. 
 
 
______________________________________ 
Printed name of Investigator obtaining consent 
 
 
______________________________________ 
 
/ 
 
Signature of Investigator obtaining consent 
Date 
Time (00:00)