Clinical trial NCT02901899
Conditions: Recurrent Fallopian Tube Carcinoma Recurrent Ovarian Carcinoma Recurrent Primary Peritoneal Carcinoma
Sponsor: Northwestern University
Start date: 2016-11-11; Completion date: 2023-03-31
Enrollment: 45 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this study is to look at how patients respond to treatment with guadecitabine and pembrolizumab. The researchers will also be looking at the amount of time it takes for cancer to get worse when participants take the study drugs. All participants will be treated with guadecitabine and pembrolizumab. Guadecitabine interferes with the cancer cells' DNA and can increase the production of certain proteins, making cancer cells more recognizable by the immune system. Pembrolizumab helps your immune system to kill cancer cells. Thus the combination of guadecitabine and pembrolizumab may increase the ability of the immune system to eliminate cancer cells. Researchers want to find out whether the combination of guadecitabine and pembrolizumab is effective in treating ovarian cancer that has not responded to traditional chemotherapy. Participants will keep receiving treatment until their cancer gets worse, they have side effects, or they decide they don't want to receive the treatment anymore. After stopping treatment, the study doctor will watch participants for side effects and follow their condition every 6-12 weeks. The study aims to keep track of participants' medical conditions for the rest of their lives. This helps us look at the long-term effects of the study drugs.

Detailed description:
PRIMARY OBJECTIVES:

I. Measure objective response rate (RR) to guadecitabine and pembrolizumab in subjects with recurrent platinum resistant ovarian cancer (OC).

SECONDARY OBJECTIVES:

I. Measure progression free survival (PFS) for the combination of guadecitabine and pembrolizumab.

II. Progression free survival (PFS). III. Measure clinical benefit rate (CBR) for the combination of guadecitabine and pembrolizumab.

IV. Measure toxicity profiles to the combination of guadecitabine and pembrolizumab.

TERTIARY OBJECTIVES:

I. NY-ESO-1 and MAGE antigens' promoter methylation (pyrosequencing) and messenger ribonucleic acid (mRNA) expression levels (quantitative reverse transcriptase-polymerase chain reaction \[RT-PCR\]) will be measured before and after treatment in deoxyribonucleic acid (DNA) (plasma and/or tumor biopsies) and ribonucleic acid (RNA) (tumor biopsies), respectively.

II. Cytokine response (IFN gamma IL2, IL6, IL10, TNF alpha) will be measured in plasma by enzyme-linked immunosorbent assay (ELISA).

III. Measure LINE 1 methylation in DNA extracted from peripheral blood mononuclear cells (PBMCs) (measured on days 1 and 5 of cycles 1 and 2).

IV. Expression of the PD-L1 ligand will be measured by immunohistochemistry (IHC) in archival tumors.

V. Tumor infiltrating lymphocytes (TILs) will be quantified in tumor biopsies before and after treatment (IHC).

OUTLINE:

Patients receive guadecitabine subcutaneously (SC) on days 1-4 and pembrolizumab intravenously (IV) over 30 minutes on day 5. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 30 days, every 6 weeks for 1 year, and then every 9 weeks and, once a subject experiences confirmed disease progression or starts a new anticancer therapy, every 3 months thereafter.

Arms: arm 1: Patients receive guadecitabine SC on days 1-4 and pembrolizumab IV over 30 minutes on day 5. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.
Interventions: intervention 1: Guadecitabine intervention 2: Laboratory Biomarker Analysis intervention 3: Pembrolizumab
Intervention descriptions: intervention 1: Given SC intervention 2: Correlative studies intervention 3: Given IV

Protocol documents:
Prot_SAP_000.pdf: 
NU Study Number: NU 16G03
Merck Study Number: 3475-244
Version: November 18, 2020 (Amendment 11)
i
An Open Label Phase II Trial of Guadecitabine and Pembrolizumab in
Platinum Resistant Recurrent Ovarian Cancer
Principal Investigator:
Daniela Matei, MD
Northwestern University Feinberg School of Medicine
303 E. Superior St, Suite 04-107
Chicago, Il 60611
Phone: 312.472.4684 
daniela.matei@northwestern.edu
Sub-Investigator(s):
Northwestern University Feinberg School of Medicine
Emma Barber, MD 
Shohreh Shahabi, MD
Wilberto Nieves-Neira, MD 
John Lurain, MD
Northwestern Lake Forest Hospital
Valerie Nelson, MD 
Alok Pant, MD
Affiliate site:
University of Chicago
Gini Fleming, MD
The University of Chicago Medicine
5841 S. Maryland Avenue, MC 2115
Chicago, IL 60637
Ph: (773) 702-6712 
gfleming@medicine.bsd.uchicago.edu
Biostatistician:
Masha Kocherginsky, PhD
Northwestern University Feinberg School of Medicine 
mkocherg@northwestern.edu
Study Intervention(s):
Pembrolizumab (Keytruda) 
Guadecitabine (SGI-110)
IND Number:
131229
IND Holder:
Daniela Matei, MD
Funding Source:
Merck Sharp & Dohme Corp (Funding Support and Pembrolizumab) 
Astex Pharmaceuticals, Inc (Guadecitabine)
Version Date:
November 18, 2020 (Amendment 11)
Coordinating Center:
Clinical Research Office
Robert H. Lurie Comprehensive Cancer Center
Northwestern University
676 N. St. Clair, Suite 1200
Chicago, IL 60611 
http://cancer.northwestern.edu/CRO/index.cfm
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NU Study Number: NU 16G03
Merck Study Number: 3475-244
Version:  November 18, 2020 (Amendment 11)
ii
TABLE OF CONTENTS
TABLE OF CONTENTS ..................................................................................................................ii
LIST OF ABBREVIATIONS ............................................................................................................3
STUDY SCHEMA ............................................................................................................................4
STUDY SUMMARY .........................................................................................................................6
1.0
INTRODUCTION – BACKGROUND & RATIONALE..........................................................9
2.0
OBJECTIVES & ENDPOINTS...........................................................................................17
3.0
PATIENT ELIGIBILITY ......................................................................................................18
4.0
TREATMENT PLAN ..........................................................................................................22
5.0
STUDY PROCEDURES.....................................................................................................35
6.0
ENDPOINT ASSESSMENT...............................................................................................39
7.0
ADVERSE EVENTS ..........................................................................................................45
8.0
DRUG INFORMATION ......................................................................................................51
9.0
CORRELATIVES/SPECIAL STUDIES..............................................................................56
10.0
STATISTICAL CONSIDERATIONS ..................................................................................58
11.0
STUDY MANAGEMENT....................................................................................................60
REFERENCES ..............................................................................................................................64
APPENDICES................................................................................................................................66
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NU Study Number: NU 16G03
Merck Study Number: 3475-244
Version: November 18, 2020 (Amendment 11)
3
LIST OF ABBREVIATIONS
AE
Adverse Event
ALT
Alanine Aminotransferase 
ALC
Absolute Lymphocyte Count 
AST
Aspartate Aminotransferase 
BUN
Blood Urea Nitrogen
CBC
Complete Blood Count
CBR
Clinical Benefit rate
CMP
Comprehensive Metabolic Panel
CR
Complete Response
CT
Computed Tomography
CTCAE
Common Terminology Criteria for Adverse Events
DLT
Dose Limiting Toxicity
DSMB
Data and Safety Monitoring Board 
ECOG
Eastern Cooperative Oncology Group 
ECI
Events of Clinical interest
H&PE
History & Physical Exam
IV (or iv)
Intravenously
irAE
Immune-related Adverse Events
MTD
Maximum Tolerated Dose 
NCI
National Cancer Institute 
OC
Ovarian Cancer
ORR
Overall Response Rate or Objective Response Rate
OS
Overall Survival
PBMCs
Peripheral Blood Mononuclear Cells
PD
Progressive Disease
PFS
Progression Free Survival
PO (or p.o.)
Per os/by mouth/orally
PR
Partial Response
SAE
Serious Adverse Event
SD
Stable Disease
SGOT
Serum Glutamic Oxaloacetic Transaminase
SPGT
Serum Glutamic Pyruvic Transaminase
SQ
Subcutaneous
WBC
White Blood Cells
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Version: November 18, 2020 (Amendment 11)
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NU Study Number: NU 16G03
Merck Study Number: 3475-244
STUDY SCHEMA
PHASE II
Multi-center, Single arm, Open label
Platinum resistant recurrent 
ovarian cancer
Combination therapy:
1 cycle=21 days
Days 1-4: Guadecitabine (SGI-110) 30mg/m2 sq q day1
Day 5: Pembrolizumab 200mg IV
Tumor assessments every 2 cycles up to 
cycle 5; then every 3 cycles
Toxicity assessment every cycle
Treatment will continue until:
-Disease progression
-Unacceptable toxicity2
-Death
-Withdrawal from study
1 Guadecitabine priming can be discontinued and the patient can continue on pembrolizumab 
monotherapy after 6 months (8 cycles) at the discretion of the treating physician, if the patient has 
stable disease or response. If this is done, the previously scheduled pembrolizumab treatment on Day 
5 will become Day 1(+/-2 days).
2 If a patient is unable to tolerate the combination despite dose reduction, but has completed at least
2 cycles of combination therapy, the patient may be permitted to continue on single agent 
pembrolizumab (please see Section 4.4.1 for details and rationale).
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Cycle 1 (21 days) P
SGI-110
Cycle 2
P
SGI-110
1 
2 
3 
4 
5
1 
2 
3 
4 
5 
8
Tumor
Biopsy
•
Plasma
•
PBMC
•
Plasma
•
PBMC
Tumor
Biopsy
Schematic of proposed analyses with the phase II trial (P=Pembrolizumab). 
Tumor biopsies: RNA--tumor antigen expression, IHC for TILs subsets 
Archival tumor IHC: PD-L1
Plasma:  DNA for gene specific methylation (pyrosequencing) 
PBMC: LINE1 methylation (pyrosequencing)
Note: Guadecitabine will be administered on Days 1-4 of 21-day cycles. Pembrolizumab will be 
administered on Day 5 only of 21-day cycles.  During Cycle 2 only, subjects will have an additional 
study visit on Day 8 in order to complete blood collection and tumor biopsy for research purposes. 
Guadecitabine priming can be discontinued and the patient can continue on pembrolizumab 
monotherapy after 6 months (8 cycles) at the discretion of the treating physician, if the patient has 
stable disease or response. If this is done, the previously scheduled pembrolizumab treatment on Day 
5 will become Day 1(+/-2 days).
For patients who discontinued guadecitabine for reasons other than toxicity (i.e. disease stability of 
response > 6 months) and progress on pembrolizumab alone, a re-trial of guadecitabine in 
combination with pembrolizumab is possible, at the discretion of the treating physician, if the patient is 
clinically stable.
Please refer to Section 9.0 for more details about correlative analysis.
`
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Version: November 18, 2020 (Amendment 11)
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NU Study Number: NU 16G03
Merck Study Number: 3475-244
STUDY SUMMARY
Title
An Open Label Phase II Trial of Guadecitabine and Pembrolizumab in
Platinum Resistant Recurrent Ovarian Cancer
Short Title
Guadecitabine and pembrolizumab in platinum resistant recurrent 
ovarian cancer
Version
November 18, 2020 (Amendment 11)
Study Design
This will be an open label phase II trial with a safety run-in component 
testing the experimental combination of guadecitabine and 
pembrolizumab.
Study Center(s)
Lead site: Robert H.  Lurie Comprehensive Cancer Center 
(RHLCCC) Affiliate site: University of Chicago
Objectives
Primary Objective:
Measure Objective Response Rate (ORR) to guadecitabine and 
pembrolizumab in patients with recurrent platinum resistant ovarian 
cancer.
Secondary Objectives:
 
Measure Progression Free Survival (PFS) and Clinical Benefit Rate
(CBR) to the combination of guadecitabine and pembrolizumab.
 
Measure toxicity profiles to the combination of guadecitabine and 
pembrolizumab.
Refer to Section 2.0 for Exploratory Objectives.
Sample Size
Maximum accrual limit: 46
Evaluable subjects: 35
ESTIMATED 
ENROLLMENT PERIOD
Estimated 24 months
ESTIMATED STUDY 
DURATION
Estimated 36 months
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Diagnosis & Key
Eligibility Criteria
Inclusion Criteria:
1.   Histological or cytological evidence/confirmation of epithelial ovarian 
cancer, primary peritoneal carcinomatosis, or fallopian tube cancer.
2.    Patients must have recurrent platinum-resistant disease, defined as 
progression < 6 months after completion of platinum-based 
chemotherapy or as persistent disease that remains after completing 
the most recent line of platinum-based therapy. The platinum-free 
interval should be calculated from the last administered dose of 
platinum therapy.
3.   Measurable disease according to RECIST 1.1 ≤28 days prior to 
registration.
4.   Prior therapy allowed:
 
At least one and no more than 3 platinum based chemotherapy 
regimens.
 
Up to 2 non-platinum, cytotoxic regimens.
 
There is no limit on use of prior biological therapies (hormonal or 
targeted therapy).
 
Prior immunotherapy is not allowed.
5.   Demonstrate adequate organ function (see section 3.1).
Exclusion Criteria:
1.   Has a diagnosis of immunodeficiency or is receiving systemic steroid 
therapy or any other form of immunosuppressive therapy ≤7 days 
prior to the first dose of trial treatment.
2.   Hypersensitivity to pembrolizumab or any of its excipients.
3.   Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD- 
L2 agent.
4.   Has had a prior anti-cancer monoclonal antibody (mAb) ≤4 weeks 
prior to registration or who has not recovered (i.e., ≤ Grade 1 or at 
baseline) from adverse events due to agents administered more than
4 weeks earlier.
5.   Has had prior chemotherapy, targeted small molecule therapy, or 
radiation therapy ≤ 2 weeks prior to registration 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.
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NU Study Number: NU 16G03
Merck Study Number: 3475-244
Treatment Plan
Trial treatment should be administered on Day 1 of each cycle after all 
procedures/assessments have been completed as detailed on the 
Schedule of Events Calendar and Section 5.0. Trial treatment may be 
administered up to +28 days after the scheduled Day 1 of each cycle due 
to administrative reasons. All trial treatments will be administered on an 
outpatient basis.
Guadecitabine 30mg/m2 will be administered as a subcutaneous injection 
on Days 1-4 of every 21 day cycle.
Pembrolizumab 200 mg will be administered as a 30 minute IV infusion 
on Day 5 of every 21 day cycle.
Note: Guadecitabine priming can be discontinued and the patient can 
continue on pembrolizumab monotherapy after 6 months (8 cycles) at the 
discretion of the treating physician, if the patient has stable disease or 
response. If this is done, the previously scheduled pembrolizumab 
treatment on Day 5 will become Day 1(+/-2 days).
For patients who discontinued guadecitabine for reasons other than 
toxicity (i.e. disease stability of response > 6 months) and progress on 
pembrolizumab alone, a re-trial of guadecitabine in combination with 
pembrolizumab is possible, at the discretion of the treating physician, if 
the patient is clinically stable.
To exclude prohibitive toxicity, a safety run-in cohort of the initial 6 
patients will be done. All subjects in the safety run-in cohort will be 
observed for at least 2 weeks after completion of cycle 1 for dose limiting 
toxicity (DLT) (Refer section 4.3)
Statistical Methodology
This is a non-randomized, open label phase II study. Study endpoints are 
defined in Section 6.0
We will utilize the optimum two stage design, and we anticipate enrolling
35 evaluable patients. This two-stage design, which will test the null 
hypothesis that ORR<=0.10 versus the alternative that ORR>=0.30 
(where ORR is calculated via RECIST v1.1), has an expected sample 
size of 22.5 and a probability of early termination of 0.71 when 
ORR=0.10. If the drug combination is actually not effective, there is a 
0.047 probability of concluding that it is (the target for this value was 
0.050). If the drug is actually effective, there is a 0.098 probability of 
concluding that it is not (the target for this value was 0.100). After testing 
the drug on 18 patients in the first stage, consideration will be given to 
trial termination if 2 or fewer patients demonstrate clinical benefit (CR, 
PR, or SD for at least 3 months). If the trial goes on to the second stage, 
a total of 35 evaluable patients will be studied. If the total number 
responding is less than or equal to 6, the combination is rejected. 
Subjects who are not evaluable for response will be replaced so that up 
to 46 subjects will be enrolled.
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Relative mRNA
expression level
*
1.0
INTRODUCTION – BACKGROUND & RATIONALE
1.1
Ovarian Cancer Background
Ovarian cancer (OC) causes more deaths than any other female reproductive tract 
cancer 3,4. The majority of women diagnosed with advanced-stage epithelial OC 
experience tumor recurrence associated with the development of chemo-resistance, 
and platinum-resistant OC is uniformly fatal 5. Development of novel therapies for this 
deadly cancer is critically needed. The analysis of the ovarian cancer tumor genome 
revealed that molecular subtypes are difficult to define and target, the majority of 
tumors being characterized by complex genomic alterations with tens of mutations 
and chromosomal aberrations occurring per tumor. Targeted therapy, therefore, is 
unlikely to succeed in OC.
Immunotherapy has demonstrated efficacy in some cancers (melanoma, lung and 
renal cell carcinoma). Although preclinical evidence provides the rationale for 
investigating immunotherapy in OC, clinical trials testing immune approaches 
(vaccines, IL2, ipilimumab) have not been successful to date. New immunologic 
approaches targeting immune checkpoint pathways are showing promise in clinical 
development for other solid tumors 6. Immune checkpoint pathways such as the 
programmed cell death protein-1 (PD-1) block T-cell activation as a physiologic 
response that keeps nascent T-cells in check and prevents immune responses 
against normal tissues. During tumorigenesis, cancer cells exploit this co-inhibitory 
pathway to avoid elimination by the adaptive immune system. One such mechanism 
is aberrant expression of PD ligands (PD-L) on tumor cells which leads to impaired 
antitumor immunity and immune evasion. In an analysis of OC specimens, increased 
PD-L1 expression was correlated with decreased intratumoral CD8(+) T lymphocytes 
and worse survival 7. In addition dendritic cells expressing PD1 have been identified 
in the OC microenvironment in association with suppressed T cell activity and 
decreased infiltrating T cells in advanced ovarian tumors8. The expression of the T 
cell exhaustion marker PD1 correlated with decreased number of TILs in an OC 
xenograft model and PD-1/PD-L1 blockade restored anti-tumor immunity9. This 
evidence supports testing PD1-blockade in OC. The focus of this protocol is to 
develop a combination regimen that enhances the activity of PD1-targeted 
immunotherapy in OC.
Mage-A2 
Mage-A11 
NY-ESO-1 
Muc16
* 
*
*
DMSO   SGI-110 
DMSO   SGI-110 
DMSO  SGI-110 
DMSO  SGI-110
Figure 1. SGI-110-induced expression of tumor antigens.  SKOV3  OC cells were 
treated with DMSO (control) or SGI-110 (100 nM) for 72 hours. Quantitative RT- 
PCR measured mRNA expression levels of Mage-A2 and –A11, NY-ESO-1 and Muc
16.  Results are presented as fold change vs. control. * denote p<0.05
1.2
Intervention Background & Overview
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
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NU Study Number: NU 16G03
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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 1,2.
1.2.1
Pembrolizumab (Keytruda) background
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.On September 4, 
2014, the Food and Drug Administration (FDA) granted accelerated approval 
to pembrolizumab(Keytruda), made by Merck Sharp & dohme Corp.) for the 
treatment of patients with unresectable or metastatic melanoma whose 
disease progressed following treatment with ipilimumab and, if BRAF V600 
mutation positive, a BRAF inhibitor.
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In Oct. 2015, the U.S. Food and Drug Administration granted accelerated 
approval for Keytruda (pembrolizumab) to treat patients with advanced 
(metastatic) non-small cell lung cancer (NSCLC) whose disease has 
progressed after other treatments and with tumors that express a protein 
called PD-L1. Keytruda was approved for use with a companion diagnostic, 
the PD-L1 IHC 22C3 pharmDx test, the first test designed to detect PD-L1 
expression in non-small cell lung tumors.
1.3
Guadecitabine (SGI-110) Background
Guadecitabine is a dinucleotide incorporating decitabine (5-aza-2’-deoxycytidine) and 
deoxyguanosine that act as pro-drugs of decitabine. Guadecitabine is resistant to 
modification by cytidine deaminase leading to longer half-life compared to decitabine 
and ensuring prolonged exposure to the active compound and sustained 
hypomethylating effect in vivo16. The FDA has granted an orphan drug designation
for Astex Pharmaceuticals’ investigational drug, guadecitabine (SGI-110), in the 
treatment of acute myeloid leukemia (AML). Guadecitabine is currently being 
evaluated in a large global Phase 3 study (ASTRAL-1) in treatment naïve AML 
patients who are unfit to receive, or unsuitable for, intensive induction chemotherapy. 
For complete information on guadecitabine please refer to the Investigator’s Brochure 
(IB).
The active metabolite of guadecitabine (2’-deoxy-5-azacytidylyl-(3’→5’)-2’- 
deoxyguanosine sodium salt), a dinucleotide, is decitabine. Guadecitabine is 
resistant to modification by cytidine deaminase, a common pathway of decitabine 
metabolism and deactivation 20,21. The molecular weight of guadecitabine and 
decitabine are 580 Da and 228 Da, respectively. Therefore, the molar equivalent 
dose of 1 mg of decitabine is approximately 2.5 mg of guadecitabine. 
Guadecitabine’s activity was demonstrated with the same preclinical 
pharmacodynamic assays used to demonstrate decitabine’s efficacy e.g., re- 
expression of p15, p16, and MLH1 and induction of fetal hemoglobin, in vivo. In 
xenograft studies, guadecitabine demonstrates promising preclinical activity in both 
hematologic and solid tumors.
Guadecitabine was developed for subcutaneous administration. Guadecitabine is 
pharmacologically active both in vitro and in vivo in a variety of tumor cells and 
murine xenograft models when administered subcutaneously. Treatment is well 
tolerated via the subcutaneous route in murine xenografts. When administered 
subcutaneously to non-human primates, guadecitabine releases decitabine slowly 
compared to other species, possibly prolonging the effect over longer periods. 
Guadecitabine has been developed as a non-aqueous formulation to ensure 
formulation stability.
In vitro and in vivo evidence suggest that guadecitabine has a longer half-life than 
decitabine in the presence of cytidine deaminase. These promising observations 
suggest that guadecitabine has improved pharmaceutical properties and biological 
activities that expand on decitabine’s current clinical utility. Pharmacokinetic studies 
in a recent clinical trial in patients with ovarian cancer testing 2 dose levels of 
guadecitabine (30mg/kg QD x 5 days) and 45mg/m2 QD x 5 days) shows that in vivo 
exposure to active decitabine is much longer with guadecitabine compared to the 
parent drug decitabine (Figure 3).
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Figure 3: Decitabine exposure window after SQ injection of guadecitabine is 
prolonged compared to previously published data of decitabine IV infusion
1.3.1
Nonclinical Pharmacokinetics of Guadecitabine
The overall pharmacokinetic characteristics of guadecitabine are 
summarized as follows. The relative bioavailability of guadecitabine dosed 
subcutaneously to the rat is close to 100%. Circulating guadecitabine levels 
were very low in the mouse, rat and rabbit. However, higher levels were 
observed in the monkey post subcutaneous dosing. A rapid decline in 
systemic exposure of guadecitabine with an elimination plasma half-life 
(T1/2) in the range of 0.4-1 hours was observed in rat and monkey.
High levels of decitabine were observed after a subcutaneous dose of 
guadecitabine in the mouse, rat, and rabbit (maximum in rat, 54 μg/mL). 
Levels in the monkey (maximum 463 ng/mL) were substantially lower. A 
Rapid decline in systemic exposure of decitabine with an elimination plasma 
T1/2 of 3.7 hour in rat and 1 hour in monkey was observed.
In monkey, pharmacokinetic parameters were similar on Day 1 and Day 15 of 
a study in which they were dosed once weekly for three consecutive weeks, 
suggesting no significant accumulation of the parent or the active metabolite, 
decitabine.
The metabolic characteristics of guadecitabine are summarized as follows. 
Guadecitabine was more stable in human, dog and mouse and was less 
stable in rat and rabbit plasma. Incubation of guadecitabine with liver 
microsomes from mouse, rat, rabbit, dog and human showed little apparent 
metabolism of the compound. Incubation of guadecitabine with human 
hepatocytes also showed little apparent metabolism of the compound, based 
on disappearance of the parent. Guadecitabine does not significantly bind to 
human plasma proteins; the in vitro unbound fraction was estimated to be
91%. Guadecitabine has poor in vitro bidirectional permeability, which 
correlates well with its poor oral absorption in vivo. Guadecitabine shows no 
appreciable induction of CYP1A1/2, CYP2C9 and CYP3A4 in human 
hepatocytes. Guadecitabine does not have any CYP450 inhibitory effect on 
CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A4.
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1.3.2
Nonclinical Safety of Guadecitabine
Guadecitabine toxicity findings in rat and rabbit studies are similar to the non- 
clinical study findings of decitabine in New Drug Application (NDA)
supporting Good Laboratory Practices (GLP) toxicology studies. 
Myelosuppression, decreases in thymus weight, and testicular atrophy (the 
main findings of the guadecitabine studies) were also observed as the main 
study findings in repeat dose toxicity studies with decitabine in mice, rats, 
rabbits, and dogs. As with guadecitabine, myelosuppression and thymus 
toxicities after decitabine administration were reversible during recovery 
periods, while testicular atrophy persisted. Myelosuppression, particularly 
neutropenia, has been reported as a dose-limiting toxicity for decitabine in 
human clinical studies. Signs of testicular toxicity have not been observed in 
any of the published clinical studies of decitabine to date 17,22.
No studies have been performed to evaluate the genotoxic, mutagenic, 
carcinogenic or reproductive and developmental toxicity of guadecitabine. 
Decitabine may have genotoxic potential; decitabine is mutagenic and in 
preclinical studies in mice and rats, decitabine was teratogenic, fetotoxic, and 
embryotoxic.
1.3.3
Guadecitabine Clinical Data
For the most updated clinical data, please refer to the most recent
Investigator Brochure.
Guadecitabine was studied in a first-in-human, single-agent study (SGI-110-
01). This study was a Phase 1/2, dose escalation, multicenter study of two 
subcutaneous regimens of guadecitabine in subjects with intermediate or 
high-risk myelodysplastic syndromes (MDS) or acute myeloid leukemia 
(AML). This study had two parts: a Dose Escalation Segment and a Dose 
Expansion Segment. The study sought to evaluate the biological activity, 
preliminary safety, and efficacy of guadecitabine with two dosing schedules 
in intermediate to high risk MDS or relapsed or refractory AML subjects,
while the Dose Expansion Segment further evaluated the safety and efficacy 
at the recommended dose. The study was based on a 3 + 3 design within 
each regimen. The recommended dose going forward was 60mg/m2 QD x 5 
days, every cycle being 28 days 22.
Guadecitabine was also studied in a phase I leading into a randomized 
phase II study in combination with Carboplatin in patients with recurrent 
ovarian cancer (Study SGI-110-02). Two dose levels of guadecitabine were 
studied:  30mg/m2 QD x 5 days with Carboplatin AUC 4 and 45mg/m2 qd X
5 days with Carboplatin AUC 5. The second dose level was not tolerated, 
with neutropenic fever and thrombocytopenia being DLTs. The dose taken 
for further development in the randomized phase II portion of the trial was
30mg/m2 QD x 5 days with Carboplatin AUC, each cycle being 28 days17.
1.3.4
Clinical Efficacy/Biological Activity/Safety of Guadecitabine
Based on PD assessment of global hypomethylation from the first 7 cohorts 
in Study SGI-110-01, the LINE-1 demethylation data show dose dependent 
hypomethylation induction in the daily schedule reaching a plateau at cohort
5 (60 mg/m2). The Biologically Effective Dose or BED, therefore, was 
established as 60 mg/m2 SC daily x 5. The hypomethylation of the weekly 
schedule was inferior to the daily schedule and plateaued early (daily x 5) 22. 
In the ovarian cancer SGI-110-02 study, LINE-1 methylation was measured 
at both dose levels (Figure 4). Effective LINE-1 hypomethylation (~-17%) 
was observed and was similar at both dose levels 17. Therefore, in this
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protocol, we will use the lower dose of 30mg/m2, which has been shown to 
induce hypomethylation and gene re-expression.
Of note is that the current protocol will use a shorter cycle duration (21 days, 
as compared to 28 days in previous studies). We will use the 21 day course 
to accommodate a regimen giving pembrolizumab q 3 weeks. We anticipate 
that the shorter course will be tolerated, given that 30mg/m2 daily for 5 days 
given in combination with Carboplatin was tolerated.
Figure 4 LINE-1 Demethylation in Blood DNA B) Individual Patients Max LINE-1
Demethylation
1.4
Rationale for the Current Study
We speculate that an important mechanism of immune evasion in OC is represented 
by epigenetic silencing of tumor antigens. We and others have shown that OC 
progression is accompanied by the establishment of stable and transcriptionally 
repressive epigenetic modifications 10, 11. Some of these modifications include DNA 
methylation at promoters of genes encoding tumor antigens that serve as potent 
immunogenic stimuli in the anti-tumor response. DNA methylation is regulated by 
DNA methyl transferases (DNMT-1, -3a and -3b). Recent studies have shown that 
DNMT inhibitors (DNMTI) cause DNA hypomethylation and restore the expression of 
epigenetically silenced genes, including tumor suppressor genes 12 and tumor 
antigens. DNMTIs have become therapeutically relevant in hematologic cancers 13,14
and are being explored in solid tumors in combination with chemotherapy 15. Here we 
hypothesize that the use of a novel DNMTI (guadecitabine) will reverse
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Percent DNA methylation
silencing of tumor antigens, restore their expression, and potentiate the effects 
of immune interventions.
Our preliminary data support that treatment with guadecitabine in vitro causes 
significant up-regulation of tumor antigens including Muc16 (encoding CA-125), Mage 
A2, Mage A11, and cancer testis antigen (NY-ESO 1) in OC cell lines (Fig. 1). We 
speculate that these effects render OC cells more recognizable by the immune
system in vivo. Furthermore, analyses of tumor material obtained from another 
ongoing clinical trial using guadecitabine in combination with carboplatin in women 
with OC17 showed significant treatment-induced hypomethylation of Mage A2 and 
Mage A11 (as measured by DNA pyrosequencing, Fig. 2A) in tumor biopsies 
obtained after 2 cycles of guadecitabine compared to baseline biopsies. Re- 
expression of the tumor antigens NY-ESO-1 and MAGE A3 was confirmed by RT-
PCR in tumor biopsies obtained after 2 cycles of guadecitabine compared to baseline 
(Fig. 2), demonstrating that hypomethylating agents induce tumor antigen re- 
expression in human tumors, by reducing DNA methylation. These data support a 
strategy combining epigenome editing using guadecitabine along with 
immunomodulatory approaches, as proposed here. Based on the recent knowledge 
that the anti-PD1 antibody pembrolizumab (P) has impressive clinical activity in solid 
tumors18,19, and is well tolerated and induces durable responses in patients with 
advanced epithelial ovarian cancer, we propose to use PD-1 blockade (P) in 
combination with guadecitabine in preclinical and clinical OC models.  
A. 
B.
Fig. 2: Methylation and expression of tumor antigens in biopsies obtained from 
patients enrolled on a clinical trial testing SGI-110 and carboplatin in OC.  Tumor 
biopsies were obtained at baseline and on Cycle 3, Day 8, after 3 cycles of  SGI-110. A. 
DNA methylation measured by pyrosequencing in tumor biopsies. B. Fold change in 
expression levels measured by RT PCR in tumor biopsies before and after SGI-110 
treatment (bars are averages +/- SD).
1.4.1
Rationale for Dose Selection/Regimen/Modification
An open-label Phase I trial (Protocol 001) evaluated 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 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
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IB). Pharmacodynamic data (IL-2 release assay) suggested that peripheral 
target engagement is durable (>21 days). This early PK and 
pharmacodynamic data provides scientific rationale for testing a Q2W and 
Q3W dosing schedule.
A population pharmacokinetic analysis has been performed using serum 
concentration time data from 476 patients. Within the resulting population PK 
model, clearance and volume parameters of MK-3475 were found to be 
dependent on body weight. The relationship between clearance and body 
weight, with an allometric exponent of 0.59, is within the range observed for 
other antibodies and would support both body weight normalized dosing or a 
fixed dose across all body weights. MK-3475 has been found to have a wide 
therapeutic range based on the melanoma indication. The differences in 
exposure for a 200 mg fixed dose regimen relative to a 2 mg/kg Q3W body 
weight based regimen are anticipated to remain well within the established 
exposure margins of 0.5 – 5.0 for MK-3475 in the melanoma indication. The 
exposure margins are based on the notion of similar efficacy and safety in 
melanoma at 10 mg/kg Q3W vs. the proposed dose regimen of 2 mg/kg
Q3W (i.e. 5-fold higher dose and exposure). The population PK evaluation 
revealed that there was no significant impact of tumor burden on exposure. 
In addition, exposure was similar between the NSCLC and melanoma 
indications. Therefore, there are no anticipated changes in exposure 
between different indication settings.
The rationale for further exploration of 2 mg/kg and comparable doses of 
pembrolizumab in solid tumors is based on: 1) similar efficacy and safety of 
pembrolizumab when dosed at either 2 mg/kg or 10 mg/kg Q3W in 
melanoma patients, 2) the flat exposure-response relationships of 
pembrolizumab for both efficacy and safety in the dose ranges of 2 mg/kg 
Q3W to 10 mg/kg Q3W, 3) the lack of effect of tumor burden or indication on 
distribution behavior of pembrolizumab (as assessed by the population PK 
model) and 4) the assumption that the dynamics of pembrolizumab target 
engagement will not vary meaningfully with tumor type.
The choice of the 200 mg Q3W as an appropriate dose for the switch to fixed 
dosing is based on simulations performed using the population PK model of 
pembrolizumab showing that the fixed dose of 200 mg every 3 weeks will 
provide exposures that 1) are optimally consistent with those obtained with 
the 2 mg/kg dose every 3 weeks, 2) will maintain individual patient exposures 
in the exposure range established in melanoma as associated with maximal 
efficacy response and 3) will maintain individual patients exposure in the 
exposure range established in melanoma that are well tolerated and safe.
A fixed dose regimen will simplify the dosing regimen to be more convenient 
for physicians and to reduce potential for dosing errors. A fixed dosing 
scheme will also reduce complexity in the logistical chain at treatment 
facilities and reduce wastage.
To match the required q 3 weeks administration of pembrolizumab, the cycle 
of guadecitabine has been modified from D1-5 every 4 weeks (as previously 
administered in Study SGI-110-02) to a regimen using D1-4 every 3 weeks. 
This modification allows the administration of similar doses of guadecitabine 
over time (e.g. 480mg/m2 in 12 weeks with the 3 weekly regimen compared 
to 450mg/m2 in 12 weeks with the 4 weekly regimen). The D1-4 
guadecitabine regimen every 3 weeks has been found to be tolerable in a
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cholangiocarcinoma study (personal communication from Astex, 
unpublished).
1.4.2
Safety run-in cohort
As stated earlier, this study proposes to use the combination of 
pembrolizumab with guadecitabine in subjects with ovarian cancer. The 
combination of pembrolizumab with guadecitabine has not been previously 
tested in this subject population. Hence, a safety run-in cohort has been 
designed for the first six subjects enrolled, in order to ensure the safety of
this combination of agents. Refer to section 4.3 for details on how this will be 
conducted.
1.5
Exploratory Studies
To test the hypothesis that the combination of guadecitabine and pembrolizumab 
reactivates immune responses by allowing re-expression of tumor antigens silenced 
epigenetically, we will measure several exploratory endpoints. All biological 
parameters will be correlated with clinical endpoints (ORR, CBR, and PFS).
 
NY-ESO-1 and MAGE antigens’ promoter methylation (pyrosequencing) and 
mRNA expression levels (quantitative RT-PCR) will be measured before and 
after treatment in DNA (plasma and tumor biopsies) and RNA (tumor biopsies), 
respectively.
 
Cytokine response (IFN IL2, IL6, IL10, TNF) will be measured in plasma by
ELISA.
 
Expression of the PD-L1 ligand will be measured by IHC in archival tumors.
 
Measure LINE 1 methylation in DNA extracted from PBMCs (D5 vs. D1 of 
cycles 1 and 2).
 
Tumor infiltrating lymphocytes (TILs) will be quantified in tumor biopsies before 
and after treatment (IHC),  including in optional samples collected > 6 months 
on treatment.
.
2.0
OBJECTIVES & ENDPOINTS
2.1
Primary Objective & Endpoint
Measure objective response rate (ORR) to guadecitabine and pembrolizumab in 
subjects with recurrent platinum resistant Ovarian Cancer (OC) using RECIST 
v1.1.The objective response rate as defined by RECIST v1.1 is the proportion of all 
subjects with confirmed PR or CR according to RECIST v1.1, from the start of 
treatment until disease progression/recurrence (taking as reference for progressive 
disease the smallest measurements recorded since the start of treatment).
2.2
Secondary Objectives & Endpoints
2.2.1
Measure progression free survival (PFS) for the combination of 
guadecitabine and pembrolizumab.
Progression free survival (PFS) is defined per RECIST v1.1 as the time from 
the date of registration until the criteria for disease progression is met as 
defined by RECIST 1.1 or death occurs.
2.2.2
Measure clinical benefit rate (CBR) for the combination of guadecitabine and 
pembrolizumab.
(Note: CBR is defined as Objective Response Rate (CR + PR) plus Stable 
Disease for at least 3 months)
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2.2.3
Measure toxicity profiles to the combination of guadecitabine and 
pembrolizumab.
2.2.4   Measure objective response rate (ORR) to the combination of 
guadecitabine and pembrolizumab using the Immune Related Response 
Criteria (irRC) (Note: Response assessments will be made using both irRC 
and RECIST v1.1, allowing additional comparisons among these criteria for 
disease response assessment. Measurable and non-measurable lesions 
will be followed by both RECIST v1.1 & irRC. Disease progression will be 
determined using RECIST 1.1 criteria. (Refer to section 6.0 for details.)
2.3
Exploratory Objectives & Endpoints
 
NY-ESO-1 and MAGE antigens’ promoter methylation (pyrosequencing) and 
mRNA expression levels (quantitative RT-PCR) will be measured before and 
after treatment in DNA (plasma and/or tumor biopsies) and RNA (tumor 
biopsies), respectively.
 
Cytokine response (IFN IL2, IL6, IL10, TNF) will be measured in plasma by
ELISA.
 
Measure LINE 1 methylation in DNA extracted from PBMCs (measured on days
1 and 5 of cycles 1 and 2).
 
Expression of the PD-L1 ligand will be measured by IHC in archival tumors.
 
Tumor infiltrating lymphocytes (TILs) will be quantified in tumor biopsies before 
and after treatment (IHC), including in optional samples collected > 6 months 
on treatment.
3.0
PATIENT ELIGIBILITY
The target population for this study is patients with platinum resistant recurrent ovarian 
cancer. This will be a multicenter-trial conducted at Robert H. Lurie Comprehensive Cancer 
Center of Northwestern University (RHLCCC). Northwestern University will serve as the lead 
site and coordinating center for this study. Participating sites will include the University of 
Chicago.
A total of up to 46 subjects will be needed to obtain 35 evaluable subjects for this trial. 
Approximately 6-8 potentially eligible patients are seen per month, and it is anticipated that at 
least 1-2 per month will be accrued.
Subjects must meet all of the inclusion and none of the exclusion criteria to be registered to 
the study. Study treatment may not begin until a subject is registered. Please refer to Section
11 for complete instructions regarding registration procedures.
3.1
Inclusion Criteria
3.1.1
Patients must have a histological or cytological evidence/confirmation of 
epithelial ovarian cancer, primary peritoneal carcinomatosis, or fallopian tube 
cancer
3.1.2
Patients must have Measurable disease according to RECIST 1.1 ≤28 days 
prior to registration. (Appendix 3).
3.1.3
Patients must have recurrent platinum-resistant disease, defined as 
progression < 6 months after completion of platinum-based chemotherapy 
or as persistent disease that remains after completing the most recent line of 
platinum-based therapy. The platinum-free interval should be calculated 
from the last administered dose of platinum therapy.
3.1.4
Prior therapy allowed:
•At least one and no more than 3 platinum based chemotherapy regimens. 
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•
Up to 2 non-platinum, cytotoxic regimens.
•
There is no limit on use of prior biological therapies (hormonal or 
targeted therapy).
NOTE: Prior immunotherapy is not allowed.
3.1.5
Patients must be age ≥ 18 years.
3.1.6
Patients must exhibit an ECOG performance status of 0-1 ≤14 days prior to 
registration (Appendix 2).
3.1.7
Patients must demonstrate adequate organ function as defined in Table 1 
below; all screening labs to be obtained ≤14 days prior to registration.
(Note: Screening labs will be repeated again on C1D1 if they were performed 
outside of the ≤4 day window.)
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 
growth factor support/EPO dependency)
Renal
Serum creatinine OR
Measured or calculateda creatinine 
clearance
(GFR can also be used in place of 
creatinine or CrCl)
≤1.5 X upper limit of normal (ULN) OR
≥60 mL/min for subject with creatinine levels > 1.5 X
institutional ULN.
Hepatic
Serum total bilirubin
≤ 1.5 X ULN OR
Direct bilirubin ≤ ULN for subjects with total bilirubin 
levels > 1.5 ULN
AST (SGOT) and ALT (SGPT)
≤ 2.5 X ULN OR ≤ 5 X ULN for subjects with liver 
metastases.
Albumin
>2.5 mg/dL
Coagulation
International Normalized Ratio
(INR) or Prothrombin Time (PT)
Activated Partial Thromboplastin
Time (aPTT)
≤1.5 X ULN unless subject is receiving anticoagulant 
therapy as long as PT or PTT is within therapeutic 
range of intended use of anticoagulants.
≤1.5 X ULN unless subject is receiving anticoagulant 
therapy as long as PT or PTT is within therapeutic 
range of intended use of anticoagulants.
aCreatinine clearance should be calculated per institutional standard.
3.1.8
Be willing to allow the use of archival formalin-fixed paraffin-embedded tumor 
tissue for correlative analyses.
Note: The archived tumor tissue specimens may be from prior surgery or 
from prior diagnostic biopsy of primary or metastatic tumor specimen. 
Unavailability of archived tissue will not render subject ineligible for study.
3.1.9
Be willing and able to undergo a core or excisional tumor biopsy according to 
institutional standards (guided visually or by computed tomography [CT] or 
ultrasound), paracentesis, or thoracentesis for tumor cells.
Note: This is to be done prior to treatment at C1D1 and post-treatment (Cycle
2 Day 8), if this is clinically and safely feasible to do so. This will allow the 
use of this freshly obtained tissue for correlative analyses in the study.
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3.1.10
Females of child-bearing potential (FOCBP) must agree to use adequate 
contraception (Appendix 1)  prior to registration, for the duration of study 
participation, and for 120 days following completion of therapy. Should a 
female patient become pregnant or suspect she is pregnant while 
participating in this study, she should inform her treating physician 
immediately.
NOTE: A FOCBP is any woman (regardless of sexual orientation, having 
undergone a tubal ligation, or remaining celibate by choice) who meets the 
following criteria:
 
Has not undergone a hysterectomy or bilateral oophorectomy
 
Has had menses at any time in the preceding 12 consecutive months
(and therefore has not been naturally postmenopausal for > 12 months)
3.1.11
FOCBP must have a negative pregnancy test ≤7 days prior to registration on 
study.
3.1.12
Patients must have the ability to understand and the willingness to sign a 
written informed consent prior to registration on study.
3.2
Exclusion Criteria
3.2.1
Has had prior chemotherapy, targeted small molecule therapy, or radiation 
therapy ≤14 days prior to registration 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.
3.2.2   Has had a prior anti-cancer monoclonal antibody (mAb) ≤28 days prior to 
registration or who has not recovered (i.e., ≤ Grade 1 or at baseline) from 
adverse events due to agents administered more than 4 weeks earlier.
3.2.3
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 ≤28 days prior to registration.
3.2.4
Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy 
or any other form of immunosuppressive therapy ≤7 days prior to the first 
dose of trial treatment.
3.2.5
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.
3.2.6
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 28 days prior to registration and any neurologic 
symptoms have returned to baseline), have no evidence of new or enlarging
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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.
3.2.7
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.
3.2.8
Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 
agent. Please contact the Principal Investigator for further clarification if 
needed.
3.2.9
Hypersensitivity to pembrolizumab or any of its excipients.
3.2.10  Has a known history of active TB (Bacillus Tuberculosis).
3.2.11  Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 
antibodies) infection.
3.2.12  Has a known history of Hepatitis B and/or Hepatitis C infection.
3.2.13  Has known history of (non-infectious) pneumonitis that required steroids, or 
current pneumonitis.
3.2.14  Has an active infection requiring systemic therapy within 3 days of 
registration (NOTE: except for uncomplicated Urinary Tract Infection (UTI)).
3.2.15  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.
3.2.16  Has known psychiatric or substance abuse disorders that would interfere with 
cooperation with the requirements of the trial.
3.2.17  Has received a live vaccine ≤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.
3.2.18  Female patients who are pregnant or nursing, or expecting to conceive 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. Subjects should 
not breast feed ≤120 days of completing the trial.
3.2.19  Is or has an immediate family member (e.g., spouse, parent/legal guardian, 
sibling or child) who is investigational site or sponsor staff directly involved 
with this trial, unless prospective IRB approval (by chair or designee) is given 
allowing exception to this criterion for a specific subject.
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4.0
TREATMENT PLAN
4.1
Overview
All subjects will be treated in cycles lasting 21 days (3 weeks). The drugs being used 
in this study include pembrolizumab and guadecitabine. Guadecitabine 30mg/m2 will 
be administered as a subcutaneous injection on Days 1-4 of every 21 day cycle. 
Pembrolizumab 200 mg will be administered as a 30 minute IV infusion on Day 5 of 
every 21 day cycle. Patients must begin therapy within (+) 14 days of 
registration.
For patients on combination therapy, treatment should be initiated on Day 1 of each 
cycle. NOTE: For patients receiving the combination of guadecitabine and 
pembrolizumab, guadecitabine dosing on Day 1 of each cycle should always begin 
on a Monday in order for the patient to receive pembrolizumab on Friday (Day 5). In 
the event of holidays or scheduling difficulties for administrative reasons, Day 1 of 
each cycle may be delayed up to +28 days.  All treatments will be administered on 
an outpatient basis. Treatment will continue until disease progression, unacceptable 
toxicity, patient withdrawal, or death. NOTE: please see section 4.4.1 for conditions 
under which patients may be permitted to continue on single agent pembrolizumab 
only. One dose of guadecitabine may be skipped during a cycle due to scheduling 
constraints with holidays (e.g. if Memorial Day is on a weekday, the patient may skip 
that dose of guadecitabine).  The decision to skip a dose of guadecitabine vs dose 
delay will be at the discretion of the treating physician.
Please refer to Section 5.2 (table) for treatment details regarding patients on 
Pembrolizumab monotherapy.  
To exclude prohibitive toxicity, a safety run-in cohort of the initial 6 patients will be 
done. All subjects in the run-in cohort will be observed for at least 2 weeks after 
completion of cycle 1 for dose limiting toxicity (DLT) (Refer section 4.3)
4.2
Treatment Administration
Agent2
Dose
Route
Schedule2
Cycle
Length
Pembrolizumab
200 mg
IV infusion
Day 5 of each 3 week 
cycle
(Q3W)
.Guadecitabine1,2
30mg/m2
SQ
injection
Days 1-4 of each cycle
(QD for
4 days)
21days
(3 weeks)
1 The starting dose for guadecitabine is 30 mg/m2; in the event that dose reduction is 
necessary (see 4.4.1), dose level -1 will be 24 mg/m2. There are no further dose 
reductions. 
Note: Guadecitabine priming can be discontinued and the patient can continue on 
pembrolizumab monotherapy, after 6 months (8 cycles) at the discretion of the 
treating physician, if the patient has stable disease or response. If this is done, the 
previously scheduled pembrolizumab treatment on Day 5 will become Day 1(+/-2 
days. Please refer to Section 5.2 (table) for treatment details regarding patients on 
Pembrolizumab monotherapy.
For patients who discontinued guadecitabine for reasons other than toxicity (i.e. 
disease stability of response > 6 months) and progress on pembrolizumab alone, a 
re-trial of guadecitabine in combination with pembrolizumab is possible, at the 
discretion of the treating physician, if the patient is clinically stable.
2 After completion of the safety run in, starting on Day 5 of each cycle, growth factor 
support filgrastim or peg filgrastim can be administered 24 hours after completion of 
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guadecitabine administration, at the discretion of the treating physician.
4.2.1
Pembrolizumab
Pembrolizumab 200 mg will be administered as a 30-minute intravenous (IV) 
infusion every 3 weeks. Every effort should be made to target infusion timing 
to be as close to 30 minutes as possible. However, given the variability of 
infusion pumps, a window of -5 minutes and +10 minutes is permitted (i.e., 
infusion duration is 30 minutes: -5 min/+10 min).
Pembrolizumab does not require any pre-medications unless clinically 
indicated for an infusion reaction. Local institutional practices should be 
followed in case of an infusion reaction.
Please refer section 8.1 and to the separate Pharmacy Manual for specific 
instructions regarding the preparation of the pembrolizumab infusion fluid 
and administration of infusion solution.     
4.2.2
Guadecitabine
Guadecitabine 30mg/m2 will be administered as a subcutaneous injection on 
Days 1-4 of every 3-week cycle. Patients are required to come to the clinic 
for administration of the drug. Pre-medications are not required.
Baseline weight will be used throughout. Dose will not change with weight 
changes.
Note: Guadecitabine priming can be discontinued and the patient can 
continue on pembrolizumab monotherapy after 6 months (8 cycles), at the 
discretion of the treating physician, if the patient has stable disease or 
response. For patients who discontinued guadecitabine for reasons other 
than toxicity (i.e. disease stability of response > 6 months) and progress on 
pembrolizumab alone, a re-trial of guadecitabine in combination with 
pembrolizumab is possible, at the discretion of the treating physician, if the 
patient is clinically stable.
4.3
Safety Run-in Cohort
Drug interaction and increased toxicity is not anticipated; however, there is no clinical 
experience with the combination of guadecitabine and pembrolizumab. To exclude 
prohibitive toxicity, up to 6 subjects will be treated with combined therapy as outlined 
in Table 2. If a subject goes off study before completing the DLT observation period
of safety run-in for reasons other than DLT, then that subject should be replaced. 
Accrual will be suspended after the initial 6 subjects have been enrolled. All 
subjects in the run-in cohort will be observed for at least 2 weeks after 
completion of cycle 1 for dose limiting toxicity (DLT) as defined in Table 3 
below. An event must be at least “possibly related” to either Pembrolizumab or 
Guadecitabine to be considered as DLT
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Table 3: Definition of Dose Limiting Toxicities (DLT)
Toxicity Category
Criteria Defining a DLT
Grade 4 treatment-related neutropenia lasting for > 7 days
Grade 4 treatment-related febrile neutropenia
Hematological*
Grade 3 treatment-related thrombocytopenia lasting 7 days associated 
with bleeding or Grade 4 treatment-related thrombocytopenia lasting >4 
days
Non-hematological
Grade 3 treatment-related toxicity despite the use of adequate/maximal 
medical interventions and/or prophylaxis as dictated by local institutional 
clinical practices or the judgment of the Investigator.
Any toxicity that is possibly, probably or definitely related to study drug that results in a >14 day 
delay in cycle 2 Day 1 dosing will also be considered a DLT.
*No growth factor is allowed
If 0 or 1 out of 6 subjects in the safety cohort experiences a DLT, accrual to the rest 
of the study will commence. If 2 or more of 6 subjects in the safety lead in cohort 
experience a DLT, the study will be suspended and an amendment to explore lower 
doses or a longer treatment interval (28 day cycle) will be considered.
4.4
Toxicity Management & Dose Delays/Modifications
Any patient who receives at least one dose of study therapy will be evaluable for 
toxicity endpoints. Each patient will be assessed for the development of toxicity 
according to the timeframe referenced in the Schedule of Events table. Toxicity will 
be assessed according to CTCAE v4.03.
This section provides suggested guidelines for the management of various study 
drug-related toxicities in subjects receiving guadecitabine and pembrolizumab.
(Note: Drug-related toxicity will be defined as any event, which is considered 
possibly, probably, or definitely related to the drug. It does not include toxicities 
clearly not related to the drug such as disease progression, environmental, unrelated 
trauma, etc.)  
The treating investigator should assess to the best of his/her ability whether an 
adverse event is possibly related to study treatment, and if so, attribute it to 
guadecitabine only, pembrolizumab only, or both guadecitabine and pembrolizumab, 
and treat the subject accordingly by only reducing the study drug that has most likely 
contributed to the individual toxicity necessitating dose reduction. Preferably, only 
one study drug should be reduced at any one time.
4.4.1
Dose modifications for Guadecitabine
Guadecitabine-related AEs will be managed with dose reductions and/or 
skipped doses. Guadecitabine dosing should be held for ≥ grade 3 
neutropenia, ≥ grade 3 thrombocytopenia or other ≥ grade 3 guadecitabine-
related non-hematologic toxicities until toxicity has resolved to ≤ Grade 1 or 
baseline levels (NOTE: pembrolizumab dosing may continue for that cycle if 
the toxicity is documented to be related only to guadecitabine). Treatment 
with guadecitabine may then be resumed for the next cycle at dose level -1 
(which is 24 mg/m2 – see Section 4.2). Missed doses will not be made up. 
Exceptions for the dose reductions would include neutropenia and anemia 
which could be managed by growth factors and transfusion, and in that case 
dosing may be resumed at the same dose level. After completion of the 
safety run in, starting on Day 5 of each cycle, growth factor support 
filgrastim or peg filgrastim can be administered 24 hours after completion of 
guadecitabine administration, at the discretion of the treating physician.
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If the subject still has drug-related clinically significant toxicity that has not 
resolved to ≤ Grade 1 or baseline by the time of the next cycle, dosing for 
that cycle may be delayed 1 week (7 days). Dosing may restart at dose level
-1 (24 mg/m2) once the toxicity has resolved to ≤ Grade 1 or baseline. If 
toxicity is still not resolved after a delay of 1 week, guadecitabine will be 
discontinued. If the patient has already completed 2 cycles of combination 
therapy at this point, the patient may be a candidate for continuing on single- 
agent pembrolizumab (see below).
If grade 3-4 toxicity reoccurs after treatment has been restarted at dose level
-1 (24mg/m2), and the patient has received at least 2 cycles of guadecitabine 
priming, then guadecitabine can be discontinued permanently and 
pembrolizumab can be continued as a single agent on the same dose 
schedule.
Rationale for continuing single-agent pembrolizumab:
There is presumptive scientific rationale that treatment with a 
hypomethylating agent will cause re-expression of tumor antigens within the 
first 2 cycles, and thus epigenetic priming, which enhances the effects of 
immunotherapy. Therefore, it is reasonable to continue treatment with single 
agent pembrolizumab after epigenetic priming has been induced. If a patient 
cannot complete at least 2 cycles of guadecitabine and pembrolizumab 
combination, then she would be discontinued from the study.
Please note: Guadecitabine priming can be discontinued and the patient can 
continue on pembrolizumab monotherapy after 6 months (8 cycles),  at the 
discretion of the treating physician, if the patient has stable disease or 
response. For patients who discontinued guadecitabine for reasons other 
than toxicity (i.e. disease stability of response > 6 months) and progress on 
pembrolizumab alone, a re-trial of guadecitabine in combination with 
pembrolizumab is possible, at the discretion of the treating physician, if the 
patient is clinically stable.
4.4.2
Dose Modifications for Pembrolizumab
Pembrolizumab-related AEs will be managed with dose withholdings/delays. 
Dose reductions will not be permitted for pembrolizumab. 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.
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Table 3 Dose Modification and Toxicity Management Guidelines for Immune-related AEs 
Associated with Pembrolizumab 
General instructions:
1.
Corticosteroid taper should be initiated upon AE improving to Grade 1 or less and continue to taper over  
1- 4 weeks.
2.
For situations where pembrolizumab has been withheld, pembrolizumab can be resumed after AE has 
been reduced to Grade 1 or 0 and corticosteroid has been tapered. Pembrolizumab should be 
permanently discontinued if AE does not resolve ≤ 28 days of last dose or if corticosteroids cannot be 
reduced to ≤10 mg prednisone or equivalent per day within ≤ 28 days. 
3.
For severe and life-threatening irAEs, IV corticosteroid should be initiated first followed by oral steroid. 
Other immunosuppressive treatment should be initiated if irAEs cannot be controlled by corticosteroids.
Immune-
related AEs
Toxicity grade 
or conditions 
(CTCAEv4.0)
Action taken to 
pembrolizumab
irAE management with 
corticosteroid and/or other 
therapies 
Monitor and 
follow-up 
Grade 2
Withhold 
Pneumonitis 
Grade 3 or 4, or 
recurrent Grade 
2
Permanently 
discontinue

Administer corticosteroids 
(initial dose of 1-2 mg/kg 
prednisone or equivalent) 
followed by taper

Monitor 
participants for 
signs and 
symptoms of 
pneumonitis

Evaluate 
participants 
with 
suspected 
pneumonitis 
with 
radiographic 
imaging and 
initiate 
corticosteroid 
treatment

Add 
prophylactic 
antibiotics for 
opportunistic 
infections
Grade 2 or 3
Withhold
Diarrhea / 
Colitis 
Grade 4
Permanently 
discontinue

Administer corticosteroids 
(initial dose of 1-2 mg/kg 
prednisone or equivalent) 
followed by taper

Monitor 
participants for 
signs and 
symptoms of 
enterocolitis 
(i.e., diarrhea, 
abdominal 
pain, blood or 
mucus in stool 
with or without 
fever) and of 
bowel 
perforation 
(i.e., peritoneal 
signs and 
ileus).

Participants 
with ≥ Grade 2 
diarrhea 
suspecting 
colitis should 
consider GI 
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consultation 
and 
performing 
endoscopy to 
rule out colitis. 

Participants 
with 
diarrhea/colitis 
should be 
advised to 
drink liberal 
quantities of 
clear fluids.  If 
sufficient oral 
fluid intake is 
not feasible, 
fluid and 
electrolytes 
should be 
substituted via 
IV infusion.
Grade 2
Withhold

Administer corticosteroids 
(initial dose of 0.5- 1 mg/kg 
prednisone or equivalent) 
followed by taper
AST / ALT 
elevation or 
Increased 
bilirubin
Grade 3 or 4 
Permanently 
discontinue

Administer corticosteroids 
(initial dose of 1-2 mg/kg 
prednisone or equivalent) 
followed by taper

Monitor with 
liver function 
tests (consider 
weekly or 
more 
frequently until 
liver enzyme 
value returned 
to baseline or 
is stable
Type 1 
diabetes 
mellitus 
(T1DM) or 
Hyperglycemia
Newly onset 
T1DM or 
Grade 3 or 4 
hyperglycemia 
associated with 
evidence of -
cell failure
Withhold

Initiate insulin replacement 
therapy for participants with 
T1DM 

Administer anti-hyperglycemic 
in participants with 
hyperglycemia 

Monitor 
participants for 
hyperglycemia 
or other signs 
and symptoms 
of diabetes.
Grade 2
Withhold
Hypophysitis
Grade 3 or 4 
Withhold or 
permanently 
discontinue1 

Administer corticosteroids and 
initiate hormonal replacements 
as clinically indicated.  

Monitor for 
signs and 
symptoms of 
hypophysitis 
(including 
hypopituitaris
m and adrenal 
insufficiency) 
Grade 2
Continue 
Hyperthyroidism 
Grade 3 or 4 
Withhold or 
permanently 
discontinue1

Treat with non-selective beta-
blockers (e.g., propranolol) or 
thionamides as appropriate 

Monitor for 
signs and 
symptoms of 
thyroid 
disorders. 
Hypothyroidism
Grade 2-4
Continue 

Initiate thyroid replacement 
hormones (e.g., levothyroxine 
or liothyroinine) per standard of 
care

Monitor for 
signs and 
symptoms of 
thyroid 
disorders. 
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Grade 2
Withhold 
Nephritis and 
Renal 
dysfunction
Grade 3 or 4 
Permanently 
discontinue

Administer corticosteroids 
(prednisone 1-2 mg/kg or 
equivalent) followed by taper.

Monitor 
changes of 
renal function
Grade 1 or 2
Withhold
Myocarditis
Grade 3 or 4
Permanently 
discontinue

Based on severity of AE 
administer corticosteroids

Ensure 
adequate 
evaluation to 
confirm 
etiology and/or 
exclude other 
causes
Intolerable/ 
persistent Grade 
2
Withhold
Grade 3
Withhold or 
discontinue 
based on the 
type of event.  
Events that 
require 
discontinuation 
include and not 
limited to:  
Gullain-Barre 
Syndrome, 
encephalitis
All other 
immune-related 
AEs
Grade 4 or 
recurrent Grade 
3 
Permanently 
discontinue

Based on type and severity of 
AE administer corticosteroids 

Ensure 
adequate 
evaluation to 
confirm 
etiology and/or 
exclude other 
causes
1.
Withhold or permanently discontinue pembrolizumab is at the discretion of the investigator or treating 
physician.  
NOTE: 
For participants with Grade 3 or 4 immune-related endocrinopathy where withhold of pembrolizumab is 
required, pembrolizumab may be resumed when AE resolves to ≤ Grade 2 and is controlled with hormonal 
replacement therapy or achieved metabolic control (in case of T1DM).  
Dosing interruptions are permitted in the case of medical/surgical events or 
logistical reasons not related to study therapy (e.g., elective surgery, unrelated 
medical events, subject vacation, and/or holidays). Subjects should be placed 
back on study therapy in ≤28 days of the scheduled interruption, unless 
otherwise discussed with the Principal Investigator and NU DMC. The reason for 
interruption should be documented in the subject's study record.
Note: If dosing is delayed by more than 28 days from the start of the adverse event which is 
possibly, probably or definitely related to the drug, then the subject will be withdrawn from 
treatment. It does not include toxicities clearly not related to the drug such as disease 
progression, environmental, unrelated trauma, etc.)
4.5
Concomitant Medications/Treatments
Medications or vaccinations specifically prohibited in the exclusion criteria are not 
allowed during the ongoing trial. If there is a clinical indication for one of these or 
other medications or vaccinations specifically prohibited during the trial, 
discontinuation from trial therapy or vaccination may be required. The investigator 
should discuss any questions regarding this with the Merck Clinical team. The final 
decision on any supportive therapy or vaccination rests with the investigator and/or 
the subject's primary physician.
4.5.1   Allowed Concomitant Medications
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All treatments that the treating physician considers necessary for a subject’s 
welfare may be administered at the discretion of the treating physician in 
keeping with the community standards of medical care. All concomitant 
medication will be recorded on the electronic case report form (CRF) 
including all prescription, over-the-counter (OTC), herbal supplements, and 
IV medications and fluids. If changes occur during the trial period, 
documentation of drug dosage, frequency, route, and date may also be 
included on the CRF.
All concomitant medications received ≤14 days before the first dose of trial 
treatment and 30 days after the last dose of trial treatment should be 
recorded. Concomitant medications administered beyond 30 days after the 
last dose of trial treatment for management of study-related toxicity should be 
recorded for SAEs and Events of Clinical Interest (ECIs) (refer 
section:7.3.1.5).
4.5.2   Prohibited Concomitant Medications
Subjects are prohibited from receiving the following therapies during the 
Screening and Treatment Phase (including retreatment for post-complete 
response relapse) of this trial:
 
Antineoplastic systemic chemotherapy or biological therapy
 
Immunotherapy not specified in this protocol
 
Chemotherapy not specified in this protocol
 
Investigational agents other than those used for this study
 
Radiation therapy
 
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: intranasal flu vaccines, measles, mumps, 
rubella, varicella/zoster, yellow fever, rabies, BCG, and typhoid vaccine.
 
Systemic glucocorticoids for any purpose other than to modulate 
symptoms from an event of clinical interest of suspected immunologic 
etiology. The use of physiologic doses of corticosteroids may be 
approved after consultation with the PI. Short term steroid preparation 
prior to tumor imaging is permitted for prophylaxis (e.g., contrast dye 
allergy).
 
Subjects who, in the assessment by the Principal Investigator (PI) or 
treating physician, 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 PI or treating physician 
deems to be medically necessary.
 
Pembrolizumab may be associated with Stevens-Johnson Syndrome 
(SJS) and Toxic Epidermal Necrolysis (TEN). Risk factors for SJS and 
TEN include certain medications such as anticonvulsants, sulfonamides, 
aminopenicillins, allopurinol, and NSAIDs. These should be taken after 
consultation with the treating physician. Non-medication triggers include 
infection, contrast media, and vaccinations. Malignancy is associated 
with an increased mortality rate in patients with SJS and TEN
 
Certain medications  such  as  anthracyclines,  alkylating  agents  and 
checkpoint inhibitors as well as radiation may be risk factors for immune- 
mediated myocarditis. These should be taken after consultation with the 
treating physician.
4.6
Supportive Care with Pembrolizumab
Subjects should receive appropriate supportive care measures as deemed necessary 
by the treating physician. 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 
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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 treating physician determines the events to be related to pembrolizumab.
It may be necessary to perform conditional procedures such as bronchoscopy, 
endoscopy, or skin photography as part of evaluation of the event.
4.6.1
Pneumonitis:
 
For Grade 2 events, treat with systemic corticosteroids. When symptoms 
improve to Grade 1 or less, steroid taper should be started and continued 
over no less than 4 weeks.
 
For Grade 3-4 events, immediately treat with intravenous steroids.
Administer additional anti-inflammatory measures, as needed.
 
Add prophylactic antibiotics for opportunistic infections in the case of 
prolonged steroid administration.
4.6.2
Diarrhea/Colitis:
Subjects should be carefully monitored for signs and symptoms of 
enterocolitis (such as diarrhea, abdominal pain, blood or mucus in stool, 
with or without fever) and of bowel perforation (such as peritoneal signs 
and ileus). 
All subjects who experience diarrhea/colitis should 
be advised to drink liberal quantities of clear fluids.  If sufficient oral fluid 
intake is not feasible, fluid and electrolytes should be substituted via IV 
infusion. For Grade 2 or higher diarrhea, consider GI consultation and 
endoscopy to confirm or rule out colitis.
 
For Grade 2 diarrhea/colitis, administer oral corticosteroids.
 
For Grade 3 or 4 diarrhea/colitis, treat with intravenous steroids 
followed by high dose oral steroids.
 
When symptoms improve to Grade 1 or less, steroid taper should be 
started and continued over no less than 4 weeks.
4.6.3
Type 1 Diabetes Mellitus (T1DM)
(If new onset, including diabetic ketoacidosis [DKA]) or ≥ Grade 3
Hyperglycemia, if associated with ketosis (ketonuria) or metabolic acidosis
(DKA)
For T1DM or Grade 3-4 Hyperglycemia
 
Insulin replacement therapy is recommended for Type I diabetes mellitus 
and for Grade 3-4 hyperglycemia associated with metabolic acidosis or 
ketonuria.
 
Evaluate patients with serum glucose and a metabolic panel, urine 
ketones, glycosylated hemoglobin, and C-peptide.
4.6.4
Hypophysitis:
 
For Grade 2 events (defined as moderate per general CTCAE criteria), 
treat with corticosteroids. When symptoms improve to Grade 1 or less 
(defined as mild per general CTCAE criteria), steroid taper should be 
started and continued over no less than 4 weeks. Replacement of 
appropriate hormones may be required as the steroid dose is tapered.
 
For Grade 3-4 events (defined as either severe or medically 
significant but not immediately life-threatening, OR life-threatening 
consequences, per general CTCAE criteria), treat with an initial dose of 
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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.
4.6.5
Hyperthyroidism or Hypothyroidism:
Thyroid disorders can occur at any time during treatment. Monitor patients for 
changes in thyroid function (at the start of treatment, periodically during 
treatment, and as indicated based on clinical evaluation) and for clinical signs 
and symptoms of thyroid disorders.
 
Grade 2 hyperthyroidism events (and Grade 2-4 hypothyroidism):
o
In hyperthyroidism, non-selective beta-blockers (e.g. 
propranolol) are suggested as initial therapy.
o
In hypothyroidism, thyroid hormone replacement therapy, 
with levothyroxine or liothyroinine, is indicated per standard 
of care.
 
Grade 3-4 hyperthyroidism
o Treat with an initial dose of IV corticosteroid followed by oral 
corticosteroids. When symptoms improve to Grade 1 or less steroid taper 
should be started and continued over no less than 4 weeks. Replacement 
of appropriate hormones may be required as the steroid dose is tapered.
4.6.6
Hepatic:
 
For Grade 2 events, monitor liver function tests more frequently until 
returned to baseline values (consider weekly). Treat with IV or oral 
corticosteroids
 
For Grade 3-4 events, treat with intravenous corticosteroids for 24 to 48 
hours.
 
When symptoms improve to Grade 1 or less, a steroid taper should be 
started and continued over no less than 4 weeks.
4.6.7
Renal Failure or Nephritis:
 
For Grade 2 events, treat with corticosteroids.
 
For Grade 3-4 events, treat with systemic corticosteroids.
 
When symptoms improve to Grade 1 or less, steroid taper should be 
started and continued over no less than 4 weeks.
4.6.8 SJS and TEN management
o For signs or symptoms of SJS or TEN, withhold KEYTRUDA® and refer 
the patient for specialized care for assessment and treatment.
o If SJS or TEN is confirmed, permanently discontinue KEYTRUDA®.
4.6.9 Immune-mediated myocarditis management
o For suspected immune-mediated myocarditis, ensure adequate evaluation 
to exclude other etiologies, and administer corticosteroids as appropriate.
4.6.10 Management of Infusion Reactions:
Signs and symptoms usually develop during or shortly after drug infusion and 
generally resolve completely within 24 hours of completion of infusion.
Table 4 below shows treatment guidelines for subjects who experience an infusion reaction 
associated with administration of pembrolizumab (MK-3475).
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Table 4 Infusion Reaction Treatment Guidelines 
NCI CTCAE Grade
Treatment
Premedication at subsequent 
dosing
Grade 1
Mild reaction; infusion interruption 
not indicated; intervention not 
indicated
Increase monitoring of vital signs as 
medically indicated until the subject is 
deemed medically stable in the opinion of the 
investigator.
None
Grade 2
Requires infusion interruption but 
responds promptly to symptomatic 
treatment (e.g., antihistamines, 
NSAIDS, narcotics, IV fluids); 
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.
Subject may be premedicated
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).
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.
Grades 3 or 4
Grade 3:
Prolonged (i.e., not rapidly 
responsive to symptomatic 
medication and/or brief interruption 
of infusion); recurrence of 
symptoms following initial 
improvement; hospitalization 
indicated for other clinical sequelae 
(e.g., renal impairment, pulmonary 
infiltrates)
Grade 4:
Life-threatening; pressor or 
ventilatory support indicated
Stop Infusion.
Additional appropriate medical therapy may 
include but is not limited to:
IV fluids 
Antihistamines 
NSAIDS 
Acetaminophen 
Narcotics 
Oxygen 
Pressors 
Corticosteroids 
Epinephrine
Increase monitoring of vital signs as 
medically indicated until the subject is 
deemed medically stable in the opinion of the 
investigator.
Hospitalization may be indicated.
Subject is permanently discontinued from 
further trial treatment administration.
No subsequent dosing
Appropriate resuscitation equipment should be available in the room and a physician readily available during 
the period of drug administration.
4.7
Diet/Activity/Other Considerations
4.7.1
Diet
Subjects should maintain a normal diet unless modifications are required to 
manage an AE such as diarrhea, nausea or vomiting.
4.7.2
Use in Nursing Women
It is unknown whether pembrolizumab and guadecitabine are excreted in 
human milk. Since many drugs are excreted in human milk, and because of 
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the potential for serious adverse reactions in the nursing infant, subjects who 
are breast-feeding are not eligible for enrollment. Starting with the pre- 
screening or screening visit through 120 days after the last dose of trial 
treatment, subjects should not breast feed.
4.8
Duration of Therapy
Patients may continue to receive cycles of treatment until any of the following occur:
 
Disease progression as defined by RECISTv 1.1
 
Delay of more than 28 days due to treatment related toxicity (toxicities possibly, 
probably or definitely related to the drug) will result in discontinuation of study 
drugs.
(Note: It does not include toxicities clearly not related to the drug such as disease 
progression, environmental, unrelated trauma, etc.)
 
Development of an inter-current illness that prevents further administration of 
treatment.
 
Unacceptable adverse event(s).
 
Patient decides to withdraw from either study treatment or the study as a whole.
 
The treating investigator determines that the patient should be taken off 
treatment for any reason (i.e. changes in condition, inability to comply with study 
treatment or procedures).
 
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.
4.9
Duration of Follow Up
Patients will have the first safety follow-up visit 30 days (± 7 days) after the last 
dose of study therapy or before the initiation of a new anti-cancer treatment, 
whichever is first.
All AEs that occur prior to the Safety Follow-Up Visit (30 days (± 7 days) after the 
last dose of study therapy) will be recorded. Subjects with an AE ≥ Grade 2 that 
occurs ≥ 30 days after discontinuation of study therapy and that is attributed 
(possibly, probably, or definitely) to the agent(s) will be followed until the AE is ≤ 
Grade 1 or baseline, deemed clinically insignificant, and/or until a new anti-cancer 
treatment starts, whichever is earlier.
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 per the guidelines stated 
above.
Subjects who discontinue trial treatment for a reason other than disease progression 
will move into the Long-term follow-Up Phase and will be assessed every 9 weeks 
(± 7 days) by radiologic imaging to monitor disease status until the start of new anti- 
neoplastic therapy, disease progression, death or end of the study. Information 
regarding post-study anti- neoplastic treatment will be collected if new treatment is 
initiated.
Once a subject experiences confirmed disease progression or starts a new anti- 
cancer therapy, the subject will move into the Survival follow-up phase and should 
be contacted by telephone or email or during clinic visits, every 3 months for the first
2 years after completing study therapy and then every 6 months thereafter to assess 
for survival status until death, withdrawal of consent, or the end of the study, 
whichever occurs first.
4.10
Removal of Subjects from Study Treatment and/or Study as a Whole
Patients can be taken off the study treatment and/or study as a whole at any time at 
their own request, or they may be withdrawn at the discretion of the investigator for 
safety, behavioral or administrative reasons. The reason(s) for discontinuation must 
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be clearly documented on the appropriate eCRF and may include:
 
Patient voluntarily withdraws from treatment (follow-up permitted).
 
Patient or legal representative (such as a parent or legal guardian) withdraws 
consent (no follow-up permitted).
 
Patient is unable to comply with protocol requirements.
 
Patient demonstrates disease progression. This must be confirmed radiographic 
disease progression. At the first disease assessment, treatment can be 
continued, even in the presence of radiographic or clinical progression, if in the
opinion of the treating physician, the patient is stable or benefitting clinically. In 
that circumstance a short term follow up scan should be obtained in 4-6 weeks. 
Patient experiences unacceptable toxicity/adverse events.
(Note: If dosing is delayed by more than 28 days from the start of the adverse 
event which is possibly, probably, or definitely related to the drug then the 
subject will be withdrawn from treatment. It does not include toxicities clearly not 
related to the drug such as disease progression, environmental, unrelated 
trauma, etc.)
 
Treating physician determines that continuation on the study would not be in the 
patient’s best interest.
 
Patient becomes pregnant (confirmed positive serum pregnancy test).
 
Patient has intercurrent illness that prevents further administration of treatment.
 
Patient develops a second malignancy that requires treatment which would 
interfere with this study.
 
Noncompliance with trial treatment or procedure requirements.
 
Principal Investigator’s decision to withdraw the subject.
 
Completed 24 months of uninterrupted treatment with pembrolizumab or 35 
administrations of study medication, whichever is later.
NOTE: 24 months of study medication is calculated from the date of first dose. 
Subjects who stop pembrolizumab after 24 months may be eligible for up to one 
year of additional study treatment if they progress after stopping study treatment 
provided they meet the eligibility requirements. For any patient who has limited 
treatment options, and is currently re-responding to the combination treatment of 
pembrolizumab and guadecitabine, an additional year of this combination 
therapy, beyond cycle #35, may be given, subject to review and approval by the 
PI and drug sponsors Merck and Astex.
 
Conditions outlined in Section 4.8
 
Administrative reasons.
 
Patient becomes lost to follow-up (LTF) : This is defined as 3 attempts, made 1 
week apart, to contact patient by preferred method of contact.
4.11
Patient Replacement
If a patient is enrolled in the study but comes off study prior to the first dose of 
treatment, the patient may be replaced.
If a subject in the safety run-in portion of the trial goes off treatment before 
completing the DLT observation period of safety run-in for reasons other than DLT, 
then a patient will need to be added to the safety run-in.
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5.0
STUDY PROCEDURES AND SCHEDULE OF EVENTS
5.1 COMBINATION TREATMENT GUADECITABINE + PEMBROLIZUMAB
Screening
On Treatment15
Off Treatment
Time Period
≤28 days 
prior to 
registration
≤14 
days 
prior to 
regis- 
tration
Cycle
114
Cycle
2
Subse-
quentcycle
s
≥ 6 
months of 
treat
ment17
30 days 
post last 
dose12
Long 
term 
Follow-
up
Required
Assessments
Informed Consent
X
Medical history1
X
Physical exam2
X
D12
D12
D12
X
CBC3
X
D13
D13
D
X
CMP3
X
D13
D13
D
X
CA 1253
X
D13
D13
D
X
Mg, Phos, LDH
X
PT/INR & aPTT
X
Thyroid Function 
and Uric acid11
X
D111
Pregnancy test
X8
D18
D18
D18
Adverse events16
X
D1
D1
D1
   X
             
X
Con Meds16
X
D1
D1
D1
       X
   X
CXR or CT of chest4
X
X
   X13
CT or MRI of 
abdomen & pelvis4
X
X
   X13
Pembrolizumab15
D5
D5
D5
Guadecitabine15
D1-4
D1-4
D1-4
Archival tumor tissue5
X
Blood for DNA
analysis6
C1D1
C2D8
      X17
Blood for cytokine 
response7
C1D1
C2D1
C3D1
     X17
X
Blood for PBMC
analysis9
X
X
    X17
X
Tumor biopsy10
X
X
     X17
Survival status
X
Subsequent therapy
    X
1. Includes diagnosis and staging [pathology report and Tumor Node Metastasis (TNM) staging should be 
collected].
2. Physical exam includes vital signs [blood pressure, weight, height (screening only)] and ECOG performance 
status. Physical exam will be conducted on Day 1 (+/-4 days) of each cycle and at the safety follow-up 
visit, which occurs 30 days post last dose.
3. Labs to be done within ≤4 days of D1. Cycle 1 Day 1 CBC and CMP do not need to be repeated if screening labs 
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were done ≤4 days prior to starting treatment. CA-125 is to be drawn at screening and Day 1 of each cycle.  
Exceptions would be if CA-125 was drawn within 14 days from the screening visit or within 14 days of visits 
where doses have been delayed.  In these cases, CA-125 will not need to be re-drawn.  CBC = Complete 
Blood Cell Count with diff. CMP = Na, K, Cl, creatinine, BUN; liver function tests (LFTs) to include AST, ALT, 
total bilirubin, alkaline phosphatase.
4. Tumor response assessment will consist of evaluation by CXR or CT scans of chest and MRI or CT of 
abdomen and pelvis. Screening radiologic imaging should be done ≤28 days prior to registration. During 
treatment, radiologic imaging should be done prior to Cycle 3 and cycle 5 and then prior to every third 
cycle thereafter (e.g. prior to cycles 8, 11, 14, etc.). Radiologic imaging can be obtained ≤7 days prior to 
day 1 of the cycle. The imaging modality selected for each subject should remain the same throughout the 
study. Responses of PD, PR, or CR should be confirmed within 4-6 weeks, at the discretion of the treating 
physician. (Refer to section 6.0 for more details).
5. Formalin fixed paraffin-embedded tissue will be requested from an archived tumor specimen from all subjects 
(required to submit, if available). The archived tumor tissue specimens may be from surgery or from a 
diagnostic biopsy of primary or metastatic tumor specimen, and may be procured up to 3 months from 
registration. Unavailability of archived tissue will not render subject ineligible for study. See Section 9 and 
laboratory manual for additional details.
6. Blood for DNA analysis will be collected on Cycle 1 Day 1[≤7days] and Cycle 2 Day 8 [+2 days]. See Section
9 and laboratory manual for additional details.
7. Blood for cytokine response will be collected at pre-treatment on Cycle 1 Day 1(≤4 days), Cycle 2 Day 1(≤4 
days), Cycle 3 Day 1(≤4days), and at the safety follow up visit. See Section 9 and laboratory manual for 
additional details.
8. Pregnancy test required only for females of child-bearing potential ≤7 days prior to registration. Also, 
pregnancy test will be done on D1 (≤4 days) of each cycle for females of child bearing potential.
9. Blood for PBMC analysis will be collected at pre-treatment Cycle 1 Day 1(≤4days), Cycle 1 Day 5, pre- 
treatment on Cycle 2 Day 1(≤4 days), Cycle 2 Day 5, and at the safety follow up visit. See Section 9 and 
laboratory manual for additional details.
10. Tumor biopsies [guided by CT, ultrasound, or physical exam, according to the discretion of the treating 
physician], and/or paracentesis, and/or thoracentesis will occur after registration and prior to the start of 
treatment [(Cycle 1 Day 1 (≤7 days)] and Cycle 2 Day 8 (+2 days) if clinically feasible for the subject. See 
Section 9 and laboratory manual for additional details.
11. Thyroid Function (TSH with reflex testing only if abnormal findings) and uric acid to be performed at 
screening and D1 (≤4 days) of every odd cycle beginning with Cycle 3.
12. Safety follow-up visit will occur 30 days (± 7 days) after the last dose of study therapy or before the initiation 
of a new anti-cancer treatment, whichever is first. Please refer to section 7 for tracking and reporting of 
AEs/SAEs.
13. Subjects who discontinue trial treatment for a reason other than disease progression should be assessed 
every9 weeks (± 7 days) by radiologic imaging to monitor disease status until the start of new anti- 
neoplastic therapy, disease progression, death or end of the study. Information regarding post-study anti-
neoplastic treatment will be collected if new treatment is initiated. Once a subject experiences confirmed 
disease progression or starts a new anti-cancer therapy, the subject should be contacted by telephone, 
email, or a clinic visit every 3 months for the first 2 years and then every 6 months thereafter to assess for 
survival status until death, withdrawal of consent, or the end of the study, whichever occurs first.
14. Cycle 1 day 1 should be started within (+) 14 days following registration.
15. Patients should begin treatment within 14 days of registration. While on treatment, day 1 of each cycle may be 
delayed up to +28 days from the target date for scheduling purposes and holidays. NOTE: Due to the dosing 
of guadecitabine on days 1-4 followed by pembrolizumab on day 5, it is recommended that day 1 of each 
guadecitabine cycle should occur on a Monday.
Note: Guadecitabine priming can be discontinued and the patient can continue on pembrolizumab 
monotherapy after 6 months (8 cycles), at the discretion of the treating physician, if the patient has stable 
disease or response. If this is done, please follow the pembrolizumab monotherapy dosing table 
(section 5.2).  
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16. ConMeds and AE assessment are to be completed from on D1 of each cycle (+/-4 days). ConMeds will also 
be recorded up to 30 days after the last dose of trial treatment. Concomitant medications administered 
beyond 30 days after the last dose of trial treatment for management of study-related toxicity should be 
recorded for SAEs and Events of Clinical Interest (ECIs). 
AE assessments will also be done 30 days after the last dose of trial treatment OR until start of next anti-
cancer treatment (whichever is first). 
SAEs will be recorded for 90 days after the last dose of trial treatment.
17.OPTIONAL tests for patients who have been on treatment for ≥6 months. Samples can be collected at any 
time from ≥6 months and before the safety follow-up visit. 
       Tumor biopsies or paracentesis or thoracentesis may be done. This will be  guided by CT, ultrasound, or 
physical exam, according to the discretion of the treating physician. All samples will be for research 
purpose.
See Section 9 and laboratory manual for additional details.
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5.2  PEMBROLIZUMAB MONOTHERAPY
Pembrolizumab monotherapy is indicated for:
Patients who discontinue guadecitabine after 2 cycles due to toxicity and who continue on 
pembrolizumab monotherapy.
Patients who discontinue guadecitabine after 8 cycles due to SD or PR or CR and who continue on 
pembrolizumab.
In the above cases, D5 will become D1. D1 assessments will now be performed in respect to 
pembrolizumab D1 dosing instead of guadecitabine D1 dosing. 
On Treatment
Off Treatment
Time Period
D1 of each cycle 
(-/+ 2 days)
30 days post last 
dose11
Long term Follow-up
Required
Assessments
Physical exam1
D1
X
CBC2
D12
X
CMP2
D12
X
CA 1252
D12
X
Thyroid Function 
and Uric acid3
 D1
Pregnancy test4
D1
Adverse events5
 D1
X
          X
Con Meds5
 D1
X
X
CXR or CT of chest6
                X6
   X12
CT or MRI of 
abdomen & pelvis6
                         
X6
   X12
Pembrolizumab
monotherapy7
      D1
Archival tumor tissue8
X
Blood for cytokine 
response9
        C3D1
X
Blood for PBMC
analysis10
     X
X
Survival status
X12
Subsequent therapy
                 X
1 Physical exam includes vital signs [blood pressure, weight, height (screening only)] and ECOG performance 
status. Physical exam will be conducted on Day 1 (+/-4 days) of each cycle and at the safety follow-up visit, 
which occurs 30 days post last dose.
2 Labs to be done within ≤4 days of D1. CA-125 is to be drawn at Day 1 of each cycle.  Exceptions would be if CA-
125 was drawn within 14 days of visits where doses have been delayed.  In these cases, CA-125 will not need 
to be re-drawn. CBC = Complete Blood Cell Count with diff. CMP = Na, K, Cl, creatinine, BUN; liver function 
tests (LFTs) to include AST, ALT, total bilirubin, alkaline phosphatase.
3 Thyroid Function (TSH with reflex testing only if abnormal findings) and uric acid to be performed at D1 (≤4 days) 
of every odd cycle beginning with Cycle 3.
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4 Pregnancy test will be done on D1 (≤4 days) of each cycle for females of child bearing potential.
5 ConMeds and AE assessment are to be completed from on D1 of each cycle (+/-4 days). ConMeds will also be 
recorded up to 30 days after the last dose of trial treatment. Concomitant medications administered beyond 30 
days after the last dose of trial treatment for management of study-related toxicity should be recorded for SAEs 
and Events of Clinical Interest (ECIs). 
AE assessments will also be done 30 days after the last dose of trial treatment OR until start of next anti-
cancer treatment (whichever is first). 
SAEs will be recorded for 90 days after the last dose of trial treatment.
6 Tumor response assessment will consist of evaluation by CXR or CT scans of chest and MRI or CT of abdomen 
and pelvis. During treatment, radiologic imaging should be done prior to Cycle 3 and Cycle 5 and then prior to 
every third cycle thereafter (e.g. prior to cycles 8, 11, 14, etc.). Radiologic imaging can be obtained ≤7 days 
prior to day 1 of the cycle. The imaging modality selected for each subject should remain the same throughout 
the study. Responses of PD, PR, or CR should be confirmed within 4-6 weeks, at the discretion of the treating 
physician. (Refer to section 6.0 for more details).
7 Pembrolizumab 200 mg will be administered as a 30-minute intravenous (IV) infusion every 3 weeks. 
Pembrolizumab monotherapy dosing will be on Fridays (-/+ 2 days) and D1 assessments will now be 
performed in respect to pembrolizumab D1 dosing instead of guadecitabine D1 dosing.
8   Formalin fixed paraffin-embedded tissue will be requested from an archived tumor specimen from all subjects 
(required to submit, if available). The archived tumor tissue specimens may be from surgery or from a 
diagnostic biopsy of primary or metastatic tumor specimen, and may be procured up to 3 months from 
registration. Unavailability of archived tissue will not render subject ineligible for study. See Section 9 and 
laboratory manual for additional details. (Please contact Principal Investigator or Lead site study- coordinator 
for any questions or concerns)
9 Blood for cytokine response will be collected at pre-treatment on Cycle 3 Day 1(≤4days), and at the safety follow 
up visit. See Section 9 and laboratory manual for additional details.
10Blood for PBMC analysis will be collected at pre-treatment Cycle 1 Day 1(≤4days), Cycle 1 Day 5, pre- treatment 
on Cycle 2 Day 1(≤4 days), Cycle 2 Day 5, and at the safety follow up visit. See Section 9 and laboratory 
manual for additional details.
11Safety follow-up visit will occur 30 days (± 7 days) after the last dose of study therapy or before the initiation of a 
new anti-cancer treatment, whichever is first. Please refer to section 7 for tracking and reporting of AEs/SAEs.
12Subjects who discontinue trial treatment for a reason other than disease progression should be assessed every 9 
weeks (± 7 days) by radiologic imaging to monitor disease status until the start of new anti- neoplastic therapy, 
disease progression, death or end of the study. Once a subject experiences confirmed disease progression or 
starts a new anti-cancer therapy, the subject should be contacted by telephone, email, or a clinic visit every 3 
months for the first 2 years and then every 6 months thereafter to assess for survival status until death, 
withdrawal of consent, or the end of the study, whichever occurs first. 
6.0
ENDPOINT ASSESSMENT
6.1
Definitions
Response assessments will be made both using the Immune Related 
Response Criteria (irRC), and using RECIST v1.1 (See table below), allowing 
additional comparisons among these criteria for disease response 
assessment. Measurable and non-measurable lesions will be followed by
both RECIST v1.1 & irRC. Disease progression will be determined using
RECIST 1.1 criteria (The Response Evaluation Criteria in Solid Tumors 
(RECIST) 1.1. Eur J Can, 2009.45:p.228-247). Refer to the RECIST1.1 
publication for complete details on these criteria. At the first disease 
assessment, treatment can be continued, even in the presence of 
radiographic or clinical progression, if in the opinion of the treating physician, 
the patient is stable or benefitting clinically. In that circumstance, a short-
term follow up scan should be obtained in 4-6 weeks.
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Immunotherapeutic agents such as pembrolizumab (MK-3475) may produce 
antitumor effects by potentiating endogenous cancer-specific immune 
responses. The response patterns seen with such an approach may extend 
beyond the typical time course of responses seen with cytotoxic agents, and 
can manifest a clinical response after an initial increase in tumor burden or 
even the appearance of new lesions. Standard RECIST may not provide an 
accurate response assessment of immunotherapeutic agents such as 
pembrolizumab (MK-3475).
Therefore, RECIST 1.1 will be used with the following adaptations:
If radiologic imaging shows initial PD, tumor assessment should be repeated
≥4 weeks later in order to confirm PD with the option of continuing treatment 
per below while awaiting radiologic confirmation of progression. If repeat 
imaging shows a reduction in the tumor burden compared to the initial scan 
demonstrating PD, treatment may be continued / resumed. If repeat imaging 
confirms progressive disease, subjects will be discontinued from study 
therapy In determining whether or not the tumor burden has increased or 
decreased, investigators should consider all target lesions as well as non- 
target lesions. In subjects who have initial evidence of radiological PD, it is at 
the discretion of the treating physician whether to continue a subject on study 
treatment until repeat imaging is obtained a minimum of 4 weeks later. This 
clinical judgment decision should be based on the subject’s overall clinical 
condition, including performance status, clinical symptoms, and laboratory 
data. Subjects may receive pembrolizumab (MK-3475) treatment while
waiting for confirmation of PD if they are clinically stable as defined by the 
following criteria:
• Absence of signs and symptoms indicating disease progression
 
No decline in ECOG performance status
• Absence of rapid progression of disease
• Absence of progressive tumor at critical anatomical sites (e.g., cord 
compression) requiring urgent alternative medical intervention.
When feasible, subjects should not be discontinued until progression is 
confirmed. This allowance to continue treatment despite initial radiologic 
progression takes into account the observation that some subjects can have 
a transient tumor flare in the first few months after the start of 
immunotherapy, but with subsequent disease response. Subjects that are 
deemed clinically unstable are not required to have repeat imaging for 
confirmation of progressive disease.
Measurable Disease
Measurable disease per RECIST 1.1 is defined as the presence of at least 
one measurable lesion. Measurable lesions are defined as those that can be 
accurately measured in at least one dimension (longest diameter to be 
recorded) as >20 mm by chest x-ray, as >10 mm with CT scan, or >10 mm 
with calipers by clinical exam. For irRC, measurable lesions are defined as 
as those that can be accurately measured in at least two dimensions as
10x10mm with CT scan. All tumor measurements must be recorded in 
millimeters (or decimal fractions of centimeters).
Malignant Lymph Nodes
To be considered pathologically enlarged and measurable, a lymph node 
must be >15 mm in short axis when assessed by CT scan (CT scan slice 
thickness recommended to be no greater than 5 mm). At baseline and in 
follow-up, only the short axis will be measured and followed.
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Non-measurable Lesions
For both RECIST 1.1 and irRC, all other lesions (or sites of disease), 
including small lesions (longest diameter <10 mm or pathological lymph 
nodes with ≥ 10 to <15 mm short axis), are considered non-measurable 
disease. Bone lesions, leptomeningeal disease, ascites, pleural/pericardial 
effusions, lymphangitis cutis/pulmonitis, inflammatory breast disease, and 
abdominal masses (not followed by CT or MRI), are considered as non- 
measurable.
Note:  Cystic lesions that meet the criteria for radiographically defined simple 
cysts should not be considered as malignant lesions (neither measurable nor 
non-measurable) since they are, by definition, simple cysts. ‘Cystic lesions’ 
thought to represent cystic metastases can be considered as measurable 
lesions, if they meet the definition of measurability described above.
However, if non-cystic lesions are present in the same subject, these are 
preferred for selection as target lesions.
6.2
Primary Endpoint
Measure Objective Response Rate (ORR) to guadecitabine and pembrolizumab in 
patients with recurrent platinum resistant Ovarian Cancer. Any patient who has 
completed at least 2 cycles of treatment will be evaluable for this endpoint.
6.3
Secondary Endpoints
Measure progression free survival (PFS) and clinical benefit rate (CBR) to the 
combination of guadecitabine and pembrolizumab.
PFS will be defined as the time from first dose of study treatment until disease 
progression or death from any cause. Any patient who has completed at least 1 
cycle of treatment will be evaluable for PFS endpoint.
Clinical Benefit Rate(CBR) will be defined as patients with CR + PR or SD (SD for at 
least 3 months). Any patient who has completed at least 2 cycles of treatment will be 
evaluable for CBR endpoint.
Measure toxicity profiles for the combination of guadecitabine and pembrolizumab. 
The number, type, grade, severity, and frequency of adverse events will be tabulated; 
adverse events are assessed at least once per cycle. Any patient who receives at 
least one dose of study therapy will be evaluable for toxicity endpoints.
Measure objective response rate (ORR) to the combination of guadecitabine 
and pembrolizumab using the Immune Related Response Criteria (irRC)
(Note: Response assessments will be made both using the irRC, and using RECIST 
v1.1, allowing additional comparisons among these criteria for disease response 
assessment. Measurable and non-measurable lesions will be followed by both 
RECIST v1.1 & irRC. Disease progression will be determined using RECIST 1.1 
criteria).
6.4
Exploratory Objectives:
To test the hypothesis that the combination of guadecitabine and pembrolizumab 
reactivates immune responses by allowing re-expression of tumor antigens silenced 
epigenetically, we will measure several endpoints:
 
NY-ESO-1 and MAGE antigens’ promoter methylation (pyrosequencing) and 
mRNA expression levels (quantitative RT-PCR) will be measured before and 
after treatment in DNA (plasma and/or tumor biopsies) and RNA (tumor 
biopsies), respectively.
 
Cytokine response (IFN IL2, IL6, IL10, TNF) will be measured in plasma by
ELISA.
 
Measure LINE 1 methylation in DNA extracted from PBMCs (D5 vs. D1 of cycles
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1 and 2).
 
Expression of the PD-L1 ligand will be measured by IHC in archival tumors.
 
Tumor infiltrating lymphocytes (TILs) will be quantified in tumor biopsies before 
and after treatment (IHC).
All biological parameters will be correlated with clinical endpoints (ORR and PFS).
6.5
Immune Related Response Criteria (irRC)
6.5.1
Summary of irRC
This study will evaluate concordance of the Immune Related Response 
Criteria (irRC) with RECISTv 1.1 and OS. These response criteria were 
developed to overcome the variable and unusual patterns of response to 
immunotherapeutic agents, in particular, ipilimumab [34]. The development of 
the guidelines were prompted by observations, mostly in subjects with 
metastatic melanoma, of initial disease progression followed by later 
response, late responses, and mixed responses with an overall decrease in 
tumor burden.
6.5.2
Antitumor response based on total measurable tumor burden:
For the irRC, only index and measurable new lesions are taken into account 
(in contrast to conventional WHO criteria, which do not require the 
measurement of new lesions, nor do they include new lesion measurements 
in the characterization of evolving tumor burden). At the baseline tumor 
assessment, the sum of the products of the two largest perpendicular 
diameters (SPD) of all index lesions (5 lesions per organ, up to 10 visceral 
lesions) is calculated. At each subsequent tumor assessment, the SPD of the
index lesions and of new, measurable lesions (up to 5 new lesions per organ;
10 visceral lesions) are added together to provide the total tumor 
burden: Tumor Burden = SPDindex lesions + SPDnew, measurable lesions
Table 5: Comparison of WHO and irRC criteria:
WHO
irRC
New, 
measurable 
lesions
Always represent PD
Incorporated into tumor burden
New, non- 
measurable 
lesions
Always represent PD
Do not define progression (but preclude 
irCR)
Non-index 
lesions
Changes contribute to defining BOR of CR, PR, 
SD, and PD
Contribute to defining irCR (complete 
disappearance required)
CR
Disappearance of all lesions in two consecutive 
observations not less than 4 wk apart
Disappearance of all lesions in two 
consecutive observations not less than 4 
wk apart
PR
≥50% decrease in SPD of all index lesions 
compared with baseline in two observations at 
least 4 wk apart, in absence of new lesions or 
unequivocal progression of non-index lesions
≥50% decrease in tumor burden 
compared with baseline in two 
observations at least 4 wk apart
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SD
50% decrease in SPD compared with baseline 
cannot be established nor 25% increase
compared with nadir, in absence of new lesions or 
unequivocal progression of non-index lesions
50% decrease in tumor burden 
compared with baseline cannot be 
established nor 25% increase compared 
with nadir
PD
At least 25% increase in SPD compared with nadir 
and/or unequivocal progression of non-index 
lesions and/or appearance of new lesions (at any 
single time point)
At least 25% increase in tumor burden 
compared with nadir (at any single time 
point) in two consecutive observations at 
least 4 wk apart
6.5.3
Time-Point Response Assessment Using irRC:
Percentage changes in tumor burden per assessment time point 
describe the size and growth kinetics of both conventional and new, 
measurable lesions
as they appear. At each tumor assessment, the response in index and 
new, measurable lesions is defined based on the change in tumor 
burden (after ruling out irPD). Decreases in tumor burden must be 
assessed relative to baseline measurements (i.e., the SPD of all index 
lesions at screening). The irRC were derived from WHO criteria and, 
therefore, the thresholds of response remain the same. However, the 
irRC response categories have been modified from those of WHO 
criteria as detailed above.
6.5.4
Overall Response Using irRC:
The sum of the products of diameters at tumor assessment using the
immune-related response criteria (irRC) for progressive disease 
incorporates the contribution of new measurable lesions. Each net 
Percentage Change in Tumor Burden per assessment using irRC 
criteria accounts for the size and growth kinetics of both old and new 
lesions as they appear.
6.5.5
Definition of Index Lesions Response Using irRC
 
irComplete Response (irCR): Complete disappearance of all index 
lesions. This category encompasses exactly the same subjects as “CR” 
by the mWHO criteria.
 
irPartial Response (irPR): Decrease, relative to baseline, of 50% or 
greater in the sum of the products of the 2 largest perpendicular 
diameters of all index and all new measurable lesions (i.e., Percentage 
Change in Tumor Burden). Note: the appearance of new measurable 
lesions is factored into the overall tumor burden, but does not 
automatically qualify as progressive disease until the SPD increases by ≥
25% when compared to SPD at nadir.
 
irStable Disease (irSD): Does not meet criteria for irCR or irPR, in the 
absence of progressive disease.
 
irProgressive Disease (irPD): At least 25% increase Percentage Change 
in Tumor Burden (i.e., taking sum of the products of all index lesions and 
any new lesions) when compared to SPD at nadir.
6.5.6
Definition of Non-Index Lesions Response Using irRC
 
irComplete Response (irCR): Complete disappearance of all non-index 
lesions. This category encompasses exactly the same subjects as “CR” 
by the mWHO criteria.
 
irPartial Response (irPR) or irStable Disease (irSD): non-index lesion(s)
are not considered in the definition of PR, these terms do not apply.
 
irProgressive Disease (irPD): Increases in number or size of non-index 
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lesion(s) does not constitute progressive disease unless/until the 
Percentage Change in Tumor Burden increases by 25% (i.e., the SPD at 
nadir of the index lesions increases by the required amount).
6.5.7
Impact of New Lesions on irRC
New lesions in and by themselves do not qualify as progressive disease. 
However, their contribution to total tumor burden is included in the SPD, 
which in turn feeds into the irRC criteria for tumor response. Therefore, new 
non-measurable lesions will not discontinue any subject from the study.
6.5.8
Definition of Overall Response Using irRC
Overall response using irRC will be based on these criteria:
 
Immune-Related Complete Response (irCR): Complete disappearance 
of all tumor lesions (index and non-index together with no new 
measurable/unmeasurable lesions) for at least 4 weeks from the date of 
documentation of complete response.
 
Immune-Related Partial Response (irPR): The sum of the products of the 
two largest perpendicular diameters of all index lesions is measured and 
captured as the SPD baseline. At each subsequent tumor assessment, 
the sum of the products of the two largest perpendicular diameters of all 
index lesions and of new measurable lesions are added together to 
provide the Immune Response Sum of Product Diameters (irSPD). A 
decrease, relative to baseline of the irSPD compared to the previous
SPD baseline, of 50% or greater is considered an immune Partial
Response (irPR).
 
Immune-Related Stable Disease (irSD): irSD is defined as the failure to 
meet criteria for immune complete response or immune partial response, 
in the absence of progressive disease.
 
Immune-Related Progressive Disease (irPD): It is recommended in 
difficult cases to confirm PD by serial imaging. Any of the following will 
constitute progressive disease:

At least 25% increase in the sum of the products of all index lesions 
over nadir SPD calculated for the index lesions.

At least a 25% increase in the sum of the products of all index 
lesions and new measurable lesions (irSPD) over the baseline SPD 
calculated for the index lesions.
6.5.9
Immune-Related Best Overall Response Using irRC (irBOR):
irBOR is the best confirmed irRC overall response over the study as a whole, 
recorded between the date of first dose until the last tumor assessment before 
subsequent therapy (except for local palliative radiotherapy for painful bone 
lesions) for the individual subject in the study. For the assessment of irBOR, 
all available assessments per subject are considered.
irCR or irPR determinations included in the irBOR assessment must be 
confirmed by a second (confirmatory) evaluation meeting the criteria for 
response and performed no less than 4 weeks after the criteria for response 
are first met.
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Derivation of irRC overall responses:
Measurable response
Nonmeasurable response
Overall 
response
Index and new, measurable 
lesions (tumor burden),*%
Non-index lesions
New, nonmeasurable 
lesions
Using irRC
↓100
Absent
Absent
irCR†
↓100
Stable
Any
irPR†
↓100
Unequivocal 
progression
Any
irPR†
↓≥50
Absent/Stable
Any
irPR†
↓≥50
Unequivocal progression
Any
irPR†
↓<50 to <25↑
Absent/Stable
Any
irSD
↓<50 to <25↑
Unequivocal progression
Any
irSD
≥25
Any
Any
irPD†
*Decreases assessed relative to baseline (scan prior to start of any protocol therapy), 
including measurable lesions only
†Assuming response (irCR) and progression (irPD) are confirmed by a second, consecutive 
assessment at least 4 wk apart.
7.0
ADVERSE EVENTS
This study will be conducted in compliance with the Data Safety Monitoring Plan (DSMP) of 
the Robert H. Lurie Comprehensive Cancer Center of Northwestern University 
(http://cancer.northwestern.edu/CRO/data/DataandSafetyMonitoringPlanMay2014.pdf). The 
level of risk attributed to this study requires high, as outlined in the DSMP. In addition, the 
study will abide by all safety reporting regulations, as set forth in the Code of Federal 
Regulations.
7.1
Adverse Event Monitoring
Adverse event data collection and reporting, which are required as part of every 
clinical trial, are done to ensure the safety of subjects enrolled in the studies as well 
as those who will enroll in future studies using similar agents. Adverse events are 
reported in a routine manner at scheduled times during a trial (see Section 5 for 
time points). In addition, certain adverse events must be reported in an expedited 
manner to allow for optimal monitoring and patient safety and care.
All patients experiencing an adverse event, regardless of its relationship to study 
drug, will be followed until:
 
the adverse event resolves or the symptoms or signs that constitute the adverse 
event return to baseline;
 
any abnormal laboratory values have returned to baseline;
 
there is a satisfactory explanation other than the study drug for the changes 
observed; or
 
death.
7.2
Definitions & Descriptions
7.2.1
Adverse Event
An adverse event (AE) is any untoward medical occurrence in a patient 
receiving study treatment and which does not necessarily have a causal 
relationship with this treatment. An AE can therefore be any unfavorable and 
unintended sign (including an abnormal laboratory finding), symptom, or 
disease temporally associated with the use of an experimental intervention, 
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whether or not related to the intervention.
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.
All adverse events that occur after the consent form is signed but before 
treatment allocation/randomization must be reported by the investigator if 
they cause the subject to be excluded from the trial, or are the result of a 
protocol-specified intervention, including but not limited to washout or 
discontinuation of usual therapy, diet, or a procedure.
From the time of treatment allocation/randomization through 30 days 
following cessation of treatment, all adverse events must be reported by the 
investigator. Such events will be recorded at each examination on the 
Adverse Event case report forms/worksheets. The reporting timeframe for 
adverse events meeting any serious criteria is described in section 7.3. The 
investigator will make every attempt to follow all subjects with non-serious 
adverse events for outcome.
Recording of AEs should be done in a concise manner using standard, 
acceptable medical terms. In general, AEs are not procedures or 
measurements, but should reflect the reason for the procedure or the 
diagnosis based on the abnormal measurement. Preexisting conditions that 
worsen in severity or frequency during the study should also be recorded (a 
preexisting condition that does not worsen is not an AE). Further, a 
procedure or surgery is not an AE; rather, the event leading to the procedure 
or surgery is considered an AE.
If a specific medical diagnosis has been made, that diagnosis or syndrome 
should be recorded as the AE whenever possible.  However, a complete 
description of the signs, symptoms and investigations which led to the 
diagnosis should be provided. For example, if clinically significant elevations 
of liver function tests are known to be secondary to hepatitis, “hepatitis” and 
not “elevated liver function tests” should be recorded. If the cause is not 
known, the abnormal test or finding should be recorded as an AE, using 
appropriate medical terminology (e/g/ thrombocytopenia, peripheral edema, 
QT prolongation).
Hospitalization for elective surgery or routine clinical procedures that are not 
the result of an AE (e.g., surgical insertion of central line) need not be 
considered AEs and should not be recorded as an AE. Disease progression 
should not be recorded as an AE, unless it is attributable by the site 
investigator to the study drug.
7.2.2
Severity of AEs
All non-hematologic adverse events will be graded according to the NCI 
Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. 
The CTCAE v4 is available at http://ctep.cancer.gov/reporting/ctc.html
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If no CTCAE grading is available, the severity of an AE is graded as follows:
 
Mild (grade 1): the event causes discomfort without disruption of normal 
daily activities.
 
Moderate (grade 2): the event causes discomfort that affects normal 
daily activities.
 
Severe (grade 3): the event makes the patient unable to perform normal 
daily activities or significantly affects his/her clinical status.
 
Life-threatening (grade 4): the patient was at risk of death at the time of 
the event.
 
Fatal (grade 5): the event caused death.
7.2.3
Serious Adverse Events (SAEs)
All SAEs, regardless of attribution, occurring from time of signed informed 
consent, through 90 days after the last administration of study drug, must be 
reported upon discovery or occurrence.
An SAE is defined in regulatory terminology as any untoward medical 
occurrence that:
 
Results in death.
If death results from (progression of) the disease, the disease should be
reported as event (SAE) itself.
 
Is life-threatening.
The patient was at risk of death at the time of the event; it does not refer 
to an event that hypothetically might have caused death if it were more 
severe.
 
Requires in-patient hospitalization or prolongation of existing 
hospitalization for ≥ 24 hours.
 
Results in persistent or significant disability or incapacity.
 
Is a congenital anomaly/birth defect.
 
Is an important medical event.
Any event that does not meet the above criteria, but that in the judgment 
of the investigator jeopardizes the patient, may be considered for 
reporting as a serious adverse event. The event may require medical or 
surgical intervention to prevent one of the outcomes listed in the 
definition of “Serious Adverse Event“.
For example: allergic bronchospasm requiring intensive treatment in an 
emergency room or at home; convulsions that may not result in 
hospitalization; development of drug abuse or drug dependency.
 
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.
7.2.4
Unanticipated Problems Involving Risks to Subject or Others
A UPIRSO is a type of SAE that includes events that meet ALL of the 
following criteria:
 
Is unanticipated in terms of nature, severity, or frequency
 
Places the research subject or others at a different or greater risk of 
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harm
 
Is deemed to be at least possibly related to participation in the study.
7.2.5  Suspected Adverse Reaction (SAR)
A SAR is any adverse event for which there is a reasonable possibility that 
the drug caused the adverse event. "Reasonable possibility" means there is 
evidence to suggest a causal relationship between the drug and the adverse 
event.
7.2.6 Suspected Unexpected Serious Adverse Reaction (SUSAR)
A SUSAR is a SAR that is serious and unexpected (not consistent with the 
applicable product information).
7.2.7
Definition of Overdose according to Merck
For purposes of reporting overdose in this trial, Merck considers an overdose 
of pembrolizumab to be defined as any dose of 1,000 mg or greater (≥5
times the indicated dose). NOTE: NU IRB requires reporting of overdose of 
any amount as Reportable New Information. 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.
7.3
Adverse Event Reporting
7.3.1
Routine Reporting
All routine adverse events, such as those that are expected, or are unlikely or 
definitely not related to study participation, are to be reported on the 
appropriate eCRF. Routine AEs will be reviewed by the Data Monitoring 
Committee (DMC) according to the study’s phase and risk level, as outlined
in the DSMP.
7.3.2
Determining if Expedited Reporting is Required
This includes all events that occur within 30 days of the last dose of protocol 
treatment. Any ≥ Grade 2 event that occurs more than 30 days after the last 
dose of treatment and is attributed (possibly, probably, or definitely) to the 
agent(s) must also be reported accordingly, until the AE is ≤ Grade 1 or 
baseline, deemed clinically insignificant, and/or until a new anti-cancer 
treatment starts, whichever is earlier.
1)
Identify the type of adverse event using the NCI CTCAE v 4.03.
2)
Grade the adverse event using the NCI CTCAE v 4.03.
3)
Determine whether the adverse event is related to the protocol 
therapy.
Attribution categories are as follows:
 
Definite: AE is clearly related to the study treatment.
 
Probable: AE is likely related to the study treatment.
 
Possible: AE may be related to the study treatment.
 
Unlikely: AE not likely to be related to the study treatment.
 
Unrelated: AE is clearly NOT related to the study treatment.
4)
Determine the prior experience of the adverse event.
Expected events are those that have been previously identified as 
resulting from administration of the agent. An adverse event is 
considered unexpected, for expedited reporting purposes only, when 
either the type of event or the severity of the event is not listed in:
 
the current protocol
 
the drug package insert
 
the current Investigator’s Brochure
All AEs considered related to study drug will be followed until 
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resolution to ≤ Grade 1 or baseline, deemed clinically insignificant, 
and/or until a new anti-cancer treatment starts, whichever is earlier.
7.3.3
Expedited Reporting to the Northwestern University QAM/DMC
SAEs will be reported from the time of informed consent through 90 
days following last dose of study drug, or the initiation of new anti- 
cancer therapy, whichever comes first regardless of whether or not 
the event(s) are considered related to the study drug.
All AEs and SAEs will be recorded in the subject’s medical record
All SAEs must be reported to the assigned QAM within 24 hours of 
becoming aware of the event. Completion of the NU CRO SAE 
Form, provided as a separate document, is required.
The completed form should assess whether or not the event qualifies 
as a UPIRSO. The report should also include:
 
Protocol description and number(s)
 
The patient’s identification number
 
A description of the event, severity, treatment, and outcome (if 
known)
 
Supportive laboratory results and diagnostics
 
The hospital discharge summary (if available/applicable)
All SAEs will be reported to, and reviewed by, the DMC at their next 
meeting.
7.3.4
Expedited Reporting to the Northwestern University IRB
 
Any death of an NU subject that is unanticipated in nature and at least 
possibly related to study participation will be promptly reported to the NU 
IRB within 24 hours of notification.
 
Any death of an NU subject that is actively on study treatment 
(regardless of whether or not the event is possibly related to study 
treatment)
 
Any death of a non-NU subject that is unanticipated and at least possibly 
related and any other UPIRSOs will be reported to the NU IRB within 5 
working days of notification.
 
All other deaths of NU subjects not previously reported, other non-NU 
subject deaths that were unanticipated and unrelated, and any other 
SAEs that were not previously reported as UPIRSOs will be reported to 
the NU IRB at the time of annual continuing review.
7.3.5
Expedited Reporting to the FDA (To be done by QAM)
The FDA will be notified within 7 calendar days of any SAE that is associated 
with study treatment, is unexpected, and is fatal or life-threatening.
The FDA will be notified within 15 calendar days of any SAE that is 
associated with the study treatment, unexpected, and serious but not fatal or 
life-threatening. This includes any previous SAEs that were not initially 
deemed reportable, but are later determined to meet the criteria for reporting 
(i.e. by the DMC).
All other SAEs will be reported on an annual basis as part of the annual FDA
report.
7.3.6
Expedited Reporting to Merck and Astex (To be done by coordinator) 
SAEs will be reported to Merck within one business day of 
acknowledgement of the event, using the NU CRO SAE form. Follow-up 
information will be provided to Merck as reasonably requested. SAE/ECI 
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Submission Forms and any other relevant safety information are to be 
forwarded to the Merck Global Safety facsimile number: +1-215-993-1220.
SAEs related to guadecitabine will be reported to Astex within one 
business day of acknowledgement of the event, using the NU CRO SAE 
form. In addition, the Astex SAE Fax Cover Sheet should be used when 
faxing the form to Astex. Follow-up information will be provided to Astex as 
reasonably requested. SAE/ECI Submission Forms and any other relevant 
safety information are to be forwarded to the Astex Drug Safety facsimile 
number: 1-800-576-6568 or emailed to drugsafety@astx.com
7.3.7
Additional Merck Definitions and Reporting Requirements
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
Events of Clinical Interest
Selected non-serious and serious adverse events are also known as Events 
of Clinical Interest (ECI) and must be reported using the NU CRO SAE form 
within 24 hours to the PI and within 2 working days to Merck Global Safety. 
(Attn: Worldwide Product Safety; FAX 215 993-1220).
For the time period beginning when the consent form is signed until treatment 
allocation/randomization, any ECI, or follow up to an ECI, that occurs to any 
subject must be reported within 24 hours to the PI and within 2 working days 
to Merck Global Safety if it causes the subject to be excluded from the trial, or 
is the result of a protocol-specified intervention, including but not limited to 
washout or discontinuation of usual therapy, diet, placebo treatment or a 
procedure.
For the time period beginning at treatment allocation/randomization through
90 days following cessation of treatment, or 30 days following cessation of 
treatment if the subject initiates new anticancer therapy, whichever is earlier, 
any ECI, or follow up to an ECI, whether or not related to Merck product, 
must be reported within 24 hours to the PI and within 24 hours to Merck 
Global Safety.
Events of clinical interest for this trial include:
   an overdose of Merck product, as defined in Section 7.2.1 that is not 
associated with clinical symptoms or abnormal laboratory results.
   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.
Reporting of Overdose to Merck
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, 
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even if no other seriousness criteria are met. If a dose of Merck’s product 
meeting the protocol definition of overdose (refer section 7.2.1) 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 
using the NU CRO SAE form within 24 hours to the PI and within 2 working 
days hours to Merck Global Safety. (Attn: Worldwide Product Safety; FAX 215
993-1220).
(Note: This does not apply to Northwestern University, because, as per NU IRB 
regulations, any amount of overdose will be reported as a reportable New 
Information [RNI])(Refer Section 11.7.2).
Reporting of Pregnancy and Lactation 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/randomization must be reported by the investigator 
if they cause the subject to be excluded from the trial, or are the result of a 
protocol-specified intervention, including but not limited to washout or 
discontinuation of usual therapy, diet, placebo treatment or a procedure.
Pregnancies and lactations that occur from the time of treatment 
allocation/randomization through 120 days following cessation of product, or 30 
days following cessation of treatment if the subject initiates new anticancer 
therapy, whichever is earlier, must be reported by the investigator. All reported 
pregnancies must be followed to the completion/termination of the pregnancy. 
Pregnancy outcomes of spontaneous abortion, missed abortion, benign 
hydatidiform mole, blighted ovum, fetal death, intrauterine death, miscarriage 
and stillbirth must be reported as serious events (Important Medical Events). If 
the pregnancy continues to term, the outcome (health of infant) must also be 
reported.
Such events must be reported within 24 hours to the PI and within 2 working 
days to Merck Global Safety. (Attn: Worldwide Product Safety; FAX 215 993-
1220)
8.0
DRUG INFORMATION
8.1
Pembrolizumab
8.1.1
Other names
Pembrolizumab; MK-3475 [Anti-PD-1 Antibody MK-3475])
8.1.2
Classification - type of agent
Humanized X PD-1_mAb (H409A11) IgG4
8.1.3
Mode of action
Highly selective anti-PD-1 humanized monoclonal antibody which inhibits 
programmed cell death-1 (PD-1) activity by binding to the PD-1 receptor on 
T-cells to block PD-1 ligands (PD-L1 and PD-L2) from binding. Blocking the 
PD-1 pathway inhibits the negative immune regulation caused by PD-1 
receptor signaling (Hamid, 2013). Anti-PD-1 antibodies (including
pembrolizumab) reverse T-cell suppression and induce antitumor responses.
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8.1.4
Storage and stability
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. Pembrolizumab is 
formulated with L-histidine as buffering agent, polysorbate 80 as surfactant, 
sucrose as stabilizer/tonicity modifier, and hydrochloric acid (HCl) and/or 
sodium hydroxide (NaOH) for pH adjustment (if necessary). The drug product 
is stored as a stable lyophilized powder or liquid solution under refrigerated 
conditions (2°C - 8°C).
Clinical supplies must be stored in a secure, limited-access location under 
the storage conditions specified on the label.
Store Pembrolizumab vials under refrigeration at 2 to 8 degrees Celsius (C)
or 36 to 46 degrees Fahrenheit (F). Do not freeze; do not shake.
Storage following dilution: Store at room temperature for up to 6 hours or 
refrigerated at 2—8 degrees C (36—46 degrees F) for up to 24 hours. 
This includes room temperature storage of the diluted infusion solution 
and the duration of infusion). Do not freeze.
8.1.5
Protocol dose specifics
Pembrolizumab 200 mg will be administered as a 30-minute intravenous (IV)
infusion every 21 days (3 weeks).
8.1.6
Preparation
Please refer to the Pharmacy Manual for a comprehensive description of 
pembrolizumab preparation.
The product after reconstitution with sterile water for injection and the liquid 
drug product is a clear to opalescent solution, which may contain extraneous 
and proteinaceous particulates. The reconstituted product and liquid product 
is intended for IV administration. The reconstituted drug product solution and 
liquid drug product can be further diluted with normal saline or 5%
dextrose in the concentration range of 1 to 10 mg/mL in IV containers made 
of polyvinyl chloride (PVC) or non-PVC material. Reconstituted vials should 
be used immediately to prepare the infusion solution in the IV bag, and the 
infusion solution should be administered immediately. If the diluted 
pembrolizumab solution is not used immediately, it may be stored for no more 
than 24 hours at 2°C to 8°C. This 24-hour total hold time from reconstitution 
may include up to 6 hours at room temperature (at or below 25°C).
 
8.1.7
Route of administration for this study
Intravenous (IV)
8.1.8
Incompatibilities:
None known
8.1.9
Availability & Supply
Merck will provide investigational supply pembrolizumab directly to 
Northwestern University Investigational pharmacy, at no charge to subjects 
participating in this clinical trial.
The contact for drug ordering will be Sloan Stribling 
(sloan_stribling@merck.com). The Merck Drug Request Form should be 
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completed and emailed to these contacts.
Pembrolizumab is available in two formulations from Merck as summarized 
below. NOTE: the primary formulation that will be supplied in this study is the 
pembrolizumab 100 mg/4mL solution for injection.
Pembrolizumab 50 
mg
Lyophilized Powder for
Injection
Pembrolizumab 100 
mg/ 4mL
Solution for Injection
8.1.10  Side effects
Please see current Investigator’s Brochure for a complete list of adverse 
events.
Pembrolizumab is generally well tolerated and demonstrates a favorable 
safety profile in comparison to chemotherapy. Pembrolizumab is an 
immunomodulatory agent, and based on this mechanism of action, immune 
mediated adverse events are of primary concern. Important identified risks
for pembrolizumab are of an immune mediate nature, including: pneumonitis, 
colitis, thyroid disorders (hypothryoidism/hyperthyroidism), hepatitis, 
hypophysitis, Type I diabetes mellitis, uveitis, and nephritis. After a recent 
review of data, events newly characterized as identified risks also include 
pancreatitis, myositis, and severe skin reaction; these are included in the 
reference safety information in the current IB. The majority of immune- 
mediated adverse events were mild to moderate in severity, were 
manageable with appropriate care, and rarely required discontinuation of 
therapy.
In addition to the previously noted identified risks, infusion-related reactions 
are a risk but are not considered immune mediated; these are also further 
described in the current IB.
8.1.11  Nursing implications
Pembrolizumab will be administered as an IV infusion ((dilution as stated 
above) over approximately 30 minutes Every effort should be made to target 
infusion timing to be as close to 30 minutes as possible. However, a window 
of -5 minutes and +10 minutes is permitted (i.e., infusion time is 30 minutes: -
5 min/+10 min).
When an IV bag is used for the infusion, the IV line will be flushed with a 
volume of normal saline equal to the priming volume of the infusion set used 
after the contents of the IV bag are fully administered.
Since the compatibility of w i t h  other IV medications and solutions, other
than normal saline (0.9% [w/v] sodium chloride for injection) and D5W, is not 
known, the Pembrolizumab solution should not be infused through an IV line 
in which other solutions or medications are being administered. The date, 
start time, interruption, and completion time of Pembrolizumab administration 
must be recorded in the source documents.
8.1.12  Return and Retention of Study Drug
The site investigator is responsible for keeping accurate records of the
clinical supplies received from Funders or a designee, the amount dispensed 
to and returned by the subjects and the amount remaining at the conclusion 
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of the trial.
Upon completion or termination of the study, all unused and/or partially 
used investigational product will be destroyed at the site per institutional 
policy. It is the site 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.
8.2
Guadecitabine
8.2.1
Other names:
SGI-110
8.2.2
Classification - type of agent
Sodium (2R,3S,5R)-5-(4-amino-2-oxo-1,3,5-triazin-1(2H)-yl)-2- 
(hydroxymethyl)tetrahydrofuran-3-yl((2R,3S,5R)-5-(2-amino-6-oxo-1H-purin-
9(6H)-yl)-3-hydroxytetrahydrofuran-2-yl)methyl phosphate
Guadecitabine is a dinucleotide incorporating the approved drug, decitabine, 
and purine nucleoside, deoxyguanosine
8.2.3
Mode of action:
DNA methyltransferase inhibitor targeting
DNA (cytosine-5-)-methyltransferase 1 (DNMT1)
Targets and reverses aberrant DNA hypermethylation.  Guadecitabine- 
mediated demethylation of DNA upregulates tumor-associated antigens, and 
may sensitize tumor cells to other anticancer agents, including 
immunotherapeutics, as well as resensitizing resistant cancer cells to 
chemotherapeutics.
8.2.4
Storage and stability:
Guadecitabine product is supplied in a two-vial configuration: 

SGI-110 (guadecitabine) for Injection (SGI-110), 100 mg or 156 mg, 
containing lyophilized guadecitabine drug powder for reconstitution; and

SGI-110 Diluent for Reconstitution (Diluent), 3 mL or 1.2 mL or 1.4 mL.
SGI-110 (guadecitabine) 100 mg and 156 mg vials should be stored under 
refrigerated conditions of 2 - 8°C (36°- 46°F) in the original packaging in an 
upright position until use.  SGI-110 Diluent, 3 mL should be stored at 2° - 30°C 
(36°- 86° F); 1.2 mL and 1.4 mL should be stored at 2 - 8°C (36°- 46°F) in 
upright position until use. Both vials are preservative free and for single use 
only. 
Upon reconstitution, the admixed product is stable for 10 days under 
refrigerated conditions of 2–8°C (36°-46° F), either in the vial or in syringes. 
Therefore, if desired, sites may prepare syringes for all treatment days in a 
dosing cycle in advance (as institutional procedures allow).
Please refer to pharmacy manual Table “Temperature Excursion Guidelines 
for SGI-110 and Diluent While Stored On Site” for instructions on 
temperature excursions outside the required storage conditions for SGI-110 
for Injection and SGI-110 Diluent for Reconstitution. 
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Guadecitabine must be stored in a secure, locked facility accessible only to 
authorized study personnel 
Please refer to current pharmacy manual for additional information.
8.2.5
Protocol dose specifics:
Guadecitabine 30mg/m2 will be administered as a subcutaneous injection 
on Days 1-4 of every 3 week cycle.
(Note: Baseline weight will be used throughout. Dose will not change 
with weight changes.)
Note: Guadecitabine priming can be discontinued and the patient can 
continue on pembrolizumab monotherapy after 6 months (8 cycles),  at the 
discretion of the treating physician, if the patient has stable disease or 
response. If this is done, the previously scheduled pembrolizumab treatment 
on Day 5 will become Day 1(+/-2 days). 
For patients who discontinued guadecitabine for reasons other than toxicity 
(i.e. disease stability of response > 6 months) and progress on 
pembrolizumab alone, a re-trial of guadecitabine in combination with 
pembrolizumab is possible, at the discretion of the treating physician, if the 
patient is clinically stable.
8.2.6
Preparation
Please refer to the Pharmacy Manual of SGI-110 (guadecitabine) for a 
comprehensive description of guadecitabine preparation.
OSHA Guidelines for handling cytotoxic drugs outlined in the American 
Journal of Hospital Pharmacy must be followed 23. As with other potentially 
toxic anti-cancer agents, care should be exercised in the handling and 
preparation of guadecitabine. The use of gloves and protective garments is 
recommended. Preparation should occur in a vertical laminar flow biological 
hood or per institutional standards using proper aseptic technique. If 
guadecitabine SGI-110 contacts the skin, it should be immediately be 
treated with borax buffer solution pH 10 followed by washing immediately 
and thoroughly with soap and water. If guadecitabine contacts the mucous 
membranes, flush thoroughly with water.
Drug spilling can be inactivated by 2 N sodium hydroxide solution or Water 
and Kericide CR Biocide B which consist of a blend of stabilized chlorine 
dioxide and a quaternary ammonium compound. 
Disinfect biological safety cabinet by wiping surfaces with 70% isopropanol 
or ethanol solution or by established pharmacy standards.
Note: Please follow your institutional SOPs regarding any additional 
requirements or processes.
Reconstituted drug product is intended for subcutaneous administration at a
maximum concentration of 100 mg/mL. The required volume from the diluent 
vial is drawn into a syringe for reconstitution and emptied into the vial 
containing guadecitabine for injection. 
8.2.7
Route of administration for this study
Subcutaneous. Please refer to pharmacy manual for more details on SGI-110 
Administration.
8.2.8
Incompatibilities:
None known
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8.2.9
Availability & Supply
Astex will supply guadecitabine directly to Northwestern University at no 
charge to subjects participating in this clinical trial.  Investigational product 
resupply will need to be requested at least 2 weeks in advance Site-specific 
drug order forms will be provided prior to study activation and will be used to 
order drug supply directly from Astex.
8.2.10  Side effects
Please see current Investigator’s Brochure for a complete list of adverse 
events. 
8.2.11  Nursing implications
Ice packs can be used for painful injection site as a comfort measure
9.0
CORRELATIVES/SPECIAL STUDIES
To test the hypothesis that the combination of guadecitabine and pembrolizumab 
reactivates immune responses by allowing re-expression of tumor antigens silenced 
epigenetically, we will measure several endpoints:
 
NY-ESO-1 and MAGE antigens’ promoter methylation (pyrosequencing) and 
mRNA expression levels (quantitative RT-PCR) will be measured before and 
after treatment in DNA (plasma and/or tumor biopsies) and RNA (tumor 
biopsies), respectively.
 
Cytokine response (IFN IL2, IL6, IL10, TNF) will be measured in plasma by ELISA.
 
Measure LINE 1 methylation in DNA extracted from PBMCs (Days 1 and 5 of cycles
1 and 2)
 
Expression of the PD1 ligands (L1) will be measured by IHC in archival tumors.
 
Tumor infiltrating lymphocytes (TILs) will be quantified in tumor biopsies 
before and after treatment (IHC). All biological parameters will be 
correlated with clinical endpoints (RR and PFS).
Please see the Laboratory Manual (LM) for specific details on correlative study 
procedures, handling, preserving, and shipping. The table below summarizes the 
tests that will be performed for correlative endpoints: 
Correlative Samples summary
Correlative study
(sample type)
Archiva
l tissue
Fresh biopsy
or paracentesis 
or thoracentesis.
PBMC
Plasma
Mandatory or
Optional
Mandatory
Mandatory
except the 
sample collected 
at  >=6 months 
which is optional
Mandatory
except the 
sample 
collected at  
>=6 months 
which is 
optional
Mandatory
except the sample 
collected at  >=6 months 
which is optional    
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Timing (+/- 
windows)
Baseline 
(may be 
procured up 
to 3 months 
from 
registration) 
Pre-treatment 
C1D1 (≤7 days) 
but after 
registration); 
C2D8 (+2 days)
and
 ONE 
OPTIONAL 
sample 
collection  at 
anytime from 
≥6 months and 
before the safety 
follow-up visit.
Pre-treatment
C1D1(≤4 
days); 
C1D5;
Pre-treatment 
C2D1(-≤4 
days);
C2D5;
Follow up visit;
and
 ONE 
OPTIONAL 
sample 
collection  at 
anytime from 
≥6 months 
and before the 
safety follow-
up visit.
For cytokine response 
Pre-treatment C1D1 (≤4 
days); C2D1 (≤4 days) 
C3D1 (≤4 days) and at 
Follow up visit.
For DNA analysis
C1D1(≤7 days);
C2 D8(+2 days)-at the 
time of biopsy
/paracentesis/
thoracentesis)
and
 ONE OPTIONAL sample 
collection for both 
cytokine response  and 
DNA analysis, at any time 
from 
≥6 months and before the 
safety follow-up visit.
Volume Needed
(blood only)
NA
NA
5-8ml
5-8mL
Tube type needed 
(blood only)
NA
NA
Sodium citrate
Sodium citrate
Tissue thickness and/or 
# slides (tissue only)
5-6 microns
6-10 slides
3 core biopsies 
for research. 
Tissue should 
be tested by 
pathology for 
tumor 
confirmation
NA
Processing center
IR
PCF
PCF
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Sample handling/
processing instructions
RT, ship 
as 
described
The first core 
will be snap 
frozen upon 
collection. The 
second core will 
be
formalin-fixed, 
paraffin- 
embedded 
(FFPE). The 
third core will be 
snap frozen 
upon collection. 
Freshly 
collected
paracentesis/
thoracentesis 
samples will be 
sent immediately 
to the Matei lab 
for processing.
Separate 
PBMCs and 
plasma.
Freeze PBMCs
Freeze after plasma 
separation
Shipping/delivery info
Matei Lab
Lurie 4-220
Matei Lab
Lurie 4-220
Matei Lab
Lurie 4-220
Storage needs
Matei Lab
Lurie 4-220
Matei Lab
Lurie 4-220
Matei Lab
Lurie 4-220
Matei Lab
Lurie 4-220
Analysis center
Qualtek and
Matei Lab
Matei Lab
Matei Lab
Matei Lab
Assay methodology
IHC
DNA, RNA
extraction
DNA
extraction
DNA extraction
Cytokine ELISA
The archived tumor tissue specimens may be from surgery or from a diagnostic 
biopsy of primary or metastatic tumor specimen, and may be procured up to 3 
months from registration study. Unavailability of archived tissue will not render 
subject ineligible for study. Subjects will be consented to optional storage of any 
remaining tumor and plasma samples after protocol- specified studies are complete. 
Stored tumor and plasma samples will be reserved for future cancer-related research.
Tumor and plasma samples for future use will be stored at Northwestern 
University’s local laboratory:
Matei Lab
303 E. Superior St, Lurie 4-220
Chicago, IL 60611
Phone: 312-472-4684
10.0
STATISTICAL CONSIDERATIONS
Statistical analysis of this study will be the responsibility of the Biostatistics Core Facility of 
the Robert H. Lurie Comprehensive Cancer Center.
10.1
Study Design
This is a multi-center non-randomized, open label phase II study. Study endpoints 
are defined in Section 2.0. A safety run-in cohort has been designed for the first six 
subjects enrolled, in order to ensure the safety of this experimental combination of 
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guadecitabine and pembrolizumab.
10.2
Sample Size and Accrual
We will utilize the optimum two-stage design and we anticipate enrolling 35 evaluable 
patients. This two-stage design to test the null hypothesis that RR<=0.10 versus the 
alternative that RR>=0.30 (where RR is calculated via RECIST v1.1) has an expected 
sample size of 22.5 and a probability of early termination of 0.71 when RR=0.10.  If 
the drug combination is actually not effective, there is a 0.047 probability of 
concluding that it is (the target for this value was 0.050). If the drug is actually 
effective, there is a 0.098 probability of concluding that it is not (the target for this 
value was 0.100). Subjects who are not evaluable for response will be replaced so up 
to 46 subjects may be enrolled.
10.3
Data Analysis Plans
10.3.1
Analysis Plans for Primary Objective
The primary outcome is objective response by RECIST v1.1. The proportion 
of patients having an objective response by RECIST 1.1 will be estimated 
with a 95% exact binomial confidence interval for the efficacy population. 
These confidence intervals will be adjusted for the sequential nature of the 
two-stage procedure 24.
10.3.2
Analysis Plans for Secondary Objectives
Confidence intervals for the clinical benefit rate will be calculated similarly to 
RR. Progression-free survival times will be estimated using the Kaplan-Meier 
method. The objective response rate by irRC will be estimated similarly. 
Confidence intervals on the median will be constructed. Toxicities will be 
tabulated.
10.3.3
Analysis Plans for Exploratory Objectives
All biological parameters other than PD-L1 ligand expression will be 
measured pre and post treatment (either in plasma or tumor) or Day 1 and 
Day 5 (LINE1 methylation in PBMCs). Pre-treatmentvs post-treatment or Day 
1 to Day 5 comparisons will be made by paired t-tests (or Wilcoxon Signed-
Rank tests if the data are not normally distributed). PD-L1 ligand expression 
from archival tissue will be summarized descriptively. Pre-treatment 
(including PD-L1 ligand expression) and pre-post changes in parameters will 
be correlated
with response by Fisher-Exact test for RR, CBR, and log rank test for PFS 
(using the maximal chi-square cut-point for the parameter).
10.4
Interim
10.4.1
m Analysis/Criteria for Stopping Study
Safety Criteria
The first 6 patients will be part of an initial safety run-in. A safety analysis will
be done after all six patients have been observed for at least 2 weeks after 
completion of cycle 1. All toxicities will be tabulated.  The study will move 
forward if ≤ 1 of 6 in the safety lead in cohort 1 experience a DLT (as defined
in Section 4.3 and Table 3). If > 2 of 6 in cohort 1 experience a DLT, the 
study will be suspended and an amendment to explore alternate dosing 
schemes will be considered. Toxicity counts and rates and the results of the 
analysis will be reviewed by the DMC. The patients enrolled in the safety 
lead in cohort will be included in the efficacy analysis.
10.4.2  Efficacy Criteria
As this is a two-stage design, an interim efficacy analysis is planned after 18 
patients are evaluable (see 10.2 for additional details). After testing the drug 
on 18 patients in the first stage, consideration will be given to trial termination 
if 2 or fewer patients demonstrate clinical benefit (CR, PR, or SD for at least 3 
months). If the trial goes on to the second stage, a total of 35 evaluable 
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patients will be studied. If the total number responding is less than or equal 
to 6, the combination is rejected.
11.0
STUDY MANAGEMENT
11.1
Institutional Review Board (IRB) Approval and Consent
It is expected that the IRB will have the proper representation and function in 
accordance with federally mandated regulations. The IRB should approve the 
consent form and protocol.
In obtaining and documenting informed consent, the investigator should comply with 
the applicable regulatory requirement(s), and should adhere to Good Clinical Practice 
(GCP) and to ethical principles that have their origin in the Declaration of Helsinki.
Before recruitment and enrollment onto this study, the patient will be given a full 
explanation of the study and will be given the opportunity to review the consent form. 
Each consent form must include all the relevant elements currently required by the 
FDA Regulations and local or state regulations. Once this essential information has 
been provided to the patient and the investigator is assured that the patient 
understands the implications of participating in the study, the patient will be asked to 
give consent to participate in the study by signing an IRB approved consent form.
Prior to a patient’s participation in the trial, the written informed consent form should 
be signed and personally dated by the patient and by the person who conducted the 
informed consent discussion.
11.2
Amendments
The Principal Investigator will formally initiate all amendments to the protocol and/or 
informed consent. All amendments will be subject to the review and approval of the 
appropriate local, institutional, and governmental regulatory bodies, as well as by 
Merck and Astex.
11.3
Registration Procedures
11.3.1  Registering a Patient for the safety Run-in portion of the Study
For potential patients for the phase I portion of this study, study teams are 
asked to inform the QAM of the date and time that the patient will need to be 
registered (croqualityassurance@northwestern.edu).
BEFORE a patient can be treated on study, please complete and submit the 
following items to confirm eligibility and receive an identification number:
 
Patient’s signed and dated informed consent form (upload to NOTIS and 
keep original hard copy in a secure location/study chart)
 
Eligibility checklist (signed and dated by the treating physician – upload 
to NOTIS)
 
Eligibility eCRF (complete in NOTIS)
 
Copy of the pathology report (upload to NOTIS)
The QAM will review all source documentation required to confirm eligibility 
that is readily available in the patient’s electronic medical record (EMR). Any 
information that is not available in the EMR must be de-identified and
emailed to the QAM. Once the QAM confirms the patient is eligible, he or she 
will register the patient, assign a subject identification number, provide a 
cohort assignment, and send a confirmation of registration to involved 
personnel. Registration will then be complete and the patient may begin
study treatment.
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11.3.2  Registering a Patient to the Study (after safety run-in)
For potential patients enrolled after the safety run-in portion of this study, 
study teams are asked to inform the QAM of the date and time that the 
patient will need to be registered (croqualityassurance@northwestern.edu).
BEFORE a patient can be treated on study, please complete and submit the 
following items to confirm eligibility and receive a subject identification 
number:
• Eligibility eCRF (complete in NOTIS)
• Eligibility checklist (signed and dated by the treating physician – upload in
NOTIS)
• Signed and dated informed consent document (upload in NOTIS)
• Pathology Report (upload in NOTIS)
The QAM will review the registration, register the patient, assign an 
identification number, and send a confirmation of registration to involved 
personnel. Registration will then be complete and the patient may begin 
study treatment.
11.4
Data Submission
Once a subject is confirmed and registered to the study, eCRFs should be submitted 
according to the detailed data submission guidelines (provided in a separate 
document).  Generally, all data for Safety run-in patients during the time period 
patients are evaluated for Dose Limiting Toxicities (DLTs) must be submitted on a 
weekly basis.  Generally, for all phase II patients, data are due at the end of every 
cycle.
Please contact croqualityassurance@northwestern.edu for further details.
11.5
Instructions for Participating Sites
Before the study can be initiated at any site, the following documentation must be 
provided to the Clinical Research Office at Northwestern University:
 
Signed and completed Letter of Invitation to participate in the study.
 
Signed copy of Northwestern University’s Data Monitoring Committee policy 
pertaining to data submission.
 
Draft informed consent form should for review/approval prior to submission to the 
local IRB
 
A copy of the official IRB approval letter for the protocol and informed consent.
 
CVs and medical licensure for the local PI and any sub-investigators who will be 
involved in the study at the site.
 
Form FDA 1572 appropriately filled out and signed with appropriate 
documentation.
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Additional activities may be required prior to site activation (i.e. contract execution, 
study-specific training). Full requirements will be outlined in a memo upon receipt of 
the signed Letter of Invitation.
11.6
Data Management and Monitoring/Auditing
This study will be conducted in compliance with the Data Safety Monitoring Plan 
(DSMP) of the Robert H. Lurie Comprehensive Cancer Center of Northwestern 
University (please refer to NOTIS for additional information). The level of risk 
attributed to this study requires High Intensity Monitoring as outlined in the DSMP 
(http://cancer.northwestern.edu/CRO/data/DataandSafetyMonitoringPlanMay2014.pd 
f). The assigned QAM, with oversight from the Data Monitoring Committee, will 
monitor this study in accordance with the study phase and risk level. Please refer to 
the NOTIS for additional data submission instructions.
11.7
Adherence to the Protocol
Except for an emergency situation in which proper care for the protection, safety, and 
well-being of the study patient requires alternative treatment, the study shall be 
conducted exactly as described in the approved protocol.
11.6.1  Emergency Modifications
Investigators may implement a deviation from, or a change of, the protocol to 
eliminate an immediate hazard(s) to trial subjects without prior IRB approval.
For any such emergency modification implemented, an IRB modification form 
must be completed within 5 business days of making the change, and the 
QAM must be notified within 24 hours of such change.
11.6.2  Other Protocol Deviations
All other deviations from the protocol must be reported to the assigned QAM
using the appropriate form.
A protocol deviation is any unplanned variance from an IRB approved 
protocol that:
 
Is generally noted or recognized after it occurs.
 
Has no substantive effect on the risks to research participants.
 
Has no substantive effect on the scientific integrity of the research plan 
or the value of the data collected.
 
Did not result from willful or knowing misconduct on the part of the 
investigator(s).
A protocol deviation may be considered an instance of Reportable New
Information (RNI) if it:
 
Has harmed or increased the risk of harm to one or more research 
participants.
 
Has damaged the scientific integrity of the data collected for the study.
 
Results from willful or knowing misconduct on the part of the 
investigator(s).
 
Demonstrates serious or continuing noncompliance with federal 
regulations, State laws, or University policies.
11.8
Investigator Obligations
The Principal Investigator is responsible for the conduct of the clinical trial at the site
in accordance with Title 21 of the Code of Federal Regulations and/or the Declaration
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NU Study Number: NU 16G03
Merck Study Number: 3475-244
of Helsinki. The PI is responsible for personally overseeing the treatment of all study 
patients. The PI must assure that all study site personnel, including sub-investigators 
and other study staff members, adhere to the study protocol and all FDA/GCP/NCI 
regulations and guidelines regarding clinical trials both during and after study 
completion.
The Principal Investigator at each institution or site will be responsible for assuring 
that all the required data will be collected, entered onto the appropriate eCRFs, and 
submitted within the study-specific timeframes. Periodically, monitoring visits may be 
conducted and the Principal Investigator will provide access to his/her original 
records to permit verification of proper entry of data. The study may also be subject 
to routine audits by the Audit Committee, as outlined in the DSMP.
11.9
Publication Policy
All potential publications and/or data for potential publications (e.g. manuscripts, 
abstracts, posters, clinicaltrials.gov releases) must be approved in accordance with the 
DSMC Data Release Policies and Processes. The assigned QAM will prepare a 
preliminary data set for DSMC approval no later than 3 months after the study reaches 
its primary completion date, as defined by ClinicalTrials.gov. This is the date that the 
final subject was examined or received an intervention for the purposes of final 
collection of data for the primary outcome, whether the clinical trial concluded according 
to the pre-specified protocol or was terminated. If the investigator would like data 
release to be approved by the DSMC prior to when study design specifies, and/or prior 
to three months after a study’s primary completion date, the PI must send a written 
request for data approval to the QAM which includes justification. Requests must be 
made a minimum of six to eight weeks in advance of the expected deadline. The 
request will be presented to the DSMC at their next available meeting. Any DSMC 
decisions regarding data release will be provided to the PI. If the request is approved, 
the QAM will present the data set to the DSMC for approval. A final, DSMC-approved 
dataset, as applicable, will then be released 6-8 weeks after the request was made. The 
investigators are expected to use only DSMC-approved data and statistical analyses 
any time they are disseminating trial data. The investigators must send a copy of the 
draft abstract/poster/manuscript to the study’s biostatistician and assigned QAM to 
confirm that the DSMC-approved data and statistical analyses are used appropriately. 
Once the biostatistician and QAM gives final approval, the publication may be submitted 
to external publisher.
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Version: November 18, 2020 (Amendment 11)
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NU Study Number: NU 16G03
Merck Study Number: 3475-244
REFERENCES
1.
Adams, S.F., et al. Intraepithelial T cells and tumor proliferation: impact on the benefit from 
surgical cytoreduction in advanced serous ovarian cancer. Cancer 115, 2891-2902 (2009).
2.
Webb, J.R., Milne, K., Watson, P., Deleeuw, R.J. & Nelson, B.H. Tumor-infiltrating 
lymphocytes expressing the tissue resident memory marker CD103 are associated with 
increased survival in high-grade serous ovarian cancer. Clinical cancer research : an official 
journal of the American Association for Cancer Research 20, 434-444 (2014).
3.
Bukowski, R.M., Ozols, R.F. & Markman, M. The management of recurrent ovarian cancer.
Seminars in oncology 34, S1-15 (2007).
4.
Vaughan, S., et al. Rethinking ovarian cancer: recommendations for improving outcomes. Nat
Rev Cancer 11, 719-725 (2011).
5.
Chan, M.W., et al. Hypermethylation of 18S and 28S ribosomal DNAs predicts progression- 
free survival in patients with ovarian cancer. Clin Cancer Res 11, 7376-7383 (2005).
6.
Brahmer, J.R., et al. Safety and activity of anti-PD-L1 antibody in patients with advanced 
cancer. The New England journal of medicine 366, 2455-2465 (2012).
7.
Hamanishi, J., et al. Programmed cell death 1 ligand 1 and tumor-infiltrating CD8+ T 
lymphocytes are prognostic factors of human ovarian cancer. Proceedings of the National 
Academy of Sciences of the United States of America 104, 3360-3365 (2007).
8.
Krempski, J., et al. Tumor-infiltrating programmed death receptor-1+ dendritic cells mediate 
immune suppression in ovarian cancer. Journal of immunology 186, 6905-6913 (2011).
9.
Duraiswamy, J., Freeman, G.J. & Coukos, G. Therapeutic PD-1 pathway blockade augments 
with other modalities of immunotherapy T-cell function to prevent immune decline in ovarian 
cancer. Cancer research 73, 6900-6912 (2013).
10.
Balch, C., Fang, F., Matei, D.E., Huang, T.H. & Nephew, K.P. Minireview: epigenetic changes 
in ovarian cancer. Endocrinology 150, 4003-4011 (2009).
11.
Matei, D.E. & Nephew, K.P. Epigenetic therapies for chemoresensitization of epithelial 
ovarian cancer. Gynecol Oncol 116, 195-201 (2010).
12.
Balch, C., et al. New anti-cancer strategies: epigenetic therapies and biomarkers. Front
Biosci 10, 1897-1931 (2005).
13.
Kantarjian, H., et al. Results of a randomized study of 3 schedules of low-dose decitabine in 
higher-risk myelodysplastic syndrome and chronic myelomonocytic leukemia. Blood 109, 52-
57 (2007).
14.
Samlowski, W.E., et al. Evaluation of a 7-day continuous intravenous infusion of decitabine:
inhibition of promoter-specific and global genomic DNA methylation. J Clin Oncol 23, 3897-
3905 (2005).
15.
Matei, D., et al. Epigenetic resensitization to platinum in ovarian cancer. Cancer Research
72, 2197-2205 (2012).
16.
Yoo, C.B., et al. Delivery of 5-aza-2'-deoxycytidine to cells using oligodeoxynucleotides.
Cancer Res 67, 6400-6408 (2007).
17.
Gini Fleming, S.G., Yvonne Lin, Angeles Alvarez Secord, ... Mohammad Azab, Daniela 
Matei. Clinical epigenetic resensitization of platinum-resistant, recurrent ovarian cancer 
patients with SGI-110, a novel, second-generation, subcutaneously administered 
hypomethylating agent (HMA). AACR National Meeting; Proceedings (2014).
18.
Garon, E.B., et al. Pembrolizumab for the Treatment of Non-Small-Cell Lung Cancer. N Engl
J Med (2015).
19.
Robert, C., et al. Pembrolizumab versus Ipilimumab in Advanced Melanoma. N Engl J Med
(2015).
20.
Foulks, J.M., et al. Epigenetic drug discovery: targeting DNA methyltransferases. J Biomol
Screen 17, 2-17 (2012).
21.
Singh, V., Sharma, P. & Capalash, N. DNA methyltransferase-1 inhibitors as epigenetic 
therapy for cancer. Curr Cancer Drug Targets 13, 379-399 (2013).
22.
Jean Pierre Issa, G.R., David Rizzieri, Stefan Faderl, Casey O'Connell, Wendy Stock, Raoul 
Tibes, Elizabeth Griffiths, Karen Yee, Woonbok Chung, Gavin Choy, Aram Oganesian, Pietro 
Taverna, Mohammad Azab, Hagop Kantarjian. Interim results from a randomized Phase 1-2
IRB #: STU00203494-CR0005 Approved by NU IRB for use on or after 4/12/2021 through 4/11/2022.


Version: November 18, 2020 (Amendment 11)
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NU Study Number: NU 16G03
Merck Study Number: 3475-244
first-in-human (FIH) study of PK/PD guided escalating doses of SGI-110, a novel 
subcutaneous (SQ) second generation hypomethylating agent (HMA) in relapsed/refractory 
MDS and AML Porceedings of AACR Meeting LB-214 (2012).
23.
Yodaiken, R.E. & Bennett, D. OSHA work-practice guidelines for personnel dealing with 
cytotoxic (antineoplastic) drugs. Occupational Safety and Health Administration. Am J Hosp 
Pharm 43, 1193-1204 (1986).
24.
Atkinson EN & Brown BW. Confidence limits for probability of response in multistage Phase II
clinical trials. Biometrics 1985; 41:741-744.)
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Version: November 18, 2020 (Amendment 11)
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NU Study Number: NU 16G03
Merck Study Number: 3475-244
APPENDICES
Appendix 1: Birth control methods
Barrier Methods
Intrauterine Device Methods
Hormonal Methods
 
Male condom plus 
spermicide
 
Cap plus 
spermicide
 
Diaphragm plus 
spermicide
 
Copper T
 
Progesterone T
 
Levonorgestrel-releasing
 
Implants
 
Hormone shot or 
injection
 
Combined pill
 
Minipill
 
Patch
NOTE: choice contraception should be discussed with primary treating oncologist to discuss 
the risks and benefits of different modalities of contraception.
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IRB #: STU00203494 Approved by NU IRB for use on or after 7/24/2017 through 7/23/2018.
NU Study Number: NU 16G03
Merck Study Number: 3475-244
APPENDIX 2: ECOG PERFORMANCE STATUS 
Grade
Description
0
Normal activity. Fully active, able to carry on all pre-disease performance 
without restriction.
1
Symptoms, but ambulatory. Restricted in physically strenuous activity, but 
ambulatory and able to carry out work of a light or sedentary nature (e.g., 
light housework, office work).
2
In bed <50% of the time. Ambulatory and capable of all self-care, but unable 
to carry out any work activities. Up and about more than 50% of waking 
hours.
3
In bed >50% of the time. Capable of only limited self-care, confined to bed 
or chair more than 50% of waking hours.
4
100%  bedridden.  Completely  disabled.  Cannot  carry  on  any  self-care. 
Totally confined to bed or chair.
5
Dead.
* As published in Am. J. Clin. Oncol.: Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, 
T.E., McFadden, E.T., Carbone, P.P.: Toxicity And Response Criteria Of The Eastern 
Cooperative Oncology Group. Am J Clin Oncol 5:649-655, 1982. The Eastern Cooperative 
Oncology Group, Robert Comis M.D., Group Chair.
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Version: November 18, 2020 (Amendment 11)
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NU Study Number: NU 16G03
Merck Study Number: 3475-244
APPENDIX 3: RESPONSE EVALUATION CRITERIA IN SOLID TUMORS
(RECIST) 1.1 CRITERIA FOR EVALUATING RESPONSE IN SOLID 
TUMORS
RECIST version 1.1* will be used in this study for assessment of tumor response.
* As published in the European Journal of Cancer:
E.A. Eisenhauer, P. Therasse, J. Bogaerts, L.H. Schwartz, D. Sargent, R. Ford, J. 
Dancey, S. Arbuck, S. Gwyther, M. Mooney, L. Rubinstein, L. Shankar, L. Dodd, 
R. Kaplan, D. Lacombe, J. Verweij. New response evaluation criteria in solid 
tumors: Revised RECIST guideline (version 1.1). Eur J Cancer. 2009
Jan;45(2):228-47.
Can be accessed at:
http://ctep.cancer.gov/protocolDevelopment/docs/recist_guideline.pdf
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Version: November 18, 2020 (Amendment 11)
65
APPENDIX 4: EVALUATING ADVERSE EVENTS
An investigator who is a qualified physician will evaluate all adverse events according to the NCI Common Terminology for Adverse Events 
(CTCAE), version 4.0. Any adverse event which changes CTCAE grade over the course of a given episode will have each change of grade 
recorded on the adverse event case report forms/worksheets. All adverse events regardless of CTCAE grade must also be evaluated for 
seriousness.


NU Study Number: NU 16G03
Merck Study Number: 3475-244
V4.0 CTCAE Grading
Grade 1
Mild; asymptomatic or mid symptoms; clinical or diagnostic observations only; intervention not indicated.
Grade 2
Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental ADL.
Grade 3
Severe or medically significant but not immediately life-threatening; hospitalization or prolongation or 
hospitalization indicated; disabling; limiting self-care ADL.
Grade 4
Life threatening consequences; urgent intervention indicated.
Grade 5
Death related to AE
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.
Seriousness
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?
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)?
66
Relationship to
Merck Product
ersion:07.24.17
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
Version: November 18, 2020 (Amendment 11)
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NU Study Number: NU 16G03
Merck Study Number: 3475-244
Version: November 18, 2020 (Amendment 11)
68
APPENDIX V: HISTORY OF AMENDMENTS (SUMMARY OF CHANGES)
Amendment 1 –August 10, 2016 
(includes FDA mandated changes)
Sections(s) 
Affected
Prior Version
Amendment 1 Changes
Rationale
Section
4.3,4.4,4.8,4.10
Drug-related 
toxicity 
mentioned in 
these sections 
but was not 
defined.
Drug-related toxicity defined and 
language inserted as:
‘Drug related toxicity will be defined as 
any event which is considered possibly, 
probably, or definitely related to the 
drug. It does not include toxicities
clearly not related to the drug such as 
disease progression, environmental, 
unrelated trauma, etc.’
This has been defined in section 4.4 
and similar language has been inserted 
in all other appropriate sections.
Per FDA request 
during initial review
Exclusion 
criteria 3.2.13
Has known 
history of, or
any evidence of 
active, non- 
infectious 
pneumonitis
Has known history of (non-infectious) 
pneumonitis that required steroids, or 
current pneumonitis.
Per action letter for 
MK-3475 
(pembrolizumab, 
NSC 776864) dated 
June 24, 2016
Study 
parameters 
(5.0)
Specified TSH, 
T4, and free T3 
for baseline 
thyroid testing.
Revised to TSH with reflex testing only 
if abnormal findings noted.
Clarification
Section 9.0
Correlative
/Special studies
Details 
regarding ADA 
antibodies 
analysis 
inserted in the 
table
‘Correlative 
Sample 
summary’
The entire column containing these 
details have been removed
Administrative 
correction (removal 
of test that is no 
longer being done 
and was mistakenly 
noted there still).
Amendment 2 12/16/2016
Sections(s) 
Affected
Prior Version
Amendment 1 Changes
Rationale
Protocol page
Statistician 
Alfred 
Rademaker
No affiliate sites 
listed.
Removed Alfred Rademaker as 
statistician
Added: Masha Kocherginsky as 
statistician. Contact information 
included.
Added: University of Chicago as 
affiliate site.
Dr. Gini Fleming added as site 
PI. Contact information inserted.
Per PI
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Version: November 18, 2020 (Amendment 11)
69
Study schema
Section
3.0(eligibility) & 
Section 10.1
Statistical 
section-study 
design
Study described 
as single center
Modified to : Multicenter
Inclusion of
University of Chicago 
as affiliate site. 
Potential for more 
sites to be included.
Throughout
Grammatical 
and spelling 
errors, typos 
and wrong 
reference to 
sections
Corrected grammatical errors, 
spellings and typos and inserted the 
correct reference to sections at 
appropriate places
Correction of error
Throughout
Certain sections 
had “prior to 
Day1 of study” 
as the starting 
time point.
changed to ‘prior to registration’
For convenience and 
consistency
Study summary 
and
Section
3.0(eligibility 
criteria)
RHLCC listed 
as only site
Modified to state that
Lead site: RHLCCC
Affiliate site: University of Chicago
Language added in section 3.0 to state 
the same.
Inclusion of
University of Chicago 
as affiliate site
Inclusion 
criteria3.1.1 
and study 
summary
Inclusion 
criteria: 
“Histological or 
cytological 
evidence/confir 
mation of 
recurrent 
epithelial 
ovarian cancer, 
primary 
peritoneal 
carcinomatosis,
or fallopian tube 
cancer.”
Deleted the word “recurrent” here
To clarify that the 
patient does not need 
histological 
confirmation of 
recurrent disease,
just of disease
Inclusion 
criteria 3.1.3 
and study 
summary
Platinum 
resistant 
disease 
mentioned in 
the title and 
study summary
, but was not 
included as an 
inclusion criteria 
in section 3.1
Inserted language as inclusion criteria
3.1.3 “Patients must have recurrent 
platinum-resistant disease, defined as 
progression < 6 months after 
completion of platinum-based 
chemotherapy or as persistent disease 
that remains after completing the most 
recent line of platinum-based therapy. 
The platinum-free interval should be 
calculated from the last administered 
dose of platinum therapy.”
Study summary language also 
modified to state the same.
For clarity and 
consistency. 
Note: Recurrent 
disease has been 
used here and 
defined.
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Version: November 18, 2020 (Amendment 11)
70
Section 2.1, 2.2 
and  6.3
Primary and 
Secondary 
objectives and 
Endpoints
Primary 
objective 
included irRC 
assessment as 
well.
Removed language about irRC from 
primary objective.
Added secondary endpoint 2.2.4 and 
also in section 6.3
“Measure objective response rate 
(RR) to the combination of 
guadecitabine and pembrolizumab 
using the Immune Related Response 
Criteria (irRC).
(Note: Response assessments will be 
made both using the irRC, and using 
RECIST 
v1.1, 
allowing 
additional 
comparisons among these criteria for 
disease 
response 
assessment. 
Measurable 
and 
non-measurable 
lesions will be followed by both RECIST 
v1.1 & irRC. Disease progression will be 
determined using RECIST 1.1 criteria)”
Section 2.2.3 added in section 2.2 to 
include secondary endpoint that was 
already in section 6.2 but was excluded 
in error in section 2.2
Per PI
irRC is to be used 
only for secondary 
objective. Decision to 
go on to stage II of
the study will be 
based on assessment 
using  RECIST1.1
Study summary 
and
Section
4.1(treatment 
administration
Trial treatment 
may be 
administered up 
to 1 week (+7 
days) before or 
after the 
scheduled Day
1 of each cycle 
due to 
administrative 
reasons
deleted  “before or after” and changed 
to “after.” 7 days has been changed to
+28 days.
In order to maintain 
consistency with 
Section 4.0 and other 
windows used in the 
protocol.
Section 3.0
Eligibility
Language about 
referring
patients to
Dr. Matei at NU.
Also, language 
stating that 
eligibility 
waivers are not 
permitted
Both language removed from the 
protocol.
For clarity and to be 
in alignment with 
current policies.
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NU Study Number: NU 16G03
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Version: November 18, 2020 (Amendment 11)
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Study summary 
and section 4.1 
and 4.3 
(treatment 
administration)
All subjects in 
the safety run-in 
cohort will be 
observed for at 
least 2 weeks 
after 
administration
of cycle 1 for 
dose limiting 
toxicity (DLT)
Modification: the word ‘administration
‘changed to ‘completion’, to state that 
subjects will be observed for DLT at 
least 2 weeks after completion of 
cycle 1.
Correction of error.
Section 3.1.7
Inclusion criteria 
regarding organ 
function
Added note: (Note: Screening labs 
will be repeated again on C1D1 if they 
were performed outside of the ≤4 day 
window.)
For clarity
Throughout
‘within’ word 
used for 
windows
Modified to use : ‘≤’ instead of within 
e.g. ≤28 days;≤14 days;≤30,≤120 days
For convenience, 
accuracy and 
consistency
Section 4.1 
and study 
Summary
Patients must 
begin therapy 
within 7 days of 
registration.
Day 1 may be 
delayed up to 1 
week (7 days).
Patients must begin therapy within(+)
14 days of registration.
Day 1 of each cycle may be delayed 
up to +28 days.
For convenience and 
flexibility and 
consistency
Section 4.4.2 
dose 
modification for 
Pembrolizumab
Dose 
modification for 
Pembrolizumab 
(table). All 
windows were
‘within 12 
weeks’
Subjects should 
be placed back 
on study
therapy within 3 
weeks of 
schedule 
interruption
All windows in the table modified to
≤28 days.
Subjects should be placed back on 
study therapy in ≤ 28 days of the 
scheduled interruption.
To be consistent with 
rest of the protocol.
Section 4.5.1
Allowed 
Concomitant 
medications
and
“All treatments 
that the PI 
considers 
necessary for a 
subject’s 
welfare may be 
administered at
the discretion of 
the PI in 
keeping with the
Principal Investigator(PI) has been 
changed to ‘treating physician’
For flexibility and 
consistency
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Version: November 18, 2020 (Amendment 11)
72
Section 4.6
Supportive car 
with 
Pembrolizumab
community 
standards of 
medical care.”
“Subjects 
should receive 
appropriate 
supportive care 
measures as 
deemed 
necessary by 
the PI. The 
treatment 
guidelines are 
intended to be 
applied when 
the PI 
determines the 
events to be 
related to
pembrolizumab. 
“
“All concomitant 
medications 
received ≤ ≤28 
days before the 
first dose of trial 
treatment and
30 days after 
the last dose of 
trial treatment 
should be 
recorded”
The window for Concomitant 
medication has been changed to ≤14 
days in section 4.5.1
Section 4.5.2
Prohibited 
Concomitant 
medications
“Details about 
prohibition of 
steroids with 
restrictions.
Added: “steroid preparation prior to 
tumor imaging is permitted for 
prophylaxis (e.g., contrast dye 
allergy).”
For safety
Section 4.9
Duration of 
follow-up and 
Section
5.0(Schedule of 
events)footnote
13
Survival follow- 
up stated to be
‘every 3 months’
Modified to: “every 3 months for the 
first 2 years after completing study 
therapy and then every 6 months 
thereafter.”
For convenience. It is 
in alignment with 
standards followed 
by similar clinical 
trials.
Section 4.11
Patient
Replacement
“If a patient is 
enrolled in the 
study but comes 
off study before 
the first dose of 
guadecitabine, 
the patient may
Modified to state:
“If a patient is enrolled in the study but 
comes off study prior to the first dose 
of treatment, the patient may be 
replaced.
For clarity
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be replaced.
If a subject in
the safety run-in 
portion of the 
trial goes off 
study before 
completing the 
DLT
observation 
period of safety 
run-in for 
reasons other 
than DLT, then 
that subject 
should be 
replaced.”
If a subject in the safety run-in portion 
of the trial goes off treatment before 
completing the DLT observation period 
of safety run-in for reasons other than 
DLT, then a patient will need to be 
added to the safety run-in”.
Section 5.0
Study 
procedures
Column 
containing tests 
to be conducted 
within -5 days of 
registration.
Footnote 2 only 
stated 
assessments 
included in the 
physical exam.
Footnote3: CA
125 not 
included as an 
assessment
Footnote 4: 
During 
treatment, 
radiologic 
imaging should 
be done every 
odd numbered 
cycle starting 
with Cycle 3
Footnote 6: 
Details about 
blood for DNA 
analysis
-5 day window changed to ≤14 days. 
Table updated accordingly and with 
appropriate footnotes.
Footnote2: Added language to state 
that Physical exam will be conducted 
with a (+/-) 4 day window for D1 of 
each cycle and at the safety follow-up 
visit.
Footnote 3: Added CA 125 as a 
standard of care assessment. Footnote
3 updated.
Also, C1D1 labs need not be repeated 
if done within a window of ≤4 days 
instead of ‘within 7 days’.
Footnote 4 : added window:
Cycle 3(≤7 days prior to day 1 of the 
cycle)
Footnote 6: windows added: Cycle 1
Day 1[≤7days] and Cycle 2 Day 8 [+2 
days] (at the time of the biopsy or 
paracentesis or thoracentesis and with 
the same window.
For increased clarity, 
consistency and 
convenience.
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Footnote 7: 
details about 
blood for 
cytokine 
response.
Footnote 8: 
Details about 
pregnancy test
Footnote 9: 
Details about 
blood for PBMC 
analysis
Footnote 10 
contained
details about CT
guided biopsies.
Footnote 11
:details about
PT/INR, aPTT
Footnote
13:folllow-up 
details. Subjects 
to be contacted 
by phone every
3 months.
Footnote 7:windows added:
Cycle 1 Day 1(≤4 days), Cycle 2 Day
1(≤4 days), Cycle 3 Day 1(≤4days)
Footnote 8:
Added language that it will be done on
D1 (≤4 days) of each cycle in addition 
to the screening period.
Footnote 9:windows added
Cycle 1 Day 1(≤4days), Cycle 1 Day 5, 
pre-treatment on Cycle 2 Day 1(≤4 
days)
Footnote 10: Added language to state 
that biopsies can be guided by CT, 
ultrasound or physical exam and 
paracentesis or thoracentesis can also 
be done. Windows added: [(Cycle 1
Day 1 (≤7 days)] and Cycle 2 Day 8 
(+2 days)]
Footnote 11: Footnote and table 
updated to indicate that PT/INR & 
aPTT will not be done at the
‘subsequent cycles’ time-point.
A (≤)4 day window added for TSH
testing.
Footnote 17 added to state that 
PT/INR and aPTT is required at 
screening only, unless otherwise 
clinically indicated.
Footnote 13: Added that subjects may 
be contacted by email or a clinic visit 
as well, every 3 months for the first 2 
years and then every 6 months 
thereafter
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Footnote 14: 
C1D1 to should 
be within 7 days 
of registration.
Footnote 15: 
Treatment 
details. It states 
that while on 
treatment day 1 
can be delayed 
by 1 week.
Footnote14:
Cycle 1 day 1 should be started within 
(+) 14 days following registration.
Footnote 15: Modified to state that 
“While on treatment, day 1 of each 
cycle may be delayed up to +28 days 
from target date for scheduling 
purposes and holidays.
Additional modifications:
Footnote 16 added to the table. It 
states:
“ConMeds and AE assessment to be 
completed at the time of the D1 
physical exam. See footnote 12 
regarding windows for the D1 physical 
exam”.
Table updated at appropriate places 
with the corresponding footnotes. 
For footnotes 5, 6, 7, 9, 10: added 
language referring to laboratory 
manual
Section 6.1
Endpoint 
assessment 
definitions
“The same 
measurable and 
non-measurable 
lesions will be 
followed by both 
RECIST v1.1 & 
irRC”
Modified to: “Measurable and non- 
measurable lesions will be followed by 
both RECIST v1.1 & irRC”
For Measurable Disease, language 
added: “For irRC, measurable lesions 
are defined as those that can be 
accurately measured in at least two 
dimensions as 10x10mm with CT 
scan.”
For Non-measurable Lesions, language 
added to indicate that for both RECIST
1.1 and irRC the same criteria will be 
used.
For clarity and to 
match thresholds for 
RECIST1.1 and irRC.
Section 7.3.5
Expedited
No reference
was made as to
Added language: To be done by QAM
For clarity
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Reporting to the
FDA
who would be 
doing it.
Section 7.3.6
Expedited 
Reporting to 
Merck and 
Astex
No reference 
was made as to 
who would be 
doing it.
Language about 
SAE reporting 
stated that : 
SAEs will be 
reported to 
Merck and
Astex within one 
business day of 
receipt of the
NU CRO SAE 
Submission 
form.
Added language: To be done by 
coordinator.
Language modified to state that SAEs 
will be reported to Merck and Astex 
within one business day of 
acknowledgement of the event, 
using the NU CRO SAE form.
For clarity
Section 8.2.10
list of side- 
effects for 
Guadecitabine
Added edema (swelling of tissue) to the
‘Less Common’ side effects list
Per updated IB and 
approval of PI
Section 9.0
Correlative 
studies
Statement that 
left over 
samples will be 
stored.
Statement added to specify that left 
over samples will be stored at Dr. 
Matei’s laboratory at NU.
Other language updated in order to be 
consistent with windows and other 
updates made to section 5.0
For improved clarity 
and specificity
Section 5.0 
footnote 5  and 
Section 9.0
States that 
archived tumor 
tissue 
specimens may 
be obtained at 
any point during 
conduct of this 
study
Corrected to “may be procured up to 3 
months from registration”
To be consistent with 
information in the 
table in section 9.0 
and the lab manual.
Section 10.3
Statistics –data 
analysis plans
Analysis for 
Primary 
Objective: The 
objective 
response rate 
by irRC will be 
estimated 
similarly.
Removed the irRC language from the
Primary Objective analysis.
Correction of error, 
since irRC is to be 
used only for 
secondary objective. 
Decision to go on to 
stage II of the study 
will be based on 
assessment using 
RECIST1.1 only
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Section 10.4.2 
efficacy criteria 
in statistics 
section
interim analysis 
planned after 18 
patients using 
Clinical 
Benefit(defined 
as CR,PR, or
SD for at least 3 
month).
Changed to state that interim analysis 
is planned with 18 patients using RR
Since primary 
objective is ORR.
Section 11.5
Instructions for 
Participating 
Sites
This section 
was not in the 
protocol.
Inserted this section after University of
Chicago came on board as affiliate site
To include 
information for 
affiliate sites
Amendment 3 5/10/2017
Sections(s) 
Affected
Prior Version
Amendment 3 Changes
Rationale
Study Schema
Tumor 
assessments 
every 2 cycles
Tumor assessments every 2 cycles up 
to cycle 5; then  every 3 cycles
For safety and 
convenience
Section 2.2.4
Secondary 
objective
Statement of
RR assessment 
with RECIST1.1 
and irRC
Added language referring to section
6.0 which has new language regarding 
RECIST1.1 which will be used here 
with a few adaptations
For clarity and 
accuracy. To 
accommodate 
immune response 
adaptations of 
RECIST 1.1
Section 4.2
Treatment 
administration
Table 
containing 
details of 
administration 
of 
pembrolizumab 
and 
guadecitabine.
Added footnote:
“After completion of the safety run in, 
starting on Day 5 of each cycle, growth 
factor support filgrastim or peg 
filgrastim can be administered 24
hours after completion of 
guadecitabine administration, at the 
discretion of the treating physician.”
Similar language added to section
4.4.1 which pertains to ‘Dose 
modifications for guadecitabine’
For safety
Section 4.4.1
Dose 
modifications 
for 
Guadecitabine
In general, 
guadecitabine 
dosing should 
be held 
guadecitabine- 
related non- 
hematologic 
toxicities until 
toxicity has 
resolved to ≤
Modified to :
In general, guadecitabine dosing 
should be held for ≥ Grade 3 
neutropenia, thrombocytopenia or 
other  guadecitabine-related non- 
hematologic toxicities until toxicity has 
resolved to ≤ Grade 1 or baseline 
levels
For clarity and safety
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Grade 1 or 
baseline levels
Section 4.4.2
Table 3 Dose 
modification 
guidelines for 
pembrolizumab 
related AEs
Previous table 
which had the 
window for 
resolution of 
toxicity as ≤28 
days of last 
dose.
Updated window to ≤28 days from the 
start of the event throughout the table 
and footnotes and notes.
Similar update done in section 4.10
For safety and 
convenience
Section 4.5.2
Prohibited 
Concomitant 
Modifications
Previous 
language
Added language regarding Stevens- 
Johnson syndrome(SJS), Toxic 
Epidermal Necrolysis(TEN) and 
immune-mediated myocarditis
Based on action letter 
and updated 
pembrolizumab IB
Section 4.6.8 
and 4.6.9
N/A
Added management details for SJS , 
TEN and immune-mediated 
myocarditis
Based on action letter 
and subsequently 
updated 
pembrolizumab IB
Section 4.10
Removal of 
Subjects from 
Study 
Treatment
and/or Study as 
a Whole
One of the 
conditions 
stated: “Patient 
demonstrates 
disease 
progression. 
This must be 
confirmed 
radiographic 
disease 
progression”
Added language to this:
“At the first disease assessment, 
treatment can be continued, even in
the presence of radiographic or clinical 
progression, if in the opinion of the 
treating physician, the patient is stable 
or benefitting clinically.  In that 
circumstance a short term follow up 
scan should be obtained in 4-6 weeks”
Full details in section 6.1
To accommodate 
immune response 
adaptations of 
RECIST 1.1
Section 5.0
Study 
procedures 
table
1. Mg, Phos, 
LDH and at 
screening, 
Day1 of each
cycle and at end 
of study.
2. Uric acid at 
screening, Day1 
of each cycle 
and at end of 
study.
3. Footnote4: 
Tumor 
assessment 
every 2 cycles
1.   Mg, Phos and LDH to be done 
only at screening.
2.   Uric acid to be done D1 (≤4 
days) of every odd cycle 
beginning with Cycle 3.
Footnote 11 updated to reflect 
this.
3.   Footnote 4: During treatment, 
radiologic imaging should be 
done prior to cycles 3, 5 and 
then prior to every third cycle 
(e.g. cycles 8, 11, 14, etc.) 
CTs can be obtained ≤7 days 
prior to day 1 of the cycle.
For safety, clarity and 
convenience
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4. Footnote10: 
Tumor biopsies 
or paracentesis 
or thoracentesis
5. Footnote 15 
details about 
treatment
6. Footnote 16: 
Conmeds and 
AE assessment 
was tied to 
physical exam
7. footnote 17 
stating specifics 
about 
coagulation 
parameters
Reference to section 6.0 made 
for response assessment. 
Footnote 4 added to Chest x-
ray and CT rows in the table
4.   Footnote 10: Tumor biopsies 
and/or paracentesis and/or 
thoracentesis can be done
5.   Minor modifications made to 
Footnote 15 language for 
clarity
6.   Footnote 16 modified to state 
“ConMeds and AE 
assessment are to be
completed on D1 of each cycle
(+/-4 days).”
7.   Footnote 17 removed
8.   Other minor re-arrangements 
of footnotes in the table made 
for increased clarity
Section 6.1 
endpoint 
assessment 
definitions
previous 
definitions
Added language to describe details 
about adaptations to RECIST1.1 for 
immunotherapeutic agents like 
pembrolizumab, wherein if the first 
scan shows PD, treatment can still 
continue and a repeat scan will be 
done in 4-6 weeks for response 
assessments.
To accommodate 
immune response 
adaptations of 
RECIST 1.1 which 
incorporates the 
delayed anti-tumor 
effects of 
immunotherapy
Section 8.1.10 
side effects of 
pembrolizumab
List of side 
effects
added ‘Very common side effects seen 
in ≥20% of patients’-itching of skin, 
diarrhea, cough.
Most common side effects changed to
‘common side effects (seen in ≥10% of 
patients. Also added joint pain and 
back pain to this list.
Added ‘myasthenic syndrome’ to list of 
rare but serious/life threatening side 
effects
Based on action letter 
and subsequently 
updated 
pembrolizumab IB
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Amendment 4  7/24/17
Section 9.0
Stated
“Subjects will be 
consented to optional 
storage of any
remaining tumor 
samples after protocol- 
specified
studies are 
complete”
Added language to 
clarify that leftover 
plasma will also be 
used for future analysis. 
All other storage details 
remain the same.
Per PI, in order to 
open up possibilities 
of using both tumor 
and blood samples 
for future research
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Amendment 5  
10/25/17(re-submitted 
to SRC with version 
date 12.6.17)
  
Section 4.2, 4.2.2, 4.4.1,
  8.2.5
Treatment details 
Added language:
“Note: Guadecitabine 
priming can be 
discontinued after 6 
months (8 cycles) at 
the discretion of the 
treating physician, if 
patient has stable 
disease or response.” 
For safety. In order to 
minimize toxicity for 
patients.
(approved by sponsor 
Astex)
Section 4.4.2
Table 3
Previous pembrolizumab 
toxicity management and 
dose modification table 
for immune related AEs
Replaced with the current  
Dose Modification and 
Toxicity Management 
Guidelines for Immune-
related AEs Associated 
with Pembrolizumab.
Specifically,  Immune-
mediated Myocarditis 
management has been 
included
Based on directive 
received from 
Pembrolizumab drug 
sponsor Merck.
(Note: Myocarditis was 
included as an immune –
mediated AE in 
Amendment 3)
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Study schema and 
Sections 4.2, 4.2.2, 4.4.1,  
8.2.5
Treatment details 
Added language:
“Note: Guadecitabine 
priming can be 
discontinued after 6 
months (8 cycles) at 
the discretion of the 
treating physician, if 
patient has stable 
disease or response.” 
For safety. In order to 
minimize toxicity for 
patients.
(approved by sponsor 
Astex)
Footnote 3: C1d1 
CBC and CMP had 
a window of ≤ 4 
days prior to start 
of treatment and 
Ca-125 at 
screening had a 
window of 14 days. 
Footnote 1 was 
also inserted in the 
‘X’ accompanying 
the C1 tumor 
biopsy
Footnote 3 modified to 
state that CBC and CMC 
And CA-125 at every D1 
has a window of ≤4 days 
prior to D1. Ca-125 at 
screening will still have 
the 14 days window. 
Footnotes updated in the 
table as appropriate.
Footnote 3 in Mg, phos 
and LDH removed since 
these are only done prior 
to registration.
Footnote 1 removed 
from this position
For flexibility and clarity 
Correction of error.
Pathology not 
required for this 
biopsy
Section 5.0
Study procedures table
Footnote 15
details about 
Guadecitabine 
administration
 Footnote 15:
Added language: 
“Note: Guadecitabine 
priming can be 
discontinued after 6 
months (8 cycles) at 
the discretion of the 
treating physician, if 
patient has stable 
disease or response.”
For safety. In order to 
minimize toxicity for 
patients.
(approved by sponsor 
Astex)
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Amendment 6 –April 30, 2018 
Sections(s) 
Affected
Prior Version
Amendment 6 Changes
Rationale
Title page
Mario Pineda, MD 
listed as Sub-
investigator
Removed Mario Pineda and added Emma 
Barber, MD as Sub-Investigator
Inserted complete details for the 
Statistician
 Dr. Pineda has left 
Northwestern 
University 
Administrative
Throughout
(wherever 
applicable)
Previous 
statement 
about 
Guadecitabine 
priming 
followed by 
Pembrolizuma
b therapy
Language modified:
 “Guadecitabine priming can be 
discontinued and the patient can 
continue on pembrolizumab 
monotherapy after 6 months (8 cycles), 
at the discretion of the treating 
physician, if the patient has stable 
disease or response.” 
Language added: “If this is done, the 
previously scheduled pembrolizumab 
treatment on Day 5 will become Day 
1(+/-2 days).”
In order to 
minimize exposure 
and streamline 
scheduling for 
patients, since the 
Guadecitabine 
priming is not 
necessary after a 
time point.
Throughout
(wherever 
applicable)
Previous 
statement 
about 
Guadecitabine 
priming 
followed by 
Pembrolizuma
b therapy, 
then 
monotherapy 
with 
pembrolizuma
b. 
Language inserted: 
“For patients who discontinued 
guadecitabine for reasons other than 
toxicity (i.e. disease stability of response 
> 6 months) and progress on 
pembrolizumab alone, a re-trial of 
guadecitabine in combination with 
pembrolizumab is possible, at the 
discretion of the treating physician, if the 
patient is clinically stable.”
As an addendum to 
the provision of 
prembrolizumab 
monotherapy, in 
order to give 
patients another 
chance before 
taking them off 
study.
Section 1.1
Ovarian cancer 
background
Previous 
language
Some language deleted
Language not 
appropriate in this 
context.
Throughout
Secondary 
Objective 
stated as RR 
and ORR(for 
Objective 
Response 
Rate) in 
different 
sections of the 
protocol.
Corrected to ORR for Objective 
Response Rate
For consistency 
and accuracy
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 Section 4.1 
Treatment 
overview
Details 
regarding 
Guadecitabine 
and 
Pembrolizumab 
combination 
therapy.
Inserted language regarding 
Guadecitabine skipped dose versus 
dose delay. Language regarding 
pembrolizumab monotherapy also 
inserted.
For clarity and 
consistency
Section 2.2.2,
6.3
10.4.2
Definition of 
Clinical Benefit 
rate 
inconsistent 
between study 
summary and 
rest of the 
protocol. 
Language updated to match the 
statistical portion of the study 
summary. 
The correct plan is : “After testing the 
drug on 18 patients in the first stage, 
consideration will be given to trial 
termination if 2 or fewer patients 
demonstrate clinical benefit (CR, PR, 
or SD for at least 3 months).”
Correction of  the 
discrepancy 
between the  
sections of the 
protocol it serves 
to clarify the initial 
intent of the two 
stage study design 
per the original 
sponsor-approved 
statistical plan.
Section 4.1
Treatment 
plan overview
Previous 
language for 
treatment 
administration
Added language to clarify scheduling 
details and skipped doses and dose 
delays. 
For increased 
clarity
Section 4.4.1
Dose 
modifications 
for 
Guadecitabin
e
Previous 
language
Added details regarding grades for 
thrombocytopenia and 
Guadecitabine-related non-
hematologic toxicities. 
Added other language for clarity.
For increased 
clarity
Section 4.4.2
Table 3
Dose 
modifications 
for 
Pembrolizum
ab
Dose 
modification 
details inserted 
as per Nov 
2017 ‘Dear 
Investigator’ 
letter from 
Merck.
Modification to window for  
corticosteroid taper and AE resolution 
to fit the needs of the study. 
To align with  
specifications 
stated in the rest of 
the protocol.
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Section 5.0
Study 
Procedures 
table
All study 
procedures 
listed in one 
table
Study procedures now illustrated in two 
separate tables:
5.1  Study procedures for Combination 
treatment (Guadecitabine and 
pembrolizumab)
5.2 Study procedures for 
Pembrolizumab Monotherapy for 

Patients who discontinue 
guadecitabine after 2 cycles due 
to toxicity and who continue on 
pembrolizumab monotherapy

Patients who discontinue 
guadecitabine after 8 cycles 
due to SD or PR or CR and 
who continue on 
pembrolizumab
Footnotes have been customized as 
appropriate for each table.
To align with the 
treatment 
modifications made to 
the study and for 
increased clarity 
regarding each 
scenario.
Section 5.1 
and 5.2 
C1D1 
CA-125 
does not 
need to be 
repeated if 
screening 
CA125 was 
conducted 
within 14 
days prior 
to starting 
treatment.
Language modified to state: 
“CA-125 is to be drawn at screening 
and Day 1 of each cycle.  
Exceptions would be if CA-125 was 
drawn within 14 days from the 
screening visit or within 14 days on 
visits where doses have been 
delayed.  In these cases, CA-125 
will not need to be re-drawn.”
(Language appropriately modified 
for section 5.2).
For safety, clarity 
and convenience
Section 5.1 
footnote 16
and Section 5.2 
footnote 5 
AE and 
ConMeds 
assessmen
t were 
stated to be 
done on 
Day1 (+/-4 
days) of 
each cycle. 
Added language to state that 
      ConMeds will also be recorded 30 
days after the last dose of trial 
treatment. Concomitant medications 
administered beyond 30 days after 
the last dose of trial treatment for 
management of study-related 
toxicity should be recorded for 
SAEs and Events of Clinical Interest 
(ECIs). 
AE assessments will also be done 
30 days after the last dose of trial 
treatment OR until start of next anti-
cancer treatment (whichever is 
first). 
SAEs will be recorded for 90 days 
after the last dose of trial treatment.”
Corresponding updates to the 
table have been made. 
For clarity and for 
consistency with 
other sections of 
the protocol.
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Section 4.9 
Duration of follow-
up
Section 5.1 
Footnote 13
Section 5.2 
footnote 12
Subjects who 
discontinue trial 
treatment for a 
reason other 
than disease 
progression will 
move into the 
Long-term 
follow-Up 
Phase and will 
be assessed 
every 6 weeks (± 
7 days) by 
radiologic 
imaging to 
monitor disease 
status until the 
start of new anti- 
neoplastic 
therapy, disease 
progression, 
death or end of 
the study.
The 6 week time point has been 
moved to 9 weeks (+/-7 days).
Deleted language:
“After 1 year, subjects will continue to 
should be assessed every 9 weeks (± 7 
days) by radiologic imaging to monitor 
disease status until the start of new 
anti-neoplastic therapy, disease 
progression, death or end of the study.”
In order to reduce 
the exposure of 
patients to frequent 
imaging. 
Section 6.1 
Endpoint 
assessment 
definitions
Previous 
language
Some language deleted as it is not 
in alignment with the current 
protocol specifications, and may 
cause confusion.
For accuracy and 
clarity.
Amendment 7 –August 30, 2018
Sections(s) 
Affected
Prior Version
Amendment 1 Changes
Rationale
Section 1.5 
and 2.3 
One of the 
exploratory 
objectives 
states:”Tumor 
infiltrating 
lymphocytes 
(TILs) will be 
quantified in 
tumor biopsies 
before and after 
treatment 
(IHC).”
Added additional time point to this 
objective: 
“Tumor infiltrating lymphocytes (TILs) 
will be quantified in tumor biopsies 
before and after treatment (IHC), 
including in optional samples 
collected > 6 months on 
treatment.”
PI has determined this 
to be a critical scientific 
point, and analysis of 
samples at this point  
could advance our 
knowledge of how 
epigenetic and 
immunotherapy works.
IRB #: STU00203494-CR0005 Approved by NU IRB for use on or after 4/12/2021 through 4/11/2022.


NU Study Number: NU 16G03
Merck Study Number: 3475-244
Version: November 18, 2020 (Amendment 11)
87
Section 5.1
Study 
procedures 
and 
schedule of 
events
(Combinati
on 
treatment 
guadecitabi
ne+pembrol
izumab)
Previous details
added column 
“≥ 6 months of treat
ment” with corresponding footnote 
17.
This indicates inclusion of OPTIONAL 
research tests once anytime from ≥6 
months and before the safety follow-up 
visit. Tests will include blood for DNA 
analysis, cytokine response and PBMC 
analysis ; also tumor biopsies or 
paracentesis or thoracentesis may be 
done. This will be  guided by CT, 
ultrasound, or physical exam, 
according to the discretion of the 
treating physician.
PI has determined this 
to be a critical scientific 
point, and analysis of 
samples at this point  
could advance our 
knowledge of how 
epigenetic and 
immunotherapy works.
Section 9.0 
Correlative/
special studies
Previous 
details
Added corresponding language for 
the above mentioned OPTIONAL 
research tests once anytime from 
≥6 months and before the safety 
follow-up visit.
To be in alignment with 
updates made to rest of 
the protocol regarding 
additional optional 
research testing.
Section 10.3.3
Previous 
details
Language updated to include 
additional time point for sample 
collection.
To be in alignment with 
updates made to rest of 
the protocol regarding 
additional optional 
research testing.
                                          Amendment 8 –November 9, 2018
Sections(s) 
Affected
Prior Version
Amendment 8 Changes
Rationale
Section 
 4.10
Removal of 
subjects from 
study 
treatment 
and/or study 
as a whole
A  provision for re-
trial with 
combination 
therapy was 
available if patient 
progressed 
with 
pembrolixzumab 
monotherapy.
In order to accommodate patients who 
are benefiting from this re-trial, an 
additional flexibility has been added:
“For any patient who has limited 
treatment options, and is currently re-
responding to the combination 
treatment of pembrolizumab and 
guadecitabine, an additional year of 
this combination therapy, beyond cycle 
#35, may be given, subject to review 
and approval by the PI and drug 
sponsors Merck and Astex.”
For increased 
flexibility and 
benefit for patients
IRB #: STU00203494-CR0005 Approved by NU IRB for use on or after 4/12/2021 through 4/11/2022.


NU Study Number: NU 16G03
Merck Study Number: 3475-244
Version: November 18, 2020 (Amendment 11)
88
  Section 5.2 
Pembrolizum
ab 
monotherapy
The 
pembrolizumab 
monotherapy was 
to begin on a 
Friday, like the 
combination 
therapy schedule
This requirement has been removed.
Pembrolizumab monotherapy can 
begin any day that is feasible for the 
treating physician and clinic.
For convenience
Section 7.3.6
Expedited 
Reporting to 
Merck and Astex
Only a fax 
number was 
listed for 
Astex for 
safety 
reporting 
In addition to the fax number, an 
email ID has been included:
emailed to drugsafety@astx.com
For convenience
Section 
8.1.4, 8.1.6, 
8.1.10
Pembrolizumab 
drug information
Previous 
information 
Updated with the most current 
information based on 
Investigator’s brochure and 
pharmacy manual.
To be in alignment with 
current information 
from Merck.
Section 8.2.6,
8.2.10
Guadecitabine
drug information
Previous 
information
Updated with the most current 
information based on 
Investigator’s brochure.
To be in alignment with 
current information 
from Astex.
IRB #: STU00203494-CR0005 Approved by NU IRB for use on or after 4/12/2021 through 4/11/2022.


NU Study Number: NU 16G03
Merck Study Number: 3475-244
Version: November 18, 2020 (Amendment 11)
89
Amendment 9 –January 23rd , 2019
Sections(s) 
Affected
Prior Version
Amendment 9 Changes
Rationale
Study summary
and Section10
Statistical 
considerations. 
(Sample size 
and statistics)
Maximum 
accrual was 
stated to be 
38 in order to 
obtain 35 
evaluable 
patients. 
(with an 
anticipated 
1-3 patients 
that may be 
inevaluable).
Maximum accrual has been 
increased to 46 in order to obtain 
35 evaluable patients.
[This has been done after DSMC 
approved that 8 more patients 
can be added to reach 35 
evaluable. This request to DSMC 
was based on the fact there were 
5 patients who were enrolled and 
didn’t start study treatment.  
There were another 7 patients 
who registered and only had one 
cycle of treatment, which meant 
that they were not evaluable for 
the primary end point.  This is a 
total of 12 patients, when it was 
initially anticipated that only 1-3 
patients would not be evaluable 
for response.  Thus, it became 
essential to update the total 
enrollment to 46 in the hope that 
we will obtain 35 evaluable, with 
a drop out of 13-14 patients].
Based on the initial 
DSMC approval that 
this study can add up 
to 8 more patients to 
obtain a total of 35 
evaluable patients. 
Section 8.1
Drug Section: 
Pembrolizumab
Previous 
specifications 
regarding 
drug 
preparation.
Updated with most current 
specifications for drug 
preparation 
Based on current IB 
and pharmacy manual.
Section 8.2
Drug section 
Guadecitabine
Previous 
specifications 
regarding 
drug 
preparation.
and storage
 Updated with most current 
specifications. [Astex sent notification 
that the current stock of 3ml diluent will 
be depleted by July 2019 and they will 
start supplying 1.2ml diluent around this 
timeframe. So, all documents need to 
be updated to reflect this.] 
Based on updated 
pharmacy manual from 
Astex.
IRB #: STU00203494-CR0005 Approved by NU IRB for use on or after 4/12/2021 through 4/11/2022.


NU Study Number: NU 16G03
Merck Study Number: 3475-244
Version: November 18, 2020 (Amendment 11)
90
Section 11.9
Publication policy
Previous 
template 
language
Updated with most current 
template language for publication 
policy
Administrative.
Protocol Amendment 10 – Version date: October 15, 2020
Section
Prior Version
Changes in Amendment 10
Rationale
Cover page and 
throughout
Protocol amendment: 9
Protocol date: January 23, 
2019
Protocol amendment: 10
Protocol date: October 15, 
2020
Administrative update
Section 4.9        
(Duration of Follow 
Up)
All AEs that occur prior to 
the Safety Follow-Up Visit 
(30 days (± 7 days) after the 
last dose of study therapy) 
will be recorded. Subjects 
with an AE ≥ Grade 2 will be 
followed until the AE is ≤ 
Grade 1 or baseline, 
deemed clinically 
insignificant, and/or until a 
new anti-cancer treatment 
starts, whichever is earlier.
Addition of bolded text:
All AEs that occur prior to the 
Safety Follow-Up Visit (30 
days (± 7 days) after the last 
dose of study therapy) will be 
recorded. Subjects with an 
AE ≥ Grade 2 that occurs ≥ 
30 days after 
discontinuation of study 
therapy and that is 
attributed (possibly, 
probably, or definitely) to 
the agent(s) will be followed 
until the AE is ≤ Grade 1 or 
baseline, deemed clinically 
insignificant, and/or until a 
new anti-cancer treatment 
starts, whichever is earlier.
Section 7.3      
(Adverse Event 
Reporting)
Any event that              
occurs more than 30 days 
after the last dose of 
treatment and is attributed 
(possibly, probably, or 
definitely) to the agent(s) 
must also be reported 
accordingly.
Addition of bolded text:
Any ≥ Grade 2 event that 
occurs more than 30 days 
after the last dose of 
treatment and is attributed 
(possibly, probably, or 
definitely) to the agent(s) 
must also be reported 
accordingly, until the AE is ≤ 
Grade 1 or baseline, 
deemed clinically 
insignificant, and/or until a 
new anti-cancer treatment 
starts, whichever is earlier.
Corrects discrepancy. 
Section 4.9 and Section 
7.3.2 contained 
contradictory language and 
have been revised to align 
with one another. The 
revision clarifies the 
requirements for AE 
tracking beyond 30 days 
during the follow-up period.
IRB #: STU00203494-CR0005 Approved by NU IRB for use on or after 4/12/2021 through 4/11/2022.


NU Study Number: NU 16G03
Merck Study Number: 3475-244
Version: November 18, 2020 (Amendment 11)
91
Protocol Amendment 11 – Version date: November 18, 2020
Section
Prior Version
Changes in Amendment 11
Rationale
Cover page and 
throughout
Protocol amendment: 10
Protocol date: October 15, 
2020
Protocol amendment: 11
Protocol date: November 18, 
2020
Administrative update
Section 8.2        
(Guadecitabine)
SGI-110 (guadecitabine) 
lyophilized drug powder is 
supplied as a 100mg vial.
SGI-110 Diluent is supplied 
as 1.2mL or 3mL vials.
Upon reconstitution, the 
admixed product is good for 
8 days under refrigerated 
conditions.
SGI-110 (guadecitabine) 
lyophilized drug powder is 
supplied as either a 100mg 
or 156mg vial.
SGI-110 Diluent is supplied 
as 1.2mL, 1.4mL, or 3mL 
vials. 
Upon reconstitution, the 
admixed product is stable for 
10 days under refrigerated 
conditions.
Updates information to 
align with guadecitabine 
(SGI-110) investigator 
brochure version 10.0. 
The description of the 
guadecitabine drug 
product is updated to 
include the 156 mg vial.
The description of the 
guadecitabine diluent 
product is updated to 
include the 1.4 mL vial.
The stability of the 
reconstituted 
guadecitabine solution 
when stored refrigerated is 
extended from 8 days to 
10 days.
IRB #: STU00203494-CR0005 Approved by NU IRB for use on or after 4/12/2021 through 4/11/2022.