A Phase 1 Study of DEC205mAb-NY ESO 1 Fusion Protein (CDX-1401) Given With Adjuvant Poly-ICLC in Conjunction With 5-Aza-2'Deoxycytidine (Decitabine) and Nivolumab in Patients With MDS or Low Blast Count AML
Phase: PHASE1
Conditions: Acute Myeloid Leukemia, Blasts 30 Percent or Less of Bone Marrow Nucleated Cells, Chronic Myelomonocytic Leukemia, High Risk Myelodysplastic Syndrome, Myelodysplastic Syndrome, Refractory Anemia
Sponsor: Roswell Park Cancer Institute

Document Coversheet 
 Study Title: 
  A Phase 1 Study of DEC205mAb-NY ESO 1 Fusion Protein (CDX-1401) given with Adjuvant Poly-ICLC in 
Conjunction with 5-Aza-2'deoxycytidine (Decitabine) and Nivolumab in Patients with MDS or Low Blast 
Count AML 
Institution/Site: 
Roswell Park Comprehensive Cancer Center 
Document (Approval/Update) Date: 
12/31/2020 
NCT Number: 
NCT03358719 
IRB Number 
I 49217 

PROTOCOL TITLE: I 49217 - Phase 1 CDX-1401/ Poly-ICLC +Decitabine +Nivolumab in 
Patients with MDS or Low Blast Count AML
Page 1 of 94
PROTOCOL TITLE:
A Phase 1 Study of DEC205mAb-NY ESO 1 Fusion Protein (CDX-1401) given with Adjuvant 
Poly-ICLC in Conjunction with 5-Aza-2'deoxycytidine (Decitabine) and Nivolumab in Patients 
with MDS or Low Blast Count AML
PROTOCOL NUMBER:
I 49217
BMS STUDY NUMBER:
CA209-9HJ
PRINCIPAL INVESTIGATOR:
Elizabeth A. Griffiths, MD 
Roswell Park Cancer Institute
Elm and Carlton Street
Buffalo, New York 14263
716-845-3996
Elizabeth.Griffiths@roswellpark.org
VERSION NUMBER: 7
DATE:
14 December 2020
Confidentiality Statement
Any and all information presented in this document shall be treated as confidential and shall 
remain the exclusive property of the party (ies) mentioned above. The use of such confidential 
information must be restricted to the recipient for the agreed purpose and must not be disclosed, 
published, or otherwise communicated to any unauthorized persons, for any reason, in any form 
whatsoever without the prior written consent of the party(ies) above.
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PROTOCOL TITLE: I 49217 - Phase 1 CDX-1401/ Poly-ICLC +Decitabine +Nivolumab in 
Patients with MDS or Low Blast Count AML
Page 2 of 94
Table of Contents
1
Objectives ................................................................................................................................5
1.1
Primary Objective.................................................................................................................5
1.2
Secondary Objective.............................................................................................................5
1.3
Exploratory Objectives .........................................................................................................5
2
Background..............................................................................................................................5
2.1
Myelodysplastic Syndrome ..................................................................................................5
2.2
NY-ESO-1 Vaccination Trial ...............................................................................................6
2.3
Study Drugs ..........................................................................................................................9
2.3.1
Vaccine (Anti DEC-205-NY-ESO-1 Fusion Protein (CDX-1401)/ Poly ICLC)..............9
2.3.2
Nivolumab.......................................................................................................................11
2.3.3
Decitabine .......................................................................................................................15
2.4
Rationale.............................................................................................................................15
3
Inclusion and Exclusion Criteria ...........................................................................................16
3.1
Inclusion Criteria ................................................................................................................16
3.2
Exclusion Criteria ...............................................................................................................17
3.3
Special Populations.............................................................................................................18
3.4
Inclusion of Women and Minorities...................................................................................18
4
Local and Study-Wide Number of Subjects ..........................................................................18
5
Local and Study-Wide Recruitment Methods .......................................................................18
6
Multi-Site Research ...............................................................................................................18
7
Study Timelines.....................................................................................................................19
8
Study Endpoints.....................................................................................................................20
8.1
Primary Endpoint................................................................................................................20
8.2
Secondary Endpoint(s)........................................................................................................20
8.3
Exploratory Endpoints........................................................................................................20
9
Design....................................................................................................................................21
9.1
Study Design.......................................................................................................................21
9.2
Replacing Patients ..............................................................................................................22
10
Treatment...............................................................................................................................22
10.1
Dosing and Administration.................................................................................................22
10.1.1
Vaccine (Anti DEC-205-NY-ESO-1 Fusion Protein (CDX-1401)/ Poly ICLC)............23
10.1.2
Nivolumab.......................................................................................................................24
10.1.3
Decitabine .......................................................................................................................24
10.2
Treatment Protocol for the Expansion Cohort....................................................................27
10.3
Definition of Dose-Limiting Toxicity ................................................................................28
10.4
Dose Modifications and Treatment Delays ........................................................................28
10.4.1
Vaccine............................................................................................................................28
10.4.2
Decitabine .......................................................................................................................28
10.4.3
Nivolumab.......................................................................................................................29
10.5
General Concomitant Medication and Supportive Care.....................................................31
10.6
Duration of Treatment ........................................................................................................31
10.7
Compliance.........................................................................................................................31
11
Procedures Involved ..............................................................................................................32
11.1
Participant Randomization and Registration ......................................................................32
11.2
Baseline Evaluations...........................................................................................................32
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PROTOCOL TITLE: I 49217 - Phase 1 CDX-1401/ Poly-ICLC +Decitabine +Nivolumab in 
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11.3
Evaluations Performed on Day -14.....................................................................................33
11.4
Evaluations Performed on Day 1 of each Cycle.................................................................33
11.5
Evaluations Performed on Day 15 of each Cycle...............................................................34
11.6
Evaluations Performed Specifically at End of Cycle 1 ......................................................34
11.7
Evaluations Performed on Cycle 5 Day 1 and every 4th Cycle thereafter ..........................34
11.8
Evaluations Performed at End of Treatment ......................................................................35
11.9
Post-Treatment Follow-Up Evaluations .............................................................................35
11.10
Schedule of Procedures and Observations......................................................................36
11.11
Correlative Studies..........................................................................................................37
11.11.1
Blood Sample Collection.............................................................................................37
11.11.2
Bone Marrow Sample Collection................................................................................37
11.11.3
Molecular (Epigenetic) Markers of Response.............................................................39
11.11.4
Immunological Markers of Response..........................................................................39
11.11.5
Humoral Immunity......................................................................................................39
11.11.6
Cellular Immunity .......................................................................................................40
11.11.7
14.1.5 Dendritic Cell Function....................................................................................40
11.11.8
Additional Exploration of the T cell Response ...........................................................41
12
Withdrawal of Subjects..........................................................................................................41
12.1
Treatment Discontinuation .................................................................................................41
13
Risks to Subjects....................................................................................................................42
13.1
Vaccine (Anti DEC-205-NY-ESO-1 Fusion Protein (CDX-1401)/ Poly ICLC) ...............42
13.2
Nivolumab ..........................................................................................................................42
13.2.1
Management of Immune-Related Adverse Events .........................................................43
13.3
Decitabine...........................................................................................................................43
14
Potential Benefits to Subjects ................................................................................................44
15
Data and Specimen Banking..................................................................................................44
16
Measurement of Effect ..........................................................................................................44
17
Safety Evaluation...................................................................................................................44
17.1
Adverse Events ...................................................................................................................44
17.1.1
Diagnosis Versus Signs and Symptoms..........................................................................45
17.1.2
Adverse Events Occurring Secondary to Other Events ..................................................45
17.1.3
Abnormal Laboratory Values..........................................................................................45
17.1.4
Preexisting Medical Conditions (Baseline Conditions)..................................................46
17.2
Grading and Relationship to Drug......................................................................................46
17.3
Reporting Adverse Events ..................................................................................................46
17.4
Serious Adverse Events ......................................................................................................47
17.4.1
Reporting Serious Adverse Events .................................................................................47
17.5
Investigator Reporting: Notifying the Study Sponsor ........................................................47
17.5.1
Suspected/ Unexpected Serious Adverse Reaction.........................................................49
17.6
Follow-Up for Serious Adverse Events..............................................................................49
17.7
Unanticipated Problems......................................................................................................49
17.8
FDA Reporting ...................................................................................................................50
18
Data Management and Confidentiality..................................................................................51
18.1
Data Collection ...................................................................................................................51
18.2
Maintenance of Study Documents......................................................................................51
18.3
Revisions to the Protocol....................................................................................................51
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PROTOCOL TITLE: I 49217 - Phase 1 CDX-1401/ Poly-ICLC +Decitabine +Nivolumab in 
Patients with MDS or Low Blast Count AML
Page 4 of 94
18.4
Termination of the Study....................................................................................................51
18.5
Confidentiality ....................................................................................................................52
19
Statistical Plan .......................................................................................................................52
19.1
Sample Size Determination ................................................................................................52
19.2
Other Safety Analysis.........................................................................................................52
19.3
Efficacy Analysis................................................................................................................52
19.4
Secondary Analysis ............................................................................................................53
19.5
Demographics and Baseline Characteristics.......................................................................53
19.5.1
Adverse Event.................................................................................................................53
19.6
Correlative Data Analysis...................................................................................................53
20
Provisions to Monitor the Data to Ensure the Safety of Subjects..........................................53
21
Vulnerable Populations..........................................................................................................53
22
Community-Based Participatory Research............................................................................53
23
Sharing of Results with Subjects ...........................................................................................53
24
Setting....................................................................................................................................54
25
Provisions to Protect the Privacy Interests of Subjects .........................................................54
26
Resources Available ..............................................................................................................54
27
Prior Approvals......................................................................................................................54
28
Compensation for Research-Related Injury...........................................................................54
29
Economic Burden to Subjects................................................................................................54
30
Consent Process.....................................................................................................................54
31
Process to Document Consent in Writing..............................................................................55
32
Drugs or Devices ...................................................................................................................55
32.1
Vaccine (Anti DEC-205-NY-ESO-1 Fusion Protein (CDX-1401)/ Poly ICLC) ...............55
32.1.1
Active Substance and Source..........................................................................................55
32.1.2
Drug Shipment ................................................................................................................56
32.1.3
Preparation ......................................................................................................................56
32.1.4
Storage and Stability .......................................................................................................56
32.1.5
Handling and Disposal....................................................................................................56
32.2
Nivolumab ..........................................................................................................................57
32.2.1
Active Substance and Source..........................................................................................57
32.2.2
Drug Shipment ................................................................................................................57
32.2.3
Preparation ......................................................................................................................57
32.2.4
Storage and Stability .......................................................................................................57
32.2.5
Handling and Disposal....................................................................................................58
32.3
Decitabine...........................................................................................................................58
33
REFERENCES ......................................................................................................................59
34
APPENDICES/SUPPLEMENTS..........................................................................................65
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PROTOCOL TITLE: I 49217 - Phase 1 CDX-1401/ Poly-ICLC +Decitabine +Nivolumab in 
Patients with MDS or Low Blast Count AML
Page 5 of 94
1
OBJECTIVES
1.1
Primary Objective

Evaluate the safety of NY-ESO-1 vaccination (Anti-DEC-205-NY-ESO-1 fusion protein 
+ poly-ICLC) given in combination with decitabine 20 mg/m2 intravenously and 
nivolumab 3 mg/kg in patients with MDS or low blast count AML.
1.2
Secondary Objective

Assess immune and molecular epigenetic responses following combination therapy with 
nivolumab, decitabine and NY-ESO-1 vaccination.
1.3
Exploratory Objectives

To record the response rate (Complete Response, Partial Response and Hematological 
Improvement) in MDS or low blast count AML patients treated with the combination in 
order to provide descriptive characteristics.

To record the Overall Survival (OS), Progression Free Survival (PFS) and time to AML 
transformation (TTT) (for patients with MDS at diagnosis) enrolled on the study.
2
BACKGROUND
2.1
Myelodysplastic Syndrome
Myelodysplastic Syndrome (MDS) is a hematologic disorder of adults, with an estimated overall 
incidence of 5 cases per 100,000 people annually in the United States (1). MDS is characterized 
by ineffective hematopoiesis with progressive cytopenias and a variable risk of transformation to 
acute myeloid leukemia (AML) (2). For patients with intermediate-2 (Int-2) or high-risk disease 
as defined by the International Prognostic Scoring System (IPSS) (a designation which includes 
patients with low blast count AML (<30% blasts) for the purpose of this study), the median overall 
survival (OS) is 1.2 years or 0.4 years, respectively, and these patients have a high risk of 
transformation to high-blast count AML (3). The goal of therapy for these patients is, therefore, to 
modify the natural history of the disease and extend the survival and time to AML transformation 
(>30% blasts). With the exception of allogeneic stem cell transplantation (SCT), for which most 
patients are unsuitable due to age and comorbidities, there is currently no curative treatment for 
MDS.
Development of specific MDS treatments has been challenging not only due to limitations of 
treatment tolerance, but also by the frequent unfavorable biological features of the malignant clone 
which include adverse cytogenetics, limited normal stem cell reserve, and higher levels of 
multidrug resistance. The development of non-intensive “epigenetic” therapy with azanucleosides 
like azacitidine and decitabine, so called hypomethylating agents (HMAs), has been driven by the 
goal of "re-programming" growth and differentiation, rather than eradication by cytotoxic effects, 
of the abnormal cells and this strategy has been the first to demonstrate a survival advantage in 
patients with MDS (4). Unfortunately, responses to this therapy are relatively short lived, lasting 
months to years, and following disease progression on these treatments survival is dismal on the 
order of 4-6 months (5).
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PROTOCOL TITLE: I 49217 - Phase 1 CDX-1401/ Poly-ICLC +Decitabine +Nivolumab in 
Patients with MDS or Low Blast Count AML
Page 6 of 94
The mechanism(s) responsible for response to HMAs therapy remain a matter of some debate. 
Historically, cytotoxicity or re-expression of epigenetically silent tumor suppressor genes were 
thought to be critical to response, but recent work suggests that immunological mechanisms may 
play a role (6). HMAs have been adopted as the standard of care for treatment of patients with 
MDS and select patients with AML, but despite multiple attempts to combine them with other 
agents, responses have not been pushed substantially beyond the originally described40% rate.
2.2
NY-ESO-1 Vaccination Trial
Recent advances in cancer immunotherapy led us to develop a novel approach that utilizes the 
ability of HMAs to induce expression of tumor antigens that can be exploited to unleash the anti-
tumor potential of the immune system.
We previously showed that AML/MDS patients receiving HMAs demonstrate increased 
expression of the immunogenic tumor antigen NY-ESO-1 (7). Induction of NY-ESO-1 expression 
occurred in both clinical responders and non-responders to HMAs, and was sufficient to induce 
cytotoxicity in HLA-compatible T-cells recognizing NY-ESO-1. This data provided the rationale 
for our recently completed phase I study combining NY-ESO-1 vaccination with decitabine in 
patients with MDS or low blast count AML (Figure 1A). In all, 9 patients of median age 64 years 
were enrolled and treated on protocol (Table 1). The most frequently observed adverse events, 
related to decitabine and the underlying hematological malignancy, included cytopenias 
(predominantly grades 3/4), elevated liver enzymes (grade 3), fatigue (grade 2), edema (grade 2/3) 
and diarrhea (grade 1/2) (Table 2). Two patients did not complete four cycles of therapy due to 
serious adverse events; one patient with a history of myocardial infarction (MI) developed in-stent 
restenosis and recurrent MI; a second patient suffered a terminal intracranial hemorrhage due to 
thrombocytopenia (deemed decitabine related).
Figure 1
Summary of Prior Study Results
100 
80 
60 
40 
20 
0 
Pre
C1 D11-20
C2 D1
C2 D11-20
C3 D1
C3 D11-20
C4 D1
C4 D11-20
% NY-ESO-1 Methylation
CD11b+ Cells
Plasma 
Pre
C1D8
C1D22
C2D15
C3D1
+ Ctl
NTC
C2D22
Patient 3 
Patient 9 
Pre
C1D9
C1D15
C2D1
C2D9
C4D9
C4D15
+ Ctl
NTC
C2D15
C3D1
C3D9
C3D15
C3D23
C4D23
NY-ESO-1 
GAPDH
NY-ESO-1 
GAPDH
A 
B 
C 
D 
Clinical Trial Schema 
105 
104 
103 
0
105 
104 
103 
0
0
103 104 105 
Pretreatment  
Decitabine:C2D15 
NY-ESO-1 Specific T-Cell Clone
+ Patient 9 PBMCs (HLA-B35) 
0.02% 
1.31% 
0.35% 
4.14% 
IFN-γ
CD107 
E 
Cycle 1 
Day 1 
Cycle 1 
Day 15 
Cycle 2-4 
Day 1 
Cycle 2-4 
Day 15 
Cycle 4   
Day 29 
Day -14 
Decitabine
Vaccine
End of  
Study Testing 
20mg/m2/day 
 x 5 days
20mg/m2/day 
 x 5 days
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PROTOCOL TITLE: I 49217 - Phase 1 CDX-1401/ Poly-ICLC +Decitabine +Nivolumab in 
Patients with MDS or Low Blast Count AML
Page 7 of 94
Patients demonstrated the expected transient effects on both global and NY-ESO-1 specific 
methylation (Figure 1B). Importantly, the methylation signature from CD11b selected peripheral 
blood cells was recapitulated entirely in the plasma cell free DNA harvested from patients, 
allowing us the opportunity to use cell free DNA rather than cells to assess changes in DNA 
methylation in future studies. A majority of patients treated on this study demonstrated induced 
expression of NY-ESO-1 in circulating CD11b selected cells (exemplar patients demonstrated in 
Figure 1C and Figure 1D) and developed NY-ESO-1 specific T-cell (exemplar in Figure 1E) 
responses but this response was relatively small compared to the historical use of this vaccine in 
patients with solid tumors (Table 3) (8)
Table 1
Demographics
Table 2
Adverse Events
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PROTOCOL TITLE: I 49217 - Phase 1 CDX-1401/ Poly-ICLC +Decitabine +Nivolumab in 
Patients with MDS or Low Blast Count AML
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Table 3
Correlation of Vaccine Response with Induced NY-ESO-1 Expression
We and others have demonstrated that PD-L1 is expressed on CD34+ myeloid cells from patients 
with MDS and AML (7, 9) (Figure 2). Previous studies have demonstrated that NY-ESO-1+ tumor 
infiltrating lymphocytes express the immune checkpoint protein PD-1. In addition, PD-1 
expression is induced in lymphocytes of AML/MDS patients receiving decitabine [(7) and 
unpublished]. These results provide a rationale for the inclusion of the PD-1 inhibitor nivolumab 
in combination with our vaccine approach.
Figure 2
A) PD-L1 expression on AML blasts; B-D) PD-1 hypomethylation in 
lymphoid cells from patients receiving decitabine.
In this Phase 1 study we propose to combine our backbone NY-ESO-1 vaccination/decitabine 
approach with the PD-1 checkpoint inhibitor nivolumab in HMA naïve, non-transplant eligible, 
MDS patients. We hypothesize that the addition of nivolumab to our combination of standard-dose 
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PROTOCOL TITLE: I 49217 - Phase 1 CDX-1401/ Poly-ICLC +Decitabine +Nivolumab in 
Patients with MDS or Low Blast Count AML
Page 9 of 94
decitabine and NY-ESO-1 vaccination will improve the qualitative and quantitative antigen 
specific CD4+ and CD8+ T-cell response to NY-ESO-1 vaccination in MDS patients. We will use 
this study to test this hypothesis with the three specific objectives as described in 1.0.
2.3
Study Drugs
2.3.1
Vaccine (Anti DEC-205-NY-ESO-1 Fusion Protein (CDX-1401)/ Poly ICLC)
DEC205mAb-NY ESO 1 fusion protein is being developed by Celldex Therapeutics, Inc, under 
the code designation CDX-1401. CDX-1401 is a fusion protein consisting of a fully human 
monoclonal antibody (HuMab) of IgG1 (kappa) isotype with specificity for the dendritic cell 
receptor, DEC-205, genetically linked to the full length NY-ESO-1 tumor antigen (Ag) protein 
(10). A letter of authorization to refer to the Celldex IND 14090 for relevant data on clinical studies 
with CDX-1401 will be provided with this submission and a companion IND for the use of this 
protein in this trial will be filed prior to the opening of this study.
The cancer-testis (CT) antigen NY-ESO-1 is expressed in a wide range of different tumor types, 
but its expression in normal adult tissues is limited to the testis (11, 12). It has been shown that 
NY-ESO-1 is highly immunogenic and able to induce spontaneous immune responses in patients 
with NY-ESO-1–expressing tumors but not in healthy individuals (13). Furthermore, the presence 
of a spontaneous anti–NY-ESO-1 antibody (Ab) response is typically associated with spontaneous 
NY-ESO-1–specific CD8+ and CD4+ T cell responses in melanoma patients (14-16). Because of 
its frequent expression in tumors and high immunogenicity, NY-ESO-1 has been an attractive 
target for cancer immunotherapy and has been used in a series of clinical vaccine trials, although 
it has not been evaluated in MDS since the antigen is not spontaneously expressed in this 
malignancy (17, 18). 
Extensive immune monitoring during a variety of studies has revealed that NY-ESO-1–specific 
immune responses are inducible by a variety of NY-ESO-1–based vaccines such as HLA class I 
and/or class II-binding peptides, recombinant viruses, and recombinant protein with or without 
adjuvants or delivery systems, even in patients without spontaneous immunity (19-24). Compared 
to vaccination with HLA-binding short peptides, vaccination with full-length tumor Ag such as 
recombinant proteins or viruses is considered to be more attractive because of the potential to 
induce a wider repertoire of specific Ab and T cell responses. Furthermore, recombinant proteins 
or viruses are expected to induce high-avidity T cells, whereas short peptide vaccination often 
induces low avidity T cells that fail to recognize naturally processed Ag (25, 26). Full-length tumor 
Ags intrinsically contain all possible CD4+ and CD8+ T cell epitopes for any type of HLA allele 
and thus they should potentially activate both CD4+ and CD8+ T cell subsets. However, it was 
found that vaccination with recombinant NY-ESO-1 protein in the presence of vaccine adjuvant, 
bacillus Calmette-Gue´rin plus GM-CSF or imiquimod, induced CD4+ T cell responses in most 
immunized patients, whereas cross-priming of NY-ESO-1–specific CD8+ T cells was rare unless 
NY-ESO-1 protein was formulated in ISCOMATRIX or strong adjuvant like CpG was used (19, 
23, 24, 27). In contrast, vaccination with recombinant viruses inducing intracellular NY-ESO-1 
expression elicited frequent CD8+ T cell responses, though not always accompanied by the 
induction of specific CD4+ T cells (10). These observations are consistent with distinct pathways 
for MHC class I and class II Ag presentation and thus for separate processing and presentation of 
endogenous and exogenous protein via MHC class I and class II, respectively. Because both tumor 
Ag-specific CD8+ and CD4+ T cells cooperatively play important roles in eradicating cancer (28), 
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PROTOCOL TITLE: I 49217 - Phase 1 CDX-1401/ Poly-ICLC +Decitabine +Nivolumab in 
Patients with MDS or Low Blast Count AML
Page 10 of 94
using vaccine constructs that can simultaneously activate NY-ESO-1–specific CD8+ and CD4+ T 
cells is a much desired strategy to immunologically reverse the clinical course of cancer.
Preclinical Studies with CDX-1401
The DEC-205 receptor has been shown to be an efficient mAb-based target to enhance the 
induction of strong Ag-specific immune responses and cross-presentation in mice (29) and humans 
(30). The receptor is also expressed on human monocyte-derived dendritic cells (DCs) along with 
other endocytic receptors, such as the mannose receptor/CD206 and DC-SIGN/CD209 [reviewed 
in (30)]. In a recent study at Roswell Park Cancer Institute, full-length NY-ESO-1 was fused to 
the C terminus of human anti-DEC-205 (DEC205mAb-NY-ESO- 1 fusion protein) (10). Whereas 
non-targeted and antibody-targeted NY-ESO-1 proteins similarly activated CD4+ T-cells, cross-
presentation to CD8+ T-cells was only efficiently induced by targeted NY-ESO- 1 (10). In 
addition, DEC-205 targeting elicited specific CD4+ and CD8+ T-cells from peripheral blood 
lymphocytes of cancer patients. In this study, the DEC-205 mAb-NY-ESO-1 fusion protein will 
be directly injected subcutaneously in an effort to prime endogenous DCs with full length NY-
ESO-1 full length protein and thereby sensitize the immune system to NY-ESO-1 induced in MDS 
cells following exposure to decitabine and nivolumab. Our previously completed phase I study has 
demonstrated that the combination of NY-ESO-1 vaccination with decitabine is safe.
A detailed discussion of the preclinical pharmacology, pharmacokinetics, and toxicology of Anti 
DEC-205-NYESO-1 Fusion Protein can be found in the Celldex Investigator’s Brochure.
Poly-ICLC
Poly-ICLC (Hiltonol, manufactured by Dalton for Oncovir, Inc., to be provided by Celldex 
Therapeutics) is an experimental viral mimic and broad activator of innate immunity. While 
initially developed as an interferon inducer, poly-ICLC has much broader biological effects in 
humans, including specific antiviral, immune activating, vaccine adjuvant, and antitumor actions.
Synthetic double stranded RNA (dsRNA) such as poly-IC, which consists of a pair of strands of 
poly-inosinic and poly-cytidylic acids, are not normally found in mammalian cells, but they are 
the basic genetic material or are replication byproducts of many viruses (31). Plain Poly-IC itself 
proved to be ineffective in primates because it is rapidly inactivated by natural enzymes in the 
blood. However stabilized poly-IC with poly-lysine is a very stable dsRNA that is a potent 
interferon inducer in man. Early, short term, high dose cancer trials showed that high dose poly-
ICLC could induce very large amounts of interferon production in man, but with only modest 
therapeutic effects and moderate transient toxicity (31). Low dose poly-ICLC is a potent clinical 
activator of a variety of host defense mechanisms that go well beyond simple induction of 
interferons and which include reversal or preemption of certain viral or tumor induced inhibitions, 
broad immune stimulation, gene regulatory and specific antiviral, and anticancer effects, with little 
or no toxicity (31, 32).
In this study low dose poly-ICLC will be used as a direct immune-enhancer in order to activate T-
cells, natural killer cells, and, dendritic cells, release of cytokines such as interferons, interleukins, 
corticosteroids, and tumor necrosis factor (TNF). Its recently demonstrated effect on dendritic cells 
through Toll-like receptors (TLR3) may be especially important since CDX-1401 directly targets 
these cells (33). As described above, dendritic cells play a critical role in the immune response by 
recognizing pathogens and presenting their antigens to the immune system. The poly-ICLC used 
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PROTOCOL TITLE: I 49217 - Phase 1 CDX-1401/ Poly-ICLC +Decitabine +Nivolumab in 
Patients with MDS or Low Blast Count AML
Page 11 of 94
in this study will provide an adjuvant effect for the CDX-1401 with increased antibody and cellular 
immune response to NY-ESO-1antigen.
Clinical Studies with CDX-1401 and adjuvants
One open-label, dose-escalation study (Protocol CDX1401-01) has been conducted with CDX-
1401 (8). In this trial, 45 patients with treatment refractory solid tumors were treated with CDX-
1401 (0.1 to 3 mg) in combination with the TLR7/8 agonist, resiquimod (applied topically or 
injected subcutaneously); the TLR 3 agonist poly-ICLC (injected subcutaneously); or both TLR 
agonists. Treatment was administered over ~6 weeks of a 12-week cycle, with repeated 12-week 
cycles if tolerated in the absence of progression. Treatment was well-tolerated with no dose-
limiting toxicity (DLT). Administration site reactions (erythema, pain, pruritus, rash, induration, 
swelling; mild in nearly all cases) were frequent, occurring in 78% of the patients. Additional 
adverse events thought potentially related to treatment included fatigue (24%), nausea (9%), chills 
(9%), decreased appetite (7%), influenza like illness (7%), arthralgia (7%) and myalgia (7%). No 
Grade 3, 4 or 5 events were reported as potentially related to study treatment. Thirteen patients 
had stable disease, with a median duration of 6.7 months (range = 2.4+ to 13.4). Four patients had 
measurable tumor shrinkage (% shrinkage of the sum of the diameters of target lesions = -2, -8, -
20 & -21%). Significant anti-NY-ESO-1 titers (up to 1:800,000) occurred in 80% of patients. 
Approximately 60% of patients with NY-ESO-1+ tumors had significant anti-NY-ESO-1 titers at 
baseline and most increased after vaccination. Humoral responses were elicited in both NY-ESO-1 
positive and negative patients. NY-ESO-1-specific T cell response (IFN-γ ELISPOT) was absent 
or low at baseline, but increased post-vaccination in approximately half of the patients. Evidence 
of NY-ESO-1 specific CD4 or CD8 T cell responses were observed using intracellular cytokine 
secretion and pentamer analysis in selected samples. Similar immune responses were observed 
with adjuvants, individually or in combination, with no clear dose response in these small cohorts. 
Interestingly, 5 of 8 patients treated with checkpoint inhibitors within 3 months of CDX-1401 
administration reportedly had objective tumor regression (CDX 1401 Investigator Brochure, 
2013). In conclusion, preliminary data from study CDX-1401 show that dendritic cell targeting 
through DEC-205 can safely lead to robust humoral and cellular immunity when combined with 
TLR agonists in cancer patients. Results provide the basis for further study, including novel 
combination immunotherapy strategies such as that involving checkpoint blockade.
2.3.2
Nivolumab
Nivolumab (also referred to as BMS-936558 or MDX1106) is a human monoclonal antibody 
(HuMAb; immunoglobulin G4 [IgG4]-S228P) that targets the programmed death-1 (PD-1) cluster 
of differentiation 279 (CD279) cell surface membrane receptor. PD-1 is a negative regulatory 
molecule expressed by activated T and B lymphocytes.1 Binding of PD-1 to its ligands, 
programmed death–ligands 1 (PD-L1) and 2 (PD-L2), results in the down-regulation of 
lymphocyte activation. Inhibition of the interaction between PD-1 and its ligands promotes 
immune responses and antigen-specific T-cell responses to both foreign antigens as well as self-
antigens. Nivolumab is expressed in Chinese hamster ovary (CHO) cells and is produced using 
standard mammalian cell cultivation and chromatographic purification technologies. The clinical 
study product is a sterile solution for parenteral administration. OPDIVO™ (nivolumab) is 
approved for use in multiple countries including the United States (US, Dec-2014), the European 
Union (EU, Jun-2015), and Japan (Jul-2014).
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PROTOCOL TITLE: I 49217 - Phase 1 CDX-1401/ Poly-ICLC +Decitabine +Nivolumab in 
Patients with MDS or Low Blast Count AML
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The clinical use of monoclonal antibodies to T-cell inhibitory receptors has provided 
transformative information on the nature of the immune system and cancer. An emerging picture 
suggests that endogenous immune responses can mediate effective tumor regression and/or 
improved survival even in patients with large volume tumors resistant to other forms of therapy. 
Some of the unique features of this type of therapy, based largely on experience in advanced 
melanoma, include: improved overall survival (OS) with or without radiographic responses or 
improved progression-free survival (PFS); responses that may be delayed or occur after 
radiographic disease progression; combinations of immune modulators with enhanced or novel 
activities (in the example of ipilimumab and nivolumab); and toxicity that is almost exclusively 
immune or inflammatory in nature. It is not yet clear what factors determine responses and which 
components of the immune system are needed for this to occur. It seems likely that both memory 
helper and effector cells would be needed to sustain long-term responses. Increasing emphasis has 
been placed on understanding the relationships of the tumor, cellular infiltrate, and immunologic 
milieu surrounding each tumor. PD-1, a 55-kDa type 1 transmembrane protein, is a member of the 
CD28 family of T-cell co-stimulatory receptors that include Ig super family member CD28, 
CTLA-4, inducible co-stimulator (ICOS), and B and T lymphocyte attenuator (BTLA) 
(Investigator Brochure, 2013). PD-1 is transiently but highly expressed on activated T cells 
functioning to limit immune effectors at the site of activation. Chronic stimulation may prevent 
the re-methylation of the PD-1 gene leading to continuous expression and characterizes a state of 
“exhausted” T cells that lose function and proliferative capacity while enhancing a suppressive 
tumor microenvironment. PD-1 may act together with other T-cell modulating molecules, 
including CTLA-4, TIM-3, lymphocyte-activation gene 3 (LAG-3) as well as indoleamine-pyrrole 
2, 3-dioxygenase 1 (IDO-1), cytokines, and transforming growth factor beta (TGF-beta).
Two ligands specific for PD-1 have been identified: PD-ligand 1 (PD-L1, also known as B7-H1 
or CD274, expressed on tumor, antigen-presenting cells [APCs], and dendritic cells [DCs]) and 
PD-L2 (also known as B7-DC or CD273, expressed on endothelial cells). The interaction of PD-1 
with PD-L1 and PD-L2 results in negative regulatory stimuli that down-modulate the activated T-
cell immune response through SHP-1 phosphatase.
PD-1 knockout mice develop strain-specific lupus-like glomerulonephritis (C57BL/6) and 
cardiomyopathy (BALB/c). In transplantable tumor models that expressed PD-1 and LAG-3 on 
tumor-infiltrating CD4+ and CD8+ T cells dual anti-LAG-3/anti-PD-1 antibody treatment cured 
most mice of established tumors that were largely resistant to single antibody treatment (Woo et 
al., 2012). Despite minimal immunopathologic sequelae in PD-1 and LAG-3 single knockout mice, 
dual knockout mice abrogated self-tolerance with resultant autoimmune infiltrates in multiple 
organs, leading to eventual lethality.
PD-L1 expression is found on a number of tumors, and is associated with poor prognoses based 
on OS in many tumors, including melanoma (34), renal (35-37), esophageal (38), gastric (39), 
ovarian (40), pancreatic (41), lung (42), and other cancers (Nivolumab Investigator Brochure, 
2014).
The PD-1/PD-L1 axis plays a role in human infections, particularly in hepatitis C virus (HCV) and 
human immunodeficiency virus (HIV). In these cases, high expression levels of PD-1 were found 
in viral-specific CD8+ T cells that also display a non-responsive or exhausted phenotype. Non-
responsive PD-1-high T cells were observed in simian immunodeficiency virus (SIV) infection in 
rhesus macaques. Treatment of SIV-infected macaques with an anti-PD-1 mAb (3 mg/kg x4) 
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PROTOCOL TITLE: I 49217 - Phase 1 CDX-1401/ Poly-ICLC +Decitabine +Nivolumab in 
Patients with MDS or Low Blast Count AML
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resulted in decreased viral loads and increased survival along with expanded T cells with increased 
T-cell functionality.
Nivolumab monotherapy is approved in multiple countries, including the US and EU, for 
unresectable or metastatic melanoma, previously treated metastatic NSCLC, and previously 
treated advanced RCC; it is also approved for the treatment of cHL and urothelial carcinoma in 
the US. In addition, nivolumab has been approved for use in combination with ipilimumab for 
unresectable melanoma in multiple countries, including the US and EU.
Clinical Safety
The overall safety experience with nivolumab, as a monotherapy or in combination with other 
therapeutics, is based on experience in approximately 12,300 subjects treated to date (Nivolumab 
Investigator Brochure, 2016). For monotherapy, the safety profile is similar across tumor types. 
There is no pattern in the incidence, severity, or causality of AEs to nivolumab dose level. In Phase 
3 controlled studies, the safety profile of nivolumab monotherapy is acceptable in the context of 
the observed clinical efficacy, and manageable using established safety guidelines. Clinically 
relevant AEs typical of stimulation of the immune system were infrequent and manageable by 
delaying or stopping nivolumab treatment and timely immunosuppressive therapy or other 
supportive care. In several ongoing clinical trials, the safety of nivolumab in combination with 
other therapeutics such as ipilimumab, cytotoxic chemotherapy, anti-angiogenics, and targeted 
therapies is being explored.
Combinations with HMAs in Myeloid Malignancy
Although limited activity was previously shown for single agent PD-1 blockade in patients with 
active myeloid malignancy (43), recently authors at the MD Anderson Cancer Center reported 
preliminary results from two studies suggesting that combinations of PD-1 blockade with 
hypomethylating drugs may have substantial activity (44-46).
The first of these studies reported on 66 patients with relapsed or refractory AML (median number 
of prior regimens 2, range 1-7). Patients received standard dose/schedule azacitidine (75 mg/m2 x 
7 days) in combination with nivolumab at 3 mg/kg every 2 weeks given on days 1, 14 of each 
cycle. Courses were repeated indefinitely every 4-5 weeks and patients were deemed eligible for 
response assessment if they had received at least 3 cycles of therapy. Six patients were initially 
enrolled to a safety cohort and only 1 had a dose limiting toxicity (grade 3 pneumonitis) thus this 
dose/schedule was declared the recommended phase 2 dose and to date an additional 60 patients 
have been accrued and treated. At the 2017 EHA meeting in June, 63 patients were eligible for 
response assessment and these included 14 patients who have demonstrated CR or CR with 
incomplete count recovery (3;11; 22%), 7 hematological improvements (11%). Responses were 
observed after a median of 2 courses. Early mortality at 4 and 8 weeks was observed in 5 and 11% 
of patients respectively. Immune toxicities were observed in 15 (23%) patients with grade 3 or 4 
events seen in 8 patients (12%) and grade 2 events in 7 patients. The most frequently reported 
grade 3 or 4 events were pneumonitis, colitis, nephritis, skin rash and hypophysitis. One patient 
died related to pneumonitis, the remaining 14 patients were managed with steroids and 13 of them 
were retreated with nivolumab. Immune toxicities presented both early and late (range 4 days to 
3.5 months). Responses in this cohort were compared favorably with the historical response to 
salvage therapy in this population at MD Anderson.
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PROTOCOL TITLE: I 49217 - Phase 1 CDX-1401/ Poly-ICLC +Decitabine +Nivolumab in 
Patients with MDS or Low Blast Count AML
Page 14 of 94
The second study was recently updated at the 2017 EHA meeting and presented by Dr. Garcia-
Manero and colleagues reported on 63 patients with MDS either previously untreated or relapsed 
after HMA failure (45). The study design allowed previously untreated patients to receive upfront 
azacitidine at a dose of 75 mg/m2 sq x 5 days with either nivolumab 3 mg/kg IV on day 6 and 20 
of each cycle, ipilimumab 3 mg/kg IV on day 1 of a 21 day cycle or nivolumab 3 mg/kg IV on 
days 1 and 15 in combination with ipilimumab 3 mg/kg IV on day 1 of a 28 day cycle. Patients 
who had previously failed an HMA were randomized receive either single agent nivolumab 
3 mg/kg IV days 1 and 15, single agent ipilimumab 3 mg/kg IV on day 1 of a 21 day cycle or 
nivolumab 3 mg/kg IV on days 1 and 15 in combination with ipilimumab 3 mg/kg IV on day 1 of 
a 28 day cycle. After 6 cycles of the checkpoint inhibitors, patients were allowed to resume 
azacitidine if there had been no response or disease progression. A maximum of 20 patients may 
be enrolled to each cohort for a total of 180 patients potentially enrolled to study. At the time of 
abstract presentation, 63 patients had been enrolled with 2 screen failures. At the time of the most 
recent update, 54 (86%) patients were evaluable for response and toxicity including 21 previously 
untreated MDS patients who received azacitidine in combination with nivolumab, and 15 and 18 
patients who had previously failed a hypomethylating agent who received single agent nivolumab 
or ipilimumab respectively. The median age for enrolled patients to date is 69 years (range 39-85). 
Median number of treatment cycles is 3 with a range of 1 to 11. Related grade > 3 non-hematologic 
AEs have been reported in 3 (27%) pts in the azacitidine + nivolumab cohort, 6 (40%) in the single 
agent nivolumab cohort, and 3 (33%) in the single agent ipilimumab cohort, thus the stopping rule 
for toxicity was not met in any cohorts. Delays of therapy due to adverse events were required in 
9 patients. These adverse events were reported as rash (N=1), adrenal insufficiency (N=1), colitis 
(N=1), thyroiditis (N=2), pneumonitis (N=3), and nephritis (N=1). A previous report from this 
cohort described the most commonly reported > Grade 3 adverse events in the combination arm in 
11 patients (45 hemorrhage, hyperglycemia, fever and elevated LFTs (in 9% each). Commonly 
reported AEs irrespective). These included pulmonary infections (seen in 18% of patients), 
followed by intracranial of attribution in these patients of any grade included constipation and 
maculopapular rash in 45%, nasal congestion in 36%, arthralgia, cough, and stomach pain in 27% 
each, diarrhea, edema, fatigue, hyperkalemia, and insomnia in 18%, and anorexia, dyspnea, 
GERD, hyperglycemia, hyponatremia, hypotension, mucositis, nausea, pneumonitis, and weight 
loss in 9%.Early mortality was reported in 1 patient (at the 8 week time point) due to a non-related 
intracranial hemorrhage. The response rate in the previously untreated cohort who received 
azacitidine + nivolumab was reported as 62% (13/21) with 6 patients reported to have CR. 
Nivolumab as a single agent had a 0% response rate (thus this arm has been stopped) and single 
agent ipilimumab was reported to produce responses in 5/18 patients (30%).
These data support the safety and tolerability of combination strategies using nivolumab and 
HMAs in patients with myeloid malignancy. We would predict that the present combination 
strategy would have a similar toxicity profile and will adopt the best practice with respect to 
aggressive management of immune related adverse events.
2.3.3
Decitabine
Decitabine is known to be well tolerated, with a favorable extramedullary toxicity profile and 
infrequent treatment-related mortality. Decitabine is a nucleoside analog that is unsuitable for 
methylation due to the replacement of carbon with nitrogen at the 5’ position of the pyrimidine 
ring. Decitabine is activated intracellularly by deoxycytidine kinase and other nucleotide kinases 
to the active metabolite 5-aza-2’-deoxycytidine-triphosphate (5-aza-2 ’-dCTP) that can be 
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PROTOCOL TITLE: I 49217 - Phase 1 CDX-1401/ Poly-ICLC +Decitabine +Nivolumab in 
Patients with MDS or Low Blast Count AML
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incorporated into DNA during the S-phase of the cell cycle and forms irreversible covalent bonds 
with DNA methyltransferases (DNMT) at cytosine sites targeted for methylation (32). Decitabine 
is believed to exert its antineoplastic effects by inhibition of DNA methyltransferases, causing 
DNA hypomethylation and activation of genes involved in differentiation or apoptosis. Decitabine 
was the first drug to demonstrate significant activity against MDS and has been shown to induce 
transfusion independence for red blood cells and platelets as well as improvements in neutropenia 
(47).
Based upon these results decitabine was approved by the US food and drug administration for all 
MDS subtypes in 2006 and it remains a frequent standard approach to the treatment of patients 
with MDS (2). It has been hypothesized that low dose, prolonged exposure to decitabine correlates 
with clinical response as a result of changes in gene expression induced by a reduction in DNA 
methylation; rather than cytotoxicity which occurs with higher doses of decitabine (48). Recently 
we and others have shown that exposure of myeloid cells to decitabine and azacitidine (an analog 
of decitabine which incorporates into both DNA and RNA), can induce expression of CT antigens 
when given in vitro to AML cell lines, and further that patients treated with these drugs can induce 
expression of some CT antigens as well (17, 18, 49).
2.4
Rationale
The hypomethylating agents (HMAs) azacitidine and decitabine are the standard of care for the 
treatment of myelodysplastic syndromes (MDS) but only about 40% of patients respond. We have 
demonstrated that AML/MDS patients receiving HMAs express the immunogenic tumor antigen 
NY-ESO-1 in circulating CD34+ blasts after treatment in both clinical responders and non-
responders. These data provided the rationale for our recently completed phase I study combining 
NY-ESO-1 vaccination with decitabine in newly diagnosed MDS patients. Nine patients, all at the 
Roswell Park Cancer Institute, were enrolled and treated on our study. A majority of the treated 
patients developed NY-ESO-1 specific T-cells in response to vaccination, but these were less 
robust than the responses observed in patients with solid tumors who got the same vaccine. We 
and others have shown that PD-L1 is expressed on myeloid cells from patients with MDS and 
AML (7, 9) and further, that that expression of the immune checkpoint protein PD-1 is induced in 
lymphocytes from AML/MDS patients receiving decitabine. Based on these results, we propose a 
Phase 1 study that adds the PD-1 inhibitor nivolumab to our backbone combination of standard-
dose decitabine and NY-ESO-1 vaccination in HMA naïve, non-transplant eligible, MDS patients 
and low blast count AML patients. We will test the hypothesis that the addition of nivolumab will 
improve the qualitative and quantitative antigen specific CD4+ and CD8+ T-cell response to NY-
ESO-1 vaccination in MDS/AML patients.
3
INCLUSION AND EXCLUSION CRITERIA
3.1
Inclusion Criteria
Subjects who present with a suspected or confirmed diagnosis of MDS/AML, and who are 
interested in potential participation on a clinical trial, will be screened for enrollment. Only patients 
who are willing to sign a written informed consent form will be screened. Patients must undergo 
bone marrow aspirate and biopsy with sample acquisition for protocol screening.
To be included in this study, participants must meet the following criteria:
1. Have a confirmed diagnosis of:
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Patients with MDS or Low Blast Count AML
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a.
IPSS intermediate-1, intermediate-2 or high-risk MDS including Chronic 
Myelomonocytic Leukemia (CMML) OR
b. Low blast count AML with ≤ 30% blasts previously classified as Refractory 
Anemia with excess blasts in transformation.
2. Age ≥ 18 years of age.
3. Have an ECOG Performance Status of ≤ 2. Refer to Appendix C.
4. Have adequate organ function defined by the following laboratory values:

Hepatic: 
o
Total bilirubin ≤ 3 X upper limit of normal (ULN) (except subjects with 
Gilbert Syndrome, who can have total bilirubin up to 3.5 X ULN)
o
Aspartate Transaminase (AST/SGOT) and Alanine Transaminase 
(ALT/SGPD) ≤ 3 X ULN

Renal:
o
Serum creatinine ≤ 2.5 X ULN

Cardiac:
o
Troponin-I, CK-MB≤ ULN
o
LVEF ≥ LLN (institutional limit)
5. Participants of child-bearing potential must agree to use adequate contraceptive methods 
(e.g., hormonal or barrier method of birth control; abstinence) prior to study entry. Should 
a woman become pregnant or suspect she is pregnant while she or her partner is 
participating in this study, she should inform her treating physician immediately.
6. Participant or legal representative must understand the investigational nature of this study 
and sign an Independent Ethics Committee/Institutional Review Board approved written 
informed consent form prior to receiving any study related procedure.
7. No prior exposure to nivolumab. 
8. No prior investigational therapy within 2 weeks prior to study enrollment.
Refer to Appendix A for the ELIGIBILITY VERIFICATION FORM: INCLUSION 
CRITERIA checklist.
3.2
Exclusion Criteria
Because this study is designed to examine survival as a secondary endpoint we will exclude 
patients who are eligible for an allogeneic bone marrow transplant at the time of study enrollment. 
If an enrolled patient subsequently becomes eligible for transplant, they will not be prevented from 
proceeding to the appropriate clinical treatment indicated.
Participants will be excluded from this study for the following:
1. Subjects with life-threatening illnesses other than MDS, uncontrolled medical conditions 
or organ system dysfunction which, in the investigator’s opinion, could compromise the 
subject’s safety, or put the study outcomes at risk.
2. AML associated with inv(16); t(16;16); t(8;21) or t(15;17).
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Patients with MDS or Low Blast Count AML
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3. Previously untreated MDS with isolated del5q (for which lenalidomide is approved an 
approved therapy) and chronic myelomonocytic leukemia (CMML) with rearrangements 
of the PDGF receptor (for which imatinib is approved therapy), unless they have previously 
failed these approaches.
4. Subjects with symptomatic central nervous system (CNS) disease which is not adequately 
controlled.
5. Subjects who have received prior radiation therapy for extramedullary disease within 2 
weeks of first dose.
6. Has known immunosuppressive disease (e.g. HIV, AIDS or other immune depressing 
disease). Testing is not required, only to be done for a possible diagnosis which is not 
confirmed.
7. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, 
symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or 
psychiatric illness/social situations that would limit compliance with study requirements. 
In addition, subjects will be excluded for any of the following:

Myocardial infarction or arterial or venous thromboembolic events within 6 months 
prior to baseline or severe or unstable angina, New York Heart Association 
(NYHA) Class III or IV disease

Active congestive heart failure (New York Heart Association functional 
classification III or IV).

Documented history of cardiomyopathy with EF< 30%.

Uncontrolled hypertension (SBP>160/DBP>100 despite medical intervention).

History of myocarditis of any etiology
8. Subjects who have hypersensitivity to decitabine, CDX-1401, poly-ICLC or nivolumab.
9. History of auto-immune disease (e.g., thyroiditis, lupus), except vitiligo.
10. Pregnant or nursing female subjects.
11. Unwilling or unable to follow protocol requirements.
12. Any condition which in the Investigator’s opinion deems the participant an unsuitable 
candidate to receive study drug.
13. Regular use of immunosuppressant drugs such as steroids (>20mg prednisone equivalents), 
azathioprine, tacrolimus, cyclosporine, etc. Use is not permitted within 4 weeks before 
recruitment.
Refer to Appendix B for the ELIGIBILITY VERIFICATION FORM: EXCLUSION 
CRITERIA checklist.
3.3
Special Populations
Only adult patients who are able to provide informed consent will be eligible. Adult patients 
without capacity, infants and children will be excluded. No pregnant women or prisoners will be 
eligible for enrollment on this study.
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PROTOCOL TITLE: I 49217 - Phase 1 CDX-1401/ Poly-ICLC +Decitabine +Nivolumab in 
Patients with MDS or Low Blast Count AML
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3.4
Inclusion of Women and Minorities
Both men and women and members of all races and ethnic groups are eligible for this study.
4
LOCAL AND STUDY-WIDE NUMBER OF SUBJECTS
A maximum of 18 evaluable participants (minimum of 3) at multiple sites, including RPCI will be 
enrolled and treated on this study.
5
LOCAL AND STUDY-WIDE RECRUITMENT METHODS

Potentially eligible patients will be recruited from the population of newly diagnosed MDS 
patients referred to the protocol investigators. Patients will have a suspected or known 
diagnosis of MDS or low blast count AML with MDS related changes and be appropriate 
for therapy with a hypomethylating agent (HMA).

Patients will be referred to any of the leukemia doctors where the study is open and, will 
be offered the opportunity to enroll on protocol should they wish to do so. Information 
regarding this study will be conveyed to local hematologists who see patients with newly 
diagnosed MDS in a letter approved by the IRB.

A letter will be distributed to local hematologists/oncologist who sees potentially eligible 
patients. These physicians can then refer patients to us for consideration of trial 
participation. The study will be registered on clinicaltrials.gov and RPCI will hold the IND 
for this study. Patients may review the study on this website or on the RPCI and MDACC 
external websites.

All study related advertising documents used at any site will first be reviewed by the RPCI 
IRB and by the local IRB at any participating institution prior to their use.
6
MULTI-SITE RESEARCH
Refer to Appendix K: Instructions for Network Sites.

The proposed project will be opened initially at Roswell Park Cancer Institute and at one 
potential additional site. In order to ensure that all patients are treated appropriately and in 
a consistent fashion we will ensure the following:
o
All sites will have the most current version of the protocol, consent document, and 
HIPAA authorization.
o
All required approvals (initial, continuing review and modifications) have been 
obtained at each site (including approval by the site’s IRB of record).
o
All modifications have been communicated to sites, and approved (including 
approval by the site’s IRB of record) before the modification is implemented.
o
All engaged participating sites will safeguard data, including secure transmission 
of data, as required by local information security policies.
o
All local site investigators will conduct the study in accordance with applicable 
federal regulations and local laws.
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Patients with MDS or Low Blast Count AML
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o
All non-compliance with the study protocol or applicable requirements will be 
reported in accordance with local policy.

This study will have up to two total sites including RPCI. If the study opens at a second 
site, the investigators will have a biweekly (i.e., once every 2 weeks) conference call to 
discuss the results of all patients enrolled and treated on study, otherwise the investigator 
will review the records of all patients enrolled at least every 2 weeks. At this review the 
principal investigators will review the following:
o
Problems (inclusive of reportable events).
o
Interim results.
o
The closure of the study according to the described stopping rules below

As a phase 1 study, all AEs will be reviewed weekly by the Early Phase Clinical Trials 
committee at RPCI.
7
STUDY TIMELINES

During the 3+3 component, accrual will be suspended until the three patients in each cohort 
have completed the DLT window (6 weeks after the last patient has begun therapy).

Patients will be enrolled and treated on study for as long as they are deriving clinical 
benefit. Treatment on study has no specified end time.
o
Median progression free survival for patients with MDS receiving hypomethylating 
agents on clinical trials is between 18 and 24 months.
o
This study is therefore likely to enroll all 18 patients within 2 years and all patients 
are likely to have completed the study within 7 years of study opening.

An interim analysis of correlative studies will be performed after every 3 patients have 
been enrolled and treated on the study for at least 5 months or come off treatment, 
whichever comes first.

Given the long half-life for nivolumab and the known risk of late presenting adverse events, 
patients enrolled and treated on study will be followed for AEs for 180 days after the last 
dose of nivolumab.

Patients will stay on study for 5 years after the last patient has been enrolled or until disease 
progression, whichever occurs first.
8
STUDY ENDPOINTS
8.1
Primary Endpoint

To determine the safety of NY-ESO-1 vaccination (Anti-DEC-205-NY-ESO-1 fusion 
protein (CDX-1401)/poly ICLC) given in combination with decitabine and nivolumab.
o
This is a modified 3+3 design with a 12 patient expansion cohort at the maximum 
tolerated dose (MTD) or the maximum administered dose (MAD). We expect 18 
patients to be enrolled (all at Dose Level +1(DL1)), given experience with these 
treatments in other studies. In DL1, decitabine will be given at 20 mg/m2/day, 
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Patients with MDS or Low Blast Count AML
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intravenously, over 1 hour on days 1-5 followed by 23 days without decitabine. If 
required, dose de-escalation of decitabine to 15 mg/m2 is provided for during the 
safety portion of the study.
o
The DLT window will begin on day -14 of cycle 1 and end on day 1 of cycle 2. The 
first cohort will enroll 3 patients and the DLT window for these 3 patients will end 
when the last patient in this group has reached cycle 2 day 1 of therapy. A second 
group of 3 patients will then be enrolled and treated. 
All AEs and DLTs will be collected and used for descriptive characteristics for the purposes of the 
study. 
8.2
Secondary Endpoint(s)

To evaluate the induction of NY-ESO-1 specific cellular and humoral immunity by 
determination of NY-ESO-1 specific antibody, and NY-ESO-1 specific T-cell responses 
following standard treatment with decitabine in conjunction with immune sensitization 
with CDX-1401/poly-ICLC and nivolumab.
o
To evaluate the Immune cell profile in the peripheral blood and bone marrow 
following combination therapy using mass cytometry
o
To determine the impact of combination treatment on peripheral blood and bone 
marrow cells from patients treated in this manner on NY-ESO-1 target gene 
expression, NY-ESO-1 protein expression, NY-ESO-1 promoter methylation, and 
global DNA methylation.
8.3
Exploratory Endpoints

To record the response rate (Complete Response (CR), Partial Response (PR) and 
Hematological Improvement (HI)) in MDS or low blast count AML patients treated with 
the combination in order to provide descriptive characteristics.
o
This will be assessed using results of blood counts on day 1 of each cycle.
o
A formal assessment of response will be performed Day 1 of Cycle 5 and every 4th 
cycle thereafter as long as patients remain on decitabine and at end of study 
including results of blood counts and a bone marrow biopsy.  After 2 years on study, 
bone marrow assessments may be done every 6 cycles rather than every 4 cycles. 
Retrospective response assessment will include measurement of molecular 
measurable residual disease at serial time points.
9
DESIGN
This is an open-label, non-randomized Phase 1 study of CDX-1401 1 mg (intracutaneous) + poly-
ICLC 1.8 mg (poly-ICLC will be given subcutaneously on each day of CDX-1401) vaccination, 
given in conjunction with decitabine x 5 days and nivolumab 3 mg/kg every 2 weeks. In dose level 
1, Decitabine is dosed at 20 mg/m2/day for 5 days/28 day cycle (Day 1-Day 5 of each cycle).
9.1
Study Design
The primary objective of this Phase I study is to determine safety of the combinatorial regimen. 
The secondary objective is to assess immune and molecular epigenetic response. An exploratory 
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objective will be to record the response rate (including Complete Response (CR), Partial Response 
(PR) and Hematological Improvement (HI)) in the enrolled patients who will have a diagnosis of 
MDS or low blast count AML patients in order to provide descriptive characteristics.
This is a modified 3+3 design with a 12 patient expansion cohort at the maximum tolerated dose 
(MTD) or the maximum administered dose (MAD). We expect 18 patients to be enrolled (all at 
Dose Level +1), given experience with these treatments in other studies. 
Three patients will be accrued at dose level 1. If 0 or 1 of the first 3 patients has a dose limiting 
toxicity (DLT, defined in section 10), then 3 more patients will be enrolled at the same dose. If a 
maximum of 1 of these six patients has a DLT, dose level 1 will be declared the maximum 
administered dose (MAD) and an additional 12 patients will be enrolled in an expansion cohort. 
Dose level +1 is considered the most likely MAD, given the low observed toxicity rates with NY-
ESO-1 vaccine therapy. If the true DLT rate is 20%, there is an 85% probability of ending the trial 
with these 18 patients. Observed toxicity rates associated with NY-ESO-1 treatment have been 
below 20%. The accrual decision rules are shown in Table 4.
If either of the DLT thresholds at dose level 1 is exceeded, the same rules will be followed for 
dose level -1. If more than one third of patients at dose level -1 have a DLT, the study will be 
terminated.
Table 4
Dose De-Escalation Plan
Dose 
Level
Number of Subjects with a 
Dose-Limiting Toxicity at a 
Given Dose Level
Escalation Decision Rule
DL 1
2,3 out of 3
De-escalate to Dose -1. Enroll 3 patients
0,1 out of 3
Maintain Dose Level 1. Enroll three more patients
0,1 out of 6
Declare Dose Level 1 the maximum administered dose (MAD). 
Enroll expansion cohort of 12 additional patients.
≥2 out of 6
De-escalate to Dose -1. Enroll 3 patients
DL –1
2,3 out of 3
Stop the study
0,1 out of 3
Maintain Dose Level -1. Enroll three more patients
0,1 out of 6
Declare Dose Level -1 the maximum tolerated dose (MTD). Enroll 
expansion cohort of 12 additional patients.
≥2 out of 6
Stop the study.
Patients may elect to discontinue nivolumab and/or vaccine after Cycle 8 and remain on study 
receiving single agent decitabine to allow collection of the secondary and exploratory endpoints 
as described above.
9.2
Replacing Patients 
Patients enrolled in the 3+3 part who withdraw before receiving any protocol therapy will be 
replaced. 
In the expansion cohort, patients who come off study before the end of cycle 4 for any reason not 
related to toxicity (and prior to the first formal response assessment following cycle 4) will be 
replaced.
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Patients who do not complete the study through Day 29 for reasons other than DLTs will be 
replaced.
10 TREATMENT
Treatments will be administered predominantly on an outpatient basis. Reported adverse events 
(AEs) and potential risks are described in Section 13. Appropriate dose modifications are 
described in Section 10.3.2. No other investigational or commercial drugs or therapies other that 
those described below may be administered with the intent to treat the subject for their myeloid 
neoplasms. Patients may receive all their usual medications.
10.1 Dosing and Administration
The vaccine is comprised of CDX-1401 (1 mg) given intracutaneously with 1.8 mg of Poly-ICLC. 
The first dose of the vaccine is given on Day -14 and then, on Day 15 of each decitabine cycle for 
the first 4 cycles (total of 5 vaccines). Thereafter, patients will receive a booster vaccine on Day 1 
of every 4th cycle, indefinitely. 
Nivolumab is to be given at a fixed dose of 3 mg/kg every 2 weeks starting on Day 1 of Cycle 1 
through cycle 4 day 15.  After cycle 5 nivolumab will be given as a flat dose of 480mg every 4 
weeks on day 1 of each decitabine cycle  (+/-7 day window).  Nivolumab administration may 
continue on protocol until disease progression or the patient elects to discontinue nivolumab. 
Decitabine/nivolumab cycles will be given on schedule every 4 weeks unless a delay is deemed 
clinically necessary by the treating physician/investigator. If the patient requires a delay of more 
than 6 weeks, they will come off study. The study schema is depicted in Figure 3.
Figure 3: Study Schema
For the purposes of this study, 1 cycle = 28 days and is comprised of 5 doses of IV decitabine 
(days 1-5), 2 doses of nivolumab during cycles 1-4 and 1 dose of nivolumab cycles 5 and above 
(day 1and day 15 during cycles 1-4 or day 1 cycles 5 and above) and 1 vaccination (day 15). 
Protocol therapy may be given at the discretion of the treating physician within a +/-7 day window 
to accommodate patient’s preference, clinical judgement and schedule or outside this window after 
discussion with the PI.
Note: When nivolumab and decitabine are administered on the same day, decitabine is 
administered first, followed by nivolumab.
10.1.1 Vaccine (Anti DEC-205-NY-ESO-1 Fusion Protein (CDX-1401)/ Poly ICLC)
CDX-1401 and poly-ICLC will be administered on Day -14 prior to the first course of decitabine 
and then Day 15 of every cycle for the first 4 cycles. After Cycle 4, CDX-1401 and poly-ICLC will 
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be administered on Day 1 of every 4th cycle as a booster (i.e. on day 1 of cycles 8, 12, 16, 20, 24) 
(see study calendar below: Section 10.1.3).
The CDX-1401 will be given as an intracutaneous injection (a mixture of subcutaneous and 
intradermal administration, at a dose of 1 mg); poly-ICLC will be given subcutaneously at a flat 
dose of 1.8 mg on each day of CDX-1401 vaccination.
Administration: Within a vaccine treatment session (consisting of one intracutaneous 
administration of CDX-1401 with poly-ICLC) dosing should be given within the same 
administration site (a 5 x 5 cm area on the extremities or the abdomen). The administration site 
should be free of potentially complicating dermatologic conditions, and should not be located in 
an area where integrity of the draining lymph node bed is potentially compromised (i.e., an 
extremity where a nodal resection was previously performed). For each subsequent administration 
session, a new administration site should be selected, with the aim of stimulating a new draining 
lymph node bed for each of the five administrations (Note: After the first 5 vaccinations, the 
vaccine may be administered in location of patient’s preference). All nurses administering this 
vaccine will be trained to administer the doses intracutaneously prior to study implementation.
Intracutaneous injections are a combination of intradermal and subcutaneous injection. The 
maximum volume which can be administered intradermally is 0.1 ml and the maximum volume 
administered subcutaneously is considered to be 1-2 ml. Intracutaneous injections are a 
combination of the standard subcutaneous (many drugs) and intradermal (like a TB test) routes 
which are in routine use throughout the hospital. Drug will be administered using a 25G or smaller 
needle of ¼ to ⅝ inches in length.

CDX-1401 will be administered via intracutaneous injection (with approximately half of 
the planned dose administered by each route). Each CDX-1401 dose will be administered 
in a maximum volume of 1 ml, and may be split into up to 4 intracutaneous injections given 
within the 5 x 5 cm administration site. An appropriate needle for intracutaneous 
administration (25-gauge or smaller) is recommended. We have suggested that the CDX-
1401 be administered in 2 injections so that no more than 0.75 ml will be given in any one 
spot and to avoid excess administration of drug intradermal.

Poly-ICLC dosing will consist of one subcutaneous injection of 1.8 mg, within the 5 x 5 
cm administration site. Poly-ICLC will be administered as soon as possible after the CDX-
1401 injections, with the goal to administer all drugs within a one hour period. 
Note: Poly-ICLC drug product used to be labeled as 2 mg/mL but as per IB V.14 dated 
January 25, 2018, the labeled claim is being changed to incorporate a correction for the 
water content in the lyophilized components (Poly I and Poly C) and will now be listed as 
1.8 mg/ml Poly-ICLC. This represents no change in the product or formulation, but simply 
a calculation correction. In effect, the prior 2.0 mg/mL label represented the “wet” Poly-
IC concentration which is equivalent to the current 1.8 mg/mL label representing the “dry” 
Poly-IC concentration.
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10.1.2 Nivolumab
Nivolumab will be given every two weeks (±7 days) (four weeks (two doses of nivolumab) is 
equivalent to one cycle of nivolumab) at a dose of 3 mg/kg/dose for the first 4 cycles of decitabine, 
for cycles 5 and above, nivolumab, if continued,  will be given at a flat dose of 480mg every 4 
weeks on day 1 of each decitabine cycle. The dosing calculations should be based on the actual 
body weight. If the patient’s weight on the day of dosing differs by >10% from the weight used to 
calculate the original dose, the dose must be recalculated. All doses should be rounded to the 
nearest milligram if dose rounding is allowed as per institutional guidelines. There will be no dose 
modifications allowed.
Administration: Nivolumab is to be administered as a 30-minute (+/- 10 minutes) IV infusion, 
using a volumetric pump with a 0.2-1.2 micron in-line filter at the protocol-specified dose. It is not 
to be administered as an IV push or bolus injection. Nivolumab injection can be infused undiluted 
(10 mg/mL) or diluted with 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP 
to protein concentrations as low as 0.35 mg/mL. At the end of the infusion, flush the line with a 
sufficient quantity of normal saline.
Reported adverse events (AEs) and potential risks are described in Section 13. Appropriate dose 
modifications are described in Section 10.4.
10.1.3 Decitabine
Decitabine will be given starting at dose level 1, which is the standard dose and schedule currently 
in use: 20 mg/m2/day for 5 consecutive days following standard of care guidelines (50).
Decitabine will be given at 20 mg/m2/day, intravenously, over 1 hour on days 1-5 followed by 23 
days without decitabine at the discretion of the treating physician per their standard practice. 
Delays in dosing are allowed per standard institutional practice.  Decitabine should be given Days 
1-5 unless a delay is deemed necessary by the treating physician for patient safety. If required, 
dose de-escalation of decitabine to 15 mg/m2 is provided for during the safety portion of the study. 
Table 5
Dose Levels
Dose Level
CDX-1401/Poly-ICLC
Decitabine
Nivolumab
  1
1mg/1.8mg
20mg/m2 days 1-5 
3mg/kg days 1,15
-1
1mg/1.8mg
15mg/m2 days 1-5 
3mg/kg days 1,15
There will be no dose modifications to the decitabine dose during the first 8 cycles of treatment. 
After cycle 8, dose reductions may be made at the discretion of the treating physician per their 
standard practice, but cycles should be given every 4 weeks unless a delay is deemed necessary by 
the treating physician for patient safety. 
Delays in dosing up to 6 weeks are acceptable if deemed necessary for patient safety. Grade 4 
neutropenia, transfusion dependence for platelets and red blood cells and the possibility of 
hospitalization for infections are expected toxicities of the underlying disease process and of 
standard treatment with decitabine.
Please see below for a detailed study calendar:
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Treatment Plan: Cycle 1
Cycle 1
Day
-14
….
1
2
3
4
5
6
7
8
…
15
…
28
CDX-1410
X
X
Poly ICLC
X
X
Decitabine
(DAC)
X
X
X
X
X
Nivolumab
(NIVO)
X
X
Treatment Plan: Cycles 2-4
Cycles 2-4
Day
1
2
3
4
5
6
7
8
9
10
…
15
…
28
CDX-1410
X
Poly ICLC
X
Decitabine
(DAC)
X
X
X
X
X
Nivolumab
(NIVO)
X
X
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Treatment Plan: Non-Vaccine Cycles:
Cycles 5-7, 9-11, 13-15, 17-19, 21-23, 25…
Day
1
2
3
4
5
6
7
8
9
10
…
15
…
28
CDX-1410
Poly ICLC
Decitabine
(DAC)
X
X
X
X
X
Nivolumab
(NIVO)
X
Treatment Plan: Vaccine Booster Cycles:
Cycles 8, 12, 16, 20, 24…
Day
1
2
3
4
5
6
7
8
9
10
…
15
…
28
CDX-1410
X
Poly ICLC
X
Decitabine
(DAC)
X
X
X
X
X
Nivolumab
(NIVO)
X
Treatment is intended for an outpatient setting. However, at the investigator’s/physician’s 
discretion, the participant may receive treatment as an inpatient, if deemed necessary.
10.2 Treatment Protocol for the Expansion Cohort 
Decitabine is dosed at the MAD determined in the safety portion of the study for 5 days/28 day 
cycle (Day 1-Day 5 of each cycle per standard of care).

After cycle 8, dose reductions of decitabine are permitted at the discretion of the treating 
investigator per the standard of care.
The vaccine is comprised of CDX-1401 (1 mg) given intracutaneously with 1.8 mg of Poly-ICLC. 
The first dose of the vaccine is given on Day -14 and then, on Day 15 of each decitabine cycle for 
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the first 4 cycles (total of 5 vaccines). Thereafter, patients will receive a booster vaccine on Day 1 
of every 4th cycle, indefinitely.
Nivolumab is to be given at a fixed dose of 3 mg/kg every 2 weeks starting on Day 1 of Cycle 1.  
For cycles 5 and above, nivolumab is given at a fixed dose of 480mg every 4 weeks on day 1 of 
every cycle and may continue on protocol until disease progression or the patient elects to 
discontinue nivolumab.
Decitabine/nivolumab cycles will be given on schedule every 4 weeks unless a delay is deemed 
clinically necessary by the treating physician/investigator. If the patient requires a delay of more 
than 6 weeks, they will come off study.
10.3 Definition of Dose-Limiting Toxicity
Dose limiting toxicities (DLTs) are defined as any non-hematologic grade 4/5 toxicities that are 
definitely, probably, or possibly related to the administration of the investigational agent(s) (see 
Appendix H for organ specific auto-immune grading of toxicity).
All AEs will be graded according to the NCI-CTCAE scale Version 4.0. 
Hematological toxicities are expected in patients with MDS undergoing therapy with decitabine 
and will not be considered dose limiting. Hematological toxicities will not be deemed dose 
limiting, in agreement with other studies in patients with MDS and AML.
The initial DLT period will be defined as 28 days after the first dose of decitabine. Given that 
toxicities related to checkpoint inhibitors may not be immediately manifested, after the first 3 
patients have been enrolled, accrual to the expansion cohort will be delayed to monitor for late 
developing toxicities until all patients in the first 3 patient cohort have been followed until cycle 4 
day 29 of decitabine. 
Patients will be monitored throughout the study and according to the schedule of procedures and 
observations. Any auto-immune related events which occur between days 29 and the end of study 
may be sufficient to interrupt the nivolumab therapy if they are grade 4 or 5 as described below. 
Patients may be withdrawn from study even if DLT is due to decitabine alone. 
Safety monitoring will include careful assessment and appropriate reporting of adverse events, as 
well as the construction and implementation of a data and safety-monitoring plan (Auditing, 
Monitoring and Inspecting). Medical monitoring will include a regular assessment of the number 
and type of serious adverse events. As this is a phase I study, all AEs will be reviewed by the Early 
Phase Clinical Trials committee at RPCI on a weekly basis.
Management and dose modifications associated with the above AEs are outlined in Section 10.3 
and Appendix H.
10.4 Dose Modifications and Treatment Delays
10.4.1 Vaccine
There will be no dose modifications to the doses of CDX-1401 or poly ICLC.
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10.4.2 Decitabine
If a dose limiting toxicity is observed with combination therapy, decitabine may be dose reduced 
to 15mg/m2 per the safety lead in. Following the establishment of our MAD, there will be no dose 
reductions of decitabine in the first 8 cycles of therapy. After Cycle 8, in patients with <5% bone 
marrow blasts, dose reductions of decitabine are at the discretion of the investigator per the 
following table. Dose reductions will be recorded for informational purposes only.
Table 6
Acceptable Dose Reductions of Decitabine after Cycle 8
SOC Dose Reduction Schedule
Decitabine
1
20 mg/m2/day for 5 days
25% dose reduction
15 mg/m2/day for 5 days
50% dose reduction
10 mg/m2/day for 5 days
10.4.3 Nivolumab
In the event that a patient experiences a Grade 4 treatment related toxicity due to nivolumab, 
myocarditis of any grade or intolerable Grade 2 or 3 toxicity, felt to be associated with Nivolumab 
alone, despite optimal supportive care, treatment with Nivolumab should be permanently 
discontinued. Refer to Table 7 for recommended nivolumab dose modifications. If toxicities have 
resolved to <grade 1, nivolumab may be reintroduced following a period of holding.
Table 7
Nivolumab Dose Modifications and Dosing Delays
Adverse Reaction
Severity
Dose Modification
Myocarditis
Any grade
Permanently discontinue
Grade 2 diarrhea or colitis
Withhold dose a
Grade 3 diarrhea or colitis:

Single-agent Nivolumab
Permanently discontinue
Colitis
Grade 4 diarrhea or colitis
Permanently discontinue
Grade 2 pneumonitis
Withhold dose a 
Pneumonitis
Grade 3 pneumonitis
Permanently discontinue
Aspartate aminotransferase (AST)/or 
alanine aminotransferase (ALT) more 
than 3 and up to 5 times the upper limit 
of normal or total bilirubin more than 
1.5 and up to 3 times the upper limit of 
normal
Withhold dose a
Hepatitis
AST or ALT more than 5 times the 
upper limit of normal or total bilirubin 
more than 3 times the upper limit of 
normal
Permanently discontinue
Grade 2 or Grade 3 hypophysitis
Withhold dose a 
Hypophysitis
Grade 4 hypophysitis
Permanently discontinue 
Adrenal Insufficiency
Grade 2 adrenal insufficiency
Withhold dose a 
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Adverse Reaction
Severity
Dose Modification
Grade 3 or 4 adrenal insufficiency
Permanently discontinue
Grade 3 hyperglycemia
Withhold dose a 
Type 1 Diabetes Mellitus
Grade 4 hyperglycemia
Permanently discontinue
Serum creatinine more than 1.5 and up 
to 2 times the upper limit of normal
Withhold dose a 
Nephritis and Renal 
Dysfunction
Serum creatinine more than 2 times the 
upper limit of normal
Permanently discontinue 
Grade 3 rash
Withhold dose a 
Rash
Grade 4 rash
Permanently discontinue
New-onset moderate or severe 
neurologic signs or symptoms
Withhold dose a 
Encephalitis
Immune-mediated encephalitis
Permanently discontinue
Other Grade 3 adverse reactions:

First occurrence
Withhold dose a

Recurrence of same Grade 3 
adverse reactions
Permanently discontinue

Life threatening or Grade 4 
adverse reaction
Permanently discontinue

Requirement for 10 mg per 
day or greater prednisone or 
equivalent for more than 12 
weeks
Permanently discontinue
Other

Persistent Grade 2 or 3 adverse 
reactions lasting 12 weeks or 
longer 
Permanently discontinue
a: withhold dose and resume nivolumab with the next cycle if resolution of toxicity to ≤ Grade 1. 
10.4.3.1
Guidelines on Myocarditis attributed to Nivolumab
For all cardiac safety marker elevations (troponin, CK-MB, BNP), whether in isolation or in 
combination, nivolumab will be held until investigations can exclude nivolumab. Consult 
cardiology immediately. If there is high clinical suspicion for nivolumab-induced myocarditis, 
high-dose steroids (1 gram IV methylprednisolone or equivalent) must be started during 
hospitalization regardless of availability of cardiac MRI or echocardiogram findings.
If patient is asymptomatic/at baseline but there is new isolated BNP elevation, obtain 
echocardiogram immediately. Daily clinic assessment including cardiac biomarkers should be 
performed if patient’s symptoms are unchanged from baseline, echocardiogram normal or 
baseline, additional safety markers and vital signs remain normal. If patient has new symptoms 
e.g. weakness, fatigue, dyspnea, edema, etc. regardless of severity accompanied by isolated BNP 
elevation, cardiac MRI must be obtained as soon as possible regardless of echocardiogram 
findings. Hospital admission for cardiac monitoring must be considered along with institution of 
supportive medications.
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If patient is asymptomatic/at baseline with normal renal function but troponin rises to greater than 
0.10, investigate for the presence of acute pulmonary embolism and acute coronary syndrome in 
addition to guidelines above.
Hold treatment if patient is asymptomatic but new persistent ECG changes noted on triplicate 
readings along with normal troponin, CK-MB, BNP and echocardiogram. Consult 
cardiology. Repeat ECG and labs no earlier than 12 hours later. If ECG changes are transient, may 
continue treatment.
For documented echocardiographic changes regardless of cardiac safety marker levels, cardiac 
MRI must be obtained. Hold study treatment. If treatment-induced myocarditis is suspected, high-
dose steroids must be instituted as detailed above.
10.5 General Concomitant Medication and Supportive Care
Subjects will receive standard pre-treatment with anti-emetics prior to decitabine administration. 
Subjects may be treated for breakthrough nausea and vomiting with appropriate anti-emetics.
The use of all standard supportive medication is permitted, although concurrent treatment with 
immunosuppressive or immunomodulatory agents is strongly discouraged. Concomitant systemic 
corticosteroids are to be avoided if at all possible. If used, doses of steroids should be the minimum 
necessary for appropriate clinical management. If clinically necessary, topical or systemic non-
steroidal anti-inflammatory or antihistamines may be used as alternatives.
Subjects should not be receiving concomitant long-term corticosteroids at a dose greater than 
15 mg of prednisone equivalents. The use of corticosteroids for management of nausea, 
osteoarthritis gout, or other symptoms at doses less than 15 mg of prednisone equivalents is 
permitted.
The Investigator may, at his/her discretion, arrange for a patient to have an unscheduled visit, 
especially in the case of AEs that require follow-up. If a patient is experiencing an AE considered 
by the Investigator to be possibly related to the study drug, an unscheduled visit should be 
performed; the unscheduled visit pages for the eCRF must be completed.
10.6 Duration of Treatment
Participants may remain on study and continue to receive treatment in the absence of disease 
progression, unacceptable toxicity or withdrawal from study, intercurrent illness that prevents 
further administration of treatment, participant demonstrates an inability/refusal to comply with 
study therapy or participant withdraws from study. Patients who remain on study (receiving 
combination therapy, decitabine/nivolumab, or single agent nivolumab) will continue to have 
response assessment every 4 cycles for the first 2 years and every 6 cycles thereafter.  Patients can 
withdraw from study at any time. Patients who proceed to allogeneic bone marrow transplant or 
who require a change of therapy for disease progression will come off study. 
10.7 Compliance
All study related medications will be provided either subcutaneously, intracutaneously 
(combination of subcutaneously and intradermally) or intravenously. Patients will come for lab 
checks for routine monitoring and to obtain study blood work. Blood work may be done on a 
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± 2 day window from the day indicated on the study calendar in order to minimize subject 
noncompliance and with the recognition that there are sometimes commitments which cannot be 
re-scheduled. Patients must be seen on day 1 of each course of therapy and undergo a complete 
physical examination and review of toxicity.
11 PROCEDURES INVOLVED
The study-specific assessments are detailed in this section and outlined in Appendix J (Schedule 
of Procedures and Observations). Baseline and/or Screening assessments must be performed 
within 14 days prior to the first dose of investigational product. Any results falling outside of the 
reference ranges may be repeated at the discretion of the investigator. All on-study visit procedures 
are allowed a window of ± 2 days unless otherwise noted.
11.1 Participant Randomization and Registration
Eligibility of each participant will be established prior to enrollment.
Informed consent MUST be completed prior to receiving any study related procedures.
11.2 Baseline Evaluations
Confirmation of Eligibility: The following will be performed within 4 weeks prior to first dose of 
CDX-1401/poly ICLC (unless otherwise indicated):

Medical history with pre-existing conditions

Physical examination

Vital signs (i.e., temperature, heart rate, respiratory rate, O2 saturation, blood pressure), 
body weight and, height. Height collected at baseline only

Hematology: CBC with manual differential

Chemistry: CMP. In addition: LDH, uric acid, amylase and, lipase

Pregnancy test urine, in females of childbearing potential (within 1 week prior to first dose 
of study drug)

ECOG Performance Status

HLA Typing: May use historical sample if available (patients who do not require HLA 
typing for determination of transplant eligibility will have HLA typing sent for study 
purposes)

IPSS/ IPSSR (Refer to Appendix E and Appendix F for calculation instructions)

Testing for HIV I/II Ab, HBsAg, HCV Ab+/- PCR (should be done only in patients for 
whom there is a concern for prior infection with one of these viral pathogens. Testing is 
NOT required if there is no history of infection)

Bone Marrow Aspirate and Biopsy (with Flow Cytometry, Conventional Cytogenetics +/- 
FISH as appropriate).In addition:
o
Study Bone marrow samples for T-cell and methylation and gene expression studies 
(Section 11.11.2)
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
Correlative blood sampling

Endocrine Function Evaluation: TSH, blood glucose testing

Concomitant Medications (List any ongoing medications with an onset within 1 week of 
first dose of study drug.). 
The following will be performed within 4 weeks prior to first dose of study drug:

Cardiac safety markers: troponin-I, BNP, CK-MB

Electrocardiogram (ECG)

Echocardiogram

Urinalysis
11.3 Evaluations Performed on Day -14

Physical examination including vital signs

Hematology: CBC with manual differential

Chemistry: CMP. In addition: LDH, uric acid, amylase and, lipase

ECOG Performance Status

Correlative blood sampling (see Section 11.11.1)

CDX-1401/ poly-ICLC administration

Concomitant medications

Adverse events
11.4 Evaluations Performed on Day 1 of each Cycle
The following evaluations will be performed prior to CDX-1401/poly ICLC dosing or infusion of 
decitabine on Day 1 of each cycle or prior to premedication, if administered (may be performed 
up to 3 days prior to day of infusion), unless otherwise indicated:

Physical examination 

Vital signs (i.e., temperature, heart rate, respiratory rate, oxygen saturation, blood pressure, 
body weight) 

Hematology: CBC with manual differential (Once per week of each cycle during cycles 1-
4, from cycles 5 onward on day 1 and as clinically indicated) 

Hematological Improvement (HI)) in MDS or low blast count AML patients treated with 
the combination in order to provide descriptive characteristics.
o
This will be assessed using results of blood counts on day 1 of each cycle.

Chemistry: CMP, LDH, uric acid, amylase and, lipase (Once per week each cycle during 
cycles 1-4, from cycles 5 onward on day 1 and as clinically indicated)

ECOG performance status
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
Correlative blood sampling prior to study drug dosing Once per week each cycle during 
Cycles 1-4; from Cycle 5 onward once every 2 weeks (see Section 11.11.1)

Decitabine administration: Day 1-Day 5 of each cycle (per standard of care for patient 
safety) 

Nivolumab administration: Day 1 and Day 15 of each cycle (+/-7 days)

Concomitant Medications 

Adverse events
11.5 Evaluations Performed on Day 15 of each Cycle

Vital signs

Hematology: CBC with manual differential (see Section 11.4)

Chemistry: CMP, LDH, uric acid, amylase and, lipase (see Section 11.4)

CDX-1401/poly-ICLC administration (Day 15 of every cycle for the first 4 cycles: 
thereafter, to be given on Day 1 of every 4th cycle as a booster (i.e. on Day 1 of cycles 8, 
12, 16, 20, 24).

Nivolumab administration ( Day 15 for first 4 cycles: thereafter, to be given on Day 1 of 
every 4th cycle)

Adverse events
11.6 Evaluations Performed Specifically at End of Cycle 1

Endocrine Function Evaluation: TSH and blood glucose

Bone Marrow Aspirate and Biopsy (Note: At the end of Cycle 1, if a bone marrow aspirate 
is not able to be done, a bone marrow biopsy may be performed instead). In Addition:
o
Study Bone marrow samples for T-cell and methylation and gene expression studies 
(Section 11.11.2)

The following cardiac safety tests will be performed at the end of Cycle 1 and as clinically 
indicated:
o
Cardiac Safety Markers: Troponin-I, CK-MB, BNP
o
ECG

Adverse events

Urinalysis
11.7 Evaluations Performed on Cycle 5 Day 1 and every 4th Cycle thereafter
The following evaluations will be performed on or after day 28 of every 4th cycle of decitabine, 
and prior to initiation of any further therapy. In general samples and bone marrow should be done 
on day 29 (i.e., day 1 of a cycle) at cycles 5, 9, 13, 17, etc… of decitabine, per standard of care:
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
Physical examination, including vital signs (i.e., temperature, heart rate, respiratory rate, 
blood pressure) and body weight

Hematology: CBC with manual differential 

Chemistry: CMP, LDH, uric acid, amylase, lipase

Urinalysis

Correlative blood sampling prior to study drug dosing: once every 2 weeks (see Section 
11.11.1) 

IPSS/ IPSSR (Refer to Appendix E and Appendix F for calculation instructions)

Concomitant medication

Adverse events

Bone Marrow Aspirate and Biopsy (with flow cytometry, conventional cytogenetics and 
FISH studies as deemed appropriate by the treating physician). In addition:
o
Study Bone marrow samples for T-cell and methylation and gene expression studies 
(Section 11.11.2)

Response assessment per modified International Working Group criteria for MDS (refer to 
Appendix D, Appendix E and Appendix F) and TTT
11.8 Evaluations Performed at End of Treatment
The following evaluations will be performed ± 4 days from day 29 of the last cycle of decitabine, 
and prior to initiation of any further therapy:

Physical examination and vital signs

Hematology: CBC with manual differential 

Chemistry: CMP

ECOG Performance Status

IPSS/ IPSSR (Refer to Appendix E and Appendix F for calculation instructions)

Bone marrow aspirate and biopsy (with flow cytometry, conventional cytogenetics and 
FISH studies as deemed appropriate by the treating physician). In addition:
o
Bone marrow samples for T-cell and methylation and gene expression studies 
(Section 11.11.2)

Blood sample for immune correlates (Section 11.11.1)

Concomitant medications

Adverse events

Response assessment per modified International Working Group criteria for MDS (refer to 
Appendix D, Appendix E and Appendix F) and TTT
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11.9 Post-Treatment Follow-Up Evaluations
Follow-up safety evaluations will occur 30 days (± 3 days), 60 days (± 3 days), 90 days (± 3 days), 
and 180 days (± 3 days) after last dose of study drug or until resolution of any drug-related toxicity 
(telephone contact is acceptable). Patients will be asked to report any possible auto-immune 
reactions (including rashes, skin changes, new symptoms of arthritis or other auto-immune 
phenomena) in order to capture possible late manifestations of auto-immunity. 

Concomitant medications

Adverse events

Survival Status: Disease progression/change in treatment
Patients remaining on study for ≥ 2 years will have a bone marrow biopsy performed every 
6 months (± 2 months) per standard of care follow up.
11.10 Schedule of Procedures and Observations
The schedule of procedures and observations for this study is summarized in Appendix J.
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11.11 Correlative Studies
11.11.1
Blood Sample Collection
Blood samples will be collected via venipuncture (green tops) for analysis of molecular markers, 
NY- ESO-1 cellular immune response (T-cell), (ELISPOT and ICS) and assessment of T-
Regulatory cell frequency (CD4+CD25+FOXP3+ regulatory T cells) and, cell differentiation by 
transcription factor distribution (T-bet, GATA-3, RORγ) and, gold-top tubes will be used for 
analysis of antibody response (NY-ESO-l-ELISA).

Blood will be collected at the following time points:
o
Baseline:

 4, 10 mL green-top (sodium heparin) tubes (Dr. Griffith’s lab)

2, 10 mL green-top (sodium heparin) tubes (Immune Analysis Facility)

1, 3.5 mL gold-top tube (Immune Analysis Facility)
o
Day -14 (prior to Cycle 1 Day 1):

4, 10 mL green-top (sodium heparin) tubes (Dr. Griffith’s lab)

2, 10 mL green-top (sodium heparin) tubes (Immune Analysis Facility)

1, 3.5 mL gold-top tube (Immune Analysis Facility)
o
Cycles 1-4 (once weekly):

4, 10 mL green-top (sodium heparin) tubes (Dr. Griffith’s lab)

2, 10 mL green-top (sodium heparin) tubes (Immune Analysis Facility)
o
Cycle 5 and onward until end of treatment (Day 1 and Day 15) and, end of 
treatment:

4, 10 mL green-top (sodium heparin) tubes (Dr. Griffith’s lab)

2, 10 mL green-top (sodium heparin) tubes (Immune Analysis Facility)

1, 3.5 mL gold-top tube (Immune Analysis Facility)
Note: If it is determined that there is an inadequate cell number for cryopreservation and 
immunomonitoring at any visit, sample acquisition may be repeated at the next scheduled blood 
draw.
11.11.2
Bone Marrow Sample Collection
Study Bone marrow samples for T-cell and methylation and gene expression studies: 4, 10 mL 
green-tops tubes (sodium heparin) to be obtained each time a bone marrow assessment is to be 
done.

Bone marrow samples will be collected at the following time points:
o
Baseline
o
End of Cycle 1 (Note: At the end of Cycle 1, if a bone marrow aspirate is not able 
to be done, a bone marrow biopsy may be performed instead)
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o
Day 1 Cycle 5 and, Day 1 of every 4th cycle thereafter (+/- 14 day window 
acceptable)
o
End of treatment
o
If bone marrow is unable to be collected at noted time point and clinically 
appropriate, a bone marrow samples should be performed next cycle to document 
disease status.
o
If a bone marrow is unable to be collected due to dry tap, collect 4 additional, 10 
mL green-tops tubes (sodium heparin) of peripheral blood
Blood and Bone Marrow Processing
Samples (blood and/or bone marrow) will be processed at each site (Appendix G). The cryovials 
are to be labeled with the clinical study number and patient study ID, collection date/study cycle 
and day and “Blood” or “Bone marrow.” 
The cryovials will immediately be frozen in liquid nitrogen and stored until requested for batch 
mailing. Samples are to be batch shipped frozen, on dry ice to:
Roswell Park Cancer Institute
Dr. Griffiths Laboratory
Attn: Pragya Srivastava, I 49217 Samples
CGP L5-201
Elm and Carlton Streets
Buffalo, NY 14263
Telephone #: (716) 845-1724 (lab) or,
(716) 430-1152 (cell)
Pragya.Srivastava@RoswellPark.org
For Network Sites: Follow directions above for sample collection and processing. The cryogenic 
tubes are to be labeled with the clinical study number and patient study ID, collection date/study 
cycle and day and, “Blood” or “Bone marrow”. The processed samples will immediately be frozen 
in liquid nitrogen and stored until requested for batch mailing. Samples are to be batch shipped 
frozen, on dry ice.
Frozen samples will be shipped via Fed Express Overnight on dry ice with delivery on Mon-Fri. 
NO SATURDAY DELIVERY. Do not ship on a Friday or the day before a holiday.
Note: All investigator or analyzing research laboratories housing research samples need to 
maintain current Temperature Logs and study-specific Sample Tracking and Shipping Logs. The 
Principal Investigator/Laboratory Manager must ensure that the stated lab(s) have a process in 
place to document the receipt/processing/storage/shipping of study-related samples/specimens. 
This is required for both observational and interventional clinical studies collecting clinical 
samples
Cellular and/or humoral immune response assays (see below) will be performed by the RPCI 
Immune Analysis Facility under the direction of Dr. Junko Matsuzaki:
Roswell Park Cancer Institute
Immune Analysis Facility Shared Resource
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Cancer Cell Center, 4th Floor, Room 416
Elm and Carlton Streets
Buffalo, NY 14263
Telephone #: (716) 845-8459
Junko.Matsuzaki@RoswellPark.org
11.11.3
Molecular (Epigenetic) Markers of Response
Assays of samples to determine if circulating cells demonstrate the expected changes in global and 
gene specific (NY-ESO-1) methylation, gene expression (NY-ESO-1) and protein expression 
(NY-ESO-1) responses will be performed in the Griffiths Laboratory at the RPCI, Buffalo, NY. 
Assessment of molecular response, by error corrected sequencing, to protocol therapy will be sent 
out to Dr. Hourigan’s Laboratory at the National Institutes of Health.
These assays are in routine use in my laboratory (see Figure 1) and we anticipate no difficulties 
performing them. Myeloid cells will be enriched from whole blood using CD11b MicroBeads and 
the MACS® Column separation method (Miltenyi Biotec, Bergisch-Gladbach, Germany). DNA, 
RNA and protein will be extracted using QIAamp DNA/RNA/Protein Mini and QIAamp DNA 
Blood Maxi kits (Qiagen, Valencia, CA). Given that some patients with MDS have very low 
numbers of circulating cells, isolation of the myeloid compartment may limit sample quality, and 
thus if separation proves unsuccessful, we will isolate DNA, RNA and protein from whole blood 
instead as this method has also been validated in MDS patients receiving HMA therapy (51). We 
have successfully collected informative samples from other MDS patients in this manner without 
difficulty. Any samples that are not informative will be censored. At each time point NY-ESO-1 
promoter methylation (by bisulfite pyrosequencing) and NY-ESO-1 mRNA (by RT-PCR) will be 
determined. Assessment of LINE-1 methylation (also by bisulfite pyrosequencing) will be done as 
a marker for changes in global methylation over the course of each cycle (4, 52). One sample per 
week will be assayed for NY-ESO-1 protein expression by Western Blot (maximum 16 per 
patient). These analyses will allow us to demonstrate changes in NY-ESO-1 over the course of the 
treatment cycle and correlate them with the immunological parameters described below
11.11.4
Immunological Markers of Response
Assays to determine whether vaccination with CDX-1401/poly ICLC in series with decitabine and 
nivolumab can induce NY-ESO-1 specific cellular and/or humoral immune responses will be 
performed by the Immune Analysis Facility. MDS is characterized by bone marrow 
hypercellularity in association with peripheral blood cytopenias, increased rates of infection and 
autoimmune phenomena (53-55). Despite overt cytopenias and the possibility that in MDS the 
immune system does not function normally, we and other authors have successfully induced 
antigen specific T-cells following neo-antigen vaccination in patients with MDS and endogenous 
humoral immunity has also been shown [(56, 57) and Srivastava P et al. Blood 2016;128: 4326]. 
Therefore, we anticipate that induction of NY-ESO-1-specific immune responses is feasible. We 
are eager to test if the addition of nivolumab to our prior backbone will result in substantial 
enhancement of such responses. Furthermore, since induction of interferon-gamma (IFNγ) 
producing CD4+ and CD8+ T-cells are associated with improved clinical outcome in ovarian 
cancer patients expressing NY-ESO-1, documentation of a sustained immunological response in 
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MDS is of significant potential clinical interest (58, 59). Two major potential mechanisms that 
could account for a failure to induce NY-ESO-1 specific T- and B-cell responses include APC 
dysfunction and the activity of Tregs.
11.11.5
Humoral Immunity
We will test patients treated on the study for the production of NY-ESO-1 specific antibodies. 
Since documentation of a humoral immune response is associated with the activity of cancer 
vaccines in solid tumors such a response would be of interest (60). Induction of NY-ESO-1 specific 
antibody will be tested serially at baseline, at the end of cycle 4 and every 4th-8th cycle of decitabine 
therapy. An ELISA assay will be used to measure anti-NY-ESO-1 antibody titers (61). Comparison 
of antibody titers over the course of therapy will allow us to determine the humoral 
immunogenicity of this combination.
Specific antibody against NY-ESO-1 will be measured by ELISA [(62) for methodology]. Assays 
will be performed by the Roswell Park Cancer Center Immune Analysis Facility.
11.11.6
Cellular Immunity
The ability of the vaccine alone and in combination with decitabine and nivolumab to induce NY-
ESO-1 specific, IFNγ secreting CD4+ and CD8+ T-cells will be measured. Samples will be 
obtained at baseline, and serially as described above. NY-ESO1 specific T-cell responses will be 
assessed using an in vitro T cell pre-sensitization, a method for the amplification of broadly HLA 
reactive NY-ESO-1-specific CD8+ and CD4+ T cells (51). Positive control stimulation with CEFT 
peptide (cytomegalovirus, Epstein-Barr virus, flu viruses (collectively) and tetanus toxoid (T) 
epitopes) is set up in parallel. Ten to 14 days after pre-sensitization, the frequency and the response 
of NY-ESO-1 specific cells will be analyzed by intracellular cytokine staining and ELISPOT 
assays for IFNγ as previously described (63). Comparison of the frequency of NY-ESO-1-specific 
T cells at baseline with samples derived serially will allow us to determine the immunogenicity of 
our combination. In addition to the peripheral blood studies described here, pre-treatment and off 
study bone marrow samples will be assessed for the presence of NY-ESO-1 specific T-cells as 
above and analyzed by flow cytometry for frequency of CD4+, CD8+, FOXP3+ and CD19+ cells.
11.11.7
Dendritic Cell Function
In the event that we do not observe antigen specific immune responses, this could reflect APC 
dysfunction related either to the underlying malignancy, or to treatment with decitabine. The 
function of APCs in MDS has not been tested, thus we will determine whether cultured APCs from 
our enrolled MDS patients are able to effectively process and present antigen in order to activate 
T-cells. Exposure to decitabine has been previously shown to enhance the development and 
maturation of APCs in solid tumor models (64), as well as to enhance immune recognition in other 
hematological malignancies (65). We will examine APC function at baseline and following 2 and 
4 cycles of decitabine treatment (3 time points). For these assays, blood samples will be obtained 
and cultured under conditions known to induce APC differentiation (66, 67). The ability of these 
cells to activate NY-ESO-1 specific T-cells derived from either autologous peripheral blood 
mononuclear cells or from ovarian cancer patients with NY-ESO-1 expressing tumors, (depending 
upon the HLA type of the patient) will be determined by the ELISPOT technique for IFNγ, as 
above. We will also assess the ability of these cells to induce an allo-reactive T-cell response from 
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healthy donor T-cells. These assays will test the function of APCs in MDS patients and determine 
if exposure to decitabine has an effect upon this function.
The induction of antitumor T-cell responses associated with IFNγ production are believed to be 
critical to the effects of cancer vaccination in solid tumors, however such responses are limited by 
the action of immunosuppressive Tregs which allow escape by malignant cells (59, 60, 68). 
Recently Tregs have been demonstrated to be complex, differentiating and migrating in response 
to signals from the immune system (60). Specific subsets of Tregs have been demonstrated to have 
differential suppressive effects upon anti-tumor immune responsiveness (60, 69). One study in 
MDS and AML patients treated with azacitidine following BMT suggests that HMAs alter Treg 
function by promoting graft versus leukemia effects over graft versus host effects, while another 
has demonstrated enhanced immuno-suppressive effects (49, 68). In order to determine if MDS 
patients undergoing therapy with CDX-1401/poly ICLC decitabine and nivolumab demonstrate 
changes in Treg differentiation favoring anti-tumor immune responsiveness over immune 
suppression, we will analyze Tregs sampled serially for changes in the expression of markers 
(including CD127, CD45RA, CXCR3 and Helios) associated with Treg biological function using 
flow cytometry (56, 59, 70, 71). Significant changes in Treg subsets with therapy would suggest 
that decitabine can alter the immune milieu in patients with MDS.
The methods to analyze the T cell response to cancer antigens used in this study are well 
established. However, as T cell biology and immune regulation are very active fields of discovery, 
the opportunity exists to refine and extend the analysis of the T cell response. Therefore, although 
most of the blood drawn for the analysis of the immune response will be used for the assays listed 
in this section, a small part may be used to explore other aspects of the T cell response using novel 
techniques such as time of flight cytometry. This work may also involve establishing T cell lines 
and clones in culture, and collaborations with investigators outside of Roswell Park Cancer 
Institute. As these exploratory approaches, by definition, have not yet been validated, the results 
will not be endpoints in the evaluation of the current study.
11.11.8
Additional Exploration of the T cell Response
Specimens will be stored for future use/analysis: The subjects enrolled at RPCI will have signed a 
separate consent for the taking, storage, and future research upon these samples under protocol 
CIC 98-05.
12 WITHDRAWAL OF SUBJECTS
Participants may remain on study and continue to receive treatment in the absence of disease 
progression, unacceptable toxicity or withdrawal from study, intercurrent illness that prevents 
further administration of treatment, participant demonstrates an inability/refusal to comply with 
treatment or, participant withdraws from study.
12.1 Treatment Discontinuation
Upon treatment discontinuation all end of treatment evaluations and tests will be conducted. All 
participants who discontinue due to an AE must be followed until the event resolves or stabilizes. 
Appropriate medical care should be provided until signs and symptoms have abated, stabilized, or 
until abnormal laboratory findings have returned to acceptable or pre-study limits. The final status 
of the AE will be reported in the participant’s medical records and the appropriate eCRF. Patients 
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with dose limiting toxicities requiring drug discontinuation will be removed from the study and 
will not be replaced.
Reasons for treatment discontinuation should be classified as follows:

Death

Progressive disease

Toxicity; treatment related or unrelated

Investigator judgment
o
The Investigator may discontinue a participant if, in his/her judgment, it is in the 
best interest of the participant to do so.

Noncompliance

Participant voluntary withdrawal
o
A participant may withdraw from the study at any time, for any reason. If a 
participant discontinues treatment, an attempt should be made to obtain information 
regarding the reason for withdrawal.

Sponsor Investigator’s decision.
13 RISKS TO SUBJECTS
13.1 Vaccine (Anti DEC-205-NY-ESO-1 Fusion Protein (CDX-1401)/ Poly ICLC)
Expected toxicities with CDX-1401/poly ICLC include injection site reactions, including rash, 
erythema, pruritus, pain, induration and swelling. Additional reported treatment-related toxicities 
with this agent have been mild to moderate in severity, and include fatigue (24%), decreased 
appetite (14%), nausea (10%), arthralgia (10%), headache (10%) and pruritus (10%).
13.2 Nivolumab
In ongoing studies that combine nivolumab and HMAs in patients with myeloid malignancy (45, 
46), the following adverse events have been reported: 

In 39 patients with MDS either previously untreated or relapsed after HMA failure (45):
o
45%: constipation and maculopapular rash 
o
36%: nasal congestion
o
27%: arthralgia, cough, stomach pain 
o
18%: diarrhea, edema, fatigue, hyperkalemia, insomnia
o
9%: anorexia, dyspnea, GERD, hyperglycemia, hyponatremia, hypotension, 
mucositis, nausea, pneumonitis, weight loss
The most commonly reported > Grade 3 adverse events in the combination arm (n=11) were 
pulmonary infections (seen in 18% of patients), followed by intracranial hemorrhage, 
hyperglycemia, fever and elevated LFTs (in 9% each).

In 51 patients with relapsed or refractory AML treated to date and analyzed after a total of 
3 courses of therapy (46), notable toxicities reported included:
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o
Grade 3/4 and Grade 2 immune mediated toxicities in 7 (14%) and 6 (12%) pts.
o
Pulmonary toxicity was prominent in this population with 8 episodes of 
pneumonitis
o
Other toxicities included 2 reports of nephritis, 2 reports of transaminitis, and 1 skin 
rash. 
o
There was one death on study deemed related to grade 4 pneumonitis/epiglottitis
o
Four patients were post-SCT and one had a grade 3 flare of GVHD of the skin and 
gut
Toxicities were reported to respond rapidly to steroids. Patients were successfully re-treated with 
nivolumab after resolution of toxicity. Time to onset of toxicities ranged from 4 days to 3.5 months.
Refer to Appendix I for reported adverse drug reactions for nivolumab monotherapy. 
Note: All adverse drug reactions for nivolumab monotherapy are also adverse drug reactions for 
nivolumab in combination with ipilimumab and other agents. A description of adverse drug 
reactions nature and frequency observed with nivolumab in combination with ipilimumab can be 
found in the nivolumab Investigator Brochure (v16, Table 5.6.1-2)
13.2.1 Management of Immune-Related Adverse Events
Nivolumab is approved in multiple solid tumor indications as well as for Hodgkin lymphoma based 
on its favorable benefit/risk assessment. In hematological malignancies including multiple 
myeloma, nivolumab monotherapy was generally well tolerated and toxicity profile was similar to 
that observed in solid tumors. Nivolumab has the potential for clinically relevant immune-related 
AEs potentially caused by an inflammatory mechanism. These include pulmonary toxicity, 
hepatotoxicity, diarrhea/colitis, endocrinopathies, and nephrotoxicity. 
To date, these immune-related AEs have been manageable with frequent monitoring, prompt 
diagnosis, and initiation of corticosteroids, dose interruption, and adequate supportive care. 
Refer to Appendix H for algorithm guidelines for the management of immune-related adverse 
events.
13.3 Decitabine
Autoimmune reaction (antiplatelet antibodies, erythema nodosum), decreased hemoglobin, 
decreased leukocytes (total WBC), decreased neutrophils/granulocytes (ANC/AGC), decreased 
platelets, febrile neutropenia with or without infection, fatigue (lethargy, malaise, asthenia), 
alopecia, diarrhea, peritonitis, nausea, vomiting, anorexia, stomatitis /pharyngitis (oral/ 
pharyngeal, mucositis), increase bilirubin, increased SGOT (AST) (serum glutamic oxaloacetic 
transaminase), increased SGPT (ALT) (serum glutamic pyruvic transaminase), depressed level of 
consciousness, abdominal pain or cramping.
The following have been reported on decitabine trials with the relationship to decitabine still 
undetermined: Allergy, GVHD, atrial fibrillation, thrombosis, phlebitis, cardiac ischemia, cardiac 
arrest (one case), face edema, hypotension, cardiac failure/arrest (MI), congestive heart failure, 
veno-occlusive disease, ascites, cardiac decompensation, fever, chills, drug fever, weight loss, skin 
rash, itching, taste disturbance, constipation, cholecystitis, perianal abscess, ileus, hematuria, liver 
failure, increased alkaline phosphatase, reactivation of herpes simplex, hyponatremia, neuropathy, 
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depression, dizziness, headache, lightheadedness, restlessness, sleep disorder, seizures, 
hemiparesis, somnolence, myalgia, bone pain, dyspnea, hiccups, pulmonary edema, ARDS, cough, 
increased creatinine, dysuria, renal failure, bone marrow aplasia, infectious complication 
(including sepsis, infection cellulites, pneumonia), GI bleed, cerebral hemorrhage, cerebral 
ischemia, lung hemorrhage, differentiation syndrome, infection with normal absolute neutrophil 
count.
14 POTENTIAL BENEFITS TO SUBJECTS
Based on the results of pre-clinical and clinical studies, the addition of nivolumab to standard NY-
ESO-1 vaccine/decitabine may improve T cell immune response to NY-ESO-1vaccination in 
MDS/AML patients.
15 DATA AND SPECIMEN BANKING
As this is a Phase 1 study, the secondary endpoints are entirely correlative and designed to 
determine if CDX-1401/poly ICLC in combination with nivolumab and decitabine can induce anti-
NY-ESO1 specific immune responses. If these responses are observed in the absence of toxicity, 
the data will be used to justify a larger study to determine the efficacy of the combination in 
patients with MDS.
Patients will be sampled serially in this trial in order to determine the degree to which MDS 
patients treated with decitabine develop NY-ESO-1 promoter hypomethylation and induce NY-
ESO-1 mRNA and/or protein expression in circulating myeloid cells. The induction of global and 
gene specific hypomethylation has been repeatedly documented in patients with MDS and AML 
treated with hypomethylating drugs (4, 17, 72). We and others have shown that decitabine 
treatment induces NY-ESO-1 as well as a variety of other CTAs in circulating blasts (Figure 1),(17, 
18) and furthermore that such induction of gene expression can be immunogenic (49, 73). In our 
previous study combining NY-ESO-1 vaccination with decitabine in MDS patients we 
demonstrated induction of NY-ESO-1 mRNA in circulating CD11b myeloid cells (See Figure 1). 
We further showed that the cell free DNA compartment recapitulates the methylation signature in 
circulating cells. In this study samples will be analyzed to confirm induced expression of NY-
ESO-1 mRNA in circulating CD11b selected cells. Cell free DNA will be used to assess changes 
in methylation status at the LINE-1 and NY-ESO-1 promoters. These data will be correlated with 
observations of NY-ESO-1 specific immune responses.
For subjects enrolled at the Roswell Park Cancer Institute, if a subject does not have enough 
sampled peripheral blood taken at any time point to conduct these studies, we will add to that by 
using samples that subject has on hand in the Roswell Park Hematologic Procurement Facility.
Subjects enrolled at RPCI have signed a separate consent for the taking, storage, and future 
research upon these samples under protocol CIC 98-05.
16 MEASUREMENT OF EFFECT
Objective responses will be recorded and graded at the end of every 4th cycle of treatment using 
the modified International Working Group Criteria for MDS and AML patients as detailed in 
Appendix D, Appendix E and Appendix F. Molecular assessment of measurable residual disease 
(using accrued blood and/or bone marrow samples) will be assessed serially in a retrospective 
fashion in collaboration with Dr. Christopher Hourigan at the National Institutes of Health. 
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Samples will be sent de-identified to Dr. Hourigan’s laboratory and results will be reviewed and 
analyzed by the study team and correlated with immunological response to therapy. 
17 SAFETY EVALUATION
17.1 Adverse Events
An adverse event or adverse experience (AE) is any untoward medical occurrence associated with 
the use of a drug in humans, whether or not considered drug related. Therefore, an AE can be ANY 
unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease 
temporally associated with the use of a medicinal (investigational) product, whether or not 
considered related to the medicinal (investigational) product (attribution of ‘unrelated’, ‘unlikely’, 
‘possible’, ‘probable’, or ‘definite’).
An AE is considered “unexpected” if it is not listed in the investigator brochure or is not listed at 
the specificity or severity that has been observed; or if an investigator brochure is not required or 
available, is not consistent with the risk information described in the general investigational plan 
in other study-related documents.
17.1.1 Diagnosis Versus Signs and Symptoms
If known, a diagnosis should be recorded on the CRF rather than individual signs and symptoms 
(e.g., record only liver failure or hepatitis rather than jaundice, asterixis, and elevated 
transaminases). However, if a constellation of signs and/or symptoms cannot be clinically 
characterized as a single diagnosis or syndrome at the time of reporting, each individual event 
should be recorded as an AE or SAE on the CRF. If a diagnosis is subsequently established, it 
should be reported as follow-up information.
17.1.2 Adverse Events Occurring Secondary to Other Events
In general, AEs occurring secondary to other events (e.g., cascade events or clinical sequelae) 
should be identified by their primary cause. For example, if severe diarrhea is known to have 
resulted in dehydration, it is sufficient to record only diarrhea as an AE or SAE on the CRF. 
However, clinically significant AEs occurring secondary to an initiating event that are separated 
in time should be recorded as independent events on the CRF. For example, if a severe 
gastrointestinal hemorrhage leads to renal failure, both events should be recorded separately on 
the CRF.
17.1.3 Abnormal Laboratory Values
Only clinically significant laboratory abnormalities that require active management will be 
recorded as AEs or SAEs on the CRF (e.g., abnormalities that require study drug dose 
modification, discontinuation of study treatment, more frequent follow-up assessments, further 
diagnostic investigation, etc.).
If the clinically significant laboratory abnormality is a sign of a disease or syndrome (e.g., alkaline 
phosphatase and bilirubin 5 x the upper limit of normal associated with cholecystitis), only the 
diagnosis (e.g., cholecystitis) needs to be recorded on the Adverse Event CRF.
If the clinically 
significant laboratory abnormality is not a sign of a disease or syndrome, the abnormality itself 
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Patients with MDS or Low Blast Count AML
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should be recorded as an AE or SAE on the CRF. If the laboratory abnormality can be characterized 
by a precise clinical term, the clinical term should be recorded as the AE or SAE. For example, an 
elevated serum potassium level of 7 mEq/L should be recorded as “hyperkalemia”.
Observations of the same clinically significant laboratory abnormality from visit to visit should 
not be repeatedly recorded as AEs or SAEs on the CRF, unless their severity, seriousness, or 
etiology changes.
17.1.4 Preexisting Medical Conditions (Baseline Conditions)
A preexisting medical condition should be recorded as an AE or SAE only if the frequency, 
severity, or character of the condition worsens during the study. When recording such events on 
an Adverse Event CRF, it is important to convey the concept that the preexisting condition has 
changed by including applicable descriptors (e.g., “more frequent headaches”).
17.2  Grading and Relationship to Drug
The descriptions and grading scales found in the CTEP Version 4 of the NCI Common 
Terminology Criteria for Adverse Events (CTCAE) will be utilized for AE reporting. CTEP
Version 4 of the CTCAE is identified and located at:
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.
AEs not covered by specific terminology listed should be reported with common medical 
terminology, and documented according to the grading scales provided in the CTCAE Version 4.
The relationship of event to study drug will be documented by the Investigator as follows:

Unrelated: The event is clearly related to other factors such as the participant’s clinical 
state, other therapeutic interventions or concomitant drugs administered to the participant.

Unlikely: The event is doubtfully related to investigational agent(s). The event was most 
likely related to other factors such as the participant’s clinical state, other therapeutic 
interventions, or concomitant drugs.

Possible: The event follows a reasonable temporal sequence from the time of drug 
administration, but could have been produced by other factors such as the participant’s 
clinical state, other therapeutic interventions or concomitant drugs.

Probable: The event follows a reasonable temporal sequence from the time of drug 
administration, and follows a known response pattern to the study drug. The event cannot 
be reasonably explained by other factors such as the participant’s clinical state, therapeutic 
interventions or concomitant drugs.

Definite: The event follows a reasonable temporal sequence from the time of drug 
administration, follows a known response pattern to the study drug, cannot be reasonably 
explained by other factors such as the participant’s condition, therapeutic interventions or 
concomitant drugs; AND occurs immediately following study drug administration, 
improves upon stopping the drug, or reappears on re-exposure.
17.3 Reporting Adverse Events
Routine AEs occurring between the start date of intervention until 180 days after the last 
intervention, or until the event has resolved, the study participant is lost to follow-up, the start of 
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a new treatment, or until the study investigator assesses the event(s) as stable or irreversible, will 
be reported. New information will be reported after it is received.
Guidelines for Routine Adverse Event Reporting for Phase 1 Studies (Regardless of 
Expectedness)
Attribution
Grade 1
Grade 2
Grade 3
Grade 4
Unrelated
X
X
X
X
Unlikely
X
X
X
X
Possible
X
X
X
X
Probable
X
X
X
X
Definite
X
X
X
X
17.4 Serious Adverse Events
A serious adverse event (SAE) is any adverse event (experience) that in the opinion of either the 
investigator or supporter results in ANY of the following:

Death.

A life-threatening adverse event (experience). Any AE that places a participant or 
participants, in the view of the Investigator or supporter, at immediate risk of death from 
the reaction as it occurred. It does NOT include an AE that, had it occurred in a more severe 
form, might have caused death.

Inpatient hospitalization or prolongation of existing hospitalization (for > 24 hours).

A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions.

A congenital anomaly or birth defect.

Important Medical Event (IME) that, based upon medical judgment, may jeopardize the 
participant and may require medical or surgical intervention to prevent one of the outcomes 
listed above.
17.4.1 Reporting Serious Adverse Events
All new SAEs related to study procedures occurring from the date the participant signs the study 
consent until the start date of intervention or date of screen fail will be reported. All new SAEs 
occurring from the start date of intervention until 180 days after the last intervention or a new 
treatment is started, whichever comes first, will be reported. The RPCI SAE Source Form is to be 
completed with all available information, including a brief narrative describing the SAE and any 
other relevant information. 
SAEs occurring after the 180 day follow-up period that the investigator determines to be possibly, 
probably or definitely related to the study intervention should be reported.
SAEs identified as an Unanticipated Problem by the Investigator must be reported. Please refer to 
Section 17.7 for details on reporting Unanticipated Problems.
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17.5 Investigator Reporting: Notifying the Study Supporter
All Serious Adverse Events (SAEs) that occur following the subject’s written consent to participate 
in the study through 30 days of discontinuation of dosing must be reported to BMS Worldwide 
Safety, whether related or not related to study drug. If applicable, SAEs must be collected that 
relate to any later protocol-specified procedure (e.g., a follow-up skin biopsy).
Follow-up safety evaluations will occur 30 days (± 3 days), 60 days (± 3 days), 90 days (± 3 days), 
and 180 days (± 3 days) after last dose of study drug (last immunization with CDX-1401/poly 
ICLC/nivolumab) .or until resolution of any drug-related toxicity. Assessment may be collected 
via telephone if the patient elects to come off study and is no longer coming to clinic.

Following the subject’s written consent to participate in the study, all SAEs, whether 
related or not related to study drug, are collected, including those thought to be associated 
with protocol-specified procedures. The investigator should report any SAE occurring after 
these aforementioned time periods, which is believed to be related to study drug or 
protocol-specified procedure.

An SAE report should be completed for any event where doubt exists regarding its 
seriousness.

If the investigator believes that an SAE is not related to study drug, but is potentially related 
to the conditions of the study (such as withdrawal of previous therapy or a complication of 
a study procedure), the relationship should be specified in the narrative section of the SAE 
Report Form.
Investigators MUST report within 1 business day upon becoming aware, to the supporter ANY 
Serious Adverse Events, whether or not they are considered related to the investigational 
agent(s)/intervention.
The investigator must inform Bristol Myers Squibb (BMS) and Celldex in writing using a BMS 
SAE form or MEDWATCH 3500A form of any SAE within 24 hours of being aware of the event. 
The written report must be completed and supplied to Celldex by facsimile within 24 hours/1 
business day. 

The BMS protocol ID number must be included on whatever form is submitted by the 
Sponsor/Investigator.
The initial report must be as complete as possible, including an assessment of the causal 
relationship between the event and the investigational product(s), if available. Information not 
available at the time of the initial report (e.g., an end date for the adverse event or laboratory values 
received after the report) must be documented on a follow-up report.
Celldex and BMS consider an SAE to be any adverse event that is life-threatening or that results 
in any of the following outcomes: death; inpatient hospitalization or prolongation of existing 
hospitalization; persistent or significant disability or incapacity; or a congenital anomaly or birth 
defect. 
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Completed SAE reports are to be submitted to:
Bristol-Myers Squibb
SAE Email Address: Worldwide.Safety@BMS.com
SAE Facsimile Number: +1 609-818-3804
AND
Celldex Therapeutics, Inc.
Clinical Research/Operations
Hotline: 908-323-2233
Fax No: 781-644-6434
Email: SAE@celldex.com
17.5.1 Suspected/ Unexpected Serious Adverse Reaction
In accordance with local regulations, BMS will notify investigators of all reported SAEs that are 
suspected (related to the investigational product) and unexpected (i.e., not previously described in 
the IB). An event meeting these criteria is termed a Suspected, Unexpected Serious Adverse 
Reaction (SUSAR). Investigator notification of these events will be in the form of a SUSAR 
Report. 

Other important findings which may be reported by BMS as an Expedited Safety Report 
(ESR) include: increased frequency of a clinically significant expected SAE, an SAE 
considered associated with study procedures that could modify the conduct of the study, 
lack of efficacy that poses significant hazard to study subjects, clinically significant safety 
finding from a nonclinical (e.g., animal) study, important safety recommendations from a 
study data monitoring committee, or supporter decision to end or temporarily halt a clinical 
study for safety reasons.

Upon receiving an ESR from BMS, the investigator must review and retain the ESR with 
the IB. Where required by local regulations or when there is a central IRB/IEC for the 
study, the Sponsor/Investigator will submit the ESR to the appropriate IRB/IEC. The 
investigator and IRB/IEC will determine if the informed consent requires revision. The 
investigator should also comply with the IRB/IEC procedures for reporting any other safety 
information.

In addition to the Sponsor Investigator’s responsibility to report events to their local HA, 
suspected serious adverse reactions (whether expected or unexpected) shall be reported by 
BMS to the relevant competent health authorities in all concerned countries according to 
local regulations (either as expedited and/or in aggregate reports).
17.6 Follow-Up for Serious Adverse Events
All related SAEs should be followed to their resolution, until the study participant is lost to 
follow-up, the start of a new treatment, or until the study investigator assesses the event(s) as stable 
or irreversible. New information will be reported when it is received.
17.7 Unanticipated Problems
An Unanticipated Problem (UP) is any incident, experience, or outcome that meets all of the 
following criteria:
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
Unexpected (in terms of nature, severity, or frequency) given:
o
The research procedures that are described in the study-related documents, 
including study deviations, as well as issues related to compromise of participant 
privacy or confidentiality of data.
o
The characteristics of the participant population being studied.

Related or possibly related to participation in the research (possibly related means there is 
a reasonable possibility that the incident, experience, or outcome may have been caused by 
the procedures involved in the research).

Suggests that the research places participants or others at a greater risk of harm (including 
physical, psychological, economic, or social harm) than was previously known or 
recognized and if in relation to an AE is also deemed Serious per Section 17.3.
Reporting Unanticipated Problems:
Unanticipated problem reporting will begin at the time of participant consent. The Reportable New 
Information (RNI) Form will be submitted to the CRS Compliance Office within 1 business day 
of becoming aware of the Unanticipated Problem. After review, CRS Compliance will submit the 
RNI to the IRB.
When becoming aware of new information about an Unanticipated Problem, submit the updated 
information to CRS Compliance with an updated Reportable New Information Form. The site 
Investigator or designated research personnel will report all unanticipated problems to the IRB in 
accordance with their local institutional guidelines.
17.8 FDA Reporting
When RPCI is the IND holder the following describes the FDA reporting requirements by timeline 
for AEs and new safety findings that meet the criteria outlined below:
Within 7 Calendar Days
Any adverse event that meets ALL the following criteria:

Related or possibly related to the use of the study drug;

Unexpected; and

Fatal or life-threatening.
Within 15 Calendar Days
Any adverse event that meets ALL the following criteria:

Related or possibly related to the use of the study drug;

Unexpected; and

Serious but not fatal or life-threatening;
Or, meets ANY of the following criteria:

A previous adverse event that is not initially deemed reportable but is later found to fit the 
criteria for reporting (report within 15 days from when event was deemed reportable).
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
Any findings from other studies, including epidemiological studies, pooled analysis of 
multiple studies, or other clinical studies conducted with the study drug that suggest a 
significant risk in humans exposed to the drug.

Any findings from animal or in vitro testing that suggest a significant risk for human 
participants including reports of mutagenicity, teratogenicity, or carcinogenicity or reports 
of significant organ toxicity at or near the expected human exposure.

Any clinically important increase in the rate of occurrence of a serious, related or possibly 
related adverse event over that listed in the protocol or investigator brochure.
Supporters are also required to identify in IND safety reports, all previous reports concerning 
similar adverse events and to analyze the significance of the current event in the light of the 
previous reports.
Reporting Process
The principal investigator or designee will complete and submit a FDA Form 3500A MedWatch 
for any event that meets the above criteria. Forms will be submitted to the CRS Compliance Office 
via email to CRSCompliance@RoswellPark.org.
18 DATA MANAGEMENT AND CONFIDENTIALITY
18.1 Data Collection
Full build studies are managed by RPCI CRS Data Management for analysis by RPCI 
Biostatisticians. All electronic case report form (eCRF) data are captured for these studies.
Data management activities are performed using a CTMS system that enables the collection, 
cleaning and viewing of clinical trial data. CRS data management designs the study-specific 
database and facilitates development by the Information Technology team. Once the database 
design is approved by the Investigator, Statistician, and Clinical Research Coordinator, the 
database is put into production and data entry can begin. Data can be entered and changed only by 
those with the rights to do so into the eCRFs.
18.2 Maintenance of Study Documents
Essential documents will be retained per RPCI’s policy for 6 years from the study termination 
date. These documents could be retained for a longer period, however, if required by the applicable 
local regulatory requirements or by an agreement with RPCI.
18.3 Revisions to the Protocol
RPCI may make such changes to the protocol as it deems necessary for safety reasons or as may 
be required by the U.S. FDA or other regulatory agencies. Revisions will be submitted to the 
IRB/ERC for written approval before implementation. Any significant protocol amendments will 
also be provided to FDA.
18.4 Termination of the Study
It is agreed that, for reasonable cause, either the RPCI Investigators or the supporter, may terminate 
this study, provided a written notice is submitted within the time period provided for in the Clinical 
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Trial Agreement. In addition, RPCI may terminate the study at any time upon immediate notice if 
it believes termination is necessary for the safety of participants enrolled in the study.
18.5 Confidentiality
Any data, specimens, forms, reports, video recordings, and other records that leave the site will be 
identified only by a participant identification number (Participant ID, PID) to maintain 
confidentiality. All records will be kept in a limited access environment. All computer entry and 
networking programs will be done using PIDs only. Information will not be released without 
written authorization of the participant.
19 STATISTICAL PLAN
This is an open-label, non-randomized, dual center, fixed dose, Phase 1 study of CDX-1401 1 mg 
+ poly-ICLC 1.8 mg (Vaccine) given in conjunction with decitabine 20 mg/m2/d x 5 days and 
nivolumab 3 mg/kg every 2 weeks. Details of the study design are provided in Section 9.
The primary objective of this study is to evaluate the safety of Anti-DEC-205-NY-ESO-1 fusion 
protein + poly-ICLC given in combination with decitabine 20 mg/m2 intravenously and nivolumab 
3 mg/kg in in patients with MDS or low blast count AML.
19.1 Sample Size Determination
A maximum of 18 evaluable participants will be enrolled in this study. The number of participants 
required is a function of the unknown relationship between this treatment combination and the 
toxicity rate. Accrual is expected to take 2-4 years. We expect 18 patients will be accrued, all at 
Dose Level 1.
The primary statistical endpoint is the proportion of n=12 evaluable patients in the expansion 
cohort experiencing a DLT. A DLT rate ≥0.60 is considered unacceptable.
The DLT rate will be estimated as a binomial proportion of evaluable patients with any DLT. If 
the upper 1-sided 95% Jeffreys credible interval exceeds 0.60, the protocol therapy will be 
considered too toxic. With n=12 evaluable patients, this occurs if 5 or more patients experience a 
DLT. With n=12 evaluable patients, the upper confidence limit is less than 0.60 in 80% of similar 
experiments when the true DLT rate is 0.27.
19.2 Other Safety Analysis
The primary objective of safety will be quantified using the observed rates of the adverse events, 
serious adverse events (SAE) and Dose Limiting Toxicities. Toxicity rates will be described using 
upper 1-sided 95% Jeffreys binomial confidence intervals. 
19.3 Efficacy Analysis
All efficacy evaluations will be for correlative measures of immune response. Given the small 
sample size it will be impossible to compare responses with historical controls or speculate about 
the response over and above the historical response anticipated with single agent decitabine. 
Objective responses will be recorded and graded using the International Working Group Criteria 
for MDS and modified International Working Group Criteria for AML as detailed in Appendix D, 
Appendix E and, Appendix F.
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19.4 Secondary Analysis
The secondary objectives consider immune and molecular epigenetic response to treatment. Levels 
of CD8+ and CD4+ T cells, NYESO-1 specific antibodies, and other quantitative variables will be 
measured at baseline (before treatment) and at designated time points during treatment. These 
measures will be summarized by descriptive statistics (means, medians, quartiles, etc.). 
Confidence intervals will be constructed for the median and the mean. Exploratory graphical 
analysis will be used to discover associations among variables.
The statistical significance of the change in marker values resulting from treatment will be assessed 
using the (paired sample) Wilcoxon Signed Rank test. With a significance threshold of 0.05 and 
two observations (pre/post) for each of 18 patients, this test has 80% power to detect a shift in 
means of at least 1.1 standard deviations.
19.5 Demographics and Baseline Characteristics
Descriptive statistics (as appropriate: n, percent, mean, median, min and max) will be used to 
summarize demographic and baseline characteristics.
19.5.1 Adverse Event
The frequency of toxicities will be tabulated by grade across all dose levels and cycles. The 
frequency of toxicities will also be tabulated for the dose estimated to be the MTD/MAD. All 
participants who receive any study treatment will be considered evaluable for toxicity.
19.6 Correlative Data Analysis
Epigenetic and immunologic response outcomes will be measured at baseline (before treatment) 
and at designated time points during treatment. These measures will be summarized by descriptive 
statistics (means, medians, quartiles etc.). Confidence intervals will be constructed for the median 
and the mean. Exploratory graphical analysis will be used to discover associations among 
variables.
20 PROVISIONS TO MONITOR THE DATA TO ENSURE THE SAFETY OF 
SUBJECTS
The Early Phase Clinical Trials Committee will assess the progress of the study, the safety data, 
and critical efficacy endpoints. The EPCTC will review the study annually and will make 
recommendations that include but not limited to; (a) continuation of the study, (b) modifications 
to the design (c) or termination of the study.
21 VULNERABLE POPULATIONS
Not Applicable. Refer to Section 3.3: Special Populations.
22 COMMUNITY-BASED PARTICIPATORY RESEARCH
Not Applicable
23 SHARING OF RESULTS WITH SUBJECTS
Individual response data is shared with the participant as a part of their clinical care.
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24 SETTING
Potentially eligible patients will be recruited from the population of newly diagnosed MDS patients 
referred to the treating centers. Patients will have a suspected or known diagnosis of MDS or low 
blast count AML with MDS related changes and be appropriate for primary therapy with a 
hypomethylating agent (HMA).
Potential study participants will be identified and recruited from current Leukemia Service patients 
and from community referral.
25 PROVISIONS TO PROTECT THE PRIVACY INTERESTS OF SUBJECTS
Any data, specimens, forms, reports, video recordings, and other records that leave the site will be 
identified only by a participant identification number (Participant ID, PID) to maintain 
confidentiality. All records will be kept in a limited access environment. All computer entry and 
networking programs will be done using PIDs only. Information will not be released without 
written authorization of the participant.
26 RESOURCES AVAILABLE
Not Applicable
27 PRIOR APPROVALS
Not Applicable
28 COMPENSATION FOR RESEARCH-RELATED INJURY
Please refer to the informed consent form (Section 13) related to this study:
29 ECONOMIC BURDEN TO SUBJECTS
The participant and /or their insurance company will be responsible for charges related to the 
administration of drugs used in this clinical research study and for charges for medications that 
may be needed to prevent or control side effects.
30 CONSENT PROCESS
This study will not be initiated until the protocol and informed consent document(s) have been 
reviewed and approved by a properly constituted Institutional Review Board (IRB) or Independent 
Ethics Committee (IEC). Each participant (or legal guardian) shall read, understand, and sign an 
instrument of informed consent prior to performance of any study-specific procedure. It is the 
responsibility of the investigator to ensure that the participant is made aware of the investigational 
nature of the treatment and that informed consent is given.
The Investigator is responsible for the retention of the participant log and participant records; 
although personal information may be reviewed by authorized persons, that information will be 
treated as strictly confidential and will not be made publicly available. The investigator is also 
responsible for obtaining participant authorization to access medical records and other applicable 
study specific information according to Health Insurance Portability and Accountability Act 
regulations (where applicable).
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This study will be conducted in compliance with all applicable laws and regulations of the state 
and/or country and institution where the participant is treated. The clinical trial should be 
conducted in accordance with the ethical principles embodied in the Belmont Report: Ethical 
Principles and Guidelines for the Protection of Human Subjects of Research, consistent with good 
clinical practice and the applicable regulatory requirements and according to the guidelines in this 
protocol, including attached appendices.
31 PROCESS TO DOCUMENT CONSENT IN WRITING
The Investigator (or IRB specified designee) is responsible for obtaining written consent from each 
participant or the participant's legally authorized representative in accordance with GCP guidelines 
using the approved informed consent form, before any study specific procedures (including 
screening procedures) are performed. The informed consent form acknowledges all information 
that must be given to the participant according to applicable GCP guidelines, including the purpose 
and nature of the study, the expected efficacy and possible side effects of the treatment(s), and 
specifying that refusal to participate will not influence further options for therapy. Any additional 
information that is applicable to the study must also be included. Additional national or 
institutionally mandated requirements for informed consent must also be adhered to. The 
participant should also be made aware that by signing the consent form, processing of sensitive 
clinical trial data and transfer to other countries for further processing is allowed.
The Investigator or designee shall provide a copy of the signed consent form to the participant and 
the signed original shall be maintained in the Investigator File. A copy of the signed consent form 
must be filed in the participant file. At any stage, the participant may withdraw from the study and 
such a decision will not affect any further treatment options.
32 DRUGS OR DEVICES
32.1 Vaccine (Anti DEC-205-NY-ESO-1 Fusion Protein (CDX-1401)/ Poly ICLC)
32.1.1 Active Substance and Source
CDX-1401 
The clinical trial product will be formulated as a sterile solution intended for parenteral use. CDX-
1401 will be provided in 2 ml vials containing approximately 1 ml of solution, at a concentration 
of 1 mg/ml. 
Poly-ICLC
Poly-ICLC is an Investigational Product manufactured by Dalton for Oncovir, Inc. and supplied 
by Oncovir, Inc.
Poly-ICLC 
(polyinosinic-polycytidylic 
acid 
stabilized 
with 
poly-L-lysine 
and 
carboxymethylcellulose) is a synthetic double-stranded ribonucleic acid (dsRNA) with broad 
immune-enhancing effects mediated through TLR-3 activation.
Poly-ICLC will be provided in single-dose vials containing 1 ml of 1.8 mg/ml opalescent solution.
The poly-ICLC vials should be refrigerated at about 40ºF (2-8ºC) but should not be frozen. Poly-
ICLC is also stable at room temperature for brief periods (days).
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Page 55 of 94
Because the product is not formulated with a preservative, once the sterile vials are entered or the 
poly-ICLC is drawn into a syringe, the drug should be used as soon as possible (typically within 6 
hours if kept at room temperature or within 24 hours if refrigerated and the syringe(s) had been 
filled under aseptic conditions) or in accordance with any applicable institutional guidance. Poly-
ICLC is to be withdrawn from the vial under sterile conditions and administered subcutaneously 
as supplied.
32.1.2 Drug Shipment
Clinical grade DEC205mAb-NY-ESO-1 fusion protein (CDX-1401) and poly-ICLC 
(manufactured by Dalton for Oncovir, Inc. and provided by Oncovir, Inc., Inc through their 
agreement with Celldex Therapeutics) are supplied by Celldex Therapeutics Inc., Fall River, MA. 
CDX-1401 will be provided by the company and shipped to the participating sites.
The date of receipt and the amount of drug received will be documented. Drug shipment records 
will be retained by the investigational pharmacist or designee.
32.1.3 Preparation
CDX-1401 will be provided as a 1 mg/mL solution. It will be given intracutaneously as outlined 
in Section 10. 
32.1.4 Storage and Stability
The Investigator or designate will be responsible for ensuring that the investigational product is 
securely maintained in a locked, limited-access facility, as specified and, in accordance with the 
applicable regulatory requirements.
CDX-1401 vials should be stored at -20 ± 5˚C.
Once thawed, vials should be stored at 2 to 8°C and used within 7 days. Vials left at room 
temperature should be used within 24 hours. Celldex should be contacted if thawed vials are stored 
at 2 to 8° C for more than 7 days or at room temperature for more than 24 hours.
CDX-1401 is not formulated with a preservative. Therefore, once the sterile vials are entered (i.e., 
once CDX-1401 is drawn into a syringe), the drug should be used as soon as possible (typically, 
within 3 hours if kept at room temperature or within 6 hours if refrigerated; or in accordance with 
any applicable institutional guidance).
Drug storage temperature will be maintained and recorded, as applicable.
32.1.5 Handling and Disposal
The Investigator or designee will be responsible for dispensing and accounting for all 
investigational drug provided by the Supporter exercising accepted medical and pharmaceutical 
practices. Study drugs must be handled as cytotoxic agents and appropriate precautions taken per 
the institution’s environmentally safe handling procedures. All investigational drugs will be 
dispensed in accordance with the Investigator’s prescription or written order.
All products dispensed will be recorded on a product accountability record. Records of product lot 
numbers and dates received will be entered on a product accountability form. This record will be 
reviewed by the Supporter’s staff or representative during periodic monitoring visits. It is the 
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Page 56 of 94
Investigator’s responsibility to ensure that an accurate record of investigational drug issued and 
returned is maintained.
Used vials (excess drug) will be destroyed according to standard practices after properly 
accounting for the dispensing. Partially used vials of study drug will not be re-used for other 
participants.
Under no circumstances will the Investigator supply investigational drug to a third party or allow 
the investigational drug to be used in a manner other than as directed by this protocol.
32.2 Nivolumab
32.2.1 Active Substance and Source
Nivolumab Injection, 100 mg/10 mL (10 mg/mL), is a clear to opalescent, colorless to pale yellow 
liquid, which may contain light (few) particulates. The drug product is a sterile, non-pyrogenic, 
single-use, isotonic aqueous solution formulated at 10 mg/mL in sodium citrate, sodium chloride, 
mannitol, diethylenetriaminepentaacetic acid (pentetic acid), and polysorbate 80 (Tween™ 80), 
pH 6.0 and includes an overfill to account for vial, needle, and syringe holdup. It is supplied in 10-
cc Type I flint glass vials, stoppered with butyl rubber stoppers and sealed with aluminum seals. 
32.2.2 Drug Shipment
Nivolumab will be provided by Bristol-Myers Squibb and shipped to the participating site.
The date of receipt and the amount of drug received will be documented. Drug shipment records 
will be retained by the investigational pharmacist or designee.
32.2.3 Preparation
During drug product preparation and handling, vigorous mixing or shaking is to be avoided. Care 
must be taken to assure sterility of the prepared solution as the product does not contain any 
antimicrobial preservative or bacteriostatic agent. Nivolumab infusions are compatible with 
polyvinyl chloride (PVC) or polyolefin containers and infusion sets, and glass bottles.
32.2.4 Storage and Stability
The Investigator or designate will be responsible for ensuring that the investigational product is 
securely maintained in a locked, limited-access facility, as specified and, in accordance with the 
applicable regulatory requirements.
Vials of nivolumab injection must be stored at 2C to 8C (36°F to 46°F) and protected from light 
and freezing.
The administration of nivolumab infusion must be completed within 24 hours of preparation. If 
not used immediately, the infusion solution may be stored under refrigeration conditions (2°C to 
8°C, 36°F to 46°F) for up to 24 hours, and a maximum of 8 hours of the total 24 hours can be at 
room temperature (20°C to 25°C, 68°F to 77°F) and room light. The maximum 8-hour period 
under room temperature and room light conditions includes the product administration period.
Drug storage temperature will be maintained and recorded, as applicable.
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Page 57 of 94
32.2.5 Handling and Disposal
The Investigator or designee will be responsible for dispensing and accounting for all 
investigational drug provided by Bristol-Myers Squibb (BMS), exercising accepted medical and 
pharmaceutical practices. Study drugs must be handled as cytotoxic agents and appropriate 
precautions taken per the institution’s environmentally safe handling procedures. All 
investigational drugs will be dispensed in accordance with the Investigator’s prescription or 
written order.
All products dispensed will be recorded on a product accountability record. Records of product lot 
numbers and dates received will be entered on a product accountability form. This record will be 
reviewed by the Supporter’s staff or representative during periodic monitoring visits. It is the 
Investigator’s responsibility to ensure that an accurate record of investigational drug issued and 
returned is maintained.
Used vials (excess drug) will be destroyed according to standard practices after properly 
accounting for the dispensing. Partially used vials of study drug will not be re-used for other 
participants.
Under no circumstances will the Investigator supply investigational drug to a third party or allow 
the investigational drug to be used in a manner other than as directed by this protocol.
32.3 Decitabine
Decitabine is commercially available and will be dispensed per standard of care. Decitabine will 
not be provided by this study and will be paid for by the patient’s insurance carrier as part of the 
standard of care treatment.
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Page 58 of 94
33
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Patients with MDS or Low Blast Count AML
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Patients with MDS or Low Blast Count AML
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Patients with MDS or Low Blast Count AML
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Patients with MDS or Low Blast Count AML
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34 APPENDICES/SUPPLEMENTS
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Patients with MDS or Low Blast Count AML
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Appendix A
ELIGIBILITY VERIFICATION FORM: 
INCLUSION CRITERIA
Participant Name: (Network sites use participant initials): ___________________________
Medical Record No.: (Network sites use participant ID): _____________________________
Title: A Phase 1 Study of DEC205mAb-NY ESO 1 Fusion Protein (CDX-1401) given with 
Adjuvant Poly-ICLC in Conjunction with 5-Aza-2'deoxycytidine (Decitabine) and 
Nivolumab in Patients with MDS or Low Blast Count AML
INCLUSION CRITERIA
Yes
No
N/A
All answers must be “Yes” or “N/A” for participant enrollment.
Date
1.
Have a confirmed diagnosis of:
a.
IPSS intermediate-1, intermediate-2 or high-risk MDS 
including Chronic Myelomonocytic Leukemia (CMML) OR
b.
Low blast count AML with ≤ 30% blasts previously classified 
as Refractory Anemia with excess blasts in transformation.
2.
Age ≥ 18 years of age.
3.
Have an ECOG Performance Status of ≤ 2. Refer to Appendix “C”.
4.
Have adequate organ function defined by the following laboratory 
values: 

Hepatic: 
o
Total bilirubin ≤ 3 X upper limit of normal (ULN) (except 
subjects with Gilbert Syndrome, who can have total 
bilirubin up to 3.5 X ULN)
o
Aspartate Transaminase (AST/SGOT) and Alanine 
Transaminase (ALT/SGPD) ≤ 3 X ULN

Renal:
o
Serum creatinine ≤ 2.5 X ULN

Cardiac:
o
Troponin-I, CK-MB≤ ULN
o
LVEF ≥ LLN (institutional limit)
5.
Participants of child-bearing potential must agree to use adequate 
contraceptive methods (e.g., hormonal or barrier method of birth 
control; abstinence) prior to study entry, for the duration of study 
participation, and for 6 months after the last treatment. Should a woman 
become pregnant or suspect she is pregnant while she or her partner is 
participating in this study, she should inform her treating physician 
immediately.
6.
Participant or legal representative must understand the investigational 
nature of this study and sign an Independent Ethics 
Committee/Institutional Review Board approved written informed 
consent form prior to receiving any study related procedure.
7.
No prior exposure to nivolumab. 
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Page 66 of 94
INCLUSION CRITERIA
Yes
No
N/A
All answers must be “Yes” or “N/A” for participant enrollment.
Date
8.
No prior investigational therapy within 2 weeks prior to 
study enrollment
Investigator Signature: ___________________________________
Date: ___________
Printed Name of Investigator: __________________________________________________
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Appendix B
ELIGIBILITY VERIFICATION FORM:
EXCLUSION CRITERIA
Participant Name: (Network sites use participant initials): ___________________________
Medical Record No.: (Network sites use participant ID): _____________________________
Title: A Phase 1 Study of DEC205mAb-NY ESO 1 Fusion Protein (CDX-1401) given with 
Adjuvant Poly-ICLC in Conjunction with 5-Aza-2'deoxycytidine (Decitabine) and 
Nivolumab in Patients with MDS or Low Blast Count AML
EXCLUSION CRITERIA
Yes
No
N/A
All answers must be “No” or “N/A” for participant enrollment.
Date
1.
Subjects with life-threatening illnesses other than MDS, uncontrolled 
medical conditions or organ system dysfunction which, in the 
investigator’s opinion, could compromise the subject’s safety, or put 
the study outcomes at risk.
2.
AML associated with inv(16); t(16;16); t(8;21) or t(15;17).
3.
Previously untreated MDS with isolated del5q (for which lenalidomide 
is approved an approved therapy) and chronic myelomonocytic leukemia 
(CMML) with rearrangements of the PDGF receptor (for which imatinib 
is approved therapy), unless they have previously failed these 
approaches.
4.
Subjects with symptomatic central nervous system (CNS) disease 
which is not adequately controlled
5.
Subjects who have received prior radiation therapy for extramedullary 
disease within 2 weeks of first dose.
6.
Has known immunosuppressive disease (e.g. HIV, AIDS or other 
immune depressing disease). Testing is not required, only to be done 
for a possible diagnosis which is not confirmed.
7.
Uncontrolled intercurrent illness including, but not limited to, ongoing 
or active infection, symptomatic congestive heart failure, unstable 
angina pectoris, cardiac arrhythmia, or psychiatric illness/social 
situations that would limit compliance with study requirements. In 
addition, subjects will be excluded for any of the following:

Myocardial infarction or arterial or venous thromboembolic events 
within 6 months prior to baseline or severe or unstable angina, 
New York Heart Association (NYHA) Class III or IV disease

Active  congestive heart failure (New York Heart Association 
functional classification III or IV).

Documented history of cardiomyopathy with EF< 30%.

Uncontrolled hypertension (SBP>160/DBP>100 despite medical 
intervention).•History of myocarditis of any etiology
8.
Subjects who have hypersensitivity to decitabine, CDX-1401, poly-
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EXCLUSION CRITERIA
Yes
No
N/A
All answers must be “No” or “N/A” for participant enrollment.
Date
ICLC or nivolumab.
9.
History of auto-immune disease (e.g., thyroiditis, lupus), except 
vitiligo.
10. Pregnant or nursing female subjects.
11. Unwilling or unable to follow protocol requirements.
12. Any condition which in the Investigator’s opinion deems the 
participant an unsuitable candidate to receive study drug.
13. Regular use of immunosuppressant drugs such as steroids (>20mg 
prednisone equivalents), azathioprine, tacrolimus, cyclosporine, etc. 
Use is not permitted within 4 weeks before recruitment.
Participant meets all entry criteria:
  Yes
  No
If “NO”, do not enroll participant in study.
Investigator Signature: ___________________________________
Date: __________
Printed Name of Investigator: _________________________________________________
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Appendix C
ECOG Performance Status Scores
Description
Status
Fully active, able to carry on all pre-disease performance without restriction.
0
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.
1
Ambulatory and capable of all self-care but unable to carry out any work activities.
2
Capable of only limited self-care, confined to bed or chair more than 50% of waking hours.
3
Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair.
4
Dead
5
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Appendix D
Response Criteria for MDS and AML According to Modified International 
Working Group Criteria
Response Criteria for MDS and AML patients according to modified IWG criteria
Designation
Criteria for Response
Morphologic Leukemia 
Free state
<5% blasts in the marrow
Complete Response (CR)
Morphologic CR: BM blasts <5% with no dysplasia, in combination 
with CBC demonstrating: 
1) platelets > 100K/mm3,
2) neutrophils > 1000/mm3
Cytogenetic CR: As above + cytogenetics normal
Molecular CR: As above + Molecular testing negative
Partial Remission (PR)
For MDS:
BM blasts decreased by ≥50%, or
less advanced MDS FAB classification than pretreatment.
For AML:
Blasts decreased by ≥50% or decrease to 5-25; Blasts ≤ 5% if 
Auer rod positive
Platelets >100,000 
Stable Disease (SD)
No PR, but no evidence of progression ≥ 2 months
Hematological 
Improvement (HI)
Erythroid Response  (HI-E)
1)
Major:  Transfusion independence or 2g increase in Hg
2)
Minor: 1 to 2g increase in Hg or 50% decrease in transfusion 
requirements
Platelet Response (HI-P)
1)
Major: absolute increase in platelets of 30K/mm3 or  development 
of transfusion independence
2)
Minor 50% increase, net 10-30K/mm3
Neutrophil Response (HI-N)
1)
Major: 100% increase or absolute increase ≥500/mm3
2)
Minor: 100% increase with value ≤500/mm3
1. Cheson BD, Bennett JM, Kopecky KR, Buchner T, Willman CL, Estey EH, Schiffer CA, 
Doehner H, Tallman MS, Lister TA, Lo-Coco F, Willemze R, Biondi A, Hiddemann W, Larson 
RA, Lowenberg B, Sanz MA, Head DR, Ohno R, Blomfield CD. Revised recommendations of the 
international working group for diagnosis, standardization of response criteria, treatment outcomes 
and reporting standards for therapeutic trials in acute myeloid leukemia. J Clin Oncol 2003; 
21:4642-4649.
2. Cheson BD, Bennett JM, Kantarjian H, Pinto A, Schiffer CA, Nimer SD, Lowenberg B, Beran 
M, de Witte TM, Stone RM, Mittelman M, Sanz GF, Wijermans PW, Gore S, Greenberg PL, 
World Health Organization(WHO) international working group: Report of an international 
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working group to standardize response criteria for myelodysplastic syndromes. Blood 
2000;96:3671-3674.
3. Cheson BD, Cassileth PA, Head DR, Schiffer CA, Bennett JM, Bloomfield CD, Brunning R, 
Gale RP, Grever MR, Keating MJ: Report of the National Cancer Institute-sponsored workshop 
on definitions of diagnosis and response in acute myeloid leukemia. J Clin Oncol 1990;8:813-
819.
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Appendix E
International Prognostic Scoring System for MDS

Cytopenias are designated by the following: ANC<1800, platelets< 100K, Hg<10g

Karyotype risk groups:
o
Good: Normal (46 XX or 46 XY), isolated -Y,  isolated del(5q), or isolated del(20q)
o
Intermediate: All karyotypes not otherwise designated good or poor 
o
Poor: complex karyotype (≥3 abnormalities) or any chromosome 7 abnormalities
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Appendix F
Revised International Prognostic Scoring System
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Appendix G
Sample Processing
Bone marrow:
Add 40 mL Phosphate buffered saline (PBS) to 40 mL 
bone marrow
Add 20 mL Ficoll-Paque in a 50 mL falcon tube and 
layer 40 mL diluted blood on top of Ficoll 
Remove buffy coat into a 50 mL Falcon tube containing 
10-50 mL of RBC lysis buffer (may increase the volume 
if incomplete RBC lysis occurs), thus allowing 
resuspension of cells 
Centrifuge at 1800 rpm for 30 mins in a swinging rotor 
without brake at room temperature (RT)
Incubate on ice for 10 mins
Remove the upper layer without disturbing the 
interphase which contains mononuclear cells
Centrifuge at 1500 rpm for 5 mins
Carefully transfer the interphase containing 
mononuclear cells to a new 50 mL falcon and add 20 
ml PBS and centrifuge at 3000 rpm for 5mins
Centrifuge at 1500 rpm for 5 mins
Centrifuge at 1500 rpm for 5 mins
Discard supernatant. Resuspend pellet in freezing media* to achieve a concentration of 5-10 x 106 cells/mL
Appendix H
Management Algorithms for Immune-Related Adverse Events
These general guidelines constitute guidance to the Investigator and may be supplemented by 
discussions with the Medical Monitor representing the Supporters. The guidance applies to all 
immuno-oncology agents and regimens.
Research Coordinator informs lab before phlebotomy
RPCI:716-845-1724 (lab) OR 716-430-1152 (Pragya Srivastava)
Peripheral blood (4 green top tubes) or Bone marrow (4 green top tubes) collected
Collected blood gets tubed to
RPCI: 611 for processing (Attn: Griffiths Lab, x1724)
Collect heparinized peripheral blood or bone marrow into a 50 ml Falcon tube
Peripheral blood:
Centrifuge at 3000 rpm for 5 mins
Pipette 2-4 ml of plasma into a 2 mL cryovial (1 ml/vial) 
and store at -80°C. Discard the remainder of plasma
Discard supernatant. Resuspend pellet in 5-10 mL of PBS and count cells (if clumps of cells observed pass the cells through 
70um strainer to get rid of clumps)
Divide into 2 mL cryovials (1ml/vial)
Freeze first at -80°C and then transfer to 
liquid nitrogen
* Thermo Fisher Scientific 
product-Recovery cell culture 
freezing medium-12648010
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A general principle is that differential diagnoses should be diligently evaluated according to 
standard medical practice. Non-inflammatory etiologies should be considered and appropriately 
treated.
Corticosteroids are a primary therapy for immuno-oncology drug-related adverse events. The oral 
equivalent of the recommended IV doses may be considered for ambulatory patients with low-
grade toxicity. The lower bioavailability of oral corticosteroids should be taken into account when 
switching to the equivalent dose of oral corticosteroids.
Consultation with a medical or surgical specialist, especially prior to an invasive diagnostic or 
therapeutic procedure, is recommended.
The frequency and severity of the related adverse events covered by these algorithms will depend 
on the immuno-oncology agent or regimen being used.
Algorithms (Nivolumab Investigator Brochure, v16, Appendix 3):

GI Adverse Event Management Algorithm

Renal Adverse Event Management Algorithm

Pulmonary Adverse Event Management Algorithm

Hepatic Adverse Event Management Algorithm

Endocrinopathy Management Algorithm

Skin Adverse Event Management Algorithm

Neurological Adverse Event Management Algorithm
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GI Adverse Event Management Algorithm
Rule out non-inflammatory causes. If non-inflammatory cause is identified, treat accordingly and continue I-O therapy. 
Opiates/narcotics may mask symptoms of perforation. Infliximab should not be used in cases of perforation or sepsis.
Grade of Diarrhea/ 
Colitis
(NCI CTCAE v4)
Management
Follow-up
• Continue  I-O therapy per 
protocol
• Symptomatic treatment
Grade 1
Diarrhea: < 4 stools/day over baseline; 
Colitis: asymptomatic
• Close monitoring for worsening symptoms.
• Educate patient to report worsening immediately 
If worsens:
• Treat as Grade 2 or 3/4
• Delay I-O therapy per protocol
• Symptomatic treatment
If improves to grade 1:
• Resume I-O therapy per protocol 
If persists > 5-7 days or recur:
• 0.5-1.0 mg/kg/day methylprednisolone or oral equivalent
• When symptoms improve to grade 1, taper steroids over 
at least 1 month, consider prophylactic antibiotics for 
opportunistic infections, and resume I-O therapy per 
protocol.
If worsens or persists > 3-5 days with oral steroids:
• Treat as grade 3/4
Grade 2
Diarrhea: 4-6 stools per day over 
baseline; IV fluids indicated <24 hrs; 
not interfering with ADL
Colitis: abdominal pain; blood in stool
• Discontinue I-O therapy per 
protocol
• 1.0 to 2.0 mg/kg/day 
methylprednisolone  IV or  IV 
equivalent
• Add prophylactic antibiotics for 
opportunistic infections
• Consider lower endoscopy
Grade 3-4
Diarrhea (G3): ≥ 7 stools per day over 
baseline; incontinence; IV 
fluids ≥ 24 hrs; interfering with ADL
Colitis (G3):  severe abdominal pain, 
medical intervention indicated, 
peritoneal signs
G4: life-threatening, perforation
If improves:
• Continue steroids until grade 1, then taper over at 
least 1 month
If persists > 3-5 days, or recurs after improvement:
• Add infliximab 5 mg/kg (if no contraindication). 
Note: Infliximab should not be used in cases of 
perforation or sepsis
Patients on IV steroids may be switched to an equivalent dose of oral corticosteroids (e.g. prednisone) at start of tapering or earlier, once sustained clinical improvement is observed. 
Lower bioavailability of oral corticosteroids should be taken into account when switching to the equivalent dose of oral corticosteroids.

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Renal Adverse Event Management Algorithm
Rule out non-inflammatory causes. If non-inflammatory cause, treat accordingly and continue I-O 
therapy
Grade of Creatinine 
Elevation
(NCI CTCAE v4)
Management
Follow-up
Grade 1
Creatinine > ULN and > 
than baseline but ≤ 1.5x 
baseline
• Continue I-O therapy per protocol
• Monitor creatinine weekly
If returns to baseline:
•Resume routine creatinine monitoring per protocol 
If worsens:
•Treat as Grade 2 or 3/4
Grade 2-3
Creatinine > 1.5x baseline 
to ≤ 6x ULN
• Delay I-O therapy per protocol
• Monitor creatinine every 2-3 days
• 0.5 to 1.0 mg/kg/day 
methylprednisolone  IV or oral 
equivalent
• Consider renal biopsy with 
nephrology consult
If returns to Grade 1:
•Taper steroids over at least 1 month, consider prophylactic 
antibiotics for opportunistic infections, and resume I-O therapy 
and routine creatinine monitoring per protocol
If elevations persist > 7 days or worsen:
•Treat as Grade 4
Grade 4
Creatinine > 6x ULN
• Discontinue I-O therapy per 
protocol
• Monitor creatinine daily
• 1.0-2.0 mg/kg/day 
methylprednisolone IV or IV 
equivalent
• Consult nephrologist
• Consider renal biopsy
If returns to Grade 1 :  Taper steroids over at least 1 month and 
add prophylactic antibiotics for opportunistic infections
Patients on IV steroids may be switched to an equivalent dose of oral corticosteroids (e.g. prednisone) at start of tapering or earlier, once sustained clinical improvement is observed. 
Lower bioavailability of oral corticosteroids should be taken into account when switching to the equivalent dose of oral corticosteroids.

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Pulmonary Adverse Event Management Algorithm
Rule out non-inflammatory causes. If non-inflammatory cause, treat accordingly and continue I-O therapy. Evaluate with imaging 
and pulmonary consultation.
Grade of 
Pneumonitis
(NCI CTCAE v4)
Management
Follow-up
Grade 1
Radiographic changes only
• Consider delay of I-O therapy
• Monitor for symptoms every 2-3 
days
• Consider Pulmonary and ID 
consults
• Re-image at least every 3 weeks 
If worsens:
• Treat as Grade 2 or 3-4
Grade 2
Mild to moderate new 
symptoms
• Delay I-O therapy per protocol
• Pulmonary and ID consults
• Monitor symptoms daily, consider 
hospitalization
• 1.0 mg/kg/day methyl- 
prednisolone IV or oral equivalent
• Consider  bronchoscopy , lung 
biopsy
• Re-image every 1-3 days 
If improves:
• When symptoms return to near baseline, taper steroids over 
at least 1 month and then resume I-O therapy per protocol 
and consider prophylactic antibiotics
If not improving after 2 weeks  or worsening:
• Treat as Grade 3-4
• Discontinue  I-O therapy per 
protocol
• Hospitalize
• Pulmonary and ID consults
• 2-4  mg/kg/day 
methylprednisolone IV or IV 
equivalent
• Add prophylactic antibiotics for 
opportunistic infections
• Consider bronchoscopy, lung 
biopsy
Grade 3-4
Severe new symptoms; 
New/worsening hypoxia; 
Life-threatening
If improves to baseline:
• Taper steroids over at least 6 weeks
If not improving after 48 hours or worsening:
• Add additional immunosuppression
Patients on IV steroids may be switched to an equivalent dose of oral corticosteroids (e.g. prednisone) at start of tapering or earlier, once sustained clinical improvement is observed. 
Lower bioavailability of oral corticosteroids should be taken into account when switching to the equivalent dose of oral corticosteroids.

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Hepatic Adverse Event Management Algorithm
Rule out non-inflammatory causes. If non-inflammatory cause, treat accordingly and continue I-O therapy. Consider imaging for 
obstruction.
Grade of Liver 
Test Elevation
(NCI CTCAE v4)
Management
Follow-up
Grade 1
AST or ALT > ULN -2.5 x
ULN and/or T. bili > ULN - 1.5 
x ULN
• Continue I-O therapy per protocol
• Continue LFT monitoring per protocol 
If worsens:
• Treat as Grade 2 or 3-4
Grade 2
AST or ALT > 2.5 to ≤  5 
x ULN and/or Total 
bili. > 1.5 to ≤ 3 x ULN
• Delay I-O therapy per protocol
• Increase frequency of monitoring 
to every 3 days
• Discontinue  I-O therapy*
• Increase frequency of monitoring 
to every 1-2 days
• 1.0 to 2.0 mg/kg/day 
methylprednisolone IV or IV 
equivalent**
• Add prophylactic antibiotics for 
opportunistic infections
• Consult gastroenterologist
If returns to baseline:
•Resume routine monitoring, resume I-O therapy per protocol
If elevations persist > 5-7 days or worsen :
• 0.5-1 mg/kg/day methylprednisolone or oral equivalent and 
when LFT returns to grade 1 or baseline, taper steroids over at 
least 1 month, consider prophylactic antibiotics for 
opportunistic infections, and resume I-O therapy per protocol
If returns to grade 2:
• Taper steroids over at least 1 month
Grade 3-4
AST or ALT > 5 x ULN or 
Total bilirubin > 3 x ULN
If does not improve in >3-5 days, worsens or rebounds:
• Add  mycophenolate mofetil 1 g BID
• If no response within an additional 3-5 days, consider other 
immunosuppressants per local guidelines
Patients on IV steroids may be switched to an equivalent dose of oral corticosteroids (e.g. prednisone) at start of tapering or earlier, once sustained clinical 
improvement is observed. Lower bioavailability of oral corticosteroids should be taken into account when switching to the equivalent dose of oral corticosteroids.
*I-O therapy may be delayed rather than discontinued if AST/ALT s 8 x ULN or T.bili ≤ 5 x ULN.
**The recommended starting dose for grade 4 hepatitis is 2 mg/kg/day methylprednisolone IV.

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Endocrinopathy Management Algorithm
Rule out non-inflammatory causes. If non-inflammatory cause, treat accordingly and continue I-O therapy. Consider visual field testing, 
endocrinology consultation, and imaging.
Asymptomatic 
TSH elevation
• Continue I-O therapy per protocol
• If TSH < 0.5 x LLN, or TSH > 2 x ULN, or consistently out of range in 2 subsequent measurements: include fT4 at 
subsequent cycles as clinically indicated; consider endocrinology consult
Symptomatic 
endocrinopathy
• Evaluate endocrine function
• Consider pituitary scan
Symptomatic with abnormal lab/pituitary scan:
• Delay I-O therapy per protocol
• 1-2 mg/kg/day methylprednisolone IV or  PO equivalent
• Initiate appropriate hormone therapy
No abnormal lab/pituitary MRI scan but symptoms persist:
• Repeat labs in 1-3 weeks / MRI in 1 month
If improves  (with or without 
hormone replacement):
• Taper steroids over at least 1 
month and consider prophylactic 
antibiotics for opportunistic 
infections
• Resume I-O therapy per protocol
• Patients with adrenal 
insufficiency may need to 
continue steroids with 
mineralocorticoid component
Suspicion of adrenal 
crisis (e.g. severe 
dehydration, 
hypotension, shock 
out of proportion to 
current illness
• Delay or discontinue I-O therapy per protocol
• Rule out sepsis
• Stress dose of IV steroids with mineralocorticoid activity
• IV fluids
• Consult endocrinologist
• If adrenal crisis ruled out,  then treat as above for symptomatic 
endocrinopathy
Patients on IV steroids may be switched to an equivalent dose of oral corticosteroids (e.g. prednisone) at start of tapering or earlier, once sustained 
clinical improvement is observed. Lower bioavailability of oral corticosteroids should be taken into account when switching to the equivalent dose of 
oral corticosteroids.

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Skin Adverse Event Management Algorithm
Rule out non-inflammatory causes. If non-inflammatory cause, treat accordingly and continue I-O therapy.
Grade of 
Rash
(NCI CTCAE v4)
Management
Follow-up
If persists > 1-2 weeks or recurs:
• Consider skin biopsy
• Delay I-O therapy per protocol
• Consider 0.5-1.0 mg/kg/day methylprednisolone IV or 
oral equivalent. Once improving , taper steroids over 
at least 1 month, consider prophylactic antibiotics for 
opportunistic infections, and resume I-O therapy per 
protocol
If worsens:
• Treat as Grade 3-4
Grade 1-2
Covering s 30% 
BSA*
• Symptomatic therapy (e.g. antihistamines, 
topical steroids)
• Continue I-O therapy per protocol
Grade 3-4
Covering >30% BSA; 
Life threatening 
consequences*^
• Delay or discontinue I-O therapy per 
protocol
• Consider skin biopsy
• Dermatology consult
• 1.0-2.0 mg/kg/day IV methylprednisolone 
IV or IV equivalent
If improves to Grade 1:
• Taper steroids over at least 1 month and add 
prophylactic antibiotics for opportunistic infections
• Resume I-O therapy per protocol
Patients on IV steroids may be switched to an equivalent dose of oral corticosteroids (e.g. prednisone) at start of tapering or earlier, once sustained clinical 
improvement is observed. Lower bioavailability of oral corticosteroids should be taken into account when switching to the equivalent dose of oral corticosteroids.
*Refer to NCI CTCAE v4 for term-specific grading criteria.
^If SJS/TEN is suspected, withhold I-O therapy and refer patient for specialized care for assessment and treatment. If SJS or TEN is diagnosed, permanently discontinue I-O 
therapy.

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Neurological Adverse Event Management Algorithm
Rule out non-inflammatory causes. If non-inflammatory cause, treat accordingly and continue I-O therapy.
Grade of 
Neurological 
Toxicity
(NCI CTCAE v4)
Management
Follow-up
Grade 1
Asymptomatic or 
mild symptoms; 
Intervention not 
indicated
• Continue I-O therapy per protocol
Continue to monitor the patient. 
If worsens:
• Treat as Grade 2 or 3-4
Grade 2
Moderate symptoms; 
Limiting instrumental 
ADL
• Delay I-O therapy per protocol
• Treat symptoms per local guidelines
• Consider  0.5 to 1.0 mg/kg/day 
methylprednisolone  IV or  PO 
equivalent
If improves to baseline:
•Resume I-O therapy per protocol when improved to baseline 
If worsens:
• Treat as Grade 3-4
Grade 3-4
Severe symptoms; 
Limiting self-care 
ADL;
Life-threatening
• Discontinue I-O therapy per protocol
• Obtain neurology consult
• Treat symptoms per local guidelines
• 1.0-2.0 mg/kg/day IV 
methylprednisolone  IV or IV equivalent
• Add prophylactic antibiotics for 
opportunistic infections
If improves to Grade 2:
• Taper steroids over at least 1 month
If worsens or atypical presentation:
• Consider IVIG or other immunosuppressive therapies per 
local guidelines
Patients on IV steroids may be switched to an equivalent dose of oral corticosteroids (e.g. prednisone) at start of tapering or earlier, once sustained 
clinical improvement is observed. Lower bioavailability of oral corticosteroids should be taken into account when switching to the equivalent dose of 
oral corticosteroids.

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Appendix I
Nivolumab Monotherapy Adverse Drug Reactions
Adverse drug reactions in patients treated with nivolumab monotherapy in clinical studies 
(N= 9, 212), Investigator Brochure, v16, Table 5.6.1-1.
System Organ Class
Preferred Term
Overall 
Frequency
N (%)
Serious 
ADRs
N (%)
Life 
Threatening 
ADRs
N (%)
Fatal 
ADRs
N (%)
Cardiac Disorder
Tachycardia
Uncommo
n
17 (0.18)
n
n
n
Arrhythmia
(including Ventricular 
arrhythmia, atrial fibrillation a)
Uncommo
n
9 (0.10)
Y
3 (0.03)
n
n
Ear and
Labyrinth Disorders
Vertigo
Uncommo
n
22 (0.24)
n
n
n
Endocrine
Disorders
Hypothyroidism
(including Autoimmune 
hypothyroidism)
Common
443 (4.81)
Y
14 (0.14)
n
n
Hyperthyroidism
Common
141 (1.53)
Y
5 (0.05)
n
n
Hyperglycemia
Uncommo
n 
72 (0.78)
Y
16 (0.17)
Y b
1 (0.01)
n
Adrenal Insufficiency
Uncommo
n
52 (0.56)
Y
28 (0.31)
Y b
1 (0.01)
n
Thyroiditis 
(including Autoimmune 
thyroiditis)
Uncommo
n
36 (0.39)
Y b
1 (0.01)
n
n
Hypophysitis
Uncommo
n 
32 (0.35)
Y
16 (0.17)
n
n
Diabetes mellitus
Uncommo
n 
19 (0.21)
Y
4 (0.04)
n
n
Hypopituitarism
Uncommo
n
16 (0.17)
Y
5 (0.05)
n
n
Diabetic ketoacidosis
Rare
3 (0.03)
Y
3 (0.03)
Y b
1 (0.01)
n
Eye Disorders
Dry eye a
Uncommo
n 
42 (0.46)
n
n
n
Vision blurred a
Uncommo
n
32 (0.35)
n
n
n
Uveitis 
(including iridocyclitis)
Uncommo
n 
15 (0.16)
Y
3 (0.03)
n
n
Gastrointestinal
Diarrhea
Common 
Y
n
n
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System Organ Class
Preferred Term
Overall 
Frequency
N (%)
Serious 
ADRs
N (%)
Life 
Threatening 
ADRs
N (%)
Fatal 
ADRs
N (%)
Disorders
783 (8.50)
68 (0.74)
Nausea
Common 
783 (8.50)
Y
23 (0.25)
n
n
Vomiting
Common 
700 (7.60)
Y
26 (0.28)
n
n
Constipation
Common 
223 (2.42)
n
n
n
Abdominal Pain
Common 
222 (2.41)
Y
13 (0.14)
n
n
Stomatitis (including
Mucosal inflammation, 
Mucosal ulceration, Mouth 
ulceration)
Common 
159 (1.73)
Y
9 (0.10)
n
n
Dry mouth
Common 
157 (1.70)
n
n
n
Colitis (including Autoimmune 
colitis)
Common
103 (1.12)
Y
72 (0.78)
n
Y
2 
(0.02)
Pancreatitis(including 
Autoimmune pancreatitis, 
Pancreatitis acute
Uncommo
n
19 (0.21)
Y
10 (0.11)
n
n
Gastritis (including Gastritis 
erosive)
Uncommo
n
16 (0.17)
Y
4 (0.04)
n
n
General disorders and 
administration site 
conditions
Fatigue (including Asthenia)
Very 
Common
1701 
(18.47)
Y
30 (0.33)
n
n
Pyrexia
Common 
326 (3.54)
Y
41 (0.45)
n
n
Edema (including Edema 
peripheral, Generalized edema, 
Peripheral swelling, Localized 
edema, Periorbital edema, 
Face edema, Swelling face)
Common 
182 (1.98)
Y
5 (0.05)
n
n
Chills a 
Common
146 (1.58)
Y
4 (0.04)
n
n
Hepatobiliary Disorders
Hepatitis (including 
Autoimmune hepatitis, 
Hepatitis acute)
Uncommo
n 
32 (0.35)
Y
25 (0.27)
Y b
1 (0.01)
n
Immune System 
Disorders
Infusion related reaction
Common 
152 (1.65)
Y
21 (0.23)
Y b
1 (0.01)
n
Hypersensitivity
Uncommo
n 
70 (0.76)
Y
9 (0.10)
Y b
1 (0.01)
n
Anaphylactic reaction
Rare
4 (0.04)
Y
3 (0.03)
Y b
2 (0.02)
n
Infections and 
Infestations
Upper respiratory tract 
infection
Uncommo
n
31 (0.34)n
n
n
n
Bronchitis
Common
n
n
n
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System Organ Class
Preferred Term
Overall 
Frequency
N (%)
Serious 
ADRs
N (%)
Life 
Threatening 
ADRs
N (%)
Fatal 
ADRs
N (%)
10 (0.11)
Investigations
Aspartate aminotransferase 
increased
Common
257 (2.79)
Y
23 (0.25)
n
n
Alanine aminotransferase 
increased
Common
239 (2.59)
Y
27 (0.29)
n
n
Lipase increased
Common
163 (1.77)
Y
13 (0.14)
n
n
Blood alkaline phosphatase 
increased a
Common
127 (1.38)
Y
6 (0.07)
n
n
Amylase increased
Common
102 (1.11)
Y
4 (0.04)
n
n
Blood creatinine increased a
Common 
100 (1.09)
Y
3 (0.03)
n
n
Blood thyroid stimulating 
hormone increased a
Common 
92 (1.00)
n
n
n
Blood bilirubin increased
Uncommo
n
49 (0.53)
Y
4 (0.04)
n
n
Metabolism
and Nutrition Disorders
Decreased appetite
Common
536 (5.82)
Y
5 (0.05)
n
n
Hyponatremia
Uncommo
n
87 (0.94)
Y
17 (0.18)
n
n
Musculoskeletal
and Connective Tissue 
Disorders
Musculoskeletal pain 
(including Back pain, Bone 
pain, Musculoskeletal chest 
pain, Musculoskeletal 
discomfort, Myalgia, Neck 
pain, Pain in extremity, Pain in 
jaw)
Common
427 (4.64)
Y
4 (0.04)
Arthralgia (including Arthritis, 
Polyarthritis, and 
Osteoarthritis)
Common
400 (4.34)
Y
10 (0.11)
Myositis (including
Polymyositis)a
Rare
6 (0.07)
Y
4 (0.04)
Polymyalgia rheumatica
Rare
6 (0.07)
Y b
1 (0.01)
Rhabdomyolysis a, b
Rare
1 (0.01)
Y
1 (0.01)
Y
1 (0.01)
Nervous System 
Disorders
Headache
Common
215 (2.33)
Y
4 (0.04)
n
n
Neuropathy peripheral 
(including Burning sensation, 
Peripheral motor neuropathy, 
Polyneuropathy, Peripheral 
sensory neuropathy)
Common
102 (1.11)
Y
9 (0.10)
n
n
Dizziness
Uncommo
n
83 (0.90)
Y
3 (0.03)
n
n
Cranial nerve disorder a
Uncommo
Y
n
n
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System Organ Class
Preferred Term
Overall 
Frequency
N (%)
Serious 
ADRs
N (%)
Life 
Threatening 
ADRs
N (%)
Fatal 
ADRs
N (%)
n
12 (0.13)
6 (0.07)
Myasthenic syndrome 
(including Myasthenia gravis)
Rare
3 (0.03)
Y
3 (0.03)
n
n
Guillain-Barre syndrome
Rare
2 (0.02)
Y
2 (0.02)
n
n
Demyelination (including 
Demyelinating 
polyneuropathy)
Rare
2 (0.02)
Y
2 (0.02)
n
n
Encephalitis including 
Autoimmune encephalitis)
Rare
2 (0.02)
Y
2 (0.02)
n
Y b
1 (0.01)
Renal and Urinary 
Disorders
Renal failure (including Acute 
kidney injury)
Uncommo
n
41 (0.45)
Y
24 (0.26)
Y
2 (0.02)
n
Nephritis (including 
Autoimmune nephritis, 
Tubulointerstitial nephritis)
Uncommo
n
14 (0.15)
Y
11 (0.12)
n
n
Respiratory, Thoracic, 
and Mediastinal 
Disorders
Pneumonitis ( including 
Interstitial lung disease, 
Organizing pneumonia)
Common
276 (3.00)
Y
152 
(1.65)
Y
7 (0.08)
Y
9 
(0.10)
Dyspnea
Common
231 (2.51)
Y
35 (0.38)
Y
1 (0.01)
Y
3 (0.03)
Cough
Common
222 (2.41)
Respiratory failure (including 
Respiratory distress) a
Uncommo
n
18 (0.20)
Y
16 (0.17)
Y
2 (0.02)
Y
7 (0.08)
Lung infiltration
Rare
7 (0.08)
Y
2 (0.02)
n
n
Skin and Subcutaneous 
Tissue Disorders
Rash (including Rash maculo- 
papular, Rash generalized, 
Rash erythematous, Rash 
pruritic, Rash follicular, Rash 
macular, Rash papular, Rash 
pustular, Rash vesicular, 
Dermatitis, Dermatitis 
acneiform, Dermatitis allergic, 
Dermatitis exfoliative, and 
Drug eruption)
Very 
Common 
1010 
(10.96)
Y
20 (0.22)
n
n
Pruritus (including Pruritus 
generalized)
Common 
722 (7.84)
Y
2 (0.02)
n
n
Dry skin
Common
182 (1.98)
n
n
n
Vitiligo
Common
99 (1.07)
n
Erythema
Uncommo
n
75 (0.81)
n
Alopecia
Uncommo
n
60 (0.65)
n
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Patients with MDS or Low Blast Count AML
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System Organ Class
Preferred Term
Overall 
Frequency
N (%)
Serious 
ADRs
N (%)
Life 
Threatening 
ADRs
N (%)
Fatal 
ADRs
N (%)
Urticaria
Uncommo
n
40 (0.43)
n
Psoriasis
Uncommo
n
18 (0.20)
Y
3 (0.03)
Erythema multiforme
Rare
7 (0.08)
Y
3 (0.03)
Rosacea
Rare
2 (0.02)
n
Toxic epidermal necrolysis
Rare
1 (0.01)
Y
1 (0.01)
Y
1 (0.01)
Vascular Disorders
Hypotension a 
Uncommo
n
43 (0.47)
Y
5 (0.05)
n
n
Hypertension
Uncommo
n
42 (0.46)
n
n
n
Vasculitis
Rare
2 (0.02)
n
n
n
a ADR not included in previous IB version 14.
b Despite single reported occurrence, this event is considered to be ADR based on observed nivolumab safety profile 
across treatment groups. 
Appendix J
Schedule of Procedures and Observations
Schedule of Procedures and Observations
Evaluation
Baseline1 Day -
14
Each 
Cycle 
Day 1
Each 
Cycle 
Day 15
End of 
Cycle 
1
Day 1 of 
Cycle 5 and 
every 4th cycle 
thereafter 
End of 
Treatment
Follow-
Up2
Medical History with Pre-
existing Conditions
X1
Physical Examination4  
and/or vital signs5 
X3
X4,5
X4,5
X5
X4,5
X4, 5
Hematology6
X
X
X7
X7
X
X
Chemistry8
X
X
X8
X8
X
X
Pregnancy Test (Urine) 
X1a
ECOG Performance 
Status
X
X
X
X
HLA Typing 
X1b
IPSS/ IPSS-R 
(Appendix E and 
Appendix F)
X20
X
X
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Evaluation
Baseline1 Day -
14
Each 
Cycle 
Day 1
Each 
Cycle 
Day 15
End of 
Cycle 
1
Day 1 of 
Cycle 5 and 
every 4th cycle 
thereafter 
End of 
Treatment
Follow-
Up2
HIV, HBV, HBC
X19
Response Assessment 
(Appendix D, Appendix 
E, Appendix F) and TTT
X
X
Bone Marrow Aspirate 
and Biopsy9
X
X18
X
X14
X21
Endocrine Function 
Evaluation 17: TSH
X
X
Cardiac Safety Markers 15
X1a
X
Electrocardiogram 16
X1a
X
Echocardiogram 16a
X1a
Urinalysis
X1a
X
X
Research Samples
Correlative Blood 
Sampling
X12
X12
X12
X12
X12
X12
Bone Marrow Aspirate
X13
X13
X13
X13,14
X13
Study Drugs
CDX-1401/ Poly-ICLC 
injection 
X10,11
X10, 11
X10,11
Decitabine
Day 1 through Day 5 of each treatment 
cycle10 a
Nivolumab
Day 1 and Day 15 of each treatment 
cycle10 b
Concomitant Medications
X1
X
X
X
X
X
Adverse Events
X
X
X
X
X
X
X
Survival Status
X
1
Performed within 4 weeks prior to first dose of CDX-1401/poly-ICLC) unless otherwise indicated.
1a: Performed within 3 week prior to first dose of CDX-1401/poly-ICLC) unless otherwise indicated
1b: Patients who do not require HLA typing for determination of transplant eligibility will have HLA 
typing sent for study purposes: Each site will perform their own HLA analysis according to institutional 
guidelines. Samples taken at RPCI: 1, 10 mL lavender-top tube to be sent to RPCI Immune Analysis 
Facility c/o Junko Matsuzaki, CCC room 416, x-8459).
2
Performed 30 days, 60 days, 90 days, and 180 days (± 3 days) following last dose of study drug (last 
immunization with CDX-1401/poly ICLC/nivolumab). Assessment may be collected via telephone if the 
patient elects to come off study and is no longer coming to clinic.
3
Height collected at baseline only.
4
Physical examination on day -14 and day 1 of each cycle (or up to 3 days prior to the beginning of a cycle) 
and at end of treatment
5
Vital signs including temperature, heart rate, oxygen saturation, respiratory rate, body weight and blood 
pressure prior to CDX-1401/poly ICLC dosing on day -14 and day 15 of each cycle (cycles 1-4) or day 1 of 
each 4th cycle (cycles 5+) and prior to decitabine dosing on day 1 of each cycle
6
CBC with manual differential
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7
Once per week each cycle during cycles 1-4, from cycles 5 onward on Day 1 and as clinically indicated. 
Used to assess hematologic improvement per modified International Working Group criteria for MDS on 
Day 1 every cycle 1.
8
CMP, LDH, uric acid, amylase and, lipase. Once per week each cycle during cycles 1-4 and, on Day 1from 
cycle 5 and onward and, as clinically indicated.
9
Bone Marrow Aspirate and Biopsy, Flow Cytometry, Conventional Cytogenetics+/- FISH as appropriate. 
At the end of cycle 1 a Bone Marrow aspirate is to be done purely for collection of correlative specimens, 
unless the patient has demonstrated sufficient clinical response to warrant disease assessment at the 
discretion of the treating physician. Note: At the end of Cycle 1, if a bone marrow aspirate is not able to be 
done, a bone marrow biopsy may be performed instead Thereafter a complete bone marrow assessment to 
be done every 4th cycle (per standard of care) for response assessment. If bone marrow is unable to be 
obtained due to dry tap, collected 4 additional green top tubes of peripheral blood.
10
CDX-1401/poly-ICLC administered on day -14 of cycle 1 and then day 15 of every cycle for the first 4 
cycles. 
NOTE: After Cycle 4: to be given on day 1 of every 4th cycle as a booster (i.e. on day 1 of cycles 8, 12, 16, 
20, 24).
10a: Decitabine administered on days 1-5 of each cycle. 
10b: Nivolumab administered every 2 weeks on days 1 and 15 of each cycle for the first 4 cycles.
Note: After Cycle 4: to be given on day 1 of every cycle 5 and above
11
 Following administration of the CDX-1401/poly ICLC patients will be observed for 1 hour and undergo 
temperature, blood pressure and heart rate monitoring every 30 minutes.
12
Study blood work includes the following: At Baseline: Six green top tubes, 1 gold top tube; Cycle 1 day -
14: 6 green top tubes, 1 gold top; Cycles 1-4 once weekly: 6 green top tubes; Cycles 5-end of study, every 2 
weeks: 6 green tops and 1 gold top (see section 11.11.1). If it is determined that there is an inadequate cell 
number for cryopreservation and immunomonitoring, at any visit, sample acquisition may be repeated at 
the next scheduled blood draw.
13
Study Bone marrow samples for T-cell and methylation and gene expression studies, 4 green tops tubes to 
be obtained each time a bone marrow assessment is to be done (see Section 11.11.2).
14
End of study bone marrow may be done +/- 14 days from day 29 of the last cycle of decitabine for 
convenience.
15 Troponin-I, CK-MB, will be obtained at baseline (within 4 weeks prior to first dose of study drug) and at 
the end of Cycle 1 and as clinically indicated.
16
Electrocardiogram will be performed at baseline and at the end of Cycle 1 and as clinically indicated.
16a: Echocardiogram will be performed at baseline or anytime as clinically indicated.
17
For endocrine function monitoring: Follow up- 6-8 weeks with repeat labs (may be done sooner if patient 
is symptomatic): refer to Endocrinology if abnormal labs. If patient is symptomatic, start initial treatment 
(most commonly thyroid replacement and/or hydrocortisone): always replace steroids first and thyroid 
hormone a few days later to prevent worsening of adrenal insufficiency. In cases of thyroiditis (low TSH, 
high free T4), treat symptomatically with beta-blockers and refer to Endocrinology. Note: Some patients 
with hypophysitis will require high dose steroids with taper and MRI pituitary. Refer to Appendix H for 
immune-related adverse event management guidelines.
18
At the end of cycle 1 a Bone Marrow aspirate is to be done purely for collection of correlative specimens 
(see Section 11.9.2) unless the patient has demonstrated sufficient clinical response to warrant disease 
assessment at the discretion of the treating physician. Note: At the end of Cycle 1, if a bone marrow 
aspirate is not able to be done, a bone marrow biopsy may be performed instead. Thereafter,  a complete 
bone marrow assessment to be done every 4th cycle (per standard of care) for response assessment.
19
Testing for HIV I/II Ab, HBsAg, HCV Ab+/- PCR should be done only in patients for whom there is a 
concern for prior infection with one of these viral pathogens. Testing is NOT required if there is no history 
of infection.
20
Refer to Appendix E and Appendix F for calculation instructions.
21 Bone marrow biopsy per institutional guidelines for patients on study < 2 years. Bone marrow biopsy every 
6 months (± 2 months) for patients on study for ≥ 2 years with correlative samples.  Correlative samples to 
be collected at any time point when patient has a bone marrow biopsy for standard of care.
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Appendix K
Network Site Instructions
1.
CONTACT INFORMATION
All questions related to the protocol or study implementation should be directed to:
Roswell Park Cancer Institute
CRS Network Office
ASB K 104
Buffalo, New York 14263
Telephone:
Monday - Friday; 8: 30 AM to 5: 00 PM EST
716-845-4169
After hours, weekends, and holidays request the RPCI Investigator
716-845-2300
Fax: 716-845-8743
2.
INFORMED CONSENT

Informed consent must be obtained by the site Investigator/designee from any participants 
wishing to participate, prior to any procedures or treatment.

An informed consent template is provided by RPCI and can be amended to reflect 
institutional requirements.

All consent changes must be reviewed by RPCI Network Office prior to submission to the 
site IRB.

The informed consent must be IRB approved.

Always check that the most up to date version of the IRB approved consent is being used.

Within 5 business days, notify the RPCI Network Office of all participant withdrawals or 
consent to limited study participation and appropriately document the discontinuation and 
the reason(s) why.
3.
PARTICIPANT REGISTRATION
The participant completes the Gender, Race, and Ethnicity Form and this is placed in the study 
binder.
RPCI does not grant exceptions to eligibility criteria.
Phase 1 Protocol Registration Instructions
Contact the RPCI Network Monitor to verify that a slot is available in the open cohort when a 
participant has been identified. Do not have the participant sign consent prior to verifying an 
open slot.

After the participant signs consent, the Subject Screening and Enrollment Log must be 
faxed or emailed to the RPCI Network Monitor within 1 business day. The RPCI Network 
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Monitor will confirm receipt of the Subject Screening and Enrollment Log and email the 
participant ID number.

When the participant has met eligibility, a signed eligibility checklist and other requested 
documentation will be faxed or emailed to the RPCI Network Monitor.

Within 1 business day of receipt of the eligibility check list, the RPCI Network Monitor 
will fax or email the cohort assignment and dose level.

An email must be sent by the site to confirm receipt of the cohort assignment and to provide 
the planned treatment start date.
4.
STUDY DEVIATIONS

If a deviation has occurred to eliminate hazard, this must be reported to the RPCI Network, 
site IRB and any other regulatory authority involved in the study.

ALL study deviations will be recorded on the Study Deviation Log.

Participants inadvertently enrolled with significant deviation(s) from the study-specified 
criteria will be removed from the study, at the discretion of the Principle Investigator.
5.
STUDY DOCUMENTATION

Study documents must be filled out completely and correctly. Ditto marks are not allowed.

If an entry has been documented in error put a single line through the entry and initial and 
date the change. The RPCI Network Monitor must be able to read what has been deleted.

Do NOT use white-out, magic marker, scratch-outs.

Do NOT erase entries.

Use only black ink for documentation on the accountability form and any other study 
forms.

It is the responsibility of RPCI to inform the Investigator/ institution as to when these 
documents no longer need to be retained. If, for any reason, the Investigator desires to no 
longer maintain the study records, they may be transferred to another institution, another 
investigator, or to RPCI upon written agreement between the Investigator and RPCI.
6.
DRUG ACCOUNTABILITY
Drug accountability must be strictly maintained.

Responsibility rests solely with the Investigator but can be delegated as appropriate (e.g., to 
pharmacy personnel).

A drug accountability record form (DARF) will record quantities of study drug received, 
dispensed to participants and wasted, lot number, date dispensed, participant ID number 
and initials, quantity returned, balance remaining, manufacturer, expiration date, and the 
initials of the person dispensing the medication.
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
Study drug supply will only be used in accordance with the IRB approved study.

Drug accountability forms are protocol and agent specific, they are study source documents 
and will be used to verify compliance with the study.

An inventory count must be performed with each transaction. Any discrepancies shall be 
documented and explained.

Drug accountability forms must be stored with study related documents.

Each medication provided for this study and each dosage form and strength must have its 
own DARF.

Dispensing the wrong study supply is considered a medication error.

NEVER replace investigational agents with commercial product.

Do NOT “transfer”, “borrow” or “replace” supplies between studies.
7.
SERIOUS ADVERSE EVENT REPORTING
The site Investigator or designated research personnel will report all SAEs, whether related or 
unrelated to the investigational agent(s) to the IRB in accordance with their local institutional 
guidelines. The site will notify the RPCI Network Monitor within 1 business day of being made 
aware of the SAE. In addition AEs must be reported to the drug supporters. See Section 17.4.1 of 
the protocol and Section 17.5 regarding additional notification requirements to BMS and 
Celldex. A preliminary written report must follow within 1 business day of the first notification 
using the following forms:

MedWatch 3500A 

RPCI SAE Source Form 
A complete follow-up report must be sent to the RPCI Network Monitor when new information 
becomes available.

If this is a Phase 1 study the site Investigator or designated research personnel will 
complete and send the Serious Adverse Event / Possible Dose Limiting Toxicity Memo 
to notify the appropriate RPCI personnel of an SAE or potential DLT via email: 
Phase1DLTnetwork@Roswellpark.org.
8.
UNANTICIPATED PROBLEM REPORTING
An unanticipated problem (UP) is any incident, experience, or outcome that meets all of the criteria 
in Section 17.6.
For all adverse events occurring that are unanticipated and related or possibly related to the 
research drug, biologic or intervention, the participating physician or delegated research staff from 
each site will notify their local IRB in accordance with their local institutional guidelines. The 
site must also notify the RPCI Network Monitor within 1 business day of being made aware of the 
Unanticipated Problem by completing the RPCI Unanticipated Problem Report Form and 
faxing or emailing it to the RPCI Network Monitor.
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9.
DATA AND SAFETY MONITORING 
Weekly or bi-weekly teleconferences will be scheduled to review participant adverse events and 
study status. The site Investigator and study coordinator are expected to attend.
Click here to enter text.
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