A Multicenter, Open-Label, Exploratory Platform Study to Evaluate Biomarkers and Immunotherapy Combinations for the Treatment of Patients With Metastatic Castration-resistant Prostate Cancer
Phase: PHASE1
Conditions: Metastatic Castration-resistant Prostate Cancer
Sponsor: Parker Institute for Cancer Immunotherapy

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Protocol Title:  A Multicenter, Open-Label, Exploratory Platform Study to Evaluate Biomarkers 
and Immunotherapy Combinations for the Treatment of Patients with Metastatic Castration-
resistant Prostate Cancer 
Appendix Cohort B 
Protocol Number:  PICI0033 
Amendment Number: Not applicable 
Compound Number:  CDX-301, Poly-ICLC, Nivolumab 
Short Title:  Platform Study for Prostate Researching Translational Endpoints Correlated to 
Response to Inform Use of Novel Combinations (PORTER) 
Sponsor Name and Legal Registered Address:   
Parker Institute for Cancer Immunotherapy 
1 Letterman Drive 
Suite D3500 
San Francisco, CA 94129 
Tel: 415-985-7311 
Fax: 415-872-5305 
Regulatory Agency Identifying Number(s):  
IND NUMBER: 139269 
EudraCT NUMBER:  Not applicable 
Approval Date:  Final Protocol: 11 December 2018  
 
Amendment 1: 24 January 2019 
 
CONFIDENTIAL 
This document and its contents are the property of and confidential to Parker Institute for Cancer 
Immunotherapy. Any unauthorized copying or use of this document is prohibited. 
 
 

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INVESTIGATOR PROTOCOL AGREEMENT PAGE 
I agree: 
• 
To assume responsibility for the proper conduct of the study at this site. 
• 
To conduct the study in compliance with this protocol, any future amendments, and with 
any other study conduct procedures provided by Parker Institute for Cancer 
Immunotherapy. 
• 
Not to implement any changes to the protocol without written agreement from Parker 
Institute for Cancer Immunotherapy and prior review and written approval from the 
Institutional Review Board or Independent Ethics Committee except where necessary to 
eliminate an immediate hazard to participants. 
• 
That I am thoroughly familiar with the appropriate use of the study drug(s), as described 
in this cohort appendix and any other information provided by Parker Institute for Cancer 
Immunotherapy including, but not limited to, the current Investigator’s Brochure(s). 
• 
That I am aware of, and will comply with, the International Conference on 
Harmonisation for Good Clinical Practice (GCP) and all applicable regulatory 
requirements. 
• 
To ensure that all persons assisting me with the study are adequately informed about the 
study drugs, the Parker Institute for Cancer Immunotherapy study protocol, and of their 
study-related duties and functions as described in the protocol. 
• 
That I agree that persons debarred from conducting or working on clinical studies by any 
court or regulatory agency will not be allowed to conduct or work on studies for the 
Parker Institute for Cancer Immunotherapy or for a partnership in which the Parker 
Institute for Cancer Immunotherapy is involved, and that I will immediately disclose in 
writing to the Parker Institute for Cancer Immunotherapy if any person who is involved 
in the study is debarred, or if any proceeding for debarment is pending. 
 
 
Signature: 
 
 
Date: 
 
 
Name 
(print): 
 
  
 
Site 
Number: 
Principal Investigator 
 
___________ 
  
 
 
  
 

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Amendment(s) to Appendix Cohort B 
Text revisions resulting from the amendment(s) are incorporated in the synopsis and body of the 
Appendix Cohort Amendment. Major changes to the appendix cohort are summarized below. 
Key Revisions in Amendment 1 (24 January 2019) 
Section # and Name 
Description of Change 
Study Design 
1.3 Schema, Figure 2 
Modified to improve identification of key research procedure time points. 
Study Intervention 
6.6.4 Dose Modifications for 
CDX-301 
Added text to reinforce that doses of CDX-301 should be withheld (eg, 
skipped) for toxicity attributed to CDX-301. 
Add text to clarify that toxicities attributed to CDX-301 that require dose 
delays greater than 6 weeks will require Medical Monitor approval for 
the participant to restart treatment. 
6.6.5 Dose Modifications for Poly-
ICLC 
Add text to clarify that toxicities attributed to poly-ICLC that require 
dose delays greater than 6 weeks will require Medical Monitor approval 
for the participant to restart treatment. 
Clarification of Document 
General Revisions 
Document updated to address minor typographical errors and editorial 
changes for clarity. 
Appendix B-1 
Reordered the management algorithms to match the order on the 
appendix cover page. 
 
 

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TABLE OF CONTENTS 
 
TABLE OF CONTENTS .................................................................................................................5 
LIST OF TABLES ...........................................................................................................................8 
LIST OF FIGURES .........................................................................................................................8 
1 
PROTOCOL SUMMARY ...................................................................................................9 
1.1 
SYNOPSIS ...............................................................................................................9 
1.2 
SCHEMA ...............................................................................................................11 
1.3 
SCHEDULE OF ACTIVITIES..............................................................................13 
2 
INTRODUCTION .............................................................................................................17 
2.1 
STUDY RATIONALE ..........................................................................................17 
2.2 
BACKGROUND ...................................................................................................17 
2.2.1 
Background on Radiation Therapy ..........................................................19 
2.2.2 
Background on rhuFLT3L/CDX-301 (Celldex Therapeutics, Inc.) ........20 
2.2.3 
Background on Poly-ICLC (Oncovir, Inc.) .............................................22 
2.2.4 
Background on Nivolumab (Bristol-Myers Squibb Company) ...............23 
2.2.5 
Rationale for SBRT + CDX-301+ Poly-ICLC+ Nivolumab 
Immunotherapy Combination ..................................................................24 
2.3 
BENEFIT/RISK ASSESSMENT ..........................................................................27 
3 
OBJECTIVES AND ENDPOINTS ...................................................................................28 
4 
STUDY DESIGN...............................................................................................................29 
4.1 
OVERALL DESIGN .............................................................................................29 
4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN ...........................................30 
4.3 
JUSTIFICATION FOR DOSE ..............................................................................30 
4.3.1 
Rationale for Nivolumab Dose and Schedule .........................................30 
4.3.2 
Rationale for CDX-301 Dose and Schedule ............................................31 
4.3.3 
Rationale for Poly-ICLC Dose and Schedule ..........................................32 
4.3.4 
Rationale for Stereotactic Body Radiation Therapy Dose and Schedule 33 
4.4 
TREATMENT BEYOND DISEASE PROGRESSION ........................................33 
4.5 
END OF STUDY DEFINITION ...........................................................................34 
5 
STUDY POPULATION ....................................................................................................34 
5.1 
INCLUSION CRITERIA.......................................................................................34 

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5.1.1 
Common Inclusion Criteria .....................................................................34 
5.1.2 
Combination-specific Inclusion Criteria .................................................36 
5.2 
EXCLUSION CRITERIA .....................................................................................36 
5.2.1 
Common Exclusion Criteria ....................................................................36 
5.2.2 
Combination-specific Exclusion Criteria ................................................38 
5.3 
LIFESTYLE CONSIDERATIONS .......................................................................38 
5.4 
SCREEN FAILURES ............................................................................................38 
6 
STUDY INTERVENTION ................................................................................................38 
6.1 
STUDY INTERVENTION(S) ADMINISTERED ................................................38 
6.2 
PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY ......................39 
6.3 
RANDOMIZATION AND BLINDING................................................................40 
6.4 
STUDY INTERVENTION COMPLIANCE .........................................................40 
6.5 
CONCOMITANT THERAPY...............................................................................40 
6.5.1 
Permitted Therapy ...................................................................................40 
6.5.2 
Prohibited Therapy ..................................................................................40 
6.6 
DOSE MODIFICATIONS ....................................................................................40 
6.6.1 
Dose Modifications for the Combination of Nivolumab, CDX-301, and 
Poly-ICLC ...............................................................................................40 
6.6.1.1 
Potential for Overlapping Toxicities with the Combination of 
SBRT, Nivolumab, CDX-301, and Poly-ICLC .....................42 
6.6.1.2 
Dose Modifications and Toxicity Management for Adverse 
Events Associated with the Combination of Nivolumab, 
CDX-301, and Poly-ICLC .....................................................43 
6.6.1.3 
Dose Modifications and Toxicity Management for 
Infusion/Injection-related Reactions Associated with the 
Administration of CDX-301, Poly-ICLC, and/or Nivolumab
 ...............................................................................................44 
6.6.1.4 
Dose Delays and Interruptions of Nivolumab, CDX-301, and 
Poly-ICLC .............................................................................46 
6.6.2 
Dose Modification for SBRT ..................................................................46 
6.6.3 
Dose Modifications for Nivolumab .........................................................46 
6.6.4 
Dose Modifications for CDX-301 ...........................................................48 
6.6.5 
Dose Modifications for Poly-ICLC .........................................................49 
7 
DISCONTINUATIONS OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL..........................................................................49 

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7.1 
DISCONTINUATION OF STUDY INTERVENTION ........................................49 
7.2 
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM STUDY ........50 
7.3 
LOST TO FOLLOW-UP .......................................................................................50 
8 
STUDY ASSESSMENTS AND PROCEDURES .............................................................50 
8.1 
EFFICACY ASSESSMENTS ...............................................................................50 
8.1.1 
Laboratory Assessments of Clinical Activity ..........................................50 
8.2 
SAFETY ASSESSMENTS ....................................................................................50 
8.2.1 
Clinical Safety Laboratory Assessments .................................................50 
8.2.1.1 
Local Laboratory Assessments ..............................................50 
8.3 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS ..............................51 
8.3.4 
Regulatory Reporting Requirements for SAEs .......................................51 
8.3.7 
Adverse Events of Special Interest ..........................................................52 
8.4 
TREATMENT OF OVERDOSE ...........................................................................52 
8.5 
PHARMACOKINETICS .......................................................................................52 
8.6 
ANTI-DRUG ANTIBODIES ................................................................................52 
8.7 
BIOMARKERS .....................................................................................................52 
8.8 
MEDICAL RESOURCE UTILIZATION AND HEALTH ECONOMICS ..........52 
9 
STATISTICAL CONSIDERATIONS...............................................................................52 
9.5.1 
Interim Safety Monitoring .......................................................................52 
10 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS ....54 
10.1 
APPENDIX B-1: MANAGEMENT ALGORITHMS ..........................................55 
10.2 
APPENDIX B-2: LISTS OF TERMINOLOGY AND ABBREVIATIONS .........63 
10.2.1 
List of Terminology .................................................................................63 
10.2.2 
List of Abbreviations ...............................................................................63 
10.3 
APPENDIX B-3: APPENDIX COHORT B AMENDMENT HISTORY ............67 
11 
REFERENCES ..................................................................................................................68 
 

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LIST OF TABLES 
Table 1: 
Schedule of Activities ............................................................................................14 
Table 2: 
Clinical Studies Supporting the Co-administration of Components of this Study 
Intervention ............................................................................................................25 
Table 3: 
Cohort-Specific Objectives and Corresponding Endpoints ...................................28 
Table 4: 
Study Intervention ..................................................................................................38 
Table 5: 
Toxicity Criteria Requiring Permanent Treatment Discontinuation ......................42 
Table 6:  
Dose Modification and Toxicity Management Guidelines for Infusion/Injection-
related Reactions Associated with the Administration of CDX-301, Poly-ICLC, 
and/or Nivolumab ..................................................................................................45 
Table 7: 
Dose Modification and Toxicity Management Guidelines for Adverse Events 
Associated with Nivolumab ...................................................................................47 
Table 8: 
Dose Modification and Toxicity Management Guidelines for Adverse Events 
Associated with CDX-301 .....................................................................................49 
Table 9: 
Laboratory Tests Sent to the Study Site’s Local Laboratory for Analysis of 
Disease-related Endpoints ......................................................................................50 
Table 10: 
Laboratory Tests Sent to the Study Site’s Local Laboratory for Analysis of Safety
................................................................................................................................51 
Table 11: 
Probability of Proceeding to Full Enrollment ........................................................53 
Table 12: 
Incidence with 95% Confidence Intervals of Possible Observed Adverse Events 
Described in Table 5 ..............................................................................................53 
 
 
LIST OF FIGURES 
Figure 1: 
Mechanism of Action for SBRT + CDX-301 + Poly-ICLC + Nivolumab ............10 
Figure 2: 
Study Schema.........................................................................................................12 
Figure 3: 
Correlation Between Tumor Mutational Burden and Objective Response Rate 
with Anti-PD-1 or Anti-PD-L1 Therapy in 27 Tumor Types ................................17 
Figure 4: 
Spectrum of Inflamed Tumor Microenviroment Phenotype and Tumor Mutational 
Burden Across Human Cancer Types ....................................................................18 
 

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1 
PROTOCOL SUMMARY 
1.1 
SYNOPSIS 
Protocol Title: 
A Multicenter, Open-Label, Exploratory Platform Study to Evaluate Biomarkers and 
Immunotherapy Combinations for the Treatment of Patients with Metastatic Castration-resistant 
Prostate Cancer 
Appendix Cohort B 
Short Title: 
Platform Study for Prostate Researching Translational Endpoints Correlated to Response to 
Inform Use of Novel Combinations (PORTER) 
Note to Investigators:  This cohort appendix is intended to supplement the core protocol, and as 
such, will focus on combination-specific (stereotactic body radiation therapy [SBRT], CDX-301, 
poly-ICLC [polyinosinic-polycytidylic acid stabilized with polylysine and 
carboxymethylcellulose], and nivolumab) information that is not already available in the core 
protocol. 
Rationale: 
This study cohort is designed to explore a multi-pronged approach to induce immunogenic cell 
death, mobilizing and activating dendritic cells (DCs), and overcoming adaptive immune 
resistance (T cells) in metastatic castration-resistant prostate cancer (mCRPC) (Figure 1). 
Immunogenic cell death induces the release of tumor antigens. Maturation and activation of DCs, 
an antigen presenting cell, mediates antigen presentation to CD8 T cells to stimulate antitumor 
immunity. Programmed cell death 1 (PD-1) blocking antibodies allow for the activation of 
tumoral CD8 T cells and the promotion of antitumor immunity. Specifically: 
• Radiation therapy to induce immunogenic cell death of the tumor 
• Flt3 ligand (CDX-301) to induce mobilization and activation of DCs 
• Poly-ICLC and radiation therapy to induce maturation/activation of DCs 
• Anti-PD-1 monoclonal antibody (nivolumab) to overcome immune suppression of 
tumoral T cells 
 

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Figure 1: 
Mechanism of Action for SBRT + CDX-301 + Poly-ICLC + Nivolumab 
 
 
Objectives and Endpoints: 
Refer to the core protocol. 
Combination-specific exploratory objectives include: 
Combination-specific Exploratory Objectives 
Endpoints 
• To evaluate the PK of CDX-301 and/or nivolumab. 
• To evaluate the immunogenicity (ADA) of 
CDX-301 and/or nivolumab. 
• Sparse PK analysis. 
• Presence of ADA against CDX-301 and/or 
nivolumab. 
ADA = anti-drug antibodies; PK = pharmacokinetics 
 
Overall Design, Number of Participants, Follow-up, and Data Monitoring Committee: 
Refer to the core protocol. 
Intervention Groups and Duration: 
Participants will be assigned to receive one of the enrolling immunotherapy combination study 
interventions. In this cohort, participants will receive SBRT, CDX-301, poly-ICLC, and 
nivolumab as follows: 

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Intervention 
Dose 
Frequency 
Route 
Schedule 
CDX-301 
75 µg/kg 
QD 
SC 
Days 1 -5 
SBRT 
30-50 Gy in 1-5 doses. Radiation will start on Day 1 or 2 
Poly-ICLC 
1 mg 
Twice weekly x 3 weeks 
IM 
Starting on Day 1 
Nivolumab 
480 mg 
Q4W 
IV over 30 minutes 
Starting Day 1 
Gy = gray; IM = intramuscular(ly); IV = intravenous(ly); QD = daily; Q4W = every 4 weeks; SBRT = stereotactic 
body radiation therapy; SC = subcutaneous(ly) 
 
SBRT and CDX-301/poly-ICLC will be administered during the first cycle only. Nivolumab will 
be administered for up to 2 years, unless the participant: is no longer clinically benefiting (as 
evidenced by symptomatic or radiographic disease progression and/or clinical deterioration); 
experiences any toxicity meeting specified discontinuation criteria (see Section 6.6) or 
unacceptable toxicity in the best clinical discretion of the treating physician (ie, Investigator 
discretion); reaches the maximum duration of study intervention; or withdraws consent. In this 
cohort, a cycle is defined as 4 calendar weeks. 
1.2 
SCHEMA 
The study schema is depicted in Figure 2. 

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Figure 2: 
Study Schema 
 
IM = intramuscularly; IV = intravenously; mCRPC = metastatic castration-resistant prostate cancer; Q4W = every 4 weeks; SBRT = stereotactic body radiation 
therapy; SC = subcutaneously 
Note: The horizontal axis is not linearly scaled, so the interval for Cycle 1 appears to be much longer than for the subsequent cycles. 
SBRT, CDX-301, and poly-ICLC will be administered during the first cycle only. Nivolumab will be administered for up to 2 years, unless the participant: is no 
longer clinically benefiting (as evidenced by symptomatic or radiographic disease progression and/or clinical deterioration); experiences any toxicity meeting 
specified discontinuation criteria (see Section 6.6) or unacceptable toxicity in the best clinical discretion of the treating physician; reaches the maximum 
duration of study intervention; or withdraws consent. A cycle is defined as 4 calendar weeks. Participants will be followed for up to 2.5 years from the time of 
the initiation of study intervention. 
This study design is applicable to Stage 1, as well as Stage 2 if the cohort is expanded. 

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1.3 
SCHEDULE OF ACTIVITIES 
The Schedule of Activities (SOA) shown in Table 1 is specific for this combination and 
supersedes the SOA provided in the core protocol. 

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Table 1: 
Schedule of Activities 
Tests & Procedures 
Screening/ 
Enrollmenta 
On-Treatment: SBRT + CDX-301 + poly-ICLC + Nivolumab 
End of 
Treatmentb 
Follow up 
Cycle 1 (Q4W) 
Cycles 
2,3, and 4 
Cycle 5 
Onward 
Day 
Day -28 to 
Day -1 
Day 1 
Day 2 - 5 
Day 8 
Day 15 
Day 1 
Day 1 
14 - 28 days 
after last 
dose 
110 days 
after last 
dose 
Q3Mc 
Window (days) 
-28 
 
 
± 1 
± 1 
± 3 
± 3 
± 7 
± 10 
± 14 
Informed consentd 
X 
 
 
 
 
 
 
 
 
 
Review of I/E criteria 
X 
 
 
 
 
 
 
 
 
 
Medical/cancer history 
X 
 
 
 
 
 
 
 
 
 
Physical examination 
X 
X 
 
 
 
X 
X 
X 
 
 
ECOG performance status 
X 
X 
 
 
 
X 
X 
X 
X 
 
Vital signs (See Core 
Protocol Section 8.2.3) 
X 
X 
 
 
 
X 
X 
X 
 
 
Body weight 
X 
X 
 
X 
X 
X 
X 
(Cycles 5, 
8, 11, 14, 
17, 20, 23, 
and 26) 
X 
 
 
Hematology (see Table 10) 
X 
Xe 
 
Xe 
Xe 
Xe 
Xe 
X 
X 
 
Clinical chemistry (see 
Table 10) 
X 
Xe 
 
Xe 
Xe 
Xe 
Xe 
X 
X 
 
Urinalysis 
X 
 
 
 
 
 
 
X 
 
 
Prostate-specific antigen 
X 
X 
 
 
 
X 
X 
X 
X 
 
Testosterone level 
X 
 
 
 
 
 
 
 
 
 
12-lead ECG 
X 
 
 
 
 
X (Cycles 
2 and 4) 
 
 
 
 
Circulating tumor cellsf 
 
Xe 
 
 
 
Xe 
Xe 
X 
 
 
cfDNA (blood)g 
X 
 
 
 
 
Xe (Cycles 
2 and 4) 
 
X 
 
 

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Tests & Procedures 
Screening/ 
Enrollmenta 
On-Treatment: SBRT + CDX-301 + poly-ICLC + Nivolumab 
End of 
Treatmentb 
Follow up 
Cycle 1 (Q4W) 
Cycles 
2,3, and 4 
Cycle 5 
Onward 
Day 
Day -28 to 
Day -1 
Day 1 
Day 2 - 5 
Day 8 
Day 15 
Day 1 
Day 1 
14 - 28 days 
after last 
dose 
110 days 
after last 
dose 
Q3Mc 
Window (days) 
-28 
 
 
± 1 
± 1 
± 3 
± 3 
± 7 
± 10 
± 14 
Circulating soluble 
analytes/PK/ADAh 
X 
Xe 
Xe  
(Day 5) 
Xe 
Xe 
Xe (Cycles 
2, 3, and 4) 
 
X 
X 
 
Blood immune 
biomarkersh 
X 
Xe 
Xe 
(Day 5) 
X 
X 
Xe (Cycles 
2, 3, and 4) 
 
X 
 
 
Archival tumor tissue 
X 
 
 
 
 
 
 
 
 
 
Tumor biopsyi 
X 
 
 
 
 
X (Cycle 2) 
 
X (at PD 
[optional])i 
 
 
Stool collectionj 
X 
 
 
 
 
X (Cycle 2)j 
 
 
 
 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Adverse events 
All AEs and SAEs will be collected for at least 100 days after the last dose of study interventionk 
 
Radiation therapyl 
 
X 
X 
 
 
 
 
 
 
 
CDX-301 administrationm 
 
X 
X 
 
 
 
 
 
 
 
Poly-ICLC administrationn 
 
X 
X (twice 
weeklyn)  
X (twice 
weeklyn) 
X (twice 
weeklyn) 
 
 
 
 
 
Nivolumab administrationo 
 
X 
 
 
 
X 
X 
 
 
 
Radiographic disease 
assessment 
X 
At Week 8 (± 1 week), repeat every 8 weeks (± 1 week) for the first 24 weeks, and every 12 weeks (± 1 week) 
thereafter until radiographic PD or start of subsequent therapy 
Review of alternate 
anticancer therapyp 
 
 
 
 
 
 
 
 
X 
X 
Follow up for overall 
survival 
 
 
 
 
 
 
 
 
X 
X 
ADA = anti-drug antibodies; AE(s) = adverse event(s); cfDNA = cell-free deoxyribonucleic acid; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; 
EOT = end of treatment; Gy = grays; I/E = inclusion/exclusion; IM = intramuscularly; IV = intravenously; PD = progressive disease; PK = pharmacokinetics; Q3M = every 3 
months; Q4W = every 4 weeks; QD = every day; SAE(s) = serious adverse event(s); SC = subcutaneously 

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a Tests/procedures performed as standard of care prior to obtaining informed consent and within 28 days prior to the first dose of study intervention do not have to be repeated at 
screening. 
b The End of Treatment Visit will be completed following the last dose of study intervention, either at the completion of the on-treatment phase or at early discontinuation. 
c For up to 2.5 years from the initiation of study intervention, participants in the follow up phase will be contacted by the site to collect alternate anticancer therapy information 
and determine survival status. 
d Informed consent must be obtained prior to any study-specific procedures and may be obtained prior to the 28-day screening window. 
e Blood samples should be collected prior to administration of any study intervention. 
f Circulating tumor cells will be collected at baseline (ie, Day 1 of Cycle 1 prior to study intervention administration), Day 1 of each cycle (prior to study intervention 
administration), and EOT. 
g cfDNA (blood) will be collected at baseline (ie, screening visit prior to study intervention administration), Day 1 of Cycle 2 and Cycle 4, and EOT. 
h Circulating soluble analytes, PK and ADA blood sample, and/or blood immune biomarkers may be assessed at baseline (ie, screening and/or Day 1 of Cycle 1 prior to study 
intervention administration), prior to study intervention administration on Days 1, 5, 8, and 15 of Cycle 1 and Day 1 of Cycles 2-4, and at EOT and the first follow up visit. 
i Participants will undergo 2-3 tumor biopsies: prior to beginning protocol therapy (ie, baseline biopsy, mandatory for all participants, including those with bone only disease if 
medically feasible), and during treatment (ie, on-treatment biopsy during Cycle 2, if medically feasible). On- treatment biopsy should occur as early as possible after the second 
dose (Day 2 – Day 10 of Cycle 2); however, any on treatment biopsy after Day 1 of Cycle 2 will be accepted. An optional biopsy may be obtained at the time of disease 
progression, including from participants who respond and subsequently progress. Every attempt should be made for the on-treatment biopsies to be taken from the same lesion as 
the pre-treatment biopsy when feasible. 
j Stool will be collected at screening and during Cycle 2, if possible. Otherwise, any on-treatment stool sample will be acceptable. The stool sample may be collected at the clinic 
or at the participant’s home. 
k All SAEs will be collected from the time the participant signs informed consent. Prior to initiation of study intervention, only SAEs that are related to a protocol-mandated 
intervention, including those that occur prior to the assignment of study procedures should be reported. All AEs will be collected from the start of study intervention. All AEs 
and SAEs will be collected for at least 100 days after the last dose of study intervention. Refer to Section 8.3 of the core protocol for details regarding safety reporting for this 
study. 
l Radiation therapy will be administered at 30 – 50 Gy in 1 – 5 doses, starting on Day 1 or 2.  
m CDX-301 will be administered at a dose of 75 µg/kg SC QD x 5 days (Days 1 – 5 [ie, Monday – Friday]), concurrent with SBRT. 
n Poly-ICLC will be administered at a dose of 1 mg IM twice weekly, at least 2 days apart, for 3 weeks starting on Day 1. The dose may be administered at any time of the day but 
should occur at approximately the same time on poly-ICLC administration days. 
o Nivolumab will be administered at a dose of 480 mg IV over 30 minutes Q4W starting on Day 1 of Cycle 1 and will continue for up to 2 years, unless the participant: is no 
longer clinically benefiting (as evidenced by symptomatic or radiographic disease progression and/or clinical deterioration); experiences any toxicity meeting specified 
discontinuation criteria (see Section 6.6) or unacceptable toxicity in the best clinical discretion of the treating physician; reaches the maximum duration of study intervention; or 
withdraws consent. A cycle is defined as 4 calendar weeks. The time between nivolumab doses must not be less than 24 days. 
p Collection of information related to any post-study intervention alternate anticancer therapy. 
 

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2 
INTRODUCTION 
Refer to the core protocol. 
2.1 
STUDY RATIONALE 
Refer to the core protocol. 
2.2 
BACKGROUND 
Immune checkpoint blockade, particularly with programmed cell death 1 (PD-1) or programmed 
cell death ligand 1 (PD-L1) antibodies, has changed the landscape for the treatment of a variety 
of advanced solid tumors. Though the majority of patients with a specific tumor type don’t 
respond to treatment, a notable subset of patients across tumor types achieve durable responses 
in the context of relatively well tolerated therapy leading to the substantial enthusiasm for this 
therapeutic class (Figure 3). However, not only is there intra-tumor-type variability in the 
likelihood of response to PD-1/PD-L1 blockade but there is also substantial inter-tumor type 
heterogeneity (Yarchoan et al., 2017). Prostate cancer has been among the tumor types for which 
single-agent PD-1/PD-L1 blockade has been associated with relatively rare responses, and the 
responses that do occur are typically in the context of a genomically-defined subset of cancers 
(ie, mismatch repair deficient tumors) (Graff et al; 2016). Therefore, there is a critical need to 
develop rational combination strategies to extend the benefits of PD-1/PD-L1 blockade to 
patients with metastatic castration-resistant prostate cancer (mCRPC). 
Figure 3: 
Correlation Between Tumor Mutational Burden and Objective Response 
Rate with Anti-PD-1 or Anti-PD-L1 Therapy in 27 Tumor Types 
 
Source: Adapted from Yarchoan et al., 2017 

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Clues as to why prostate cancers may be less responsive to single-agent PD-1/PD-L1 blockade 
may be derived from studies exploring biomarkers predictive of response and resistance to 
treatment in tumor types associated with a higher likelihood of response. Indeed, multiple studies 
have demonstrated that patients with tumors harboring a higher tumor mutational burden (TMB) 
and/or with a pre-existing infiltration of T cells (or other measures of “hot” tumors) are more 
likely to respond to PD-1/PD-L1 blockade (Yarchoan et al., 2017; Tumeh et al., 2014). 
Interestingly, these two general categories of biomarkers have been shown to confer independent 
predictive/prognostic information in prior analyses such that patients with low TMB but high T 
cell infiltration have a similar likelihood of response compared with patients with high TMB but 
low T cell infiltration (Galsky et al., 2017). These observations may be extended to the 
heterogeneity in responses to PD-1/PD-L1 blockade across different tumor types; for example, 
renal cancer, despite generally harboring a relatively low TMB is frequently associated with high 
T cell infiltration and is felt to be a PD-1/PD-L1 treatment responsive tumor type. Prostate 
cancer, on the other hand, is generally associated with both a low TMB and low T cell 
infiltration (Figure 4). 
Figure 4: 
Spectrum of Inflamed Tumor Microenviroment Phenotype and Tumor 
Mutational Burden Across Human Cancer Types 
 
(A) the “inflamed” tumor microenvironment phenotype and (B) tumor mutational burden across human cancer types 
(Source: Spranger et al., 2016). 
 

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Consistent with observations from other groups, Spranger et al. reported a lack of correlation 
between measures of T cell infiltration and TMB across various tumor types (Figure 4; Spranger 
et al., 2016). This critical observation indicates that the lack of spontaneous immune infiltration 
in solid tumors is unlikely to be due simply to a lack of immunogenic tumor antigens. Rather, 
Spranger et al. demonstrated that tumors lacking T cell infiltration were also lacking in 
transcriptional profiles indicating the presence of dendritic cells (DCs). Together, these findings 
suggest that (a) strategies to restore T-cell entry into non-inflamed tumors should be developed 
to further improve outcomes with PD-1/PD-L1 blockade and (b) recruitment of DCs, key to the 
development of an adaptive immune response, may be a rate limiting step in the development of 
an inflamed tumor regardless of TMB, and furthermore, an immune response may be activated if 
this is combined with agents that induce immunogenic cell death.  
2.2.1 
Background on Radiation Therapy 
External beam radiotherapy induces immunogenic cell death (Obeid et al., 2007) and production 
of maturation signals for DCs leading to improved cross presentation (Rovere et al., 1998; 
Golden et al., 2014) which are likely mechanisms for recurrently observed ‘abscopal effects,’ in 
which local radiotherapy causes regression of metastatic cancer at a distant site by itself or in 
combination with immune checkpoint blockade (Postow et al., 2012; Golden et al., 2013). The 
rationale behind combining with immunotherapy is to co-localize the immunogenic cell death 
and antigen release induced by radiation with effective antigen presenting cell (APC) processing 
and cross-presentation to cytotoxic T-cells (Gulley et al., 2005). 
Given the potentially complimentary mechanisms of action of radiation therapy and immune 
checkpoint blockade, and the potential for therapeutic synergy, several studies have explored 
combination regimens. Indeed, in the randomized trial of ipilimumab versus placebo in patients 
with mCRPC progressing despite docetaxel, patients received one fraction of bone-directed 
radiotherapy (8 grays [Gy]) prior to ipilimumab versus placebo (Kwon et al., 2014). 
Unfortunately, this study failed to demonstrate a survival benefit with ipilimumab though this 
outcome may have been attributed to a variety of factors including the patient population, use of 
cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) blockade, and/or dose of radiation 
therapy.   
Luke et al. recently reported the results of a large phase 1 study for patients with metastatic solid 
tumors progressing despite standard treatment (Luke et al., 2018). The primary aim was to 
evaluate the safety of pembrolizumab given in combination with multi-organ site ablative 
stereotactic body radiation therapy (SBRT). Two to four metastases were chosen for each patient 
and not all sites of disease were targeted with SBRT. Metastases > 65 cubic centimeters were 
partially irradiated. Pembrolizumab was initiated within 7 days after the final SBRT treatment. 
Among 73 patients included and treated with SBRT and at least 1 cycle of pembrolizumab, the 

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vast majority (94.5%) had two lesions treated with SBRT. Response Evaluation Criteria in Solid 
Tumors (RECIST) overall objective response rate was 13.5% in the 68 patients with imaging 
follow-up. Superior control of irradiated lesions was observed compared to non-irradiated target 
lesions for the 52 patients with paired data (p = 0.0005) with a mean percent tumor burden 
change -21.7% (standard deviation [SD] 24.3%) for irradiated lesions vs. 1.7% (SD 46.3%) for 
non-irradiated lesions (p = 0.0008). While abscopal response defined by 30% reduction in any 
single non-irradiated measurable lesion was present in 26.9% of patients, abscopal response was 
13.2% when defined by 30% reduction in aggregate diameter of non-irradiated measurable 
lesions. Treatment was generally well tolerated with acceptable toxicity. Expression of interferon 
(IFN)-γ–associated genes from post–SBRT tumor biopsy specimens significantly correlated with 
nonirradiated tumor response. These findings provide rationale for further studies of combination 
SBRT plus PD-1 blockade.  
The safety of SBRT has been demonstrated in the treatment of adrenal metastases, in which 
SBRT was associated with excellent local control and very low toxicity rates, providing an 
alternative to image-guided ablative procedures (Toesca et al., 2018). Furthermore, the analysis 
suggested that adrenal SBRT has minimal, if any, significant impact on renal function. Further 
studies with a larger patient population are needed to confirm these findings. 
The acute toxicities associated with the use of SBRT in patients with localized prostate cancer 
have been primarily genitourinary (GU) and gastrointestinal (GI) in nature (Syed et al., 2017; 
Haque et al., 2017; King et al., 2013). In most studies, acute toxicities were limited to Grade 1 
or 2; the incidence of ≥ Grade 3 toxicities was typically < 5%. While most late toxicities were 
Grade 1 or 2, the majority of studies have reported at least 1 ≥ Grade 3 late urinary toxicity (Syed 
et al., 2017). 
2.2.2 
Background on rhuFLT3L/CDX-301 (Celldex Therapeutics, Inc.) 
rhuFLT3L/CDX-301 is the soluble recombinant human (rhu) protein form of the FMS-related 
tyrosine kinase 3 ligand (Flt3L), a hematopoietic cytokine. CDX-301 represents the 153 N-
terminal amino acids of the human Flt3L extracellular domain after the cleavage of the N-
terminal signal peptide. 
Flt3L is a hematopoietic growth factor that plays an important role in the mobilization and 
expansion of stem cells and progenitors (Lyman and Jacobsen, 1998). In particular, it has been 
shown to facilitate the differentiation of both DCs and natural killer cells from hematopoietic 
stem cell precursors (Blom et al., 2000; Chen et al., 2005; Gilliet et al., 2002; Miller et al., 1999). 
Specifically, Flt3L directly induces the differentiation of a proportion of CD34+ CD45RA- early 
progenitor cells into pre-DCs, and results in increased numbers of activated DCs (Blom et al., 
2000; Breton et al., 2016). In healthy human volunteers it has been demonstrated that Flt3L 

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administration increases the number of DCs, as well as CD14+ monocytes (Chen et al., 2005; 
Anandasabapathy et al., 2015; Maraskovsky et al., 1996; Pulendran et al., 1997). 
Numerous pre-clinical models have shown the ability of Flt3L administration to mobilize a range 
of immune cell subsets, DCs predominant among these (Brasel et al., 1996; Fernandez et al., 
1998; Kutzler and Weiner, 2004; Miller et al., 2003). Flt3L administration has demonstrated 
antitumor activity in a variety of tumor models including melanoma, lymphoma, leukemia, 
breast, colon, prostate, lung and hepatocellular carcinoma (Averbook et al., 2002; Ciavarra et al., 
2000; Drexler et al., 1999; Esche et al., 1998; Hou et al., 2007; Wang et al., 2000; Chakravarty et 
al., 1999). Several preclinical studies have suggested combining Flt3L with radiation, checkpoint 
inhibitors, and/or poly-ICLC (polyinosinic-polycytidylic acid stabilized with polylysine and 
carboxymethylcellulose) results in significant antitumor activity and the ability to elicit an 
antitumor immune response in cold or resistant tumors. Preclinical studies have demonstrated 
improved antitumor effects and tumor-specific immunity when Flt3L is combined with 
radiotherapy. In a breast adenocarcinoma model, radiotherapy alone led to growth delay only in 
the irradiated tumors, whereas growth of distant (non-irradiated) tumors was also impaired by the 
combination of radiotherapy and Flt3L. Importantly, in this breast cancer adenocarcinoma 
model, Flt3L alone had no effect without radiotherapy and systemic tumor-specific immunity, 
known as the abscopal effect, was elicited by the combined therapy and shown to be T-cell 
mediated (Demaria et al., 2004). Additionally, radiotherapy plus Flt3L administration (500 
μg/kg/day) over 10 days reduced pulmonary metastases in a murine model of Lewis lung 
carcinoma, retarded the growth of established tumors, induced tumor-specific T- cell immunity 
and significantly improved survival in C57BI/6 mice with established footpad tumors 
(Chakravarty et al., 1999). Preclinical models have also shown that Flt3L administration can 
enhance the antitumor immunity of checkpoint inhibitors such as PD-1 and CTLA-4 antibodies 
to promote tumor regression of non-immunogenic tumors (Lynch et al., 1997). When Flt3L is 
administered with poly-ICLC, a TLR3 agonist, it results in a marked increase in activated 
intratumoral DCs and renders resistant tumors susceptible to PD-1 blockage in mouse tumor 
models (Salmon et al., 2016). 
Flt3L has been used in many early phase human clinical trials of different immunotherapeutic 
approaches—as an adjuvant or in order to mobilize DCs for collection to produce a cellular 
vaccine—in patients with colorectal cancer, non-small cell lung cancer, mesothelioma, and 
prostate cancer, among others, and demonstrated safety with minimal toxicity from Flt3L 
administration through multiple routes of administration (Fong et al., 2001; Freedman et al., 
2003; Higano et al., 2004; Morse et al., 2000).  
A study in 31 patients with nonmetastatic castration-resistant prostate cancer (nmCRPC) 
evaluated the impact of Flt3L administration on peripheral blood DCs and post-treatment 

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changes in prostate-specific antigen (PSA; Higano et al., 2004). DCs increased markedly from 
baseline to Day 15, and the increase was consistently observed after administration of Flt3L in 
each cycle. Mean percentages of DCs in peripheral blood ranged from 1.4% to 1.9% pre-cycle 
and from 10.1% to 13.9% on Day 15, and after the first cycle, absolute counts on Day 15 were 
approximately 29-fold higher than pre-cycle levels. Natural killer (NK) cell counts (CD56+) 
were found to be elevated after cycle 1 (154% increase versus 2.8% decrease in placebo group at 
Day 22). The most frequently experienced toxicity was injection site reaction, followed by 
asthenia, rash, and diarrhea. Although median PSA levels did not vary during any cycle, a 
significant slowing in velocity of PSA was observed while patients were on-study (relative 
velocity = 0.002) compared with prestudy PSA velocity (relative velocity = 0.007). Given that 
Flt3L consistently produced an increase in DC numbers and the slowing of PSA velocity after 
administration, the authors concluded that Flt3L warrants further study for the immunotherapy of 
prostate cancer. 
Preliminary results of a single-arm study exploring CDX-301 plus SBRT for non-small cell lung 
cancer (NSCLC) were reported at the American Association for Cancer Research 2018 Annual 
Meeting (Ohri et al., 2018). In this study, SBRT was administered to a single lung lesion in 1-5 
fractions concurrently with CDX-301 (75 μg/kg subcutaneously [SC] daily x 5). Among 9 
patients enrolled at the time of the presentation, 7 had previously been treated with PD-1/PD-L1 
blockade. Intriguingly, partial responses (excluding the irradiated lesion) were seen in 3/9 
patients. Further, the regimen was demonstrated to be safe with no unexpected toxicities. 
Refer to the Investigator’s Brochure (IB; CDX-301/Recombinant Human Flt3 Ligand [rhuFlt3L] 
Investigator’s Brochure, 2018) for detailed background information on rhuFLT3L/CDX-301. 
2.2.3 
Background on Poly-ICLC (Oncovir, Inc.) 
Poly-ICLC (also known as Hiltonol®), is a stabilized double-stranded ribonucleic acid (dsRNA) 
‘host-targeted’ therapeutic viral-mimic that exhibits broad innate and adaptive immune 
enhancing effects. It was used as an interferon inducer at high doses (up to 300 μg/kg 
intravenously [IV]) in cancer trials; at lower doses (10 to 50 μg/kg) it achieves a broader host 
defense stimulation, a potent adjuvant effect, anti-proliferative and antiviral effects (Maluish et 
al., 1985). 
The possible antitumor and antiviral activity of poly-ICLC is thought to be dependent on its 
stimulation of at least 4 interrelated systems that may work independently or in concert with one 
another. These include the induction of IFN, the modulation of gene expression, a direct 
antiviral/antineoplastic effect, and a broad immune-enhancing effect. 
While initially developed as an IFN inducer, poly-ICLC also has much broader biological effects 
in humans, including specific antiviral and antitumor actions. It is, more accurately, a synthetic, 

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stabilized dsRNA therapeutic viral mimic or pathogen associated molecular pattern ‘danger 
signal’ that activates multiple elements of innate and adaptive immunity, including induction of 
interferons, cytokines, and chemokines, NK cells, T-cells, myeloid DCs via the TLR3 and 
MDA5, RIG-I, 2'5'oligoadenylate synthetase (OAS), the P68 protein kinase (PKR), and other 
dsRNA-dependent host defense systems. In the current study, we seek to specifically exploit the 
ability of poly-ICLC to induce maturation of DCs (Longhi et al., 2009) for tumor antigen 
presentation. However, it is possible that the other immunomodulatory effects of poly-ICLC will 
also result in enhanced antitumor effects with the other components of the treatment protocol.  
Poly-ICLC has a well-established history of use in the setting of clinical trials evaluating both its 
safety and efficacy in various malignancies. To date, over 85 clinical trials utilizing poly-ICLC 
have been registered at the clinicaltrials.gov website, dating back to a 1996 phase 1/2 trial of 
poly-ICLC for use in malignant gliomas.  
Refer to the IB (Poly-ICLC Investigator’s Brochure, 2018) for detailed background information 
on poly-ICLC. 
2.2.4 
Background on Nivolumab (Bristol-Myers Squibb Company) 
Nivolumab is a human immunoglobulin G4 (IgG4) monoclonal antibody that binds to the PD-1 
receptor and blocks its interaction with PD-L1 and PD-L2, releasing PD-1 pathway-mediated 
inhibition of the immune response, including the antitumor immune response. Opdivo® 
(nivolumab) is approved in the United States (US) for the treatment of several cancer types, 
including unresectable or metastatic melanoma (as monotherapy or in combination with 
ipilimumab) and as monotherapy in previously-treated metastatic NSCLC, advanced renal cell 
carcinoma (RCC), relapsed or refractory classical Hodgkin lymphoma (cHL), locally advanced 
or metastatic urothelial carcinoma (UC), recurrent or metastatic squamous cell carcinoma of the 
head and neck (SCCHN), microsatellite instability-high (MSI-H) or mismatch repair deficient 
(dMMR) metastatic colorectal cancer (CRC), and hepatocellular carcinoma (HCC). In phase 1 
investigation, nivolumab did not demonstrate clinical activity in 17 participants with mCRPC. 
This is consistent with mCRPC having a low level of immune cell infiltrate and TMB. Treatment 
strategies to increase antigen presentation and immune infiltration and activation may improve 
the immune responsiveness of mCRPC to nivolumab. 
Refer to the IB (Nivolumab Investigator’s Brochure, 2018) and approved US prescribing 
information (Opdivo [nivolumab] US Prescribing Information [USPI], 2018) for detailed 
background information on nivolumab. 

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2.2.5 
Rationale for SBRT + CDX-301+ Poly-ICLC+ Nivolumab 
Immunotherapy Combination 
This study cohort is designed to explore a multi-pronged approach to overcome the low T cell 
infiltrate and TMB by promoting antitumor immunity in mCRPC by inducing immunogenic cell 
death, mobilizing and activating DCs to increase tumor antigen presentation and overcoming 
adaptive immune resistance in mCRPC (Figure 1). Specifically: 
• Radiation therapy to induce immunogenic cell death of the tumor 
• Flt3 ligand (CDX-301) to induce mobilization and activation of DCs 
• Poly-ICLC and radiation therapy to induce maturation/activation of DCs, antigen 
presenting cells that mediate tumor antigen presentation to the CD8 T cells to stimulate 
antitumor immunity 
• Anti-PD-1 monoclonal antibody (nivolumab) to overcome immune suppression of 
tumoral T cells 
 
Data derived from preclinical studies support this combination approach. Salmon and colleagues, 
in mouse melanoma models, demonstrated that a specific subset of DCs, CD103+ DCs, were the 
only APCs transporting intact antigens to lymph nodes and priming tumor-specific CD8+ T cells 
(Salmon et al., 2016). CD103+ DCs were required to promote antitumoral effects upon blockade 
of the checkpoint ligand PD-L1; however, PD-L1 inhibition only led to partial responses. 
Systemic administration of the growth factor Flt3L plus poly I:C expanded and activated 
CD103+ DC progenitors in the tumor, enhancing responses to PD-L1 blockade and protecting 
mice from tumor rechallenge. Thus, similar to the in silico work described from Spranger and 
colleagues (Spranger et al., 2016), the paucity of activated CD103+ DCs in tumors was shown in 
this model by Salmon et al. to limit immune checkpoint blockade efficacy and combined Flt3L 
and poly I:C therapy was shown to enhance tumor responses to immune checkpoint blockade. 
Further, data from clinical studies support this combination approach. The combinations of 
SBRT and anti-PD-1 therapy and SBRT and CDX-301 have been studied and/or are being 
assessed in ongoing studies in a number of tumor types, including NSCLC (Table 2). Results 
demonstrate that both combinations are well tolerated, with evidence of abscopal responses. 
Similarly, CDX-301 and poly-ICLC, in combination with CDX-1401 vaccine, have been studied 
in patients with melanoma (Table 2). Results of the study demonstrated that subjects receiving 
CDX-301 pretreatment showed substantial increases in DC, monocytes, and NK cells. Further, 
subjects receiving CDX-301 developed higher anti-vaccine antibody titers than those who did 
not receive CDX-301. The authors concluded that DC mobilization with Flt3L is safe and may 
enhance responses to DC-targeted vaccines (Bhardwaj et al., 2016). A study of nivolumab and 
poly-ICLC, in combination with CDX-1401 vaccine and decitabine, is ongoing. 

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Table 2: 
Clinical Studies Supporting the Co-administration of Components of this Study Intervention 
Study 
Disease Site 
N 
Combination 
Findings  
SBRT + Anti-PD-1 Combinations 
NCT02608385 
Advanced Cancer 
79 
SBRT + anti-PD-1 
Single arm study demonstrated treatment was well tolerated, with no radiation 
dose reductions. The overall ORR was 13.2% in the 68 patients with imaging 
follow-up. When defined as a 30.0% reduction in any single nonirradiated 
measurable lesion, the abscopal response was present in 26.9% of patients. Six 
dose-limiting toxicities defined as ≥ Grade 3, related to treatment. (Luke et al., 
2018) 
NCT02492568 
NSCLC 
64 
SBRT + anti-PD-1 
Randomized study (SBRT + anti-PD-1 vs anti-PD-1 therapy alone) demonstrated 
combination was well-tolerated and a promising strategy to augment the 
antitumor immune response with checkpoint blockade. ORR at 12 weeks was 
41% vs 19%, respectively. Toxicity ≥ Grade 3 was experienced in 17% vs 22%, 
respectively. (Theelen et al., 2018) 
NCT02684253 
SCCHN 
53 
SBRT + anti-PD-1 
Randomized study (SBRT + anti-PD-1 vs anti-PD-1 therapy alone) demonstrated 
combination was safe, but addition of SBRT to anti-PD-1 therapy failed to 
improve ORR (22.2% vs. 26.9%, respectively) or 1-year OS (53% vs 64%, 
respectively) in subjects with SCCHN. Treatment-related ≥ Grade 3 toxicities 
occurred in 11% vs. 15% of patients, respectively. (McBride et al., 2018) 
NCT02826564 
Urothelial Cancer 
23 
SBRT + anti-PD-1 
Study ongoing to assess 2 groups of 10 patients each in phase 1, with an 
additional expansion of 13 patients in phase 2, to assess the safety and response 
rate of 2 different sequences of SBRT and anti-PD-1 therapy (SBRT prior to C1 
vs prior to C3 of anti-PD-1 therapy). (Sundahl et al., 2017) 
NCT02648282 
Pancreatic Cancer 
54 
SBRT + anti-PD-1 + 
GVAX 
Single arm, open-label study ongoing to assess distant metastasis free survival, 
OS, surgical resectability, pathologic response, QoL, and toxicity. (Lee et al., 
2017) 
SBRT + CDX-301 Combinations 
NCT02839265 
NSCLC 
9 
SBRT + CDX-301 
Single arm study yielded promising early results, with frequent abscopal effects 
and a high 4-month PFS (PFS4) rate. PR of lesions not targeted with SBRT 
(“abscopal effect”) was observed in 5/9 subjects. PFS4 was achieved in 5/9 
subjects overall. PR and PFS4 were achieved in 5/7 subjects who were previously 
treated with immunotherapy and in 0/2 subjects who were not previously treated 
with immunotherapy. No dose-limiting toxicities were observed. (Ohri et al., 
2018) 

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CDX-301 + Poly-ICLC Combinations 
NCT01976585 
Non-Hodgkin 
Lymphoma 
30 
CDX-301 + Poly-ICLC + 
low dose XRT 
Study ongoing to assess 2 cohorts of 15 patients each with either previously 
untreated or relapsed/refractory iNHL to test the hypothesis that in situ 
vaccination will induce clinical remissions at distant (untreated) tumor sites. Data 
from this trial suggest that non‐responders have larger populations of exhausted T 
cells. The addition of PD‐1 reverses this exhaustion in mice, and results in 
significantly improved tumor regression. (Marron et al., 2015; Marron et al., 
2017) 
NCT02129075 
Melanoma 
60 
CDX-1401 vaccine + 
Poly-ICLC ± CDX-301 
Randomized study (CDX-301 + CDX-1401+ poly-ICLC vs CDX-1401+ poly-
ICLC) demonstrated DC mobilization with Flt3L is safe and may enhance 
responses to DC-targeted vaccines. Preliminary analyses showed substantial 
(between ~15- to ~200-fold) increases of PBMC innate immune cells (DC, 
monocytes and NK cells) in subjects with CDX-301 pretreatment vs subjects 
without CDX-301. Further, there was development of higher anti-NY-ESO-1 
antibody titers in subjects with CDX-301 pretreatment vs subjects without 
CDX-301. (Bhardwaj et al., 2016) 
Anti-PD-1 + Poly-ICLC Combinations 
NCT03358719 
Myelodysplastic 
Syndrome or AML 
18 
CDX-1401 vaccine + 
Poly-ICLC + Decitabine + 
Anti-PD-1 
Single arm, open-label study ongoing to assess safety, immune and epigenetic 
responses, response rate, OS, PFS, and time to AML transformation. 
anti-PD-1 = anti-programmed cell death 1; AML = acute myeloid leukemia; C = cycle; CDX-1401 = DEC-201/NY-ESO-1 fusion protein vaccine; 
DC  = dendritic cell; Flt3L = FMS-related tyrosine kinase 3 ligand; GVAX = GM-CSF secreting allogenic pancreatic cancer vaccine; iNHL = indolent non-
Hodgkin lymphoma; NK = natural killer; NSCLC = non-small cell lung cancer; ORR = objective response rate; OS = overall survival; PBMC = peripheral blood 
mononuclear cell; PFS = progression-free survival; PR = partial response; QoL = quality of life; SBRT  = stereotactic body radiation therapy; 
SCCHN = squamous cell carcinoma of the head and neck; XRT = radiation therapy 
 
 

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2.3 
BENEFIT/RISK ASSESSMENT 
There are data supporting the use of the individual components of the study intervention in this 
cohort (ie, SBRT, CDX-301, poly-ICLC, and nivolumab), as well as clinical studies supporting 
the co-administration of the components as previously described (Table 2); however, the 
combination has not been previously studied in animal models or in human studies. Additionally, 
each component has been studied specifically in prostate cancer and was well tolerated (Higano 
et al., 2004; Brahmer et al., 2010; Patel et al., 2011; Topalian et al., 2012; Kwon et al., 2014). 
Toxicity profiles are non-overlapping. 
Nivolumab 
Nivolumab has demonstrated durable responses exceeding 6 months as monotherapy in several 
tumor types, including NSCLC, melanoma, RCC, and SCCHN. In confirmatory trials, 
nivolumab demonstrated a statistically significant improvement in overall survival (OS) as 
compared with the current standard of care in subjects with advanced or metastatic NSCLC, 
unresectable or metastatic melanoma, advanced RCC, or SCCHN. 
For monotherapy, the safety profile is similar across tumor types. Most adverse events (AEs) 
were low-grade (Grade 1 to 2) with relatively few related high-grade (Grade 3 to 4) AEs. There 
is no pattern in the incidence, severity, or causality AEs to nivolumab dose level. 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 (Nivolumab Investigator’s Brochure, 2018).  
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. Most studies are ongoing and, as such, the safety profile of nivolumab combinations 
continues to evolve. 
Overall, these findings support a favorable benefit-risk profile for nivolumab across various 
tumor types. More detailed information about the known and expected benefits and risks and 
reasonably expected AEs of nivolumab may be found in the prescribing information (Opdivo 
USPI, 2018). 
CDX-301 
Conclusions regarding the benefit/risk of CDX-301 should be considered in the context of a drug 
in the early stages of development, and therefore by definition, is uncertain and evolving. 
CDX-301 has been well-tolerated and demonstrates the potential for utility in a number of life-
threatening disease states by mobilizing and increasing the number of hematopoietic stem cells 
and DCs in healthy volunteers and cancer patients. Data collected to date indicate that CDX-301 
has an acceptable toxicity profile, and the overall benefit/risk remains in favor of continued 

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clinical evaluation (CDX-301/Recombinant Human Flt3 Ligand [rhuFlt3L] Investigator’s 
Brochure, 2018). 
SBRT, CDX-301, Poly-ICLC, and Nivolumab 
The safety profile of nivolumab is well characterized and manageable when administered alone 
or in combination, including regimens where it is administered in combination with additional 
immuno-oncology products. Data from studies of the individual components of the study 
intervention in this cohort, as well as clinical studies of the co-administration of the components 
of the combination, provide support for the study of this immunotherapy combination. 
Nonclinical data and clinical experience indicate the potential for improvement of response 
compared with nivolumab monotherapy. Thus, the potential benefit of this immunotherapy 
combination appears to outweigh the known risks of these agents and warrants clinical 
investigation. 
3 
OBJECTIVES AND ENDPOINTS 
The cohort-specific objectives and endpoints are listed in Table 3. 
Table 3: 
Cohort-Specific Objectives and Corresponding Endpoints 
Objectives 
Endpoints 
Primary 
 
• To determine the safety of SBRT + CDX-301 + 
poly-ICLC + nivolumab in participants with 
mCRPC. 
Refer to the core protocol. 
Secondary 
 
• To determine the ORR of SBRT + CDX-301 + 
poly-ICLC + nivolumab in participants with 
measurable mCRPC. 
• To determine the DCR ≥ 9 months of SBRT + 
CDX-301 + poly-ICLC + nivolumab in participants 
with measurable mCRPC. 
• To evaluate the rPFS of SBRT + CDX-301 + 
poly-ICLC + nivolumab in participants with 
mCRPC. 
• To estimate the OS of SBRT + CDX-301 + poly-
ICLC + nivolumab in participants with mCRPC. 
Refer to the core protocol 

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Exploratory 
 
• To evaluate the PK of CDX-301 and/or nivolumab. 
• To evaluate the immunogenicity (ADA) of 
CDX-301 and/or nivolumab. 
 
Refer to the core protocol for overall exploratory 
objective(s). 
• Sparse PK analysis. 
• Presence of ADA against CDX-301 and/or 
nivolumab. 
 
Refer to the core protocol for overall exploratory 
endpoint(s). Note that biomarker evaluation for this 
cohort will include DC mobilization and activation. 
ADA = anti-drug antibodies; DCR = disease control rate; mCRPC = metastatic castration-resistant prostate cancer; 
ORR = objective response rate; OS = overall survival; PK = pharmacokinetics; rPFS = radiographic progression-free 
survival 
 
4 
STUDY DESIGN 
4.1 
OVERALL DESIGN 
In this study intervention cohort, SBRT, CDX-301, and poly-ICLC will be administered during 
the first cycle only. Nivolumab will be administered every 4 weeks (Q4W) for up to 2 years 
(Figure 2), unless the participant: is no longer clinically benefiting (as evidenced by symptomatic 
or radiographic disease progression and/or clinical deterioration); experiences any toxicity 
meeting specified discontinuation criteria (see Section 6.6) or unacceptable toxicity in the best 
clinical discretion of the treating physician; reaches the maximum duration of study intervention; 
or withdraws consent. The preferred sequence when study intervention is administered on the 
same day (eg, Day 1) is:  SBRT followed by CDX-301; followed by poly-ICLC; followed by 
nivolumab. 
Participants will be monitored for safety and response and will be followed on-study for up to 
2.5 years from the time of the initiation of study intervention. All participants will be followed 
for safety for at least 100 days after discontinuation of study intervention. Approximately 15 
participants, including a minimum of 7 with a non-bone metastatic lesion that can be biopsied, 
will be enrolled in Stage 1. An additional approximately 15 participants, including a minimum of 
7 with a non-bone metastatic lesion, will be enrolled in Stage 2, if the cohort is expanded. 
A pre-treatment biopsy of a metastatic lesion is required for all participants, including those with 
bone only disease, if medically feasible. Participants must also provide consent for archival 
tissue from a prior biopsy or surgery for prostate cancer. An on-treatment biopsy is required, 
when medically feasible, usually after the second dose of study intervention. An optional biopsy 
may be obtained at the time of disease progression, including from participants who respond and 
subsequently progress following a response to treatment. The on-treatment biopsies should be 
taken from the same lesion as the pre-treatment biopsy when feasible. 

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4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN 
The scientific rationale for this combination is provided in Section 2.2.5. 
4.3 
JUSTIFICATION FOR DOSE 
The doses of CDX-301 and poly-ICLC proposed for this study have been established as being 
safe in previous and ongoing clinical trials (Section 4.3.2 and Section 4.3.3, respectively). 
Nivolumab will be administered as a fixed dose of 480 mg intravenously Q4W, an established 
dosing regimen and US Food and Drug Administration (FDA)-approved for a majority of 
approved nivolumab indications (Section 4.3.1). 
SBRT has been administered in combination with CDX-301 (Ohri et al., 2018) or anti-PD-1 
therapy (Luke et al, 2018; McBride et al., 2018; Theelen et al., 2018) and has been well tolerated 
to date without a significant safety signal. All agents are being administered at the recommended 
dose determined in prior studies in cancer patients and based on the safety profiles of the 
individual components, as well as the combinations of components that have been co-
administered (Table 2), toxicities are not expected to be overlapping when administered in 
combination Therefore, the combination of SBRT, CDX-301, poly-ICLC, and nivolumab at the 
doses proposed is warranted for the evaluation of safety and efficacy in this population. 
4.3.1 
Rationale for Nivolumab Dose and Schedule 
In the US, single-agent nivolumab was approved in 2014 at a dose of 3 mg/kg every 2 weeks 
(Q2W). Subsequently, population pharmacokinetics (PPK) and exposure response analyses were 
performed to support use of flat dosing regimens (ie, nivolumab 240 mg Q2W, 360 mg every 
3 weeks [Q3W], and 480 mg Q4W) in participants with cancer. A flat dose of nivolumab 240 mg 
Q2W was selected since it is identical to a dose of 3 mg/kg for participants weighing 80 kg, the 
observed median body weight in nivolumab-treated cancer patients, while the nivolumab 360 mg 
Q3W and 480 mg Q4W regimens allow flexibility of dosing with less frequent visits and in 
combination with other agents using alternative dosing schedules to Q2W, such as ipilimumab. 
Using a PPK model, the overall distributions of nivolumab exposures (average steady-state 
concentration [Cavgss], minimum steady-state plasma concentration [Cminss], maximum steady-
state plasma concentration [Cmaxss], and trough concentration after the first dose [Cmin1]) are 
comparable after treatment with either nivolumab 3 mg/kg or 240 mg Q2W (Nivolumab 
Investigator’s Brochure, 2018).  
Following nivolumab 480 mg Q4W, Cavgss are expected to be similar to those following 
nivolumab 3 mg/kg or 240 mg Q2W, while Cminss are predicted to be ~16% lower and are not 
considered to be clinically relevant. Cmaxss are predicted to be approximately ~43% greater 
relative to that following nivolumab 3 mg/kg Q2W dosing. However, the range of nivolumab 
exposures (median and 90% prediction intervals) following administration of 240 mg flat Q2W, 

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360 mg Q3W, and 480 mg Q4W regimens across the 35 to 160 kg weight range are predicted to 
be maintained well below the corresponding exposures observed with the well tolerated 10 
mg/kg nivolumab Q2W dosing regimen (Nivolumab Investigator’s Brochure, 2018).  
The 240 mg Q2W dose was approved in the USPI in September 2016 for use in metastatic 
melanoma, NSCLC, and RCC indications. In March 2018, the 480 mg Q4W dose was approved 
in the USPI for use in metastatic melanoma, NSCLC, RCC, cHL, SCCHN, UC, and HCC 
indications (Opdivo USPI, 2018).  
4.3.2 
Rationale for CDX-301 Dose and Schedule 
CDX-301 will be administered as a subcutaneous (SC) injection at a dose of 75 μg/kg daily (QD) 
for 5 days, the highest dose studied using the 5-day schedule in the phase 1 clinical study in 
healthy volunteers (CDX301-02), which assessed the safety, tolerability, pharmacokinetic and 
pharmacodynamic profile of daily SC injections of CDX-301 at multiple dose levels 
(1 μg/kg/day to 75 μg/kg/day) and durations (5 to 10 days; CDX-301/Recombinant Human Flt3 
Ligand [rhuFlt3L] Investigator’s Brochure, 2018). Notably, this is also the same dose and 
schedule utilized in combination with SBRT reported by Ohri et al. (Ohri et al., 2018). 
Results of CDX301-02 showed that CDX-301 exhibited a typical absorption profile for SC 
administration with mean times to maximum serum concentration (Tmax) of 19.8 hours at 
75 μg/kg/day for 5 days. Mean maximum serum concentrations (Cmax) increased linearly with 
dose across the dose range when administered over 5 days and was 667.4 ng/mL following 
75 μg/kg/day for 5 days. Similarly, area under the curve (AUC) values increased across the entire 
range in a dose-independent manner. The half-life was 28 hours at 75 μg/kg/day for 5 days. 
Treatment-related toxicity was infrequent and reported only at the 25 and 75 μg/kg/day dose 
levels (number of subjects at these dose levels was 9 and 15, respectively). One Grade 3 event, 
community acquired pneumonia, was considered treatment-related. However, no additional 
infections, dose-limiting toxicities, serious AEs (SAEs), or Grade 3 toxicities were reported. All 
other treatment-related AEs were Grade 1; these included lymphadenopathy in 6 subjects and 
single cases of diarrhea, injection site erythema, folliculitis and dry mouth. There were no 
reported clinically significant laboratory toxicities attributed to CDX-301. 
As of October 2018, of 89 subjects (cancer patients, healthy volunteers, and stem cell donors) 
tested from 5 studies (Celldex-sponsored and investigator-initiated), 1 patient (receiving 
CDX-301 25 μg/kg/day for 10 days) has tested positive for the presence of specific 
anti-CDX-301 antibodies. Subsequent characterization of this patient’s serum has shown the 
response to be non-neutralizing. 
Dosing with 75 μg/kg daily for 5 days was sufficient to increase CD34+ stem cells and DCs by at 
least 10-fold over baseline values. 

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Refer to the IB (CDX-301/Recombinant Human Flt3 Ligand [rhuFlt3L] Investigator’s Brochure, 
2018) for an additional description of overall safety, immunogenicity, and efficacy in humans. 
4.3.3 
Rationale for Poly-ICLC Dose and Schedule 
Poly-ICLC will be administered at a dose of 1 mg intramuscularly (IM) twice weekly for 
3 weeks. 
Poly-ICLC has a well-established history of use in the setting of clinical trials evaluating both its 
safety and efficacy in various malignancies. To date, over 85 clinical trials utilizing poly-ICLC 
have been registered at clinicaltrials.gov dating back to a 1996 phase 1/2 trial of poly-ICLC for 
use in malignant gliomas.  
In its earliest use in human trials, poly-ICLC was originally employed as an inducer of IFN. 
Several studies were conducted, and although interest in the efficacy of poly-ICLC mediated 
through the mechanism of IFN-induction would subsequently diminish, it was these studies 
which provided the foundation for safety profiling and dosage which would be employed in later 
trials evaluating the efficacy of poly-ICLC via different mechanisms. 
Early phase 1 trials were conducted to determine the maximum tolerated dose (MTD) under the 
assumption that this was also the most effective dose. It was found that the MTD was 12 mg/m2 
in cancer patients who were not terminally ill (Levine et al., 1979). Phase 1 and 2 clinical trials 
were subsequently conducted in patients with many types of cancers including leukemia, 
lymphoma, brain tumors, myeloma, juvenile laryngeal papillomatosis, renal cell carcinoma, 
breast cancer, ovarian cancer, and melanoma (Droller, 1987; Hawkins et al., 1985; Krown et al., 
1985; Stevenson et al., 1985; Butowski et al., 2009; Salazar et al., 1996). In most of these early 
trials, about 6 mg/m2 poly-ICLC was generally used intravenously. Fever, often with 
temperatures greater than 40°C, was a universal AE in the trials and was the primary dose-
limiting factor. Other common AEs reported in these trials included nausea, vomiting, 
hypotension, thrombocytopenia, leukopenia, arthralgia, myalgia, and fatigue. 
For patients receiving intramuscular or other non-intravenous routes of administration common 
side effects include discomfort at injection site, with transient discomfort and occasionally 
transient mild to moderate grade 1 or 2 erythematous skin reaction (Caskey et al., 2011). 
Alongside transient fever, patients occasionally experienced other flu-like symptoms 
approximately 8 to 12 hours after doses of 10 to 50 μg/kg IM, which may last for another 12 
hours, but responds readily to acetaminophen or aspirin. These symptoms include mild myalgias, 
arthralgias, sometimes nausea, and malaise can be present during this period of time. This flu-
like syndrome typically diminishes markedly after the first 2-3 poly-ICLC treatments.  
Most recent and ongoing trials are using set dosing of 1-2 mg through IM, intratumoral or 
subcutaneous administration, well below the MTD of 12 mg/m2 when given IV. More extensive 

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information regarding poly-ICLC—including pre-clinical pharmacology, toxicology and 
pharmacokinetics (PK), as well as multiple clinical studies—may be found in the poly-ICLC IB 
(Poly-ICLC Investigator’s Brochure, 2018). 
4.3.4 
Rationale for Stereotactic Body Radiation Therapy Dose and 
Schedule 
The optimal dose of radiation to administered in combination with immune checkpoint blockade 
has not been defined. As noted in the Background section, safety and intriguing activity have 
been demonstrated with SBRT in standard treatment doses in combination with PD-1 blockade. 
Therefore, this cohort will use a similar approach to that previously described (Luke et al., 2018) 
and employ standard treatment doses of SBRT. SBRT offers ablative dose-escalation to tumor 
targets with simultaneous dose-restraint to normal tissues, which is not possible using 
conventional radiotherapy. SBRT utilizes high-precision radiotherapy delivery machines, 
integrated image guidance systems, advanced planning software, and a high level of professional 
and technical expertise. Unlike conventional radiation therapy, which is delivered in multiple 
fractions of 1.8-2 Gy, SBRT is delivered in 1 to 5 fractions of typically 8 Gy or greater. 
Participants will undergo SBRT to up to 4 sites of metastases, as long as at least 1 metastasis 
remains outside the irradiated target. SBRT will be delivered in 3 to 5 fractions. SBRT 5 fraction 
regimens should deliver a total dose of 30 to 50 Gy. SBRT 3 fraction regimens should deliver a 
total dose of 24-45 Gy. Dose selection will depend on adequate sparing of normal tissue with 
maximization of dose delivered to metastatic sites. A biologically equivalent dose (BED) to 
tumor of > 100 Gy (for an alpha–beta ratio of 3) is a goal but is not required. Dose constraints 
per NRG (RTOG) B001 are recommended. Suggested regimens based on site of metastasis are 
defined as follows: 
• 45 Gy in 3 fractions for peripheral lung, liver, and abdominal/pelvic; 
• 50 Gy in 5 fractions for central lung and mediastinal/cervical; 
• 30 Gy in 3 fractions for osseous and spinal/paraspinal 
 
The optimal sequence of radiation and immune checkpoint blockade has not been established. 
Modeling studies suggest that immune checkpoint (Kosinsky et al., 2018) blockade prior to, or 
concurrent with, radiation maximizes the potential synergistic effects of these modalities. Given 
these considerations, as well as emerging data in model systems and patients also supporting a 
concurrent rather than sequential approach (Azad et al., 2017; Aliru et al., 2018; Pinnamanerni et 
al., 2017), this cohort will employ concurrent treatment. 
4.4 
TREATMENT BEYOND DISEASE PROGRESSION 
Refer to the core protocol. 

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4.5 
END OF STUDY DEFINITION 
Refer to the core protocol for the end of study definition. 
The total length of this study cohort, from screening of the first participant to the end of the 
cohort, is expected to be approximately 3 years, 9 months. 
5 
STUDY POPULATION 
Prospective requests for approval of protocol deviations to recruitment and enrollment criteria, 
also known as waivers or exemptions, is not allowed. 
5.1 
INCLUSION CRITERIA 
Participants are eligible to be included in the study only if all the following criteria apply: 
5.1.1 
Common Inclusion Criteria 
1. Participant must be ≥ 18 years of age at the time the informed consent is signed. 
2. Participants must agree to use an adequate method of contraception as outlined in 
Appendix 6 of the core protocol starting with the first dose of study intervention and for 
at least 7 months after the last dose of study intervention and refrain from donating sperm 
during this period. 
Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for 
the participant. 
3. Participants must be able and willing to comply with the study visit schedule and study 
procedures. 
4. Histologically documented adenocarcinoma of the prostate. 
5. Metastatic castration resistant prostate cancer with castrate-level testosterone 
(< 50 ng/dL) at screening. 
6. Have received and progressed on prior secondary androgen receptor signaling inhibitor 
therapy (eg, abiraterone, enzalutamide, apalutamide). Progression is defined by one or 
more of the following 3 criteria: 
a. Prostate-specific antigen (PSA) ≥ 1.0 ng/mL and rising PSA by at least 2 
consecutive measurements a minimum of 1-week apart. 
b. Soft tissue progression as defined by Response Evaluation Criteria in Solid 
Tumors (RECIST) version 1.1 (Eisenhauer et al., 2009). 
c. Bone disease progression as defined by 2 new bone lesions (as per Prostate 
Cancer Clinical Trials Working Group 3 [PCWG3; Scher et al., 2016]).  
7. Have measurable disease or non-measurable disease based on PCWG3-modified 
RECIST 1.1. 
8. Provide fresh pre-treatment core needle or incisional biopsy of a metastatic tumor lesion 
not previously irradiated. Fine needle aspiration is not acceptable. 

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a. Additionally, if a pre-treatment biopsy is not medically feasible for participants 
with bone only disease, formalin-fixed paraffin-embedded (FFPE) tumor 
specimen in a paraffin block (preferred) or at least 10 slides containing unstained, 
freshly cut, serial sections must be provided. 
b. For all participants, in addition to fresh pre-treatment biopsy, consent for archival 
tissue is required. 
9. Must be willing to undergo tumor biopsy(ies) on treatment, if medically feasible. 
10. Participants must discontinue antiandrogen therapy (ie, bicalutamide, flutamide, 
nilutamide) at least 4-6 weeks prior to registration with no evidence of PSA decline after 
washout. 
a. Bicalutamide: Washout period at least 6 weeks 
b. Flutamide and nilutamide: Washout period at least 4 weeks 
11. Participants must discontinue therapies for mCRPC for 5 half-lives or 28 days, whichever 
is shorter. 
a. Participants will remain on gonadotropin-releasing hormone (GnRH) agents 
throughout this study. 
b. Prior chemotherapy is allowed if no progression of disease on chemotherapy as 
defined by PCWG3-modified RECIST 1.1.  
c. Prior treatment with sipuleucel-T, radium-223, or poly adenosine diphosphate 
(ADP)-ribose polymerase (PARP) inhibitor (eg, olaparib) is allowed. 
d. Tissue biopsy may be performed during washout period. 
12. Participants with prior or concurrent malignancies are permitted if any one of the 
following applies: 
a. Previously treated malignancy for which all treatment of that malignancy was 
completed at least 2 years before enrollment and no evidence of disease exists, or 
b. With agreement from the Medical Monitor and Principal Investigator (PI), 
participants who have a concurrent malignancy that is clinically stable and does 
not require tumor-directed treatment are eligible to participate if the risk of the 
prior malignancy interfering with either safety or efficacy endpoints is very low, 
or 
c. With agreement from the Medical Monitor and PI, other malignancies may be 
permitted if the risk of the prior malignancy interfering with either safety or 
efficacy end points is very low. 
13. Have a performance status of 0 or 1 according to the Eastern Cooperative Oncology 
Group (ECOG) scale. 
14. Demonstrate adequate organ function on screening laboratory tests performed within 
14 days of treatment initiation and as evidenced by: 
a. Hemoglobin ≥ 9.0 g/dL or ≥ 5.6 mmol/L without transfusion or erythropoietin 
(EPO) dependency (within ≤ 7 days of assessment) 

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b. Absolute neutrophil count ≥ 1,500/mm3 without growth factor support (within 
< 28 days of assessment) 
c. Platelet count ≥ 100,000/mm3 
d. Estimated glomerular filtration rate (GFR) ≥ 45 mL/min using the Cockcroft-
Gault formula 
e. Serum total bilirubin < 1.5 x upper limit of normal (ULN) or ≤ 2.0 x ULN for 
participants with liver metastases 
i. Participants with Gilbert's syndrome must have ≤ 3 x ULN and no liver 
lesions 
f. Aspartate aminotransferase (AST) (SGOT) and alanine aminotransferase (ALT) 
(SGPT) ≤ 3.0 x ULN or ≤ 5.0 x ULN for participants with liver metastases. 
g. Albumin ≥ 2.5 mg/dL. 
h. International normalized ratio (INR) or prothrombin time (PT) ≤ 1.5 x ULN 
unless participant is receiving anticoagulant therapy, as long as PT is within 
therapeutic range of intended use of anticoagulants. 
i. Activated partial thromboplastin time (aPTT) ≤ 1.5 x ULN unless participant is 
receiving anticoagulant therapy, as long as PTT is within therapeutic range of 
intended use of anticoagulants. 
15. Willing and capable of giving signed informed consent as described in Appendix 1 of the 
core protocol, which includes compliance with the requirements and restrictions listed in 
the informed consent form (ICF) and in this protocol. 
 
5.1.2 
Combination-specific Inclusion Criteria 
1. Participants must have at least one lesion amenable to SBRT as determined by the 
treating radiation oncologist. Participants must have lesions in organs/locations that can 
be treated with at least 30 Gy. 
 
5.2 
EXCLUSION CRITERIA 
Participants are excluded from the study if any of the following criteria apply: 
5.2.1 
Common Exclusion Criteria 
1. Is currently participating and receiving study therapy or has participated in a study of an 
investigational agent and received study therapy or used an investigational device within 
4 weeks of the first dose of treatment. 
a. Recent or concurrent non-therapeutic investigational agents that are not 
anticipated to interfere with study intervention, such as certain investigational 
imaging tracers, may be permitted with written agreement from the Medical 
Monitor. 

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2. Has a diagnosis of immunodeficiency or conditions that need systemic corticosteroid 
replacement therapy > 10 mg/day prednisone (or equivalent) or other immunosuppressive 
medications within 28 days prior to the first dose of study intervention. Inhaled steroids 
are permitted if necessary. 
3. Has any active known or suspected autoimmune disease. Participants with vitiligo, type I 
diabetes mellitus, controlled autoimmune hypothyroidism, psoriasis not requiring 
systemic treatment, or other conditions under control are permitted to enroll. 
Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid replacement 
therapy ≤ 10 mg of prednisone/day for adrenal or pituitary insufficiency, etc.) is not 
considered a form of systemic treatment.  
4. Has a known history of active TB (Bacillus Tuberculosis). 
5. Has known history of, or any evidence of active, non-infectious pneumonitis. 
6. Has an active infection requiring systemic therapy. 
7. Has a history or current evidence of any condition, therapy, or laboratory abnormality 
that might confound the results of the trial, interfere with the participant’s participation 
for the full duration of the trial, or is not in the best interest of the participant to 
participate, in the opinion of the treating Investigator. 
8. Has known psychiatric or substance abuse disorders that would interfere with cooperation 
with the requirements of the trial. 
9. Is expecting to father children within the projected duration of the trial, starting with the 
pre-screening or screening visit through 7 months after the last dose of study intervention. 
10. Known history of testing positive for human immunodeficiency virus (HIV), known 
acquired immunodeficiency syndrome (AIDS), or any positive test for hepatitis B or 
hepatitis C virus representing acute or chronic disease. 
11. Has received a live vaccine within 30 days of planned start of study intervention. 
Note:  Seasonal influenza vaccines for injection are generally inactivated flu vaccines and 
are allowed; however intranasal influenza vaccines (eg, Flu-Mist®) are live attenuated 
vaccines, and are not allowed. 
12. Has known active central nervous system (CNS) metastases and/or carcinomatous 
meningitis. Participants with previously treated brain metastases may participate provided 
they are stable (without evidence of progression by imaging for at least 4 weeks prior to 
the first dose of study intervention and any neurologic symptoms have returned to 
baseline), have no evidence of new or enlarging brain metastases, and are not using 
steroids for at least 7 days prior to study intervention. This exception does not include 
carcinomatous meningitis which is excluded regardless of clinical stability. 
13. Has had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to study 
Day 1 or who has not recovered (ie, ≤ Grade 1 or at baseline) from AEs due to agents 
administered more than 4 weeks earlier. 
a. Participants with controlled autoimmune disease as described in exclusion 
criterion #3 are permitted to enroll. 

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14. Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy within 
2 weeks prior to study Day 1 or who has not recovered (ie, ≤ Grade 1 or at baseline) from 
AEs due to a previously administered agent. 
a. Note:  Participants with ≤ Grade 2 neuropathy and/or hearing loss are an 
exception to this criterion and may qualify for the study. 
b. Note:  If a participant received major surgery, he must have recovered adequately 
from the toxicity and/or complications from the intervention prior to starting 
therapy.   
15. History of allergy to any of the study intervention components. 
 
5.2.2 
Combination-specific Exclusion Criteria 
1. Has had prior therapy with any anti-PD-1 or anti-PD-L1 antibody (prior therapy with an 
anti-CTLA-4 antibody is permitted). 
2. Has a history of acute myeloid leukemia (AML). 
 
5.3 
LIFESTYLE CONSIDERATIONS 
No restrictions are required. 
5.4 
SCREEN FAILURES 
Refer to the core protocol. 
6 
STUDY INTERVENTION 
Study intervention is defined as any investigational intervention(s), marketed product(s) or 
placebo intended to be administered to a study participant according to the study protocol. 
6.1 
STUDY INTERVENTION(S) ADMINISTERED 
The study interventions to be administered in this study are summarized in Table 4. 
Table 4: 
Study Intervention 
Study 
Intervention 
Name 
Dosage Formulation 
Unit Dose 
Strength(s) 
Dosage 
Level(s) 
Route of 
Administration 
Sourcing 
SBRT 
30-50 Gy in 1-5 doses. Radiation will start on Day 1 or 2 
CDX-301 
Sterile solution for single 
use. Single-use vial 
containing CDX-301 in 
buffered solution 
composed of sodium 
phosphate and sodium 
chloride, with a pH of 7.0 
2.5 mg/mL 
75 µg/kg 
SC 
Celldex 
Therapeutics 

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Study 
Intervention 
Name 
Dosage Formulation 
Unit Dose 
Strength(s) 
Dosage 
Level(s) 
Route of 
Administration 
Sourcing 
Poly-ICLC 
Single-dose vial containing 
opalescent white 
suspension poly-IC, poly-
L-lysine, and sodium 
carboyxmethylcelluose in 
0.9% sodium chloride, 
adjusted to a pH of 6 – 8 
with sodium hydroxide 
2 mg/mL 
1 mg 
IM 
Oncovir, Inc. 
Nivolumab 
Aqueous solution 
10 mg/mL 
480 mg 
IV infusion 
Bristol-Myers 
Squibb 
Gy = gray; IV = intravenous(ly); IM = intramuscular(ly); SBRT = stereotactic body radiation therapy; 
SC = subcutaneous(ly) 
 
SBRT, CDX-301, and poly-ICLC will be administered during the first cycle only. The preferred 
sequence when study intervention is administered on the same day (eg, Day 1) is:  SBRT 
followed by CDX-301; followed by poly-ICLC; followed by nivolumab: 
• Radiation therapy will be administered at 30 – 50 Gy in 1 – 5 doses, starting on Day 1 
or 2 of Cycle 1.   
• CDX-301 will be administered at a dose of 75 µg/kg SC QD x 5 days (Days 1 – 5 [ie, 
Monday – Friday] of Cycle 1). 
• Poly-ICLC will be administered at a dose of 1 mg intramuscularly (IM) twice weekly for 
3 weeks (ie, Days 1, 5, 8, 12, 15, and 19) starting on Day 1 of Cycle 1. 
• Nivolumab will be administered at a dose of 480 mg IV over approximately 30 minutes 
Q4W, starting on Day 1 of Cycle 1, for up to 2 years, unless the participant: is no longer 
clinically benefiting (as evidenced by symptomatic or radiographic disease progression 
and/or clinical deterioration); experiences any toxicity meeting specified discontinuation 
criteria (see Section 6.6) or unacceptable toxicity in the best clinical discretion of the 
treating physician; reaches the maximum duration of study intervention; or withdraws 
consent. A cycle is defined as 4 calendar weeks. 
 
Administration of study intervention will be performed in a monitored setting in which there is 
immediate access to trained personnel and adequate equipment and medicine to manage 
potentially serious reactions. 
6.2 
PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY 
Refer to the core protocol for general guidance on handling, storage, and accountability. 

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CDX-301 should be stored in a secure, locked area at 2-8°C and protected from light. CDX-301 
should not be frozen, and CDX-301 vials should not be shaken. CDX-301 liquid should be 
withdrawn from vial gently, avoiding foaming and excess shearing. 
Poly-ICLC should be stored refrigerated at 2-8°C but should not be frozen. 
Nivolumab must be stored at 2°-8°C and protected from light and freezing.  
The instructions for reconstitution and administration of the study intervention are described in 
the Pharmacy Manual(s). 
6.3 
RANDOMIZATION AND BLINDING 
This is not a randomized study, and study intervention will be administered in an open-label 
fashion. 
6.4 
STUDY INTERVENTION COMPLIANCE 
Study intervention will be administered by authorized site personnel and tracked using drug 
accountability records. No additional measures of compliance will be instituted. 
6.5 
CONCOMITANT THERAPY 
Refer to the core protocol. 
6.5.1 
Permitted Therapy 
Refer to the core protocol. 
6.5.2 
Prohibited Therapy 
Refer to the core protocol. 
6.6 
DOSE MODIFICATIONS 
6.6.1 
Dose Modifications for the Combination of Nivolumab, CDX-301, 
and Poly-ICLC 
There will be no dose escalation or dose reductions in this study. 
The initial 6 participants enrolled in this cohort will be observed for the occurrence of any of the 
AEs described in Table 5 that are observed from the beginning of treatment through completion 
of the first cycle of nivolumab (ie, 4 weeks) and that are considered by the Investigator to be 
possibly, probably, or definitely related to nivolumab, CDX-301, poly-ICLC, or the 
immunotherapy combination, unless there is a clear alternative explanation.  
After enrollment of the initial 6 participants, enrollment will pause until all 6 participants have 
completed Cycle 1 (ie, 4 weeks). During the pause, new participants may be consented and 
screened, but not initiated on study intervention. If 1 or no AEs described in Table 5 are 
observed in the first 6 participants, enrollment will continue as planned until a total of 

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approximately 15 participants are enrolled. If AEs described in Table 5 are observed in 2 or more 
of the first 6 participants, enrollment into the cohort will be suspended, and the Safety 
Assessment Committee (refer to Section 9.5.1 of the core protocol) will be convened to review 
the available data and provide a recommendation, which may include, but is not limited to, 
modification or discontinuation of the cohort. 
Participants who experience any AE described in Table 5 will be discontinued from all study 
intervention and should continue follow-up assessments as outlined in the SOA (Section 1.3). 
Grade 3 and 4 toxicities are observed in all trials of nivolumab in multiple tumor types. As such 
toxicities are anticipated; however, given the unique nature of this protocol, monitoring for AEs 
described in Table 5 will continue throughout the study. 
The Investigator may attribute each AE to the combination or any individual component of the 
study intervention. Study participants may not have any dose escalations or reductions of 
nivolumab, CDX-301, or poly-ICLC in this study. If an Investigator believes a toxicity is 
uniquely related to one agent, then appropriate documentation is required regarding the drug to 
which the Investigator is attributing the AE. The following retreatment requirements will apply: 
• During Cycle 1 if, in the opinion of the Investigator, the toxicity is related to CDX-301 
and/or poly-ICLC, then CDX-301 and/or poly-ICLC drugs should be withheld (eg, 
skipped) according to recommended dose modifications.  
• Cycle 2, in which only nivolumab is administered, may commence as scheduled provided 
the participant meets the retreatment criteria for nivolumab. 
o Starting with Cycle 2 if toxicity does not resolve or the criteria for resuming study 
intervention are not met within 8 weeks after the last dose of nivolumab, the 
participant must be discontinued from nivolumab therapy, unless written approval 
to restart therapy is provided by the Medical Monitor. 
 
The anticipated important safety risks associated with the administration of SBRT, nivolumab, 
CDX-301, and/or poly-ICLC, as well as the measures to be taken, are outlined in the following 
sections. Guidance with respect to the individual agents is provided in Section 6.6.3, 
Section  6.6.4, and Section 6.6.5, respectively. Refer to the USPI for nivolumab (Opdivo USPI, 
2018)  to the Investigator’s Brochures for nivolumab, CDX-301, and poly-ICLC for complete 
summaries of safety information. 

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Table 5: 
Toxicity Criteria Requiring Permanent Treatment Discontinuation 
Participants should be monitored for the occurrence of any of the following AEs that are considered by the 
Investigator to be possibly, probably, or definitely related to nivolumab, CDX-301, poly-ICLC, or the 
immunotherapy combination. Treatment with all study intervention should be permanently discontinued for the 
following: 
• 
Grade 4 non-hematological toxicity (not laboratory) 
• 
Grade 4 hematologic toxicity lasting ≥ 7 days 
• 
Grade 3 thrombocytopenia in the presence of clinically significant active bleeding (eg, requiring 
transfusion or hospitalization) 
• 
Any non-hematologic toxicity ≥ Grade 3 in severity, with the following exceptions: 
o 
Grade 3 fatigue lasting ≤ 3 days 
o 
Grade 3 nausea, vomiting, or diarrhea lasting ≤ 3 days 
o 
Grade 3 rash without use of corticosteroids or anti-inflammatory agents per standard of care 
o 
Grade 4 fever 
o 
Grade 4 flu-like symptoms lasting ≥ 48 hours 
• 
Any new Grade 3 or Grade 4 non-hematologic laboratory abnormality, if 
o 
the abnormality leads to hospitalization, or 
o 
the abnormality persists for > 1 week and is believed to be clinically significant. For example, 
exceptions would include asymptomatic pancreatitis. 
• 
Febrile neutropenia Grade 3 or Grade 4 
• 
Any elevated AST or ALT laboratory value that is ≥ 3 × ULN and an elevated total bilirubin lab value that 
is ≥ 2 × ULN and an alkaline phosphatase lab value that is < 2 × ULN, in which no alternative reasons can 
be found to explain the combination of increased AST/ALT and total bilirubin, such as viral hepatitis A, B 
or C, preexisting or acute liver diseases, pre-existing known liver metastases, or another drug capable of 
causing the observed injury 
• 
Grade 5 toxicity 
ALT = alanine aminotransferase; AST = aspartate aminotransferase; ULN = upper limit of normal 
 
6.6.1.1 
Potential for Overlapping Toxicities with the Combination of 
SBRT, Nivolumab, CDX-301, and Poly-ICLC 
In general, the toxicities associated with the monotherapy administration of nivolumab, 
CDX-301, and poly-ICLC are not expected to be overlapping when administered in combination. 
The safety data for nivolumab are described in the USPI (Opdivo USPI, 2018). Nivolumab 
therapy is associated with immune-mediated adverse reactions, which can be severe and fatal in 
some cases. With appropriate medical therapy, immune-related adverse reactions resolved in 
most cases. Immune-mediated adverse reactions may involve any organ system; however, the 
most common severe immune-mediated adverse reactions are enterocolitis, endocrinopathies, 
hepatitis, dermatitis (including toxic epidermal necrolysis [TEN] and Stevens-Johnson syndrome 
[SJS]), and neuropathy. The safety profile of nivolumab combination therapy varies with the 
agent combined with nivolumab but is generally consistent with the safety profiles observed with 
either agent alone and, in some cases, both frequency and severity of AEs were greater than that 
observed with either agent alone. 

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In human studies to date, Flt3L has been well tolerated, with many AEs attributable to patients’ 
underlying malignancy or other compounds/therapies being administered concomitantly, and no 
dose reductions of Flt3L for toxicity were reported in any of these trials. Erythematous nodules 
of up to 1 to 2 cm at the skin injection sites lasting several days were the only manifestation of 
toxicity in most patients. One patient who injected doses into the same area daily for 3 
consecutive days developed diffuse erythema of the upper arm and adenopathy in the axilla that 
resolved spontaneously. Arthralgias, myalgias, and fever were not reported, nor were liver 
function test abnormalities. With CDX-301 administration, specifically, leukocytosis, especially 
monocytosis, is expected during administration. Injection site reactions have been reported and 
are generally mild to moderate, but occasionally severe. Lymphadenopathy occurred in < 20% of 
study participants, was not associated with AEs, and resolved after discontinuation of treatment 
(CDX-301/Recombinant Human Flt3 Ligand [rhuFlt3L] Investigator’s Brochure, 2018). 
In most of the early trials of poly-ICLC, about 6 mg/m2 poly-ICLC was generally administered 
IV. Fever, often with temperatures greater than 40°C, was a universal AE in these trials and was 
the primary dose-limiting factor. Other common AEs reported in these trials included nausea, 
vomiting, hypotension, thrombocytopenia, leukopenia, arthralgia, myalgia, and fatigue (Poly-
ICLC Investigator’s Brochure, 2018). 
SBRT has been associated with mild to moderate GU and GI acute and late toxicities in patients 
with localized prostate cancer (Syed et al., 2017; Haque et al., 2017; King et al., 2013). The 
incidence of ≥ Grade 3 acute toxicities was typically < 5%, while at least 1 late urinary ≥ Grade 3 
late toxicity has been reported in the majority of studies (Syed et al., 2017). 
6.6.1.2 
Dose Modifications and Toxicity Management for Adverse Events 
Associated with the Combination of Nivolumab, CDX-301, and 
Poly-ICLC 
Immuno-oncology agents are associated with AEs that can differ in severity and duration from 
AEs caused by other therapeutic classes. Early recognition and management of AEs associated 
with immuno-oncology agents may mitigate severe toxicity. Management algorithms (Appendix 
B-1) have been developed to assist Investigators in assessing and managing the following groups 
of drug-related AEs: 
• Immune-mediated colitis 
• Immune-mediated nephritis and renal dysfunction 
• Immune-mediated pneumonitis 
• Immune-mediated hepatitis 

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• Immune-mediated endocrinopathies (hypophysitis, adrenal insufficiency, hypothyroidism 
and hyperthyroidism, Type 1 diabetes mellitus) 
• Immune-mediated skin adverse reactions 
• Immune-mediated encephalitis 
 
6.6.1.3 
Dose Modifications and Toxicity Management for 
Infusion/Injection-related Reactions Associated with the 
Administration of CDX-301, Poly-ICLC, and/or Nivolumab 
Interrupt or slow the rate of infusion in participants with mild or moderate infusion reactions. 
Discontinue the immunotherapy combination in participants with severe or life-threatening 
infusion reactions. 
All Grade 3 or 4 infusion reactions must be reported within 24 hours to the study Medical 
Monitor and reported as an SAE if it meets the criteria. Infusion reactions should be graded as 
described in Section 10.5.3 of the core protocol. 
Dose modification and toxicity management guidelines for infusion/injection-related reactions 
are provided in Table 6.  
 

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Table 6:  
Dose Modification and Toxicity Management Guidelines for Infusion/Injection-related Reactions Associated 
with the Administration of CDX-301, Poly-ICLC, and/or Nivolumab 
Grade 
(NCI CTCAE v 5.0) 
 
Treatment 
Premedication at 
Subsequent Dosing 
Grade 1 
Mild reaction; infusion interruption not indicated; 
intervention not indicated 
Increase monitoring of vital signs as medically indicated until the participant is 
deemed medically stable in the opinion of the Investigator 
None 
Grade 2 
Requires therapy or infusion interruption but responds 
promptly to symptomatic treatment (eg, antihistamines, 
NSAIDs, narcotics, IV fluids); prophylactic medications 
indicated for ≤ 24 hours 
Stop Infusion 
Additional appropriate medical therapy may include but is not limited to: 
IV fluids 
Antihistamines 
NSAIDs 
Acetaminophen 
Narcotics 
Increase monitoring of vital signs as medically indicated until the participant is 
deemed medically stable in the opinion of the Investigator 
If symptoms resolve within 1 hour of stopping drug infusion, the infusion may 
be restarted at 50% of the original infusion rate (eg, from 100 mL/h to 50 mL/h). 
Otherwise dosing will be held until symptoms resolve and the participant should 
be premedicated for the next scheduled dose 
Participants who develop Grade 2 toxicity despite adequate premedication 
should be permanently discontinued from further study intervention 
Participant may be premedicated 
according to local treatment 
guidelines 
Grades 3 or 4 
Grade 3: 
Prolonged (ie, not rapidly responsive to symptomatic 
medication and/or brief interruption of infusion); 
recurrence of symptoms following initial improvement; 
hospitalization indicated for other clinical sequelae (eg, 
renal impairment, pulmonary infiltrates) 
Grade 4: 
Life-threatening; pressor or ventilatory support indicated 
Stop Infusion 
Administer urgent medical therapy as appropriate/clinically indicated 
Increase monitoring of vital signs as medically indicated until the participant is 
deemed medically stable in the opinion of the Investigator 
Hospitalization may be indicated 
**In cases of anaphylaxis, epinephrine should be used immediately 
Participant is permanently discontinued from further study intervention 
No subsequent dosing 
Appropriate resuscitation equipment should be available at the bedside and a physician readily available during the period of drug administration. 
For further information, please refer to the Common Terminology Criteria for Adverse Events v5.0 (CTCAE) at http://ctep.cancer.gov 
CTCAE = Common Terminology Criteria for Adverse Events; NCI = National Cancer Institute; NSAIDs = nonsteroidal anti-inflammatory drugs; IV = intravenous 

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6.6.1.4 
Dose Delays and Interruptions of Nivolumab, CDX-301, and Poly-
ICLC 
Dose delays and interruptions are permitted for toxicity reasons (see Section 6.6.3 and 
Section 6.6.4). 
The Investigator may attribute each AE to the combination or to either individual intervention. 
• If, in the opinion of the Investigator, the toxicity is related to the combination of the 
agents, then all drugs should be held according to recommended dose modifications. 
• If the toxicity is considered clearly related to 1 agent, but not the others, then the other 
agents can continue unless toxicity related to that study intervention would warrant a 
dose delay. 
 
6.6.2 
Dose Modification for SBRT 
The short duration time of this treatment may not require adjustments and may limit the need for 
dose modification, but due to organ sites involved with the treatment, it may be necessary to 
modify the dosage to address acute AEs related to SBRT. Dose modification of SBRT will be 
managed according to institutional guidelines. 
Appropriate documentation is required regarding the component of treatment to which the 
Investigator is attributing the AE. If toxicity does not resolve or the criteria for resuming study 
intervention are not met within 8 weeks after the last dose, the participant must be discontinued 
from the combination therapy. 
Dose delays and interruptions for reasons other than toxicity, such as surgical procedures, may 
be allowed with Medical Monitor approval. The acceptable length of interruption will depend on 
agreement between Investigator and Medical Monitor. 
6.6.3 
Dose Modifications for Nivolumab 
This study will include set dosing for nivolumab (480 mg Q4W). Dose escalation or reduction of 
nivolumab will not be allowed. If toxicity does not resolve or the criteria for resuming study 
intervention are not met within 8 weeks from the last dose, the participant must discontinue 
nivolumab therapy, unless written approval to restart therapy is provided by the Medical 
Monitor. 
Specific anticipated or potential toxicities associated with the administration of nivolumab, as 
well as the measures to be taken to avoid or minimize such toxicity in this trial, are described in 
Table 7. 
AEs associated with nivolumab exposure may represent an immunologic etiology. These 
immune-related adverse events (irAEs) may occur shortly after the first dose or several months 

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after the last dose of treatment and may affect more than one body system simultaneously. 
Therefore, early recognition and initiation of treatment is critical to reduce complications. Based 
on existing clinical study data, drug-related AEs have included pulmonary toxicity, renal toxicity 
(including acute renal failure), endocrine abnormalities, gastrointestinal toxicity, dermatologic 
toxicity (including rash), and hepatotoxicity. For nivolumab monotherapy, as well as when 
administered in combination, the majority of these AEs have been managed successfully with 
supportive care and, in more severe cases, a combination of dose delay, permanent 
discontinuation, and/or use of corticosteroids or hormone replacement therapy 
(endocrinopathies). For suspected irAEs, ensure adequate evaluation to confirm etiology or 
exclude other causes. Additional procedures or tests such as bronchoscopy, endoscopy, and skin 
biopsy may be included as part of the evaluation. 
Dose modification and toxicity management guidelines for irAEs associated with nivolumab are 
provided in Table 7. 
Table 7: 
Dose Modification and Toxicity Management Guidelines for Adverse Events 
Associated with Nivolumab 
Adverse Reaction 
Severitya 
Dose Modifications 
Colitis 
Grade 2 diarrhea or colitis 
Withhold doseb 
Grade 3 diarrhea or colitis 
Withhold doseb 
Grade 4 diarrhea or colitis 
Permanently discontinue 
Pneumonitis 
Grade 2 pneumonitis 
Withhold doseb 
Grade 3 or 4 pneumonitis 
Permanently discontinue 
Hepatitis/non-HCC 
Aspartate aminotransferase (AST) or alanine 
aminotransferase (ALT) more than 3 and up 
to 5 times the upper limit of normal (ULN) 
or total bilirubin more than 1.5 and up to 3 
times the ULN 
Withhold doseb 
AST or ALT more than 5 times the ULN or 
total bilirubin more than 3 times the ULN 
Permanently discontinue 
Hepatitis/HCC 
• If AST/ALT is within normal limits at 
baseline and increases to more than 3 and 
up to 5 times the ULN 
• If AST/ALT is more than 1 and up to 3 
times ULN at baseline and increases to 
more than 5 and up to 10 times the ULN 
• If AST/ALT is more than 3 and up to 5 
times ULN at baseline and increases to 
more than 8 and up to 10 times the ULN 
Withhold dosec 
If AST or ALT increases to more than 10 
times the ULN or total bilirubin increases to 
more than 3 times the ULN 
Permanently discontinue 
Hypophysitis 
Grade 2 or 3 hypophysitis 
Withhold doseb 
Grade 4 hypophysitis 
Permanently discontinue 

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Adverse Reaction 
Severitya 
Dose Modifications 
Adrenal insufficiency 
Grade 2 adrenal insufficiency 
Withhold doseb 
Grade 3 or 4 adrenal insufficiency 
Permanently discontinue 
Type 1 diabetes mellitus 
Grade 3 hyperglycemia 
Withhold doseb 
Grade 4 hyperglycemia 
Permanently discontinue 
Nephritis and renal 
dysfunction 
Serum creatinine more than 1.5 and up to 6 
times the ULN 
Withhold doseb 
Serum creatinine more than 6 times the 
ULN 
Permanently discontinue 
Skin 
Grade 3 rash or suspected Stevens-Johnson 
syndrome (SJS) or toxic epidermal 
necrolysis (TEN) 
Withhold doseb 
Grade 4 rash or confirmed SJS or TEN 
Permanently discontinue 
Encephalitis 
New onset moderate or severe neurologic 
signs or symptoms 
Withhold doseb 
Immune-mediated encephalitis 
Permanently discontinue 
Other 
Other Grade 3 adverse reaction 
 
• First occurrence 
Withhold doseb 
• Recurrence of the same Grade 3 adverse 
reaction 
Permanently discontinue 
Life-threatening or Grade 4 adverse reaction 
Permanently discontinue 
Grade 3 myocarditis 
Permanently discontinue 
Requirement for 10 mg per day or greater 
prednisone or equivalent for more than 12 
weeks 
Permanently discontinue 
Persistent Grade 2 or 3 adverse reactions 
lasting 12 weeks or longer 
Permanently discontinue 
Source: Opdivo USPI, 2018  
ALT = alanine aminotransferase; AST = aspartate aminotransferase; HCC = hepatocellular carcinoma; 
SJS = Stevens-Johnson syndrome; TEN = toxic epidermal necrolysis; ULN = upper limit of normal 
a Guidelines based on toxicity graded per National Cancer Institute Common Terminology Criteria for Adverse 
Events (NCI CTCAE), where applicable. 
b Resume treatment when adverse reaction improves to Grade 0 or 1. 
c Resume treatment when AST/ALT return(s) to baseline. 
 
6.6.4 
Dose Modifications for CDX-301 
Dose escalation or reduction of CDX-301 will not be allowed in this study. Doses of CDX-301 
should be withheld (eg, skipped) for toxicity attributed to CDX-301 (Table 8), and doses that are 
skipped should not be made up. Toxicities attributed to CDX-301 that require dose delays greater 
than 6 weeks will require Medical Monitor approval for the participant to restart treatment. 
Leukocytosis, especially monocytosis, is expected during administration of CDX-301 and may 
be particularly pronounced when combined with other hematopoietic growth factors. 

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Hematological parameters, including white blood cell (WBC) and differential, should be 
monitored in participants receiving CDX-301. 
Specific anticipated or potential toxicities associated with the administration of CDX-301, as 
well as the measures to be taken to avoid or minimize such toxicity in this trial, are described in 
Table 8. 
Table 8: 
Dose Modification and Toxicity Management Guidelines for Adverse Events 
Associated with CDX-301 
Adverse Reaction 
Severity 
Dose Modifications 
Leukocytosis 
WBC count > 50,000 cells/mm3 
Withhold (skip) dosea 
Injection site reaction 
Grade 1 or 2 
No action required regarding CDX-301 
dose. 
Pre-medication with diphenhydramine 
may be considered for participants who 
experience local reactions after treatment 
with CDX-301  
Grade 3 
Permanently discontinue 
Grade 4 
Permanently discontinue 
Other ≥ Grade 2 adverse 
reaction 
• First occurrence 
Withhold (skip) dosea 
• Recurrence of the same 
≥ Grade 2 adverse reaction 
Permanently discontinue 
WBC = white blood cell 
a Resume treatment at the same CDX-301 dose level when adverse reaction returns to baseline, except for instances 
where the potential recurrence of the event poses an undue risk for the participant. Doses that are withheld (eg, 
skipped) should not be made up. 
 
6.6.5 
Dose Modifications for Poly-ICLC 
Dose escalation or reduction of poly-ICLC will not be allowed in this study. Poly-ICLC may be 
withheld (eg, skipped) if the participant experiences ≥ Grade 2 AEs considered at least possibly 
related to poly-ICLC. Doses of poly-ICLC that are skipped should not be made up. Toxicities 
attributed to poly-ICLC that require dose delays greater than 6 weeks will require Medical 
Monitor approval for the participant to restart treatment. 
7 
DISCONTINUATIONS OF STUDY INTERVENTION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL 
7.1 
DISCONTINUATION OF STUDY INTERVENTION 
Refer to the core protocol. 
In addition to the discontinuation criteria described in the core protocol, refer to Table 5, 
Section 6.6.3, Section 6.6.4, and Section 6.6.5 for management of toxicities requiring permanent 
discontinuation of nivolumab, CDX-301, and/or poly-ICLC. 

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7.2 
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM 
STUDY 
Refer to the core protocol. 
7.3 
LOST TO FOLLOW-UP 
Refer to the core protocol. 
8 
STUDY ASSESSMENTS AND PROCEDURES 
Refer to the core protocol. Any combination-specific supplementary information or 
modifications from the core protocol are described in the following sections. 
In this study cohort, the time between nivolumab doses must not be less than 24 days. 
8.1 
EFFICACY ASSESSMENTS 
Refer to the core protocol. 
8.1.1 
Laboratory Assessments of Clinical Activity 
Samples for the laboratory assessments of clinical activity and hormone levels in Table 9 will be 
sent to the study site’s local laboratory for analysis: 
Table 9: 
Laboratory Tests Sent to the Study Site’s Local Laboratory for Analysis of 
Disease-related Endpoints 
Profile 
Laboratory Test 
Clinical activity 
PSA 
Hormone levels 
testosterone 
PSA = prostate-specific antigen 
 
 
8.2 
SAFETY ASSESSMENTS 
Refer to the core protocol. 
8.2.1 
Clinical Safety Laboratory Assessments 
8.2.1.1 
Local Laboratory Assessments 
Samples for the laboratory tests in Table 10 will be sent to the study site’s local laboratory for 
analysis: 

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Table 10: 
Laboratory Tests Sent to the Study Site’s Local Laboratory for Analysis of 
Safety 
Profile 
Laboratory Test 
Hematology 
RBC count 
hemoglobin 
hematocrit 
WBC count with automated differential (neutrophils, eosinophils, basophils, 
monocytes, lymphocytes, other cells) 
platelet count 
manual differential, if clinically indicated 
Clinical Chemistry 
(Serum or Plasma) 
sodium 
potassium 
chloride 
bicarbonate 
glucose 
BUN or urea 
creatinine 
total protein 
albumin 
calcium 
total bilirubin 
alkaline phosphatase 
ALT 
AST 
LDH 
TSH (T3 and FT4 should be checked if TSH is outside the normal range) 
coagulation assessments (PT, PTT, INR)a 
Urinalysis 
 
ALT = alanine aminotransferase; AST = aspartate aminotransferase; BUN = blood urea nitrogen; 
INR = international normalized ratio; LDH = lactate dehydrogenase; PT = prothrombin time; PTT = partial 
thromboplastin time; RBC = red blood cell; TSH = thyroid stimulating hormone; WBC = white blood cell 
a Coagulation assessment not required during treatment phase unless indicated 
 
 
8.3 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS 
Refer to the core protocol for the SAE and AE collection periods and for details regarding safety 
reporting. 
8.3.4 
Regulatory Reporting Requirements for SAEs 
Refer to the core protocol for the regulatory reporting requirements for SAEs. 
For this cohort, the Parker Institute for Cancer Immunotherapy Pharmacovigilance Group will 
report SAEs to regulatory authorities, the overall PI, Bristol-Myers Squibb, Celldex 
Therapeutics, Oncovir, Inc., and the Institutional Review Board/Independent Ethics Committee 
(IRB/IEC), as appropriate. The process for such reporting, including contact information and 

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specific instructions for reporting to each of these organizations, is described in the Safety 
Monitoring Plan. 
8.3.7 
Adverse Events of Special Interest 
There are no identified adverse events of special interest for this immunotherapy combination. 
8.4 
TREATMENT OF OVERDOSE 
Refer to the core protocol. 
8.5 
PHARMACOKINETICS 
Sparse PK blood sampling will be collected according to the SOA to assess the PK of CDX-301 
and/or nivolumab. 
PK profiles for CDX-301 and/or nivolumab may be performed using a validated assay method 
under the supervision of the Sponsor’s designee. 
8.6 
ANTI-DRUG ANTIBODIES 
Immunogenicity samples will be collected according to the SOA to enable evaluation of anti-
drug antibodies (ADA) to either CDX-301 and/or nivolumab. Additionally, blood samples 
should also be collected at the final visit from participants who discontinued study intervention 
or were withdrawn from the study. These samples may be tested by the Sponsor's designee. 
The detection and characterization of antibodies to CDX-301 and/or nivolumab may be 
performed using a validated assay method under the supervision of the Sponsor’s designee. 
8.7 
BIOMARKERS 
Refer to the core protocol. 
Immune profiling may be performed, including evaluation of dendritic cell numbers and 
activation using flow cytometry or other assays. 
8.8 
MEDICAL RESOURCE UTILIZATION AND HEALTH 
ECONOMICS 
Refer to the core protocol. 
9 
STATISTICAL CONSIDERATIONS 
Refer to the core protocol. 
9.5.1 
Interim Safety Monitoring 
Refer to the core protocol for details related to the Safety Assessment Committee (SAC), the 
committee charged with safety review for this study. 

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With the inclusion of a safety period for the first 6 participant for this study cohort (see 
Section 6.6.1), the likelihood of proceeding to full enrollment decreases as the risk of toxicity 
from an AE described in Table 5 increases, as demonstrated in Table 11. 
Table 11: 
Probability of Proceeding to Full Enrollment 
True Risk of Toxicity 
0.10 
0.20 
0.30 
0.40 
0.50 
0.60 
Probability of Full Enrollment 
0.89 
0.66 
0.42 
0.23 
0.11 
0.04 
Assumes P(X≤1) where X is a binomial random variable with sample size n = 6 and p = true risk of toxicity. 
 
Table 12 shows the width of 95% confidence intervals calculated for possible observed rates of 
AEs described in Table 5 within the study. 
Table 12: 
Incidence with 95% Confidence Intervals of Possible Observed Adverse 
Events Described in Table 5 
Number of Participants with Adverse 
Eventsa/Number of Participants 
Incidence of  
Adverse Eventsa 
95% Confidence Intervalb 
0/6 
0 
[0, 0.39] 
1/6 
0.17 
[0.03, 0.56] 
2/6 
0.33 
[0.10, 0.70] 
3/6 
0.50 
[0.19, 0.81] 
a Adverse events described in Table 5  
b Wilson method for computing confidence interval 
 
 

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10 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS 
Refer to the core protocol for the following appendices: 
Appendix 1: Regulatory, Ethical and Study Oversight Considerations 
Appendix 2: Eastern Cooperative Oncology Group (ECOG) Performance Status 
Appendix 3: RECIST Criteria (Version 1.1) with Modifications as Recommended by 
PCWG3 
Appendix 4: Clinical Laboratory Tests 
Appendix 5: Adverse Events: Definitions and Procedures for Recording, Evaluating, Follow-
up, and Reporting 
Appendix 6: Contraceptive Guidance and Collection of Pregnancy Information 
Appendix 7: Genetics 

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10.1 
APPENDIX B-1: MANAGEMENT ALGORITHMS 
Management algorithms have been developed to provide guidance for Investigators in assessing 
and managing immune-mediated events in participants receiving nivolumab. Section 6.6.3 
describes the criteria for dose delay and discontinuation to be followed for nivolumab in this 
cohort. These algorithms are intended to provide clinical recommendations. In cases in which the 
modification criteria in Section 6.6.3 and the algorithms differ, the criteria in Section 6.6.3 
should take precedence.  
The management algorithms are provided for the following groups of drug-related AEs: 
• Immune-mediated gastrointestinal adverse events (diarrhea, colitis) 
• Immune-mediated renal adverse events (nephritis and renal dysfunction) 
• Immune-mediated pulmonary adverse events (pneumonitis) 
• Immune-mediated hepatic adverse events (hepatitis) 
• Immune-mediated endocrinopathy adverse events (hypophysitis, adrenal insufficiency, 
hypothyroidism and hyperthyroidism, Type 1 diabetes mellitus) 
• Immune-mediated skin adverse events 
• Immune-mediated neurologic adverse events (encephalitis) 
 
 

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10.2 
APPENDIX B-2: LISTS OF TERMINOLOGY AND 
ABBREVIATIONS 
10.2.1 
List of Terminology 
Terminology 
Description 
Cohort 
A group of participants receiving the same immunotherapy 
combination. 
Cohort appendix 
A document that guides the treatment of participants in a given 
cohort. The cohort appendices are identified using a letter 
designation (eg, Appendix Cohort B).  
Core protocol 
The master document that provides the elements common 
across the study and among all cohorts, unless otherwise 
specified. 
Immunotherapy combination 
Two or more study interventions administered to a cohort of 
participants. 
 
10.2.2 
List of Abbreviations 
Abbreviation 
Definition 
ADA 
anti-drug antibody(ies) 
ADP 
adenosine diphosphate 
AE(s) 
adverse event(s) 
AIDS 
acquired immunodeficiency syndrome 
ALT 
alanine aminotransferase 
AML 
acute myeloid leukemia 
APC(s) 
antigen-presenting cell(s) 
aPTT 
activated partial thromboplastin time 
AST 
aspartate aminotransferase 
AUC 
area under the concentration-time curve 
BED 
biologically equivalent dose 
BUN 
blood urea nitrogen 
C 
cycle 
Cavgss 
average steady-state concentration 
CDX-1401 
DEC-201/NY-ESO-1 fusion protein vaccine 
cfDNA 
cell-free deoxyribonucleic acid 
cHL 
classical Hodgkin lymphoma 
Cmax 
maximum observed drug concentration 
Cmaxss 
maximum steady-state plasma concentration 
Cminss 
minimum steady-state plasma concentration 
Cmin1 
trough concentration after the first dose 

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Abbreviation 
Definition 
CNS 
central nervous system 
CRC 
colorectal cancer 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTLA-4 
cytotoxic T-lymphocyte-associated protein 4 
DC(s) 
dendritic cell(s) 
DCR 
disease control rate 
dMMR 
mismatch repair deficient 
dsRNA 
double-stranded ribonucleic acid 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
EOT 
end of treatment 
EPO 
erythropoietin 
FDA 
Food and Drug Administration 
FFPE 
formalin-fixed paraffin-embedded 
Flt3L 
FMS-related tyrosine kinase 3 ligand 
GCP 
Good Clinical Practice 
GFR 
glomerular filtration rate 
GI 
gastrointestinal 
GnRH 
gonadotropin-releasing hormone 
GU 
genitourinary 
GVAX 
GM-CSF secreting allogenic pancreatic cancer vaccine 
Gy 
gray 
HCC 
hepatocellular carcinoma 
HIV 
human immunodeficiency virus 
I/E 
inclusion/exclusion 
IB 
Investigator’s Brochure 
ICF 
informed consent form 
IFN 
interferon 
IgG4 
immunoglobulin G4 
IM 
intramuscular(ly) 
iNHL 
indolent non-Hodgkin lymphoma 
INR 
international normalized ratio 
irAE(s) 
immune-related AE(s) 
IRB/IEC 
Institutional Review Board/Independent Ethics Committee 
IV 
intravenous(ly) 
LDH 
lactate dehydrogenase 
mAb 
monoclonal antibody 
mCRPC 
metastatic castration-resistant prostate cancer 

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Abbreviation 
Definition 
MSI-H 
microsatellite instability-high 
MTD 
maximum tolerated dose 
NCI 
National Cancer Institute 
NK 
natural killer 
nmCRPC 
nonmetastatic castration-resistant prostate cancer 
NSAIDs 
nonsteroidal anti-inflammatory drugs 
NSCLC 
non–small-cell lung cancer 
OAS 
2'5'oligoadenylate synthetase 
ORR 
objective response rate 
OS 
overall survival 
PARP 
poly ADP ribose polymerase 
PBMC(s) 
peripheral blood mononuclear cell(s) 
PCWG3 
Prostate Cancer Clinical Trials Working Group 3 
PD 
progressive disease 
PD-1 
programmed cell death 1 
PD-L1 
programed cell death ligand 1 
PFS 
progression-free survival 
PI 
Principal Investigator 
PK 
pharmacokinetics 
PKR 
P68 protein kinase 
poly-ICLC 
polyinosinic-polycytidylic acid stabilized with polylysine and 
carboxymethylcellulose 
PORTER 
Prostate Researching Translational Endpoints Correlated to Response 
PPK 
population pharmacokinetics 
PR 
partial response 
PSA 
prostate-specific antigen 
PT 
prothrombin time 
PTT 
partial thromboplastin time 
Q2W 
every 2 weeks 
Q3M 
every 3 months 
Q3W 
every 3 weeks 
Q4W 
every 4 weeks 
QD 
daily 
QoL 
quality of life 
RBC 
red blood cell 
RCC 
renal cell carcinoma 
RECIST 
Response Evaluation Criteria in Solid Tumors 
rhu 
recombinant human 

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Abbreviation 
Definition 
rhuFlt3L 
recombinant human Flt3 ligand 
rPFS 
radiographic progression-free survival 
S 
screening 
SAC 
Safety Assessment Committee 
SAE(s) 
serious adverse event(s) 
SBRT 
stereotactic body radiation therapy 
SC 
subcutaneous(ly) 
SCCHN 
squamous cell carcinoma of the head and neck 
SD 
standard deviation 
SGOT 
serum glutamic-oxaloacetic transaminase 
SGPT 
serum glutamic-pyruvic transaminase 
SJS 
Stevens-Johnson syndrome 
SOA 
Schedule of Activities 
TB 
tuberculosis 
TEN 
toxic epidermal necrolysis 
Tmax 
mean time to maximum serum concentration 
TMB 
tumor mutational burden 
TSH 
thyroid stimulating hormone 
UC 
urothelial carcinoma 
ULN 
upper limit of normal 
US 
United States 
USPI 
US prescribing information 
WBC 
white blood cell 
XRT 
radiation therapy 
 

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10.3 
APPENDIX B-3: APPENDIX COHORT B AMENDMENT 
HISTORY 
 
DOCUMENT HISTORY 
Documents 
Date of Issue 
Amendment 1 
24 Jan 2019 
Original Appendix Cohort B 
11 Dec 2018 
 
 
 

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11 
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