Conditions: Metastatic Castration-resistant Prostate Cancer Prostate Cancer Prostate Neoplasm Advanced Solid Tumor Solid Tumor Non-metastatic Castration-resistant Prostate Cancer
Keywords: Immunotherapy Combined Treatment PD-1/PD-L1 Tumor-Specific T Cells Novel Cancer Vaccine
Allocation: RANDOMIZED | Intervention model: SEQUENTIAL
Enrollment: 59
Healthy volunteers: no

Brief summary:
Background:

Immunotherapy drugs help the body to fight cancer. Scientists think that combining some of these drugs will make them work better than when used alone. This may be true for many types of cancer, including castration-resistant prostate cancer (CRPC).

Objective:

To test if any of the combinations of drugs below have anti-prostate cancer activity and to test if they are safe.

1. Bavarian-Nordic (BN)-brachyury, bintrafusp alfa (M7824).
2. Bavarian-Nordic (BN)-brachyury, bintrafusp alfa (M7824) + Anktiva (N-803).
3. Bavarian-Nordic (BN)-brachyury, bintrafusp alfa (M7824) + Anktiva (N-803) + Epacadostat.

Eligibility:

People ages 18 and older with CRPC or another metastatic cancer

Design:

Participants will be screened with:

* Medical history
* Physical exam
* Computed tomography (CT) or magnetic resonance imaging (MRI) scans
* Possible bone imaging
* Blood, urine, and heart tests
* Possible tumor biopsy

Participants will be treated with a 2-, 3- or 4-drug combinations of the following study drugs in 2-week cycles:

* Participants will receive M7824 by intravenous (IV) once every 2 weeks.
* Participants will receive N-803 by injection once every 2 weeks. They will record any skin changes at the injection site in a diary.
* Participants will receive BN-brachyury as 4 injections to different limbs. They will get the first 3 doses 2 weeks apart. Then they will get doses every 4 weeks for 6 months, then every 3 months for 2 years, then every 6 months.
* Participants will take Epacadostat orally every 12 hours. They will keep a pill diary.

Participants will have physical exams and blood and urine tests at the start of each cycle. They may have scans every 12 weeks.

Participants will continue treatment until their disease gets worse or they cannot tolerate the side effects.

Participants will have a follow-up visit 4-5 weeks after they stop treatment. They will have a physical exam and blood tests. They may be asked to return for scans every 3 months.

Detailed description:
Background:

* Programmed cell death protein 1 (PD-1)/programmed death ligand 1 (PD-L1) signaling appears to be a major inhibitor of activated T cell anti-tumor immune responses. The rapid, deep and durable responses seen in various malignancies with PD-1/PD-L1 targeted agents demonstrate that blockade of this axis is key to facilitating immune responses within the tumor microenvironment (TME).
* Prostate cancer is poorly recognized by T cells. Lack of an immune response is one explanation for the lower response rates (\<15%) observed with anti-PD-1/PD-L1 therapies for prostate cancer.
* Increasing response rates will likely require therapeutic nullification of multiple immune deficits by combining immunotherapies that generate tumor-specific T cells (vaccine), dampen the inhibitory milieu of the TME, and enhance T and natural killer (NK) cell activity within the TME.
* A quick efficacy seeking trial, utilizing sequential arms offers a means to identify signals of activity for combinations of immunotherapy, added sequentially, in castration resistant prostate cancer (CRPC) participants.
* Bavarian Nordic (BN)-Brachyury is a novel recombinant vector-based therapeutic cancer vaccine designed to induce an enhanced immune response against brachyury, which is overexpressed in many solid tumor types, including prostate adenocarcinoma. BN-Brachyury collectively refers to the priming doses (modified vaccinia Ankara (MVA)-BN-Brachyury) and the boost doses (fowlpox virus (FPV)-Brachyury) of the vaccine platform.
* bintrafusp alfa (M7824) is a bifunctional fusion protein consisting of an anti-programmed death ligand 1 (PD-L1) antibody and the extracellular domain of transforming growth factor beta (TGF- beta) receptor type 2, a TGF-beta trap. M7824 can also mediate antibody-dependent cellular cytotoxicity in vitro.
* Anktiva (N-803) is an interleukin 15 (IL-15)/IL-15R alpha superagonist complex that can enhance NK cell mediated antibody-dependent cell-mediated cytotoxicity (ADCC) and T-cell cytotoxicity.
* Synergistic anti-tumor effects have been observed in vitro when combining M7824 and N-803, and in vivo when combining these agents with tumor vaccine in animal models.
* Indoleamine 2,3-dioxygenase 1 (IDO1) is overexpressed in many solid tumors and can contribute to immune escape by tumor cells. INCB024360 (Epacadostat) is an IDO1 inhibitor under investigation in combination with different immunotherapies in treatment of various malignancies.
* In treating of CRPC, we hypothesize that these agents and their effects will be complementary. Tumor-specific T cells generated by vaccine may become more functional in a TME following treatment with M7824 and Epacadostat. N-803 can further enhance the activity of antigen-specific T cells as well as NK cells.

Objective:

-To determine if there is clinical benefit to any of a set of 3 possible treatments for participants with CRPC:

* BN-Brachyury + M7824
* BN-Brachyury + M7824 + N-803
* BN-Brachyury + M7824 + N-803 + Epacadostat

Eligibility:

* Adults with histologically proven CRPC, or metastatic solid tumor of any type for which there is no standard treatment or standard treatment has failed.
* Adequate organ function as defined by liver, kidney, and hematologic laboratory testing.
* Participants with acquired immune defects, active systemic autoimmune disease, history of organ transplant, history of chronic infections, or history of active inflammatory bowel disease are excluded.

Design:

Open label Phase I/II trial with following randomization during the expansion.

Phase I: Cohort 1, Arm 1.1

-Up to 18 participants with any solid tumor will be enrolled in dose escalation Cohort 1 for treatment in Arm 1.1 (flat dose of M7824 + different dose levels of N-803).

Phase IIA: expansion with sequential enrollment into Cohort 2A, Arms 2.1A, 2.2A and 2.3 A

* Concurrently with the enrollment to Arm 1.1, 13 participants with CRPC will start enrollment in Cohort 2A for treatment in Arm 2.1A (M7824 + BN-Brachyury).
* When safe dosing of N-803 is identified during Phase I, 13 participants have enrolled in arm 2.1A and the first 6 participants, treated in Arm 2.1A, have met safety requirements, 13 participants with CRPC will start enrollment in Cohort 2A for treatment in Arm 2.2A (M7824 + BN-Brachyury + N-803).
* When 13 participants have enrolled in Arm 2.2A and the first 6 participants, treated in Arm 2.2A, have met safety requirements, 13 participants with CRPC will start enrollment in Cohort 2A for treatment in Arm 2.3A (M7824 + BN-Brachyury + N-803 + Epacadostat).

Phase IIB: expansion with randomized enrollment into Cohorts 2D and 2R, Arms 2.1B, 2.2B. and 2.3B

* Each Arm in Cohorts 2D and 2R: 2.1B, 2.2B and 2.3B will be open for additional enrollment (25 evaluable participants total) when the initial 13 participants have accrued, safety requirements are meet and a positive signal (defined as Objective Response by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 or sustained prostate-specific antigen (PSA) decrease \>= 30% sustained for \> 21 days) in \>= 2 participants is shown.
* If only one arm is open for additional enrollment, participants will be directly assigned to this arm. If 2 arms are open for additional enrollment, participants will be randomized between these 2 open arms. If 3 arms are open for additional enrollment, participants will be randomized among these 3 open arms.

If there are \>= 6 of 25 participants with a positive signal of activity in any expansion arm, that arm will be considered of interest for future studies.

Arms:
arm 1: Bintrafusp alfa (M7824) + Anktiva (N-803) arm 2: Bintrafusp alfa (M7824) + Bavarian Nordic (BN)-Brachyury during phase IIA arm 3: Bintrafusp alfa (M7824) + Bavarian Nordic (BN)-Brachyury during phase IIB arm 4: Bintrafusp alfa (M7824) + Bavarian Nordic (BN)-Brachyury + Anktiva (N-803) during phase IIA arm 5: Bintrafusp alfa (M7824) + Bavarian Nordic (BN)-Brachyury + Anktiva (N-803) during phase IIB arm 6: Bintrafusp alfa (M7824) + Bavarian Nordic (BN)-Brachyury + Anktiva (N-803) + Epacadostat during phase IIA arm 7: Bintrafusp alfa (M7824) + Bavarian Nordic (BN)-Brachyury + Anktiva (N-803) + Epacadostat during phase IIB

Interventions: intervention 1: M7824 intervention 2: N-803 intervention 3: MVA-BN-Brachyury intervention 4: FPV-Brachyury intervention 5: Epacadostat intervention 6: Acetaminophen intervention 7: Ibuprofen intervention 8: Naproxen intervention 9: Benadryl intervention 10: EKG intervention 11: Bone scan intervention 12: CT chest, abdomen and pelvis intervention 13: MRI
Intervention descriptions: intervention 1: 1,200 mg intravenous (IV) once every 2 weeks. intervention 2: 8-15 mcg/kg subcutaneous every 2 weeks. intervention 3: MVA-BN-Brachyury will be administered subcutaneously (2 doses 2 weeks apart). intervention 4: FPV-Brachyury will be given 2 weeks after second dose of modified vaccinia Ankara (MVA)-Bavarian Nordic (BN)-Brachyury, then every 4 weeks until 6 months, then every 3 months for 2 years, then every 6 months. intervention 5: 600 mg orally twice daily (1200 MG total). intervention 6: Antipyretic medication, orally, prior to infusion, up to 650mg. intervention 7: Antipyretic medication, orally, prior to infusion, up to 600mg. intervention 8: Antipyretic medication, orally, prior to infusion, up to 500mg. intervention 9: 50mg orally prior to infusion. intervention 10: Baseline and principal investigator discretion. intervention 11: Restaging every 12 weeks. intervention 12: Every 12 weeks after start of therapy. intervention 13: If clinically indicated.

Protocol document:
Prot_SAP_000.pdf: 
Abbreviated Title: QuEST1 
Version Date:05/17/2024 
 
1 
Abbreviated Title: QuEST1 
NIH Protocol #: 18-C-0078  
IBC #: RD-17-XII-04 
OSP #: 1803-1731 
Version Date: May 17, 2024 
NCT Number: NCT03493945 
 
Title: A Phase I/II Study of Immunotherapy Combination BN-Brachyury vaccine, M7824, N-
803 and Epacadostat (QuEST1) 
 
NCI Principal Investigator:  
James Gulley, MD, PhD 
  
 
 
 
 
Genitourinary Malignancies Branch (GMB)  
Center for Cancer Research (CCR)  
National Cancer Institute (NCI) 
 
 
Phone: 
 
E-mail: 
 
 
Drug Name:  BN-Brachyury  
MSB001359C 
(M7824, 
Bintrafusp alfa) 
ALT-803 (N-803) INCB024360 
(Epacadostat) 
IND Number: BB-IND 17851 
 
IND Sponsor CCR, NCI 
 
Manufacturer: Bavarian Nordic, Inc.  EMD Serono 
Immunity Bio 
Incyte 
Supplier:  
Bavarian Nordic, Inc. 
EMD Serono 
Immunity Bio 
Incyte 
 
Commercial Agents: None  


Abbreviated Title: QuEST1 
Version Date:05/17/2024 
 
2 
PRÉCIS  
Background: 
 
PD-1/PD-L1 signaling appears to be a major inhibitor of activated T cell anti-tumor 
immune responses. The rapid, deep and durable responses seen in various malignancies 
with PD-1/PD-L1 targeted agents demonstrate that blockade of this axis is key to 
facilitating immune responses within the tumor microenvironment (TME).  
 
Prostate cancer is poorly recognized by T cells. Lack of an immune response is one 
explanation for the lower response rates (<15%) observed with anti-PD-1/PD-L1 therapies 
for prostate cancer. 
 
Increasing response rates will likely require therapeutic nullification of multiple immune 
deficits by combining immunotherapies that generate tumor-specific T cells (vaccine), 
dampen the inhibitory milieu of the TME, and enhance T and NK cell activity within the 
TME. 
 
A quick efficacy seeking trial, utilizing sequential arms offers a means to identify signals 
of activity for combinations of immunotherapy, added sequentially, in castration-resistant 
prostate cancer (CRPC) participants. 
 
BN-Brachyury is a novel recombinant vector-based therapeutic cancer vaccine designed to 
induce an enhanced immune response against brachyury, which is overexpressed in many 
solid tumor types, including prostate adenocarcinoma. BN-Brachyury collectively refers to 
the priming doses (MVA-BN-Brachyury) and the boost doses (FPV-Brachyury) of the 
vaccine platform. 
 
M7824 is a bifunctional fusion protein consisting of an anti-programmed death ligand 1 
(PD-L1) antibody and the extracellular domain of transforming growth factor beta (TGF-
β) receptor type 2, a TGF-β trap. M7824 can also mediate antibody-dependent cellular 
cytotoxicity in vitro. 
 
N-803 is an IL-15/IL-15Rα superagonist complex that can enhance NK cell mediated 
ADCC and T-cell cytotoxicity. 
 
Synergistic anti-tumor effects have been observed in vitro when combining M7824 and N-
803, and in vivo when combining these agents with tumor vaccine in animal models. 
 
IDO1 is overexpressed in many solid tumors and can contribute to immune escape by 
tumor cells. INCB024360 (Epacadostat) is an IDO1 inhibitor under investigation in 
combination with different immunotherapies in treatment of various malignancies. 
 
In treating of CRPC, we hypothesize that these agents and their effects will be 
complementary. Tumor-specific T cells generated by vaccine may become more functional 
in a TME following treatment with M7824 and Epacadostat. N-803 can further enhance 
the activity of antigen-specific T cells as well as NK cells.  
Objective: 
 To determine if there is clinical benefit to any of a set of 3 possible treatments for 
participants with CRPC: 
o BN-Brachyury + M7824 


Abbreviated Title: QuEST1 
Version Date:05/17/2024 
 
3 
o BN-Brachyury + M7824 + N-803 
o BN-Brachyury + M7824 + N-803 + Epacadostat 
Eligibility: 
 Adults with histologically proven CRPC, or metastatic solid tumor of any type for which 
there is no standard treatment or standard treatment has failed. 
 Adequate organ function as defined by liver, kidney, and hematologic laboratory testing. 
 Participants with acquired immune defects, active systemic autoimmune disease, history 
of organ transplant, history of chronic infections, or history of active inflammatory bowel 
disease are excluded. 
Design:  
Open label Phase I/II trial with following randomization during the expansion. 
Phase I: Cohort 1, Arm 1.1 
 Up to 18 participants with any solid tumor will be enrolled in dose escalation Cohort 1 for 
treatment in Arm 1.1 (flat dose of M7824 + different dose levels of N-803). 
Phase IIA: expansion with sequential enrollment into Cohort 2A, Arms 2.1A, 2.2A and 2.3 A 
 Concurrently with the enrollment to Arm 1.1, 13 participants with CRPC will start 
enrollment in Cohort 2A for treatment in Arm 2.1A (M7824 + BN-Brachyury). 
 When safe dosing of N-803 is identified during Phase I, 13 participants have enrolled in 
arm 2.1A and the first 6 participants, treated in Arm 2.1A, have met safety requirements, 
13 participants with CRPC will start enrollment in Cohort 2A for treatment in Arm 2.2A 
(M7824 + BN-Brachyury + N-803).  
 When 13 participants have enrolled in Arm 2.2A and the first 6 participants, treated in Arm 
2.2A, have met safety requirements, 13 participants with CRPC will start enrollment in 
Cohort 2A for treatment in Arm 2.3A (M7824 + BN-Brachyury + N-803 + Epacadostat). 
Phase IIB: expansion with randomized enrollment into Cohorts 2D and 2R, Arms 2.1B, 2.2B. and 
2.3B 
 Each Arm in Cohorts 2D and 2R: 2.1B, 2.2B and 2.3B will be open for additional 
enrollment (25 evaluable participants total) when the initial 13 participants have accrued, 
safety requirements are meet and a positive signal (defined as Objective Response by 
RECIST 1.1 or sustained PSA decrease ≥ 30% sustained for > 21 days) in ≥ 2 participants 
is shown.  
 If only one arm is open for additional enrollment, participants will be directly assigned to 
this arm. If 2 arms are open for additional enrollment, participants will be randomized 
between these 2 open arms. If 3 arms are open for additional enrollment, participants will 
be randomized among these 3 open arms. 
If there are ≥ 6 of 25 participants with a positive signal of activity in any expansion arm, that arm 
will be considered of interest for future studies. 


Abbreviated Title: QuEST1 
Version Date:05/17/2024 
 
4 
TABLE OF CONTENTS  
PRÉCIS ........................................................................................................................................... 2 
TABLE OF CONTENTS ................................................................................................................ 4 
STATEMENT OF COMPLIANCE ................................................................................................ 7 
1. 
INTRODUCTION .................................................................................................................. 7 
1.1 
Study Objectives .............................................................................................................. 7 
1.2 
Background and Rationale ............................................................................................... 8 
2 
ELIGIBILITY ASSESSMENT AND ENROLLMENT ....................................................... 20 
2.1 
Eligibility Criteria .......................................................................................................... 20 
2.2 
Screening Evaluation...................................................................................................... 24 
2.3 
Participant Registration and Status Update Procedures ................................................. 25 
2.4 
Baseline Evaluation ........................................................................................................ 27 
3 
STUDY IMPLEMENTATION ............................................................................................ 28 
3.1 
Study Design .................................................................................................................. 28 
3.2 
Study Stopping Rule ...................................................................................................... 32 
3.3 
Drug Administration ...................................................................................................... 33 
3.4 
Dose Modifications ........................................................................................................ 37 
3.5 
Study Calendar ............................................................................................................... 43 
3.6 
Cost and Compensation .................................................................................................. 46 
3.7 
Criteria for Removal from Protocol Therapy and Off Study Criteria ............................ 46 
4 
CONCOMITANT MEDICATIONS/MEASURES .............................................................. 47 
4.1 
General guidance ............................................................................................................ 47 
4.2 
N-803 (Formerly ALT-803) ........................................................................................... 48 
4.3 
Epacadostat..................................................................................................................... 48 
5 
CORRELATIVE STUDIES FOR RESEARCH ................................................................... 49 
5.1 
Biospecimen Collection ................................................................................................. 49 
5.2 
Sample Storage, Tracking and Disposition .................................................................... 52 
6 
DATA COLLECTION AND EVALUATION ..................................................................... 55 
6.1 
Data Collection ............................................................................................................... 55 
6.2 
Data Sharing Plans ......................................................................................................... 56 
6.3 
Response Criteria ........................................................................................................... 56 
6.4 
Toxicity Criteria ............................................................................................................. 62 
7 
NIH REPORTING REQUIREMENTS/DATA AND SAFETY MONITORING PLAN .... 62 


Abbreviated Title: QuEST1 
Version Date:05/17/2024 
 
5 
7.1 
Definitions ...................................................................................................................... 62 
7.2 
OHSRP Office of Compliance and Training /IRB Reporting ........................................ 62 
7.3 
NCI Clinical Director Reporting .................................................................................... 63 
7.4 
INSTITUTIONAL BIOSAFETY COMMITTEE (IBC) REPORTING CRITERIA .................... 63 
7.5 
NIH Required Data and Safety Monitoring Plan ........................................................... 64 
8 
SPONSOR PROTOCOL/SAFETY REPORTING ............................................................... 65 
8.1 
Definitions ...................................................................................................................... 65 
8.2 
Assessment of Safety Events.......................................................................................... 67 
8.3 
Reporting of Serious Adverse Events ............................................................................ 67 
8.4 
Waiver of expedited reporting to CCR .......................................................................... 67 
8.5 
Safety Reporting Criteria to the Pharmaceutical Collaborators ..................................... 68 
8.6 
Reporting Pregnancy ...................................................................................................... 70 
8.7 
Regulatory Reporting for Studies Conducted Under CCR-Sponsored IND .................. 70 
8.8 
Sponsor Protocol Deviation Reporting .......................................................................... 71 
9 
CLINICAL MONITORING ................................................................................................. 71 
10 STATISTICAL CONSIDERATIONS.................................................................................. 72 
10.1 Statistical hypotheses ..................................................................................................... 72 
10.2 Sample size determination ............................................................................................. 72 
10.3 Populations for analysis ................................................................................................. 74 
10.4 Statistical analysis .......................................................................................................... 74 
11 COLLABORATIVE AGREEMENTS ................................................................................. 75 
11.1 Cooperative Research and Development Agreement (CRADA) ................................... 75 
12 HUMAN SUBJECTS PROTECTIONS ............................................................................... 76 
12.1 Rationale For Subject Selection ..................................................................................... 76 
12.2 Participation of Children ................................................................................................ 76 
12.3 Participation of Subjects Unable to Give Consent ......................................................... 76 
12.4 Participation of Subjects Who Refuse Blood Transfusions ........................................... 76 
12.5 Risks/Benefits Analysis.................................................................................................. 76 
12.6 Consent Process and Documentation ............................................................................. 78 
13 REGULATORY AND OPERATIONAL CONSIDERATIONS ......................................... 79 
13.1 Study Discontinuation and Closure ................................................................................ 79 
13.2 Quality Assurance and Quality Control ......................................................................... 80 
13.3 Conflict of Interest Policy .............................................................................................. 80 


Abbreviated Title: QuEST1 
Version Date:05/17/2024 
 
6 
13.4 Confidentiality and Privacy ............................................................................................ 80 
14 PHARMACEUTICAL INFORMATION ............................................................................. 81 
14.1 MVA-BN-Brachyury (BB-IND 17851) ......................................................................... 81 
14.2 FPV-Brachyury (BB-IND 17851) .................................................................................. 83 
14.3 M7824 (MSB0011359C, Bintrafusp alfa) (BB-IND 17851) ......................................... 84 
14.4 N-803, Formerly ALT-803 (BB-IND 17851) ................................................................ 87 
14.5 Epacadostat..................................................................................................................... 88 
15 REFERENCES ..................................................................................................................... 93 
APPENDICES .............................................................................................................................. 98 
15.1 Appendix A - Performance Status Criteria .................................................................... 98 
15.2 Appendix B: N-803 Injection Site Reaction Diary ........................................................ 99 
15.3 Appendix C PATIENT’S MEDICATION DIARY ________________________ .... 100 
15.4 Appendix D: UDP glucuronosyltransferase (UGT1A9) Inhibitors.............................. 101 
15.5 Appendix E: OATP1BI & 1B3 Transporters and CYP1A2, CYP2C8 and CYP2C19 
Substrates ................................................................................................................................ 102 
 
 
 


Abbreviated Title: QuEST1 
Version Date:05/17/2024 
 
7 
STATEMENT OF COMPLIANCE 
The trial will be carried out in accordance with International Conference for Harmonisation 
Good Clinical Practice (ICH GCP) and the following:  
 United States (US) Code of Federal Regulations (CFR) applicable to clinical studies (45 
CFR Part 46, 21 CFR Part 50, 21 CFR Part 56, 21 CFR Part 312, and/or 21 CFR Part 812)  
National Institutes of Health (NIH)-funded investigators and clinical trial site staff who are 
responsible for the conduct, management, or oversight of NIH-funded clinical trials have 
completed Human Subjects Protection and ICH GCP Training. 
The protocol, informed consent form(s), recruitment materials, and all participant materials will 
be submitted to the Institutional Review Board (IRB) for review and approval.  Approval of both 
the protocol and the consent form must be obtained before any participant is enrolled.  Any 
amendment to the protocol will require review and approval by the IRB before the changes are 
implemented to the study.  In addition, all changes to the consent form will be IRB-approved; an 
IRB determination will be made regarding whether a new consent needs to be obtained from 
participants who provided consent, using a previously approved consent form. 
1. INTRODUCTION 
1.1 
STUDY OBJECTIVES 
1.1.1 Primary Objective 
 
To determine if there is clinical benefit to any of a set of 3 possible treatments for 
participants with castration-resistant Prostate Cancer (CRPC): 
 
BN-Brachyury + M7824 
 
BN-Brachyury + M7824 + N-803 
 
BN-Brachyury + M7824 + N-803 + Epacadostat 
1.1.2 Secondary Objectives 
 
Evaluate PFS in CRPC participants treated with:  
 
BN-Brachyury + M7824 
 
BN-Brachyury + M7824 + N-803 
 
BN-Brachyury + M7824 + N-803 + Epacadostat 
 
To characterize the safety profile of the above combinations and M7824 + N-803 
1.1.3 Exploratory Objectives: 
 
To study M7824 pharmacokinetics;  
 
To study anti-drug antibody levels (ADA); 
 
To study tryptophan and kynurenine levels in participants treated with Epacadostat; 
 
To analyze Immunologic Parameters before and after combined treatment; 
 
To analyze Prostate-specific Membrane Antigen (PSMA) positive extracellular vesicles 
(EV) and immune EVs; 


Abbreviated Title: QuEST1 
Version Date:05/17/2024 
 
8 
 
Correlate immunologic outcomes with clinical data and outcomes.  
1.2 
BACKGROUND AND RATIONALE 
Treatment with immune checkpoint modulators can produce dramatic and sometimes durable 
responses in patients with several types of advanced cancers. Such responses demonstrate the 
power of an appropriately manipulated immune system. Unfortunately, this is only seen in 15-25% 
of unselected patients in many cancers, and even fewer in cancers such as prostate, which lack a 
robust tumor immune cell infiltrate. Data presented at ESMO 2016 from a phase I trial of 
pembrolizumab for PD-L1 positive advanced prostate cancer showed an ORR of 13%, with no 
CRs. There were no ORs observed in 17 unselected prostate cancer patients treated with nivolumab 
in a phase I trial in solid tumors[1] and no ORs in 17 unselected mCRPC patients treated with 
avelumab (anti-PD-L1) in a phase I trial in solid tumors.[2] 
Three key components of a successful anti-tumor immune response are:  
1) presence of effector cells in the form of antigen specific T lymphocytes and/or natural 
killer cells  
2) the ability of those cells to traffic to tumor  
3) effective cytotoxicity of those cells within the tumor microenvironment (TME)  
In cases of success, a given immunotherapy compensates for a deficient component of anti-tumor 
immune activity. For example, it is hypothesized that in clinical responders, anti-PD-1/PD-L1 
agents overcome PD-1 axis mediated suppression of T cell cytotoxicity within the TME. 
Alternatively, adoptive cellular therapies can introduce tumor antigen-specific T cells. The limited 
frequency of objective responses seen across the board with these strategies indicate that in most 
patients, correcting only one deficiency in the anti-tumor response is not sufficient. It is currently 
impossible to know which critical immune function(s) needs enhancement in each individual 
patient and therefore impossible to know which monotherapy will be effective in each patient. A 
multi-pronged pharmacologic approach utilizing multiple immune therapies is warranted as we 
aim to improve clinical outcomes in tumors such as prostate cancer that lack an inflamed 
phenotype. A recent report highlighted the potential for improvements in outcomes with 
combination of immunotherapy in prostate cancer. Men with mCRPC and ARV-7+ circulating 
tumors cells were treated with nivolumab 3 mg/kg plus ipilimumab 1 mg/kg every 3 weeks for 4 
doses, followed by maintenance nivolumab 3 mg/kg every 2 weeks. The PSA 50% response rate 
was 1/15 (7%). Furthermore, ORR was 2/8 (25%) and durable PFS rate was 3/15 (20%).[3] This 
minimal clinical signal was associated with significant immune related adverse events with grade 
3-4 adverse events occurring in 7/15 (46%) men with (no grade 5 irAE). 
The use of novel combination approaches is in keeping with the Cancer Moonshot Taskforce’s 
mandate which called for the use of innovative strategies to rapidly translate new agents from 
bench to bedside. Rational combination of immune therapies is a plausible strategy to achieve this 
aim and is especially warranted in treating patients who have exhausted most, if not all, therapeutic 
options. A quick efficacy seeking trial will add an immunotherapy to each sequential cohort until 
a signal of activity is identified. Enhancing immunity via several different mechanisms is a 
promising means to produce objective responses in a substantially increased portion of patients. 
Below we describe four treatment agents that possess potential to enhance anti-tumor immunity in 
CRPC patients. 


Abbreviated Title: QuEST1 
Version Date:05/17/2024 
 
9 
1.2.1 BN-Brachyury 
Epithelial-to-mesenchymal transition (EMT) is a reversible process during which cells switch from 
a polarized, epithelial phenotype into a highly mobile, mesenchymal phenotype.[4] Numerous 
observations support the concept that the EMT process plays a role in the progression of human 
carcinomas [5] and data demonstrate that the transcription factor brachyury confers upon cells a 
mesenchymal phenotype as well as migratory and invasive capabilities and enhances tumor cell 
progression.[6] Investigators in the LTIB identified the overexpression of brachyury mRNA in cell 
lines of lung, colon and prostate cancers, but not in the majority of normal tissues tested, with the 
exception of expression in the testis and low levels of expression in B cells pooled from multiple 
normal donors. However, it is likely that this expression of brachyury in B-cells is from EBV 
infected cells. Preclinical studies suggest that brachyury expression by CD19+ B cells does not 
select them for lysis by brachyury-specific CD8+ T cells [7] and clinical studies of brachyury 
specific vaccines have shown no decrease in B-cells despite good brachyury specific immune 
responses.[8] Furthermore, other studies quantified brachyury expression in normal tissue and 
demonstrated low level or no expression in normal tissue except for testis.[6, 9-11]  
Analyses of prostate tumor samples have shown higher levels of brachyury expression to be 
associated the presence of poor prognostic factors, including higher Gleason score, perineural 
invasion and capsular invasion. [12] Additionally, it is a highly immunogenic target. Brachyury-
specific T cells have been observed following vaccine targeting other antigens, a phenomenon 
referred to as antigen cascade. 
It is important to note that, as a manifestation of tumor plasticity, brachyury expression is thought 
to take place in a transient fashion along the course of tumor progression. Therefore, tumor samples 
may be negative for brachyury expression, while disseminated tumor cells might still be positive 
for expression of the target brachyury. For this reason, expression of brachyury on the primary 
tumor is not thought relevant as an inclusion criterion for patients receiving brachyury-targeted 
vaccine.[13, 14]  
MVA-BN-Brachyury and FPV-Brachyury are the components of a novel recombinant vector-
based therapeutic cancer vaccine platform developed by the LTIB in collaboration with our 
CRADA partner Bavarian Nordic, Inc. The vaccine is designed to enhance the immune response 
against brachyury. This vector-based vaccine regimen consists of two priming doses of MVA-BN-
Brachyury, followed by FPV-Brachyury booster doses. These vaccines encode the transgenes for 
brachyury as well as a triad of human T-cell costimulatory molecules (TRICOM: B7.1, LFA3, and 
ICAM-1). TRICOM has previously been evaluated in several clinical trials.[13, 15-20] These 
vaccines differ from the previous generation of TRICOM-based vaccines in that the priming vector 
is not vaccinia virus, but a replication-incompetent form of vaccinia designated Modified Vaccinia 
Ankara (MVA) or fowlpox based.  
MVA has an improved safety profile when compared with vaccinia and its inability to replicate in 
human cells also allows MVA to be administered more than once without significant host 
neutralizing immune response.[21-26] Similarly, several studies have shown recombinant fowlpox 
vectors to have an excellent safety profile. [27] They are unable to replicate in mammalian cells, 
minimizing production of host vector neutralizing immunity and enabling administration of 
multiple booster vaccinations. 
Experiments conducted at the LTIB demonstrated that MVA-BN-Brachyury is able to efficiently 
infect and direct the expression of the encoded transgenes, brachyury, B7-1, ICAM-1 and LFA-3 




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1.2.2 Anti-PD-L1 TGF- trap (M7824) 
M7824 (MSB0011359C) is a bifunctional fusion protein combining an anti-programmed death 
ligand 1 (PD-L1) antibody and the extracellular domain of transforming growth factor beta (TGF-
β) receptor type 2, a TGF-β trap.  
Transforming growth factor beta (TGF-β) has tumor-suppressor effects in the pre-malignant state. 
However, elevated levels of TGF-β have been found to correlate with poor outcomes in prostate 
cancer.[30] TGF-β has been associated with malignant progression, evasion of immune 
surveillance, invasion, and metastasis.[31-33] Its direct effects on T cells include decreases in 
perforin, granzymes, interferon gamma (IFN-γ), Fas ligand (FasL), and natural killer (NK) group 
2D (NKG2D). It can also decrease NKG2D and major histocompatibility complex (MHC) class I 
polypeptide sequence A (MICA) in NK cells.[34] TGF-β is also implicated in the expansion of 
Tregs [35]. 
Expression of PD-L1 has been linked to immune evasion by tumor cells and poor prognosis in 
several malignancies.[36] Initial data from clinical trials of anti-PD-1 therapies in mCRPC did not 
yield many clinical responses, suggesting that PD-L1 expression may not be present in CRPC.[1, 
37] However, more recent studies have observed PD-L1 expression in enzalutamide-resistant 
prostate cancer.[38, 39] Suggesting a role for anti-PD-1/PD-L1 therapy in enzalutamide resistant 
patients, a small cohort study in men with metastatic prostate cancer on enzalutamide linked 
increased numbers of circulating PD-L1/2+ DC with enzalutamide refractoriness.[38] The 
frequency of PD-L1/2 positive DCs in circulating blood was significantly lower in enzalutamide 
naïve (n=3) and enzalutamide responders (n=4), compared to non-responders(n=8). There was also 
a trend toward increasing PD-L1/2+ DC’s in patients who had been on enzalutamide longer.  
Unpublished data from the LTIB suggest that vaccinating with a pox viral vector containing a 
tumor associated antigen (which is also a self-antigen) leads to upregulation of PDL1 in T-cell 
poor murine tumor models, likely due to trafficking of activated T-cells to the tumor and 
subsequent release of IFG-gamma. This may explain why therapeutic vaccines alone rarely lead 
to objective responses and provides the rational for combination with agents targeting PD-1 or PD-
L1. 
Nonetheless, the utility of anti-PD-L1 therapy in combination approaches, especially ones that 
directly cause an anti-tumor immune response, is unknown. Another study at the NCI showed that 
PARP inhibition with durvalumab (anti-PD-L1) in patients that had progressed on either 
abiraterone or enzalutamide was associated with PSA declines in the majority of patients on 
treatment (7/16). PARP inhibition is associated with double stranded DNA breaks which are a 
potent activator of the STING pathway which leads to interferon upregulation.[40] Work aimed at 
further understanding these findings is ongoing. Taken together, the lack of signal in anti-PD-1 
trials as monotherapy in prostate cancer and activity seen with strategies designed to increase T-
cell inflammation or activation, we believe that strategies aimed at focusing an immune response 
on the tumor (e.g. vaccine) while also providing for optimal activity of anti-tumor effector cells 
within the tumor microenvironment (e.g. M7824, ALT-803, epacadostat) will be required for 
enhancing efficacy of immunotherapeutic approaches in prostate cancer. 
M7824 is a multifunctional agent. It has been shown to simultaneously bind PD-L1 and TGF-β, as 
well as block PD-L1 signaling and TGF-β signaling in vitro. Furthermore, in a murine model 
(EMT-6 breast cancer), M7824 demonstrated superior anti-tumor activity compared to treatment 
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mice in the breast cancer model had complete responses and this treatment extended survival in a 
dose-dependent manner. Depletion studies demonstrated that anti-tumor efficacy of M7824 was 
CD8 cytotoxic T-cell and NK-cell dependent, whereas M7824 decreased TGF-β in the serum, 
bound PD-L1 within the tumor, and increased CD8+ T-cell infiltration of tumor. Treatment of 
NSCLC cells with M7824 in vitro and in vivo attenuated features of TGF-1-mediated 
mesenchymalization, including mesenchymal marker expression, proliferation suppression, and 
chemoresistance. Furthermore, M7824 can mediate ADCC in vitro. Cytotoxicity assays conducted 
at the  
Figure 2: M7824 can mediate ADCC  
LTIB demonstrated that mixing normal donor or cancer patient NK cells with M7824 induces 
ADCC of human tumor cells. This effect was abrogated by addition of anti-CD16 blocking 
antibodies (Figure 2).  
Murine studies performed at the LTIB combined M7824 with a vaccine targeted to Twist1, a 
transcription factor involved in murine EMT.[5] The combination resulted in prolonged survival 
following tumor implantation, compared to either treatment alone (Figure 3). Although the EMT 
processes in human and mouse are distinct, these data suggest that combining EMT targeted 
vaccine with M7824 may be synergistic. 


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Figure 3: Antitumor effect of M7824 plus vaccination with Ad-TWIST significantly 
improves anti-tumor efficacy vs. monotherapy 
Taken together, these data provide rational for combination of M7824 with BN-Brachyury. 
Preliminary results from a phase 1, open label, 3+3 dose escalation trial of M7824 conducted by 
the Genitourinary Malignancies Branch demonstrated efficacy in subjects with advanced solid 
tumors (NCT02517398).[41] Although no patients with prostate cancer enrolled, M7824 was 
observed to have a manageable safety profile. Data from 16 subjects with advanced cancer (three, 
three, three, and seven subjects treated with M7824 at 1, 3, 10, and 20 mg/kg, respectively, every 
2 weeks) were presented at the ASCO Annual Meeting in 2017. PK data showed a dose-linear 
increase in exposure starting at a dose of 3 mg/kg; furthermore, M7824 saturates peripheral PD-
L1 and sequesters any released plasma TGF-β1, -β2, and -β3 throughout the dosing period in a 
dose-dependent manner. Grade 3 drug-related treatment-emergent adverse events (TEAEs) 
occurred in 3 pts (skin infection secondary to grade 2 bullous pemphigoid [BP], lipase increased, 
and anemia caused by underlying colitis); there were no grade 4-5 drug-related TEAEs. BP and 
colitis responded well to steroids. Colitis and its secondary events of anemia and rectal hemorrhage 
(in a previously radiated area) were considered dose limiting in 1 pt. There was preliminary 
evidence of efficacy across all dose levels, including 1 ongoing confirmed complete response 
(cervical), 1 durable partial response (pancreatic), a 25% reduction in the sum of diameters of 
target lesions after 2 doses of M7824 (cervical), and 2 cases of prolonged stable disease 


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(pancreatic; carcinoid).[41] This agent is now in multiple expansion cohorts in 120 centers 
internationally, given at a flat dose of 1,200 mg. The entire dose escalation study was completed 
at the NCI. 
EMD Serono is a CRADA partner and will supply M7824. 
1.2.3 ALT-803 (IL-15 Superagonist Complex) 
ALT-803 is an IL-15 superagonist complex that has an increased ability to bind IL-2/15Rβγ and 
enhance immunostimulatory activity compared to native IL-15. In several rodent tumor models, 
ALT-803 has increased NK cell and CD8 T-cell numbers, decreased 
tumor size, and increased survival in the absence of significant 
toxicity.[42-44] [45, 46] ALT-803 leads to about a 20-fold 
upregulation in the number of circulating NK cells but also about a 2 
log increase in the high effector (CD 111b, CD27hi) NK cells. This 
was associated with about a 3-fold increase in cytotoxic activity and 
with substantial antitumor activity in a tumor treatment model.[44] 
Purified NK cells from a normal human donor showed much greater 
lytic activity when treated with ALT-803. Unpublished experiments 
conducted by the LTIB demonstrate an increase NK-mediated lysis 
in vitro with the combination of ALT-803 plus the anti-PD-L1 TGF- 
trap (M7824), compared to either treatment alone (Figure 4). Other LTIB experiments also 
demonstrate improved survival in tumor bearing mice with ALT-803 plus a CEA vaccine, 
compared to either treatment alone Figure 5. Other reports from preclinical studies have 
suggested synergy with ALT-803 and anti-PD-L1.[47] Taken together, this provides rationale for 
a trial of ALT-803 in combination with M7824.  
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response rate was ~50%. The response rate for PD-L1- patients was ~30%. Interestingly, one 
patient who achieved a CR exhibited pseudoprogression, with an increase of tumor size 4 times 
that of baseline, prior to shrinking. Peripheral blood analyses suggest that this combination 
increases NK cell activity with a dose of 6 mcg/kg of ALT-803. CD8 T cell activity is increased 
with the combination as well. However increased activity was only seen at 15 or 20 mcg/kg dosing 
of ALT-803. The recommended phase 2 dose of ALT-803 in combination with nivolumab is 20 
mcg/kg. 
Given the phase I safety data for the combination of anti-PD-1 with ALT-803, we do not expect 
severe toxicity from the anti-PD-L1 portion of M7824 when combined with ALT-803. However, 
since both of these agents can have multi-pronged effects on the immune system including the 
TGF-beta sequestration by M7824, a safety dose finding cohort of the combination will recruit up 
to 18 patients, prior to accrual of Cohort 2. This safety cohort will be open to any solid tumor type.  
Altor is a CRADA partner and will supply ALT-803. 
1.2.4 IDO1 and Epacadostat 
Indoleamine 2,3-dioxygenase-1 (IDO1) is an enzyme overexpressed many solid malignancies. 
IDO1 catalyzes the conversion of tryptophan to N-formyl-kynurenine and enhances immune 
escape.[48, 49] Kynurenine and other metabolites of tryptophan produced by IDO1 can cause T 
cell G1 arrest, T cell and dendritic cell apoptosis, dampening of NK cell activity, and enhancement 
of regulatory T cells.[50-53] Impeding immune escape with IDO1 inhibitors is a promising 
candidate for combination with other immune therapies such as checkpoint inhibitors or other 
immunomodulators. Many trials are underway combining IDO1 inhibitors with other 
immunotherapies.  
IDO1 appears to be particularly relevant in prostate cancer patients treated with checkpoint 
inhibitors and tumor-targeted vaccine. Compared to pre-treatment biopsies, Zahm et al detected 
increased IDO1 expression in tumor from 8 patients treated with prostatatic acid phosphatase-
targeted vaccine and/or anti-PD-1. [54] Patients who experienced PSA declines following vaccine 
and/or anti-PD-1 were observed to have stable plasma kynurenine levels. In contrast, an increase 
in serum kynurenine, compared to baseline, was associated with lack of response to treatment and 
suggests that IDO1 production of kynurenine is a key obstacle to be overcome in some patients 
receiving checkpoint inhibitors and/or vaccine.  
Epacadostat (INCB024360) is a selective inhibitor of IDO1. In a phase I dose escalation trial at 
doses of 50, 100, 300, 400, 500, 600 or 700 mg twice daily, epacadostat was shown to decrease 
plasma levels of kynurenine in a dose dependent fashion.[55] Dose limiting toxicities of grade 3 
radiation pneumonitis and grade 3 fatigue occurred at the 300 mg and 400 mg dose levels, 
respectively. Seven out of 52 patients had stable disease lasting  16 weeks. Maximal inhibition 
of IDO1 was achieved at doses  100 mg twice daily. Moreover, immune mediated adverse events 
associated with checkpoint inhibitor therapies e.g. anti-PD-L1 monoclonals were not common with 
epacadostat, suggesting that toxicities of epacadostat and the anti-PD-L1 TGF- trap are unlikely 
to overlap.  
Data from a phase 1 study of Epacadostat in combination with pembrolizumab (anti-PD-1) in 
advanced melanoma patients presented at ESMO 2016 demonstrated objective responses in 5 out 
of 6 patients who received Epacadostat at a dose  100mg orally twice daily.[56]  


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Additionally, 241 patients with advanced cancer were treated in a phase I/II dose escalation 
combining epacadostat with nivolumab 3 mg/kg every 2 weeks. As with the combination of 
epacadostat and pembrolizumab, epacadostat plus nivolumab appears to be well tolerated and 
active. Patients treated in the phase II portion (n=205) received epacadostat 100 mg or 300 mg 
orally daily. In these patients, the most common treatment-related adverse events (defined as 
occurring in ≥15% of patients) were rash (33% for 300 mg and 22% for 100 mg,), fatigue (26% 
and 31%, respectively), and nausea (24% and 19%, respectively). Rash was the most common 
grade ≥3 adverse event in the 100 mg and 300 mg subgroups (10% and 12%). There were no 
treatment-related deaths. For example, head and neck cancer patients treated at the 300 mg dose 
had a preliminary disease control rate (DCR) of 70% (n = 16). Of 30 melanoma patients, 8 were 
treated at the 100 mg dose and 22 were treated with 300 mg. ORR and DCR in melanoma patients 
treated with 100 mg were 75% (n = 6; all PR) and 100% (n = 8; 2 SD), respectively.  
Despite promising early phase clinical trial results, Incyte announced in 2018 that a phase III study 
combining nivolumab and epacadostat in metastatic melanoma did not meet its co-primary 
endpoint of improved PFS. [57] Subsequent exploratory correlative analyses conducted by Incyte 
provide some insight into this clinical trial failure. Epacadostat 100 mg BID as monotherapy 
achieves an exposure that exceeds the IC50 at steady state and epacadostat 400 mg BID and greater 
(as monotherapy) achieve exposures that exceed the IC90 at steady state in peripheral blood. In 
clinical studies combining epacadostat (primarily at 100 mg or 300 mg twice daily) with PD-1 
inhibition, durable reductions in plasma kynurenine were not observed. The 100 mg dose produced 
only minor reductions in plasma kynurenine. While the 300 mg dose produced greater reductions 
in kynurenine, reductions down to the levels observed in healthy volunteers were not durable over 
time in most patients. Preliminary clinical data from cancer patients treated with epacadostat 600 
mg twice daily in combination with checkpoint inhibitors demonstrate reductions in kynurenine 
that are durable for several cycles of treatment. 
Since IDO1 expression is induced by IFN-γ [58], it is expected that IFN-γ induced IDO1 
expression will be increased in the setting of immune activity (i.e. BN-brachyury, vaccine, M7824, 
and ALT-803 administration). As suggested by the report from Zahm and colleagues [54], 
adequate control of the IDO1 metabolite kynurenine may be a crucial component in the facilitation 
of anti-tumor immune activity in these patients. Therefore, the potential for epacadostat to increase 
the activity of M7824, ALT-803, and BN-brachyury will be optimized at a dose that durably 
reduces serum kynurenine (600 mg orally twice daily). As discussed below in section 1.2.4.1, 
safety data from clinical trials combining checkpoint inhibitors with higher doses of epacadostat 
suggest the regimen is well tolerated.  Incyte is a CRADA partner and will provide Epacadostat. 
 
1.2.4.1 Expanded safety data combining higher dose of epacadostat with checkpoint inhibitors 
 
INCMGA0012-102 (ClinicalTrials.gov Identifier: NCT03589651) is a Phase 1b study to evaluate 
the safety and tolerability of combination of epacadostat and INCMGA0012, an anti-PD-1 
antibody, in participants with advanced solid tumors. Thirty-one participants received 
INCMGA00012 500 mg Q4W plus epacadostat.  Four dose levels of epacadostat were studied 
(100 mg BID, 400 mg BID, 600 mg BID and 900 mg BID).  


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All participants experienced an adverse event (AE). Sixteen participants (52%) experienced an AE 
that was considered related to epacadostat. The dose of 600 mg BID was established as the 
maximum tolerated dose of epacadostat in combination with INCMGA00012.  Two of the 3 
participants who received INCMGA00012 in combination with epacadostat 900 mg BID 
experienced diffuse maculopapular erythematous rash, which was determined to be the dose 
limiting toxicity.  
Twelve participants received INCMGA00012 in combination with epacadostat at the MTD of 600 
mg BID. Six of these participants (50%) experienced an AE related to epacadostat. One of these 
participants experienced a Grade 3 (CTCAE v.5.0) AE which was maculopapular rash and fever. 
Other AEs related to epacadostat at this dose were nausea, fatigue, dyspepsia, hypothyroidism, 
rash, pruritus, and diarrhea. 
Nine participants received INCMGA00012 in combination with epacadostat 400 mg BID. Four of 
these participants (44%) experienced an AE related to epacadostat. One of these was a Grade 3 
maculopapular rash. Other AEs related to epacadostat reported at this dose included nausea, 
fatigue, fever, diarrhea, and dyspepsia. 
Three participants received INCMGA00012 in combination with epacadostat 100 mg BID. One 
of them experienced an AE of Grade 1 anorexia that was noted as related to epacadostat. 
No significant drug related laboratory abnormalities have been reported at any dose level. 
Serious AEs have been reported in 6 of the 31 participants (19%). Only 1 participant had an SAE 
noted as related to epacadostat, which was the event of fever and maculopapular rash. 
This appears to be higher than what is expected with bintrafusp alfa alone. In conclusion, the 
combination of epacadostat plus immune checkpoint inhibitor (INCMGA00012) has been studied 
in the phase 1 setting and informs the dosing with the anti-PD-L1 agent in this study (M7824). 
Common toxicities of BN-brachyury and N-803 (fever, flu-like symptoms, and injection site 
reactions are not expected to overlap.  
1.2.4.2 Isolated Adrenocorticotropin Deficiency (IAD) 
As of July, 17th 2020, 4 of 25 patients treated on arm 2 had developed central adrenal insufficiency 
(1/13 in Arm 2.1A and 3/12 in Arm 2.2A).  
1.2.5 Rationale Summary 
 Brachyury has a tumor-restricted pattern of expression and a relevant role in several aspects 
of tumor progression, including EMT, making brachyury an ideal vaccine target for CRPC. 
 Preclinical data suggests that M7824 may have synergistic anti-tumor activity with EMT-
targeted vaccines and ALT-803. 
 IDO1 inhibition can dampen the inhibitory milieu within the TME, further augmenting 
anti-tumor activity of BN-Brachyury, M7824 and ALT-803, and is unlikely to add 
significant toxicity. 
 National initiatives such as the Cancer Moonshot Taskforce dictate initiation of trials that 
pursue innovative approaches aimed at translating novel cancer treatments from bench to 
bedside. This quick efficacy seeking trial aimed at identifying a signal of activity in 
multiple combination regimens offers a means to enhance response rates in CRPC on a 
potentially shorter timeline than with that of traditional trial designs. 


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2 
ELIGIBILITY ASSESSMENT AND ENROLLMENT  
2.1 
ELIGIBILITY CRITERIA 
2.1.1 Inclusion Criteria 
2.1.1.1 Participants must have histologically or cytologically confirmed any solid tumor (Cohort 
1) or castration-resistant prostate cancer (CRPC, Cohorts 2A, 2D and 2R).  
2.1.1.2 For the Cohort 1, eligible participants must have a histologically, cytologically or 
radiographically proven metastatic or locally advanced solid tumor of any type, for which 
there is no curative standard therapy or standard therapy has failed. 
2.1.1.3 Castrate testosterone level (<50ng/dl or 1.7nmol /L). (Participants with a malignancy other 
than prostate cancer are excluded from this criterion). 
2.1.1.4 Radiological confirmation of metastatic disease, or  
Progressive disease at study entry defined as one or more of the following criteria 
occurring in the setting of castrate levels of testosterone:  
 Radiographic progression defined as any new or enlarging bone lesions or 
growing lymph node disease, consistent with prostate cancer  
OR  
 PSA progression defined by sequence of rising values separated by >1 week 
(2 separate increasing values over a minimum of 1 ng/ml (PCWG3 PSA 
eligibility criteria). If participants had been on flutamide, PSA progression is 
documented 4 weeks or more after withdrawal. For participants on 
bicalutamide or nilutamide disease progression is documented 6 or more 
weeks after withdrawal. The requirement for a 4-6 week withdrawal period 
following discontinuation of flutamide, nilutamide or bicalutamide only 
applies to participants who have been on these drugs for at least the prior 6 
months. For all other participants they must stop bicalutamide, nilutamide or 
flutamide the day prior to enrollment.  
2.1.1.5 Asymptomatic or mildly symptomatic form prostate cancer; no use of regularly scheduled 
opiate analgesics for prostate cancer-related pain. (Participants with a malignancy other 
than prostate cancer are excluded from this criterion). 
2.1.1.6 Participants must agree to continuation of androgen deprivation therapy (ADT) with a 
gonadotropin-releasing 
hormone 
analogue/antagonist 
or 
bilateral 
orchiectomy. 
(Participants with a malignancy other than prostate cancer are excluded from this 
criterion). Participants may also continue oral androgen receptor antagonist/anti-androgen 
therapy (e.g. enzalutamide or abiraterone) unless enrolling to Arm 2.3A or 2.3B due to 
concerns regarding CYP-mediated drug-drug interactions epacadostat. 
2.1.1.7 Participants must have had the following prior therapy: 
2.1.1.7.1 Testosterone lowering therapy for CRPC 
2.1.1.7.2 In addition to continuation of ADT (unless status post bilateral orchiectomy) eligible 
patients must have received and had PSA or radiographic progression on enzalutamide 


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(or other oral androgen receptor antagonist e.g. darolutamide or apalutamdide) or 
abiraterone acetate.  
2.1.1.7.3 Participants who have tumors known to be microsatellite instability high/mismatch 
repair deficient or tumor mutational burden high must have received prior 
pembrolizumab.  
2.1.1.7.4 Participants with known pathogenic homologous recombination repair mutations for 
which there is evidence of benefit with PARP inhibitors (e.g. BRCA1. BRCA2, 
ATM,) must have received prior PARP inhibitor.  
2.1.1.8 Age >18 years.  
2.1.1.9 ECOG performance status ≤ 1 (see Appendix A).  
2.1.1.10 Participants must have adequate organ and marrow function as defined below:  
 Absolute neutrophil count  1000/mcL 
 Platelets  100,000/mcL  
 Hemoglobin  9.0 g/dL 
 Total bilirubin within normal institutional limits; in participants with 
Gilbert’s, ≤ 3.0 mg/dL 
 AST (AGOT)/ALT (AGPT)  2.5X upper limit of normal. For subjects 
with liver involvement in their tumor, AST ≤ 3.5. × ULN, ALT ≤ 3.5 × 
ULN, and bilirubin ≤ 3.0 is acceptable  
 Creatinine within 1.5X upper limit of normal institutional limits  
2.1.1.11 The effects of BN-Brachyury, M7824, N-803, and Epacadostat on the developing human 
fetus are unknown. For this reason, men and women must agree to use adequate 
contraception (hormonal or barrier method of birth control; abstinence) prior to study 
entry, during the study and maintain such contraception until 4 months following the last 
dose of any study agent. Should a woman become pregnant or suspect she is pregnant 
while she or her partner is participating in this study, she should inform her partner’s 
treating physician immediately.  
2.1.1.12 Ability of subject to understand and the willingness to sign a written informed consent 
document 
2.1.1.13 Participants with successfully treated HCV are eligible if HCV viral load is undetectable. 
2.1.2 Exclusion Criteria 
2.1.2.1 Participants who are immunocompromised as follows:  
 
Human immunodeficiency virus positivity due to the potential for decreased 
tolerance, and potential to be at risk for severe side effects with immunotherapies. 
These concerns are relevant to all drugs, as drug-drug interactions among anti-
retrovirals and immunotherapies are yet uncharacterized.  
 
Chronic administration (defined as daily or every other day for continued use >14 
days) of systemic corticosteroids or other immune suppressive drugs, within 28 


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days before treatment on study. Nasal, or inhaled steroid, topical steroid creams and 
eye drops for small body areas are allowed. Physiologic doses of steroids are 
permitted, e.g. a participant taking hydrocortisone for adrenal insufficiency or a 
patient recently on abiraterone (administered with 10 mg of prednisone daily) who 
is tapering off of prednisone is allowed to continue that taper. 
 
Participants who have undergone allogeneic peripheral stem cell transplantation, or 
solid organ transplantation requiring immunosuppression.  
 Active autoimmune disease, except participants with type 1 diabetes mellitus, 
vitiligo, psoriasis, hypo- or hyperthyroid disease not requiring current 
immunosuppression, or with other endocrine disorders on replacement 
hormones or are not excluded if the condition is well controlled.  
2.1.2.2 Prostate cancer participants with a history of brain/leptomeningeal metastasis, since these 
participants have a very poor prognosis and immunotherapy may take time to lead to 
beneficial clinical effects. Participants with brain or CNS metastases enrolling to arm 1.1 
are eligible if they are status post definitive radiotherapy or surgery and are asymptomatic.  
2.1.2.3 History of allergic reactions attributed to compounds of similar chemical or biologic 
composition to study agents to be used in the cohort the subject will be enrolled into. 
2.1.2.4 Known allergy to eggs, egg products, aminoglycoside antibiotics (for example, 
gentamicin or tobramycin). 
2.1.2.5 Any condition which, in the opinion of the investigator, would prevent full participation 
in this trial (including the long-term follow-up), or would interfere with the evaluation of 
the trial endpoints.  
2.1.2.6 Participants with prior investigational drug, chemotherapy, immunotherapy or any prior 
radiotherapy (except for palliative bone directed therapy) within the past 28 days prior to 
enrollment except if the investigator has assessed that all residual treatment-related 
toxicities have resolved or are minimal and feel the participant is otherwise suitable for 
enrollment. 
2.1.2.7 Uncontrolled intercurrent acute or chronic illness including, but not limited to, ongoing or 
active infection, symptomatic congestive heart failure (>New York Heart Association 
Class I), hepatic disease, unstable angina pectoris, serious cardiac arrhythmia, requiring 
medication, uncontrolled hypertension (SBP>170/ DBP>105) or psychiatric illness/social 
situations within 12 months that would limit compliance with study requirements.  
2.1.2.8 Use of herbal products that may decrease PSA levels (e.g. saw palmetto). 
2.1.2.9 Participants who have had cytotoxic chemotherapy for metastatic castration-resistant 
prostate cancer within the past 3 months. (Participants who have had docetaxel for 
metastatic castration sensitive per CHAARTED data may enroll as long as they did not 
have progressive disease while on docetaxel and are 3 months removed from treatment, 
with all treatment related toxicities resolving to at least grade 1.)  
2.1.2.10 Participants who have undergone major surgery within 4 weeks of enrollment. A biopsy 
will not preclude a participant from starting study. 


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2.1.2.11 Participants with a history of hepatitis B (HBV) are excluded due to potential risk for viral 
reactivation and resulting liver injury in persons with latent HBV. 
2.1.2.12 Subjects unwilling to accept blood products or blood transfusions as medically 
indicated.  As there is a risk of severe bleeding with M7824, participants must be willing 
to receive blood transfusions if medically necessary for their own safety 
2.1.2.13 For Participants enrolling in Arm 2.3A and for participants who may be randomized to 
Arm 2.3B, the following additional exclusion criteria will apply: 
2.1.2.13.1 Subjects receiving Monoamine Oxidase Inhibitors (MAOIs) or a drug which has 
significant MAOI activity (meperidine, linezolid, methylene blue) within the 21 
days before initiation of study therapy are excluded.   
2.1.2.13.2 Since epacadostat’s metabolism may be altered by drugs that inhibit UDP-
glucuronosyltransferase UGT1A9 (see Appendix D), Participants receiving such 
drugs within 21 days of initiation of study therapy are excluded. 
2.1.2.13.3 Participants receiving agents that are substrates of CYP1A2, CYP2C8, and CYP2C19 
or affected by OATP1B1 or OATP1B3 (see Appendix E) within 21 days of initiation 
of study therapy or 5 half lives of the agent (whichever is shorter) are excluded. 
Participants receiving medications that are substrates of these enzymes/transporters 
but are not listed in the appendix or participants receiving substrates of CYP2B6 and 
CYP3A will be evaluated on a case-by-case basis prior to enrollment. Patients who 
consume caffeine are eligible but must agree to moderate consumption as specified in 
Appendix E. 
2.1.2.13.4 Subjects receiving coumarin-based anticoagulants (e.g. Coumadin) are excluded.  
2.1.2.13.5 Subjects having any history of Serotonin Syndrome (SS) after receiving 
serotonergic drugs are excluded. 
2.1.2.13.6 Participants with a QTcF interval > 480 milliseconds at the screening are excluded.  
In the event that a single QTc F is > 480 milliseconds, the subject may enroll if the 
average QTcF for 3 ECGs is < 480 milliseconds.  For subjects with an 
intraventricular conduction delay (QRS interval > 120 milliseconds), the JTc 
interval may be used in place of the QTc.  The JTc must be < 340 milliseconds if 
JTc is used in place of the QTc. QTc prolongation due to pacemaker may enroll if 
the JTc is normal. 
2.1.2.13.7 Subjects with left bundle branch block are excluded. 
2.1.2.13.8  Pregnant women are excluded from this study because investigational agents used in 
this study (BN-Brachyury, M7824, N-803, and/or Epacadostat) could have teratogenic 
or abortifacient effects. Because there is an unknown but potential risk for adverse 
events in nursing infants secondary to treatment of the mother with these 
investigational agents, breastfeeding should be discontinued if the mother is treated 
with either of them.  


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24 
2.1.3 Recruitment Strategies 
This 
study 
will 
be 
listed 
on 
available 
websites 
(www.clinicaltrials.gov, 
https://ccr.cancer.gov/clinical-trials) and participants will be recruited from the current participant 
population at NIH and participating sites. This study could be posted on NIH social media forums.   
  
2.2 
SCREENING EVALUATION 
2.2.1 Screening activities performed prior to obtaining informed consent 
Minimal risk activities that may be performed before the subject has signed a consent include the 
following:  
 Email, written, in person or telephone communications with prospective subjects  
 Review of existing medical records to include H&P, laboratory studies, etc.   
 Review of existing MRI, x-ray, or CT images 
 Review of existing photographs or videos 
 Review of existing pathology specimens/reports from a specimen obtained for diagnostic 
purposes 
A waiver of consent for these activities has been requested in section 12.6.2 
2.2.2 Screening activities performed after a consent for screening has been signed 
The following activities will be performed only after the subject has signed the study consent OR 
the consent for study 01-C-0129 (provided the procedure is permitted on that study) on which 
screening activities may also be performed. Assessments performed at outside facilities or on 
another NIH protocol within the timeframes below may also be used to determine eligibility once 
a participant has signed the consent. 
 
Screening tests and procedures must be performed within 28 days prior to drug administration, 
unless otherwise specified: 
1. Complete medical history and physical examination (including height, weight, vital signs, 
and ECOG performance status). 
2. CT of chest, abdomen and pelvis * 
3. Clinical laboratory tests* 
 Chemistry: sodium, potassium, chloride, bicarbonate, calcium, glucose, BUN, creatinine, 
ALT, AST, alkaline phosphatase, total protein, albumin, and total and direct bilirubin, 
PT/PTT 
 Hematology: complete blood count (CBC) with differential and platelets 
 Serum PSA (participants with a malignancy other than prostate cancer do not need this 
test) 
 Testosterone level (participants with a malignancy other than prostate cancer do not need 
this test) 
 
Urinalysis 


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25 
 Serum pregnancy test (β-HCG) for females of childbearing-potential and women 
< 12 months since the onset of menopause (within 16 days prior to initiation of study 
therapy).  
 HBV, HCV, HIV testing including viral load for HCV and HBV (within 3 months prior to 
enrollment). 
4. Histologic confirmation* (at any time point prior to initiation of study therapy).  
5.  Electrocardiogram (EKG) for participants enrolling in arm 2.3 A and for participants who 
may be randomized to arm 2.3 B 
* Outside test results are acceptable if performed in designated time frame. 
2.3 
PARTICIPANT REGISTRATION AND STATUS UPDATE PROCEDURES 
Registration and status updates (e.g. when a participant is taken off protocol therapy and when a 
participant is taken off-study) will take place per CCR SOP ADCR-2, CCR Participant 
Registration & Status Updates found here:  
https://ccrod.cancer.gov/confluence/pages/viewpage.action?pageId=73203825.  
2.3.1 Screen Failures 
Screen failures are defined as participants who consent to participate in the clinical trial but are 
not subsequently assigned to the study intervention or entered in the study. A minimal set of 
screen failure information is required to ensure transparent reporting of screen failure 
participants, to meet the Consolidated Standards of Reporting Trials (CONSORT) publishing 
requirements and to respond to queries from regulatory authorities. Minimal information 
includes demography, screen failure details, eligibility criteria, and any serious adverse event 
(SAE). 
Individuals who do not meet the criteria for participation in this trial (screen failure) because of a 
lab abnormality or temporary condition may be rescreened. 
2.3.2 Treatment Assignment and Randomization Procedures 
Cohorts 
Number 
Name 
Description 
1 
Cohort 1 
Participants with any solid tumor 
2 
Cohort 2A 
Participants with CRPC during Phase IIA 
3 
Cohort 2D 
Participants with CRPC requiring direct assignment in phase IIB 
4 
Cohort 2R 
Participants with CRPC requiring randomization in phase IIB 
Arms 
Number 
Name 
Description 


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26 
1 
Arm 1.1 
M7824 + N-803 (accrual closed) 
2 
Arm 2.1A 
M7824 + BN-Brachyury during phase IIA (accrual closed) 
3 
Arm 2.2A 
M7824 + BN-Brachyury + N-803 during phase IIA 
4 
Arm 2.3A 
M7824 + BN-Brachyury + N-803 + Epacadostat during phase IIA
5 
Arm 2.1B 
M7824 + BN-Brachyury during phase IIB 
6 
Arm 2.2B 
M7824 + BN-Brachyury + N-803 during phase IIB 
7 
Arm 2.3B 
M7824 + BN-Brachyury + N-803 + Epacadostat during phase IIB 
Arm Assignment 
During Phase I Participants in Cohort 1 will be directly assigned to Arm 1.1. 
During Phase IIA participants in Cohort 2A, will be first assigned to Arms 2.1A (13 participants 
total) until filled, then to Arm 2.2A (13 participants total), and finally to Arm 2.3A (13 
participants total). 
Arm 2.1B will not be used, as inadequate responses were noted in 2.1A. 
During phase IIB, participants in cohort 2D will be directly assigned to the appropriate arm (either 
Arms 2.2B or 2.3B) if direct assignment to an arm is required;  participants in cohort 2R will be 
randomized among the open arms (among Arms, 2.2B and 2.3B) if randomization is required 
 
Randomization 
As safety and efficacy information about the treatments in Arms 2.1A, 2.2A and 2.3A becomes 
available, Arms 2.1B, 2.2B and 2.3B may become open for enrollment. During this expansion 
(Phase IIB portion) of this trial, more than one arm e.g. Arms 2.1B (up to 25 participants), 2.2B 
(up to 25 participants, 2.3B (up to 25 participants) may be open for accrual simultaneously. In 
order to avoid any selection bias, if more than one expansion arm is open for accrual, participants 
will be randomized among all open arms. Hence, if 2 arms are open simultaneously, randomization 
will occur between two arms. If 3 arms are open simultaneously, randomization will occur among 
three arms. If an arm completes accrual, assignment to the remaining open arms will be 
randomized between the 2 remaining open arms, or by direct assignment, if only 1 arm remains 
open. For logistical reasons involved in randomization, a cohort is not permitted to be 
heterogeneous, in terms of participants who have been randomized or directly assigned. For this 
reason, cohorts 2D and 2R are added. See Section 10.2 for further details. 
Note: Randomization will be performed by the CRO. Since the expansion phase can start with 
only one arm open, participants will be assigned directly to the first expansion arm that may open. 


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27 
2.4 
BASELINE EVALUATION 
All subjects are required to complete baseline evaluations within 3 days prior to the first planned 
dosing of the study drug (any screening evaluation done within this time period can also serve for 
the baseline evaluation): 
 Physical exam including weight, ECOG performance status and vital signs  
 Tc-99 whole body scintigraphy (Bone scan) if participant has prostate cancer (within 
30 days of first dosing of study drug) 
 CT of chest, abdomen and pelvis (within 30 days of first dosing of study drug) 
 Concomitant medications and adverse events evaluation 
 EKG 
 Serum pregnancy test (β-HCG) for females of childbearing-potential and women 
< 12 months since the onset of menopause (within 3 days prior to study therapy) 
 Chemistry: sodium, potassium, chloride, bicarbonate, calcium, glucose, BUN, 
creatinine, ALT, AST, alkaline phosphatase, total protein, albumin, and total and 
direct bilirubin 
 Serum PSA (participants with a malignancy other than prostate cancer do not need 
this test) 
 Testosterone level (participants with a malignancy other than prostate cancer do not 
need this test) 
 TSH, free T4, lipase, amylase, LDH, GGT 
 Hematology: CBC with differential and platelets 
 Urinalysis  
 HLA class I profile A,B,C and DR, DQ, Next Generation Sequencing (NGS) HLA-
ABC & DRDQ, NGS HLA-DPB1 [high resolution HLA-DPB1], NGS HLA-DQA1 
[high resolution HLA-DQA1](any time prior to study treatment initiation).  
 Levels of Prolactin, IGF1, Androstenedione, Dihydrotestosterone (DHT), 17-OH-
Progesterone, DHEA, DHEA-S, estradiol, ACTH, Cortisol (See Section 3.5 for more 
details) 




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29 
 Each Arm in Cohort 2: 2.1B, 2.2B and 2.3B will be open for additional enrollment (25 
evaluable participants total) when the initial 13 participants have accrued, safety 
requirements have been met and a positive signal (defined as Objective Response by 
RECIST 1.1 or sustained PSA decrease ≥ 30% sustained for > 21 days) in ≥ 2 participants 
has been observed.  
 If only one arm is open for additional enrollment, participants will be directly assigned to 
this arm. If 2 arms are open for additional enrollment, participants will be randomized 
between these 2 open arms. If 3 arms are open for additional enrollment, participants will 
be randomized between these 3 open arms. 
The first subject of each arm (1.1, 2.1A, 2.2A and 2.3A) will be observed for at least 13 days 
before the second subject can be treated. If no DLT is observed within that period, the second 
participant can enroll. An interval of 2 days without a DLT must pass before treatment of the 
next participant until after participant 7 begins treatment i.e. before treating participants 3, 4, 5 
and 6, 2 days must pass without any observed DLT. 
Treatment will continue until disease progression or unacceptable toxicity.  
Safety Design Summary:  
The phase I (i.e. safety evaluation) portion of this study refers to the first 6 participants treated on 
arm 1.1 (at the given dose level for arm 1.1), arm 2.1A, arm 2.2A, and arm 2.3A. These 
participants are evaluated for DLT. If there are <2 DLTs in the first 6 participants of each arm, 
the respective combination is considered to be safe. The phase II portion of the study applies to 
the potential expansion of arms 2.1, 2.2 and/or 2.3. This will also include all participants treated 
during Part A (arm 2.1A, 2.2A, and 2.3A), and Part B (on an arm that expanded based on 
prespecified efficacy endpoints). Changing the suffix to ‘B’ from ‘A’ indicates that a participant 
was enrolled during part B, the period of time when it has been determined which arms have 
expanded. During Part B, safety will have already been determined. 
3.1.1 Dose Limiting Toxicity 
Dose-limiting toxicity (DLT) will be defined as any one of the following adverse events, 
possibly attributable to study drugs, that occur within 21 days of the start of therapy. For arm 1.1, 
this applies to all participants treated on a given dose level. For arms 2.1A, 2.2A and 2.2B, this 
applies to the first 6 participants on a given arm:  
 Any grade ≥ 4 hematologic toxicity or grade 3 thrombocytopenia (platelets 25-50,000) 
with associated bleeding, except CD4 lymphocyte count or other T lymphocyte subset 
count.  
 Any grade ≥ 3 non-hematologic toxicity, except for any of the following:  
 transient (≤ 48 hour) grade 3 fatigue, local reactions, flu like symptoms, fever, 
headache, or nausea, emesis, and diarrhea not controlled with adequate medical 
management, or 
 Any CTCAE Grade 3 skin toxicity lasting less than five days.  
 Electrolyte abnormalities that can be easily managed with replacement therapy. 
 Asymptomatic Grade 3 lipase or amylase elevation. 






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32 
13 participants with CRPC will be enrolled in Arm 2.3A. Participants will be treated with 
combination of M7824, BN-Brachyury, N-803 and Epacadostat. 
Enrollment will start when 13 participants are enrolled in arm 2.2A and the first 6 participants, 
treated in Arm 2.1A, have met safety requirements. 
A treatment combination will be determined safe if < 2 of the first 6 participants enrolled in the 
arm experience a DLT (See Section 3.1.1). If 2 DLTs happen in the first 6 participants enrolled, 
the enrollment in that arm will be halted and an amendment will be submitted with another 
combination of drugs. 
3.1.3.4 General rule 
During Phase IB (when enrollment of first 6 participants has finished and safety requirements are 
met) if one drug is discontinued due to toxicity, participants can continue treatment with the other 
drug(s) at the discretion of the investigator. Applies for participants 7-12 in Arms 2.1A, 2.2A and 
2.3A. This also applies to any participant who is being evaluated for safety and has passed the 3-
week DLT period. 
3.1.4 Phase IIB: expansion with randomized enrollment into Cohorts 2D and 2R, Arms 2.1B, 
2.2B and 2.3B 
For each Arm (Cohort 2D and 2R): 2.1B, 2.2B and 2.3B will be open for additional enrollment 
(25 evaluable participants total) when the initial the 13 participants have been accrued, safety 
requirements are met and a positive signal (defined as Objective Response by RECIST 1.1 or 
sustained PSA decrease ≥ 30% sustained for > 21 days) in ≥ 2 participants is observed.  
If only one arm is open for additional enrollment, participants will be directly assigned to this arm. 
If 2 arms are open for additional enrollment, participants will be randomized between these 2 open 
arms. If 3 arms are open for additional enrollment, participants will be randomized between these 
3 open arms. If a participant is ineligible for enrollment to Arm 2.3A or randomization and 
potential enrollment to arm 2.3B due to a QT interval or due to use of a concomitant medication 
that is not allowed due to potential drug-drug interactions with epacadostat, that participant may 
be directly assigned to Arm 2.3B. 
During Phase IIB in each arm, for toxicity not requiring discontinuation of IND agent, these agents 
may be held at the discretion of the investigator and may be reinitiated after the toxicity has 
improved. 
During Phase IIB in case when one drug is discontinued due to toxicity, participants may continue 
treatment with the other drug(s) at the discretion of the investigator.  
3.2 
STUDY STOPPING RULE  
Accrual will be halted to all open study arms if there is an occurrence of a grade 5 toxicity within 
30 days of receiving any study treatment that is possibly attributable to the treatment regimen. 
Prior to resumption of the study, an expedited safety report will be sent to and reviewed by FDA. 
SAE also must be evaluated by the clinical investigators. 


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33 
3.3 
DRUG ADMINISTRATION 
3.3.1 General rule: 
A window of +7/-3 days for every two weeks study drug(s) dosing is allowed in the event of 
scheduling issues (i.e., holiday, bad weather or other scheduling issues).  
3.3.2 BN-Brachyury (MVA-BN-Brachyury and FPV-Brachyury)  
BN-Brachyury collectively refers to the priming doses (MVA-BN-Brachyury) and the boost doses 
(FPV-Brachyury). 
MVA-BN-Brachyury will be administered as 2 priming doses 2 weeks apart, on Day 1 of Cycle 1 
and Day 1 of Cycle 2. Administration of each of the 4 subcutaneous injections that comprise 1 
dose of MVA-BN-Brachyury is preferred to be given in different limbs, in the upper arm and/or 
upper outer thigh. Each 0.5mL injection of MVA-BN-Brachyury consists of a nominal virus titer 
of 2.0 x 108 infectious units (Inf.U.) 
One dose of FPV-Brachyury = one 0.5 mL injection. One injection = nominal 1 x 109 Inf.U in 0.5 
mL.  
The first dose of FPV-Brachyury will be given 2 weeks after second dose of MVA-BN-Brachyury, 
then every 4 weeks until 6 months, then every 3 months until reaching 2 years from the first dose 
of MVA-BN-Brachyury. At that point, FPV-Brachyury may be continued at 6month dosing 
intervals.  
FPV-Brachyury is to be administered via subcutaneous injection in either the upper arm or outer 
thigh. The same area of injection is preferred, but not required, for all FPV-Brachyury vaccines. 
The injection must be delivered within 4 hours of completion of preparation to ensure stability.  
3.3.3 M7824 
Subjects will be scheduled to receive M7824 at a flat dose of 1,200 mg IV once every 2 weeks. 
Subjects will receive M7824 via IV infusion over 1 hour (-10 minutes / +20 minutes, that is, over 
50 to 80 minutes) once every 2 weeks. M7824 will be administered as a "flat" dose of 1,200 mg 
independent of body weight. M7824 is administered as an intravenous infusion with a mandatory 
0.2 micron in-line filter. 
M7824 may be administered via pre-existing peripheral or central vascular access device (VAD). 
Prior to administration via a port, the primary material of the port must be confirmed to be 
titanium. If the primary material of the port is not titanium, the port must not be used for 
administration of M7824. 
Current experience revealed that infusion related reactions (IRRs) to M7824 seldom occur and 
are generally mild to moderate in severity. Therefore, administration of a premedication is 
generally not required. 
If an Investigator deems it necessary to administer a premedication to a particular participant, an 
antihistamine  and with acetaminophen (for example, 25-50 mg diphenhydramine and 500-650 
mg acetaminophen within approximately 30 to 60 minutes prior to dosing of M7824 is 
mandatory for the first 2 infusions, after which premedication is optional and at the discretion of 
the Investigator. If Grade ≥ 2 infusion reactions are seen during the first two infusions, 
premedication should not be stopped. Steroids as premedication are not permitted.  


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34 
Table 2: Treatment modifications for infusion-related reactions caused by M7824 with 
signs/symptoms occurring on the day of infusion (during or after) or the day after 
infusion irrespective of resolution. 
NCI-CTCAE Grade
Treatment Modification for M7824
Grade 1 – mild 
Mild transient reaction; infusion interruption 
not indicated; intervention not indicated. 
Consider decreasing the M7824 infusion rate by 50% 
and monitoring closely for any worsening. If the M7824 
infusion rate has been decreased by 50% or interrupted 
due to an infusion reaction, the next infusion will be 
given at the decreased rate. If no infusion reaction is 
observed at the next scheduled infusion, the infusion 
rate may be returned to baseline at the subsequent 
infusions based on investigator’s medical judgment. 
Grade 2 – moderate 
Therapy or infusion interruption indicated but 
responds promptly to symptomatic treatment 
(e.g., antihistamines, NSAIDs, narcotics, i.v. 
fluids); prophylactic medications indicated for 
≤ 24 hours. 
Consider temporarily discontinuing M7824 infusion. 
Consider resuming infusion at 50% of previous rate 
once infusion related reaction has resolved or decreased 
to at least Grade 1 in severity and monitor closely for 
any worsening. Infuse at 50% rate for all future doses. 
Grade 3 or Grade 4 – severe or life-
threatening 
Grade 3: Prolonged (e.g., not rapidly 
responsive to symptomatic medication and/or 
brief interruption of infusion); hospitalization 
indicated for clinical sequelae. 
Grade 4: Life-threatening consequences; 
urgent intervention indicated. 
Stop the M7824 infusion immediately and disconnect 
infusion tubing from the subject. 
For grade 3 events: Consider withdrawing immediately 
from M7824 treatment and not offering any further 
M7824 treatment based upon if the clinical condition 
can be safely managed. 
For grade 4 events: Withdraw immediately from 
treatment and do not offer further treatment. 
 
If hypersensitivity reaction occurs, the subject should be treated according to the best available 
medical practice. Hypersensitivity reactions may require immediate intensive care. Bintrafusp 
alfa should be administered in a setting that allows immediate access to an intensive care unit or 
equivalent environment and administration of therapy for anaphylaxis, such as the ability to 
implement immediate resuscitation measures. Potent steroids (e.g. dexamethasone), 
catecholamines (e.g. epinephrine), allergy medications (IV antihistamines), bronchodilators, or 
equivalents and oxygen should be available for immediate access.  
A complete guideline for the emergency treatment of anaphylactic reactions according to the 
Working Group of the Resuscitation Council United Kingdom and can be found at 
https://www.resus.org.uk/pages/reaction.pdf 


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For prophylaxis of flu like symptoms, a nonsteroidal anti-inflammatory drug (NSAID), e.g., 
ibuprofen 400 mg or comparable NSAID dose, may be administered 2 hours before and 8 hours 
after the start of each IV infusion. 
 
3.3.4 N-803  
N-803 will be given via subcutaneous injection at a dose of 8-15 g/kg every 2 weeks. 
The dose will be determined as described in Section 3.1.2. N-803 dosing will be calculated using 
a weight obtained within 5 days prior to the first dose. The dose will be re-calculated at the 
beginning of each subsequent cycle in the event of a 10% or greater weight change. If the weight 
at the beginning of each subsequent cycles is within 10%, the previous dose may be used or the 
dose may be re-calculated based on local site procedures.  
Injection should occur in the abdomen and injection sites should be rotated per institutional 
guidelines and each injection site separated by at least 1 inch. Depending on the injection volume 
required, the dose of N-803 may be administered as a single injection or multiple injections at the 
discretion of the investigator. 
Doses of N-803 can be administered on an outparticipant basis. If the first dose of the 1st cycle is 
well tolerated after 2 hours of monitoring, subsequent doses may be administered with 30 minutes 
of monitoring post dose. N-803 will not be self-administered.  
3.3.4.1 Pre- and post-N-803 therapy intervention guidelines for fever/chills 
 
N-803 
Condition 
Agents 
Dose 
Route 
When 
Fever/chills Antipyretic*
 
 Acetaminophen 
  
up to 650 mg; or 
 
Orally 
Prior to each dose & repeat 4 
hours after dosing. 
Repeat every 4-6 hours if fever 
present.
 
 Ibuprofen 
up to 600 mg; or 
 
Orally 
Prior to each dose & repeat 4 
hours after dosing. 
Repeat every 4-6 hours if fever 
present.
 
 Naproxen 
up to 500 mg  
Orally 
Prior to each dose & repeat 8
hours after dosing.  
Repeat every 12 hours if fever 
present.
*Antipyretic medication including acetaminophen, ibuprofen, or naproxen may be given per physician discretion following 
the recommended dosing thresholds: 
Acetaminophen: not to exceed 3000 mg (3 grams) in 24 hours 
Ibuprofen: not to exceed 3200 mg in 24 hours


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36 
3.3.4.2 Skin Rash in Association with Subcutaneous Administration of N-803 
Based on current experience, localized skin rashes are common with subcutaneous administration. 
If a rash occurs and the rash area surrounding the N-803 injection site is > 6 cm and symptomatic 
(painful and/or itchy), it may be treated (at the discretion of the treating physician) with topical 
0.05% clobetasol propionate (i.e. 0.05% Cormax) or 0.1% triamcinolone (i.e., Kenalog) cream. 
Diphenhydramine may be administered pre- (25-50 mg TID orally) and post-dosing (25-50 mg 
TID orally x 2 days) of N-803 at the discretion of the treating physician. Diphenhydramine should 
be eliminated if not tolerated. Other agents may be administered at the discretion of the treating 
physician.  
Premedication may be administered pre- (e.g. diphenhydramine 25-50mg PO or IV) and post N-
803 dose (e.g. diphenhydramine 25-50 TID PO x 2 days) at the discretion of the treating physician. 
Participants may complete and return N-803 INJECTION SITE REACTION DIARY (optional) 
after each N-803 injection (See Appendix B) 
3.3.5 Epacadostat 
Epacadostat is formulated as a 25 mg tablet, a 100 mg tablet, and a 300 mg tablet. However, only 
the 100 and 300 mg tablets are anticipated to be used for this trial. Epacadostat will be administered 
at a dose of 600 mg orally twice daily without regard to food (total daily dose = 1,200 mg). Doses 
should be taken at approximately the same time each day. If a dose is missed, it may be taken 
within 4 hours of the scheduled time. If 4 or more hours have passed, the dose will be considered 
missed and the next dose should be taken at the regularly scheduled time. Participants may 
complete and return Participant’s Diary (optional) every cycle (Appendix C). 
Epacadostat will be given first in Arm 2.3A to facilitate timing of fasting pre-dose blood sample 
on cycle 1 day 1 (can be sampled at any time before the first Epacadostat dose) and fasting pre-
dose and 2 hour post-dose blood sampling that will occur on C2D8. 
3.3.6 Sequence and Monitoring of Dose Administration 
When administering concurrent investigational agents on the same day, the following sequence 
of administration is preferred.  
Acetaminophen 650 mg and Benadryl 50 mg by mouth will be given within 30 to 60 minutes prior 
to M7824 infusion.  
3.3.6.1 Arm 1.1 
M7824 will be administered first. Participants will be monitored for symptoms of delayed infusion 
reaction for 60 +/- 10 minutes. N-803 administration is preferred to occur at 60 minutes following 
M7824 infusion completion, but may be given as long as 5 hours after the M7824 infusion finishes. 
If no M7824 infusion reactions have occurred, participants can receive N-803 immediately 
following M7824 infusion completion and forego the 60 minutes waiting period, starting at the 4th 
N-803 
Condition 
Agents 
Dose 
Route 
When 
Naproxen: not to exceed 1000 mg in 24 hours 
Note: The use of systemic steroid medications may result in loss of therapeutic effects of the study drug and should be 
avoided; however in the event of a life-threatening inflammatory reaction to N-803, the IV administration of dexamethasone 
or other steroid-based medication is warranted. Prednisone should be avoided.


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37 
M7824 infusion. Participants must be observed for 2 hours after the first N-803 dose. If no 
reactions are observed, the participants need to be monitored for only 30 +/- 10 minutes after 
subsequent doses. 
3.3.6.2 Arms 2.1A and 2.1B 
Preferably, BN-Brachyury will be injected first, followed by M7824 administration. Participants 
will be monitored for symptoms of delayed infusion reaction for 60 +/- 10 minutes.  
3.3.6.3 Arms 2.2A and 2.2B. 
Preferably, BN-Brachyury will be injected first, followed by M7824 administration. Participants 
will be monitored for symptoms of delayed infusion reaction for 60 minutes +/- 10 minutes. N-
803 administration is preferred to occur at 60 minutes following M7824 infusion completion, but 
may be given as long as 5 hours after the M7824 infusion finishes. If no M7824 infusion reactions 
have occurred, participants can receive N-803 immediately following M7824 infusion completion 
and forego the 60 minutes waiting period, starting at the 4th M7824 infusion. Participants must be 
observed for 2 hours after the first N-803 dose. If no reactions are observed, the participants need 
to be monitored for only 30 minutes +/- 10 after subsequent doses. 
3.3.6.4 Arms 2.3A and 2.3B. 
Preferably, BN-Brachyury will be injected first, followed by M7824 administration. Participants 
will be monitored for symptoms of delayed infusion reaction for 60 +/- 10 minutes. N-803 
administration is preferred to occur at 60 minutes following M7824 infusion completion, but may 
be given as long as 5 hours after the M7824 infusion finishes. If no M7824 infusion reactions have 
occurred, participants can receive N-803 immediately following M7824 infusion completion and 
forego the 60 minutes waiting period, starting at the 4th M7824 infusion. Participants must be 
observed for 2 hours after the first N-803 dose. If no reactions are observed, the participants need 
to be monitored for only 30 +/- 10 minutes after subsequent doses. Epacadostat can be given any 
time after the M7824 infusion is completed. If no reactions are observed, the participants need to 
be monitored for only 30 +/- 10 minutes after subsequent doses. 
3.3.6.5 Vital Signs Monitoring 
For all participants receiving N-803 and/or M7824, vital signs will be measured before, at least 
one time during the infusion of M7824 and after infusion. Vital signs must be measured within 30 
minutes before and 30 minutes following the N-803 injection. 
3.4 
DOSE MODIFICATIONS 
During DLT period dose modifications are not allowed. 
During expansion phase: 
3.4.1 BN-Brachyury vaccine: 
BN-Brachyury vaccine dose will not be modified. 
3.4.2 M7824 
Dose reductions to 900 mg every 2 weeks for toxicities attributed to M7824 will be allowed at the 
discretion of the investigator. 


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3.4.3 N-803 
Dose reductions to 8 or 10 mcg/kg for toxicities attributed to N-803 will be allowed at the 
discretion of the investigator. 
3.4.4 Epacadostat 
Dose reductions to 400 mg BID, 200 mg BID, 100 mg BID for toxicities attributed to Epacadostat 
will be allowed at the discretion of the investigator. 
In cases of skin toxicities grade 3 or greater that are attributed to epacadostat, epacadostat should 
be held until resolved or improved to grade 1. In such cases, epacadostat will be restarted at the 
next lower dose when improved to grade 1. 
3.4.4.1 Procedures for Subjects Exhibiting Serotonin Syndrome (SS) 
The following procedures will be implemented if there is a clinical concern for developing SS. 
The signs/symptoms of SS, including tremor; hyperreflexia; spontaneous, ocular, or inducible 
clonus; together with agitation, fever, diaphoresis, or muscle rigidity: 
 
Immediately interrupt epacadostat.  
 
Immediately interrupt any SSRI or SNRI administration. 
 
Provide appropriate medical management of the participant until all signs/symptoms are 
resolved (eg, IV fluids and/or sympathomimetic amines for hypotension, benzodiazepines 
for agitation, administration of 5-hydroxytryptamine antagonists such as cyproheptadine). 
 
If participant chooses to remain in the study, restart treatment with epacadostat after the 
SSRI or SNRI has been discontinued, no sooner than 5 half-lives have elapsed for the 
specific SSRI or SNRI in question, and after resolution of signs/symptoms of SS. The SSRI 
or SNRI dosing MAY NOT be restarted while the participant is receiving epacadostat on 
study. 
 
If participant chooses to withdraw from the study, or must restart treatment with SSRI or 
SNRI, the participant should be scheduled for a follow-up visit. Treatment with SSRI or 
SNRI may be initiated 2 weeks after resolution of signs and symptoms of SS. Epacadostat 
will not be continued in these cases.  
Table 3: Signs and Symptoms of Serotonin Syndrome 
Seriousness
Autonomic 
signs                              
Neurological 
signs                   
Mental 
status                               
Other 
Mild 
Afebrile or low-grade 
fever 
Tachycardia 
Mydriasis 
Diaphoresis or shivering 
Intermittent tremor 
Akathisia 
Myoclonus 
Mild hyperreflexia 
Restlessness 
Anxiety 
  


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Seriousness
Autonomic 
signs                              
Neurological 
signs                   
Mental 
status                               
Other 
Moderate 
Increased tachycardia 
Fever (up to 41 °C) 
Diarrhea with 
hyperactive bowel 
sounds 
Diaphoresis with normal 
skin color 
Hyperreflexia 
Inducible clonus 
Ocular clonus (slow 
continuous lateral 
eye movements) 
Myoclonus 
Easily startled 
Increased confusion 
Agitation and 
hypervigilance 
Rhabdomyolysis 
Metabolic acidosis 
Renal failure 
Disseminated 
intravascular 
coagulopathy 
(secondary to 
hyperthermia) 
Severe 
Temperature often more 
than 41 °C (Secondary 
to increased tone) 
Increased muscle 
tone (lower limb > 
upper) 
Spontaneous clonus 
Substantial 
myoclonus or 
hyperreflexia 
Delirium 
Coma 
As above 
Please refer to the Boyer NEJM 2005 [59] for more details about SS.  
A Patient card explaining the symptoms for serotonin syndrome will be provided for participants 
enrolling in arm 2.3 A and for participants who may be randomized to arm 2.3 B. 
3.4.5 Suggested evaluation of suspected bleeding or hemorrhage events and treatment 
modification  
3.4.5.1 For anemia or hemorrhage events assessed as treatment-related, items queried may 
include but are not limited to detailed relevant past medical and treatment history, bruising 
tendency, history of blood transfusions and/or dependency, and a request for an updated 
participant history including details such as concomitant medications, all laboratory data, 
updated dosing information and recent tumor evaluation scans.  
3.4.5.2 In this protocol, anemia may be due to M7824 (documented in 29% of patients) and/or 
SX-682. M7824 treatment-related anemia is an AESI (see Investigators’ Brochure). 
Notably, there are many reasons for hemorrhage and/or anemia in patients with advanced 
cancer, and Hb level of at least 9 g/dL is required for this study. A thorough investigation 
of new anemia cases of unspecified etiology is recommended: 
3.4.5.3 Participants must enter the study with Hgb values at least 9 g/dL and baseline anemia 
evaluation is conducted per recommendations below.  
3.4.6 Consider hematology consult for severe and or refractory anemias.  
3.4.6.1 All relevant hematologic testing for treatment related anemias should be done prior to 
blood transfusion, if clinically feasible. 
3.4.6.2 Transfusion should be performed at the discretion of the investigator, based on clinical 
assessment and considered when participant experiences significant anemia.  


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3.4.6.3 Guidance for evaluation of baseline anemia or suspected treatment-related anemias is 
provided below. Investigators may consider the following laboratory evaluations in 
participants with anemia.  
3.4.6.4 Hb and CBC with differential (e.g. MCV, RDW, ANC, hematocrit, reticulocytes counts) 
3.4.6.5 Peripheral blood smear for cell morphological assessment 
3.4.6.6 Complete metabolic panel including liver panel-LFTs, bilirubin, LDH, renal function, and 
serum folate, B12 values and other chemistries 
3.4.6.7 Coagulation factors (PT, PTT, INR) 
3.4.6.8 Urinalysis including culture 
3.4.6.9 Iron panel (TIBC, ferritin, Fe) 
3.4.6.10 Discuss further management with Principal Investigator for clinically significant 
treatment related anemias. 
3.4.7 Immune-Related Adverse Events 
The effects of N-803 and Epacadostat, on the irAEs that may be seen with M7824 are unknown.  
If, in the judgement of the investigator, an irAE observed outside of the DLT period is wholly or 
partially due to M7824, N-803, or Epacadostat, that agent may be held temporarily, permanently 
discontinued, or dose adjusted (See Section 3.4).  
There will be no dose modifications for BN-Brachyury. Therefore, in such cases, BN-Brachyury 
can be held or discontinued, at the discretion of the investigator.  
 
 
The management of immune-related adverse events associated with immune checkpoint inhibitors 
(e.g. M7824) should follow published national guidelines. Investigators may alter management 
plans based on published guidelines and/or best professional judgement, including consultation 
with specialists The National Comprehensive Cancer Network (NCCN Guidelines®), may be 
found here: 
https://www.nccn.org/professionals/physician gls/pdf/immunotherapy.pdf  
Additional information may also be found here: 
https://ascopubs.org/doi/pdf/10.1200/JCO.2017.77.6385  
o In addition to the above guidelines, the following recommendations should be 
considered when managing irAEs: 
 • Permanent treatment discontinuation is required in case of immune-related 
Grade 4 rash/inflammatory dermatitis, nephritis, autoimmune hemolytic 
anemia, 
hemolytic 
uremic 
syndrome, 
aplastic 
anemia, 
immune 
thrombocytopenia, 
acquired 
thrombotic 
thrombocytopenic 
purpura 
inflammatory arthritis, myositis and polymyalgia-like syndrome.  
 
 • For Grade 4 immune-related lymphopenia, permanent treatment 
discontinuation will be required, if lymphopenia is considered immune-


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related in nature, no clear alternative explanation exists for the event, and it 
does not resolve within 14 days. Permanent treatment discontinuation is not 
required when the AE is manifested by a single laboratory value out of 
normal range without any clinical correlates. In this case, treatment should 
be held until the etiology is determined. If the event is not considered 
immune-related and resolves to Grade ≤ 1, restarting treatment may be 
considered.  
 
 • For Grade 1 immune-related pneumonitis: continue treatment. If clinically 
indicated, monitor participants weekly or more frequently as needed with 
history, physical examination and pulse oximetry. If symptoms appear 
and/or changes in the physical exam are noted, treat as Grade 2.  
 
  For myositis: in case of management with rituximab, treatment should be 
discontinued.  
 
 For Grade 3 or 4 endocrinopathies: withhold until clinically stable or 
permanently discontinue depending on severity.  
 
 • For hepatitis with no tumor involvement of the liver: withhold if total 
bilirubin increases to more than 1.5 and up to 3 times ULN, permanently 
discontinue if more than 3 times ULN  
 
 Hepatitis with tumor involvement of the liver: permanently discontinue if 
total bilirubin increases to more than 3 times ULN 
3.4.8 Discontinuation 
Treatment will be discontinued in case of: 
 Any Grade 4 adverse drug reactions (ADRs), as defined by CTCAE v5 and assessed as 
related to combined treatment by the Investigator, except for laboratory values that are 
determined to not be clinically significant or single laboratory valued that resolve to Grade 
≤ 1 or baseline grade within 7 days with adequate medical management. 
 Any Grade 3 ADRs except for any of the following: 
o Transient (≤ 48 hours) Grade 3 flu-like symptoms or fever, which is controlled with 
medical management.  
o Transient (≤ 48 hours) Grade 3 fatigue, local reactions, headache, nausea, emesis 
which is controlled with medical management. 
o Tumor flare phenomenon defined as local pain, irritation, or rash localized at sites 
of known or suspected tumor. 
o Any Grade ≥ 3 drug-related amylase or lipase abnormality that is not associated 
with symptoms or clinical manifestations of pancreatitis.  


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o Grade 3 Hgb decrease (< 8.0 g/dL) that is clinically manageable with blood 
transfusions or erythroid growth factor use does not require treatment 
discontinuation.  
o Keratoacanthoma and squamous cell carcinoma of the skin.  
o Any endocrinopathy that can be medically managed with hormone replacement 
 
Any grade 3 adverse drug reaction which in the opinion of the investigator is not clinically 
relevant or can be medically managed with minimal risk to the participant (e.g. placement 
of a pleurx catheter for recurrent inflammatory pleural effusions)  
3.4.9 Dose hold  
During the DLT periods of the Phase I and IIA dose holds will result in the participant being 
replaced. Outside of DLT period, dose(s) may be held at the discretion of the investigator (e.g., in 
cases where the participant requires an elective procedure or is recovering from a non-treatment-
related illness) and continuation of study participation will be at the discretion of the investigator. 
In such cases, the planned visit and medical studies may be skipped. 
For cases in which hold of one study agent, but not the other scheduled agent(s), is indicated on a 
given cycle (N), the following cycle will be (N+1). However, in cases where all agents are held, 
the missed cycle (N) can be delayed. When the investigator determines it appropriate to resume 
study agent(s), that will be named cycle N. Since arms 2.1, 2.2 and 2.3 do not include BN-
brachyury dosing at every visit, a situation where all other agent(s) are held at cycle N, and cycle 
N dose not include BN-brachyury administration, the next scheduled visit will be cycle N+1, if 
BN-brachyury is administered. 
During Phase IIB:  
N-803 may be delayed if on the day of a planned dose for either of the following situations: 
 the participant has a fever of > 101°F (38.3 °C)  
 if in the opinion of the treating physician, holding would be of benefit to the participant  
If after a 1-week rest, the participant no longer meets either of the above criteria for dose delay; 
the participant may resume treatment with the intent of giving all remaining doses of N-803 for 
the treatment cycle, but the missed dose will not be made up.  
 Hypotension (systolic blood pressure < 90 mm Hg)  
N-803 dosing should be held for hypotension (defined as systolic blood pressure less than 90 mm 
Hg) if in the presence of any clinically significant symptoms (in the opinion of the treating 
physician), until the systolic blood pressure reading is stable. If mild dehydration is suspected, an 
IV fluid bolus may be used per standard of care. 






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11 CT scan of chest, abdomen and pelvis (or MRI of abdomen if it is clinically indicated when 
CT is not appropriate). Every 12 (+/-1) weeks after start of study therapy. If participant taken off 
treatment for reason other than disease progression, he/she should be followed by this evaluation 
every 12 weeks. If the participant came off treatment for a reason other than disease progression 
and has subsequently started another line of systemic treatment, the follow up CT imaging 
included in this evaluation may be omitted.  
12 Every 12 (+/-1) weeks after start of study therapy for patients having Prostate Cancer. If 
participant taken off treatment for reason other than disease progression, he/she should be 
followed by this evaluation every 12 weeks. If the participant came off treatment for a reason 
other than disease progression and has subsequently started another line of systemic treatment, 
the bone scan may be omitted.  
13 As indicated in section 12.3, all subjects will be offered the opportunity to complete an NIH 
Advance Directive form. This should be done preferably at baseline but can be done at any time 
during the study as long as the capacity to do so is retained. The completion of the form is 
strongly recommended but is not required. 
14 +/- 1 week. If subjects are not willing to come to NIH to FU safety visit, they will be contacted 
by phone call or e-mail for survival, adverse events and further tumor therapy.  
15 If participant taken off treatment for reason other than disease progression, he/she may remain 
on protocol to be followed every 12 weeks (to monitor for disease progression) until disease 
progression or the participant starts other cancer therapy. If subjects are not willing to come to 
NIH for these visits, they will be contacted by phone call or e-mail for disease progression and 
adverse events every 6 month. 
16 Prior to infusion and immediately after infusion on Day 1 of cycles 1 and 3. Prior to infusion 
on Day 1 of cycles 2, 6 and at the time of taking a participant off treatment (whatever comes 
first). Per PI discretion samples may be taken prior to infusion every 12 weeks. 
17 Prior to infusion of M7824 on Day 1 of cycles 1, 3, and 6 and at the time of taking a 
participant off treatment (whatever comes first). Per PI discretion, samples may be taken prior to 
infusion every 12 weeks. 
18 Only for participants assigned to be treated with Epacadostat. On Day 1 Cycle 1, a fasting 
blood sample will be drawn at any time pre-dose of Epacadostat. On Day 8 of Cycle 2, a sample 
will be drawn fasting (for 8 hours), within 10 minutes before the participant takes that dose of 
Epacadostat and 2 hours (+/- 5 minutes) post Epacadostat dose (also fasting). 
19 Prior to treatment on Day 1 of cycles 1, 2, 6 and 12. Per PI discretion additional samples might 
be collected every 12 weeks and at the time of taking a participant off treatment.  
20 Applies to females only. 
21 These may be performed any time prior to study treatment initiation. Participants who have 
had HLA typing previously performed at NIH do not require retesting.  
22 In participants who have difficulty providing a urine sample (e.g., participants with 
incontinence due to treatment for prostate cancer), urinalysis collection outside of the DLT 
period may be skipped at investigator discretion. 
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24 Prior to treatment on Day 1 of cycles 4, 6, 10 and 12 
25 Every 12 weeks +/- 2 weeks for participants receiving Epacodostat 
26Obtained between the hours of 7am-9am, after fasting for at least 8 hours. 
27 To monitor for adrenal insufficiency, every 4 weeks +/- 2 weeks, starting at cycle 4. 
Participants already diagnosed with adrenal insufficiency at baseline are excluded from this 
testing.  Participants testing positive for adrenal insufficiency will receive appropriate medical 
management 
28 +/-2 days is allowed for Day 8 visits in C1 and C2. 
       
3.6 
COST AND COMPENSATION  
3.6.1 Costs 
NIH does not bill health insurance companies or participants for any research or related clinical 
care that participants receive at the NIH Clinical Center.  If some tests and procedures are 
performed outside the NIH Clinical Center, participants may have to pay for these costs if they 
are not covered by an insurance company.  Medicines that are not part of the study treatment will 
not be provided or paid for by the NIH Clinical Center.     
3.6.2 Compensation 
Participants will not be compensated on this study. 
3.6.3 Reimbursement  
The NCI will cover the costs of some expenses associated with protocol participation.  Some of 
these costs may be paid directly by the NIH and some may be reimbursed to the 
participant/guardian as appropriate.  The amount and form of these payments are determined by 
the NCI Travel and Lodging Reimbursement Policy.  
 
3.7 
CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF STUDY CRITERIA 
Prior to removal from study, effort must be made to have all subjects complete a safety visit 
approximately 28-30 days following the last dose of study therapy. 
3.7.1 Criteria for removal from protocol therapy: 
 Participant requests to be withdrawn from active therapy.  
 Unacceptable Toxicity.  
 Positive pregnancy test or intent to become pregnant. 
 Investigator discretion.  
 Initiation of alternative anticancer therapy including another investigational agent. 
Exception: Palliative radiation given outside of the DLT period is allowed.  
 Progressive disease evidenced by radiographic or symptomatic progression (see Section 
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 Intercurrent illness that prevents further administration of treatment. 
3.7.2 Off-Study Criteria 
 Completion of 28 day follow up assessment after removal from protocol therapy for 
disease progression. If participant is taken off treatment for reason other than disease 
progression, he/she will be taken off study when there is information available about 
disease progression or the participant begins an alternative anti-cancer therapy.  
 Death. 
 Lost to follow up.  
 Participant requests to be removed from the study.  
 Investigator discretion. 
 PI decision to close the study. 
 Screen failure. 
3.7.3 Lost to Follow-up 
A participant will be considered lost to follow-up if he or she fails to return for 3 consecutive 
scheduled visits and is unable to be contacted by the study site staff.  
The following actions must be taken if a participant fails to return to the clinic for a required 
study visit: 
 The site will attempt to contact the participant and reschedule the missed visit within 2 
weeks and counsel the participant on the importance of maintaining the assigned visit 
schedule and ascertain if the participant wishes to and/or should continue in the study. 
 Before a participant is deemed lost to follow-up, the investigator or designee will make 
every effort to regain contact with the participant (where possible, 3 telephone calls and, 
if necessary, an IRB approved certified letter to the participant’s last known mailing 
address or local equivalent methods). These contact attempts should be documented in 
the participant’s medical record or study file.  
 Should the participant continue to be unreachable, he or she will be considered to have 
withdrawn from the study with a primary reason of lost to follow-up. 
4 
CONCOMITANT MEDICATIONS/MEASURES 
4.1 
GENERAL GUIDANCE  
Supportive care with blood components, antibiotics, analgesics, general medical therapy, etc., will 
be delivered as required.  
Immunotherapy including interferon, immunosuppressive drugs (for example, chemotherapy or 
systemic steroids except for short term treatment of allergic reactions, endocrine replacement 
therapy or low dose prednisone [≤ 10mg daily] or equivalent, or for the treatment of irAEs or other 
appropriate short- term steroid use), or other experimental pharmaceutical products are prohibited. 
Short term administration of systemic steroid or other immunosuppressant such as infliximab or 
mycophenolate (that is, for allergic reactions or management of irAEs) is allowed. Steroids with 
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permitted, e.g. a patient recently on abiraterone (administered with 10 mg of prednisone daily) 
who is tapering off of prednisone is allowed to continue that taper. 
Any live vaccine therapies for the prevention of infectious disease are prohibited. Administration 
of inactivated vaccines is allowed (for example, inactivated influenza vaccine).Locally approved 
COVID vaccines are permitted.  
Antiemetics may be used for the treatment of nausea and vomiting but should not be used 
prophylactically during the first cycle. Steroid-based anti-emetics are not allowed.  
4.2 
N-803 (FORMERLY ALT-803) 
Central nervous function may be affected with N-803. Caution should be used with psychotropic 
medications. 
Nephrotoxic, myelotoxic, cardiotoxic, or hepatotoxic medications should be avoided if possible as 
they may further increase toxicities that have been associated with N-803. 
Interferon-alfa is prohibited while on study.  
Beta-blockers and other antihypertensives may potentiate the hypotension seen with N-803. 
Therefore, administration of these agents should be avoided during N-803 treatment period, unless 
clinically indicated. If a participant who is to receive N-803 is on a beta-blocker or other 
antihypertensive, that agent may be discontinued starting on the day of the first treatment with N-
803, if the investigator determines that stopping the agent is safe. Anti-hypertensive management 
decisions will be made on a case by case basis. For example, an anti-hypertensive may be resumed 
or added at any point if the investigator believes it to be clinically indicated e.g. if a participant 
experiences uncontrolled hypertension while receiving N-803 treatment on study. For participants 
on antihypertensives at baseline, the agent will be resumed if clinically indicated by blood pressure 
readings in the days following N-803 treatment cessation. 
If a localized skin rash at the injection site occurs that is >6 cm and symptomatic, it may be treated 
with 0.05% clobetasol propionate or 0.1% triamcinolone cream or similar product at the discretion 
of the treating physician.  
Administration of additional glucocorticoids is discouraged during the N-803 treatment period as 
the use of systemic steroid medications may result in loss of therapeutic effects of the study drug. 
However systemic steroids may be used to treat an irAE. Sustained use of steroids or steroid use 
to treat immune-related toxicity may be an indication to permanently or temporarily discontinue 
N-803. 
4.3 
EPACADOSTAT 
The chronic use of systemic antibiotics (> 14 days) concurrently with epacadostat doses > 300mg 
BID is prohibited unless medical monitor review and approval. 
Two metabolites of epacadostat, M11 and M12, exhibit moderate inhibition of CYP1A2, CYP2C8 
(M12 only), and CYP2C19.  Metabolites of epacadostat may also inhibit CYP2B6 and CYP3A4. 
OATP1B1 and OATP1B3 may be inhibited by M9 and M11 (metabolites of epacadostat).  
Agents listed in Appendix E are prohibited while on study for patients receiving epacadostat doses 
> 300 mg BID. All other agents that are substrates of these enzymes/transporters should be 
evaluated on a case-by-case basis since the potential for a drug-drug interaction exists especially 
for agents with a narrow therapeutic index. Warfarin is prohibited in patients taking Epacadostat.  






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Please ship to the following address and notify personnel at the phone number below: 
    
 
 
 
 
 
An email will be sent to 
 with an electronic roster and tracking 
information before samples ship. 
5.1.4 Immunologic Parameters (per PI discretion in selected participants) 
Vaccination with BN-Brachyury has been shown to induce antigen specific T cells in patients 
receiving the vaccine. This may be beneficial to participants, and is hypothesized to be enhanced 
with addition of M7824, N-803 and Epacadostat. Studying the immunologic parameters below be 
useful in gaining insight into circulating the immune phenotype of a participant responding to 
treatment. This has potential to aid in biomarker development. 
Blood will be collected according to Study Calendar 3.5. 
The following immune assays may be performed at the Laboratory of Tumor Immunology and 
Biology at the NCI’s Center for Cancer Research (CCR) in select participants where adequate 
samples are available: 
PBMC: 
1. PBMCs may be analyzed for changes in standard immune cell types (CD4 and CD8 T cells, 
natural killer [NK] cells, regulatory T cells [Tregs], myeloid-derived suppressor cells 
[MDSCs], and dendritic cells) as well as 123 immune cell subsets, as described elsewhere 
[60] [61].  
2. PBMCs from selected subjects may be analyzed for function of specific immune cell 
subsets, including CD4 and CD8 T cells, NK cells, Tregs, and MDSCs. 
3. PBMCs may be analyzed for tumor antigen-specific immune responses to CEA, MUC-1 
and Brachyury using an intracellular cytokine staining assay. PBMCs will be stimulated in 
vitro with overlapping 15-mer peptide pools encoding the tumor-associated antigens listed 
above; control peptide pools will involve the use of human leukocyte antigen peptide as a 
negative control and CEFT peptide mix as a positive control. CEFT is a mixture of peptides 
of CMV, Epstein-Barr virus, influenza, and tetanus toxin. Post-stimulation analyses of 
CD4 and CD8 T cells will involve the production of IFN-γ, IL-2, TNF, and the 
degranulation marker CD107a. If sufficient PBMCs are available, assays may also be 
performed for the development of T cells to other tumor-associated antigens. A detailed 
description of this assay has been previously reported [8].  
4. Analyses of soluble factors: 


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 Sera may be analyzed pre- and post-therapy for the following soluble factors: sCD27, 
sCD40 ligand using commercial ELISA kits. 
 Sera may be analyzed for changes in cytokines (IFN-γ, IL-10, IL-12, IL-2, IL-4, etc.), 
chemokines, antibodies, tumor-associated antigens, and/or other markers using ELISA or 
multiplexed assays (e.g. Mesoscale, Luminex, cytokine bead array). 
Immunologic studies will be repeated more frequently if clinically indicated, and any 
abnormalities potentially related to treatment will be followed until they have resolved, stabilized, 
or have been determined not to be treatment-related. 
5. Prostate-specific Membrane Antigen (PSMA) positive extracellular vesicles (EV) and 
immune EVs. 
This is an exploratory endpoint. Samples collected as described under immunologic parameters 
be used for EV analysis. 
There is an unmet need for biomarkers predictive of clinical response pre-treatment, as well as 
early on in treatment of CRPC. Extracellular vesicles (EVs) are biologically active particles 
produced in large quantities by tumor and immune cells in response to stressors. Circulating EVs 
display multiple cell surface markers expressed on the cells that produce them. This biological 
information can potentially be exploited for development of personalized and adaptive treatments 
for participants. Prostate specific membrane antigen (PSMA) is over expressed on all prostate 
cancers and is also expressed on EVs. Recent data suggests that PSMA+ EV concentration may 
reflect prostate cancer disease status, making PSMA+ EV concentration a promising biomarker 
for response to immunotherapy.  
Schedule is in study calendar 3.5 
The nanoFACS technique of high -resolution analyses and sorting of single EVs by flow cytometry 
was developed at the NCI. EV subset phenotypes may serve as a potential biomarker for response 
to treatment. Serum and/or plasma samples may be evaluated for EV subsets in collaboration with: 
 
 
 
 
 
 
5.2 
SAMPLE STORAGE, TRACKING AND DISPOSITION 
Samples will be ordered in CRIS and tracked through a Clinical Trial Data Management system. 
Should a CRIS screen not be available, the CRIS downtime procedures will be followed. Samples 
will not be sent outside the National Institutes for Health (NIH) without appropriate approvals 
and/or agreements, if required. 
5.2.1 Sample Management and Storage at Clinical Services Program – Leidos Biomedical 
Research, Inc. (CSP) 
Clinical Services Program - Leidos Biomedical Research, Inc. 


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Attn:
  
 
 
 
On days samples are drawn, 
 at CSP (part of NCI Frederick Central Repositories) should 
be notified (phone: [
; fax [
). She will arrange same-day courier 
delivery of the specimens.  
All data associated with the participant samples is protected by using a secure database. All 
samples drawn at the NIH Clinical Center will be transported to the Clinical Support Laboratory 
at the Frederick National Laboratory for Cancer Research by couriers. 
Samples will be tracked and managed by Central Repository database, where there is no link to 
personal identifiable information. All samples will be stored in either a -80ºC freezer or vapor 
phase liquid nitrogen. These freezers are located at NCI Frederick Central Repository in Frederick, 
Maryland. 
NCI Frederick Central Repositories (managed under a subcontract) store, among other things, 
biological specimens in support of NIH clinical studies. All specimens are stored in secure, 
limited-access facilities with sufficient security, backup, and emergency support capability and 
monitoring to ensure long-term integrity of the specimens for research.  
Specimens are stored in accordance with applicable HHS and FDA Protection of Human Subjects 
Regulations in accordance with the subcontractor’s Federal-wide Assurance. The subcontractor’s 
role limited to clinical research databases and repositories containing participant specimens. The 
subcontractor does not conduct or have any vested interest in research on human subjects but does 
provide services and support the efforts of its customers, many of which are involved in research 
on human subjects. The subcontractor’s IRB reviews policies and procedures for labeling, data 
collection and storage, access, and security. The IRB will review protection of privacy issues prior 
to acceptance of any new work and in the event of change impacting privacy issues in existing 
work.  
It is the intent and purpose of the subcontractor to accept only coded, linked samples and sample 
information. To the limit of our ability, every effort will be made to ensure that protected 
information is not sent electronically or by hard copy or on vial labels.  
Sample data is stored in the BioSpecimen Inventory System II (BSI). This inventory tracking 
system is used to manage the storage and retrieval of specimens as well as to maintain specimen 
data. BSI is designed for controlled, concurrent access. It provides a real-time, multi-user 
environment for tracking millions of specimens. The system controls how and in what order 
database updates and searches are performed. This control prevents deadlocks and race conditions. 
For security, BSI has user password access, 3 types of user access levels, and 36 user permissions 
(levels of access) that can be set to control access to the system functions. BSI provides audit 
tracking for processes that are done to specimens including shipping, returning to inventory, 
aliquoting, thawing, additives, and other processes. BSI tracks the ancestry of specimens as they 
are aliquoted, as well as discrepancies and discrepancy resolution for specimens received by the 
repository. If a specimen goes out of the inventory, the system maintains data associated with the 
withdrawal request. Vials are labeled with a unique BSI ID which is printed in both eye-readable 
and bar-coded format. No participant-specific information is encoded in this ID.  


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Investigators are granted view, input, and withdrawal authority only for their specimens. They may 
not view specimen data or access specimens for which they have not been authorized. Access to 
specimen storage is confined to repository staff. Visitors to the repositories are escorted by 
repository staff at all times. 
5.2.2 Samples Managed by 
 Blood Processing Core (BPC)  
5.2.2.1 BPC contact information  
Please e-mail 
 at least 24 hours before transporting samples (the 
Friday before is preferred). 
For sample pickup, page 
. 
For immediate help, call 
 (main blood processing core number) or, if no answer, 
 (main clinical pharmacology lab number). 
For questions regarding sample processing, contact 
 
5.2.2.2 Sample Data Collection 
All samples sent to the Blood Processing Core (BPC) will be barcoded, with data entered and 
stored in the Labmatrix utilized by the BPC. This is a secure program, with access to Labmatrix 
limited to defined 
 lab personnel, who are issued individual user accounts. Installation of 
Labmatrix is limited to computers specified by 
. These computers all have a password 
restricted login screen.  
Labmatrix creates a unique barcode ID for every sample and sample box, which cannot be traced 
back to participants without Labmatrix access. The data recorded for each sample includes the 
participant ID, name, trial name/protocol number, time drawn, cycle time point, dose, material 
type, as well as box and freezer location. Participant demographics associated with the clinical 
center participant number are provided in the system. For each sample, there are notes associated 
with the processing method (delay in sample processing, storage conditions on the ward, etc.). 
5.2.2.3 Sample Storage  
Barcoded samples are stored in barcoded boxes in a locked freezer at either -20 or -80C according 
to stability requirements. These freezers are located onsite in the BPC and offsite at NCI Frederick 
Central Repository Services in Frederick, MD. Visitors to the laboratory are required to be 
accompanied by laboratory staff at all times.  
Access to stored clinical samples is restricted. Samples will be stored until requested by a 
researcher named on the protocol. All requests are monitored and tracked in Labmatrix. All 
researchers are required to sign a form stating that the samples are only to be used for research 
purposes associated with this trial (as per the IRB approved protocol) and that any unused samples 
must be returned to the BPC. It is the responsibility of the NCI Principal Investigator to ensure that 
the samples requested are being used in a manner consistent with IRB approval. 
5.2.3 Protocol Completion/Sample Destruction 
All specimens obtained in the protocol are used as defined in the protocol. Any specimens that are 
remaining at the completion of the protocol will be stored in the conditions described above. The 
study will remain open so long as sample or data analysis continues. Samples from consenting 
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for their continued use, at which time they will be destroyed. If the participant withdraws consent 
the participant’s data will be excluded from future distributions, but data that have already been 
distributed for approved research use will not be able to be retrieved. 
The PI will record any loss or unanticipated destruction of samples as a deviation. Reporting will 
be per the requirements of section 7.2.  
Sample barcodes are linked to participant demographics and limited clinical information. This 
information will only be provided to investigators listed on this protocol, via registered use of the 
Labmatrix. It is critical that the sample remains linked to participant information such as race, age, 
dates of diagnosis and death, and histological information about the tumor, in order to correlate 
genotype with these variables. 
6 
DATA COLLECTION AND EVALUATION  
6.1 
DATA COLLECTION 
The PI will be responsible for overseeing entry of data into a 21 CFR Part 11-compliant data 
capture system provided by the NCI CCR and ensuring data accuracy, consistency and timeliness. 
The principal investigator, associate investigators/research nurses and/or a contracted data 
manager will assist with the data management efforts. Primary and final analyzed data will have 
identifiers so that research data can be attributed to an individual human subject participant. 
All adverse events, including clinically significant abnormal findings on laboratory evaluations, 
regardless of severity, will be followed until return to baseline or stabilization of event.  
Document AEs from the first study intervention, study day 1, through 30 days after the subject 
received the last product administration. After 30 days, only adverse events which are serious and 
related to the study investigational agent need to be recorded.   
An abnormal laboratory value will be recorded in the database as an AE only if the laboratory 
abnormality is characterized by any of the following: 
 
Results in discontinuation from the study 
 
Is associated with clinical signs or symptoms  
 
Requires treatment or any other therapeutic intervention 
 
Is associated with death or another serious adverse event, including hospitalization.  
 
Is judged by the Investigator to be of significant clinical impact 
 
If any abnormal laboratory result is considered clinically significant, the investigator will 
provide details about the action taken with respect to the test drug and about the 
participant’s outcome. 
End of study procedures: Data will be stored according to HHS, FDA regulations, and NIH 
Intramural Records Retention Schedule as applicable.  
Loss or destruction of data: Should we become aware that a major breach in our plan to protect 
subject confidentiality and trial data has occurred, this will be reported expeditiously per 
requirements in section 7.2.1.  


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6.2 
DATA SHARING PLANS 
6.2.1 Human Data Sharing Plan 
What data will be shared? 
I will share human data generated in this research for future research as follows: 
 Coded, linked data in an NIH-funded or approved public repository.  
 Coded, linked data in BTRIS (automatic for activities in the Clinical Center) 
 Identified or coded, linked data with approved outside collaborators under appropriate 
agreements. 
Data will be shared through: 
 An NIH-funded or approved public repository: clinicaltrials.gov. 
 BTRIS (automatic for activities in the Clinical Center) 
 Approved outside collaborators under appropriate individual agreements. 
 Publication and/or public presentations. 
When will the data be shared?  
 Before publication. 
 At the time of publication or shortly thereafter. 
6.2.2 Genomic Data Sharing Plan 
GDS policy does not apply to this protocol. 
6.3 
RESPONSE CRITERIA 
Restaging bone scans and CT scan of chest, abdomen and pelvis will be obtained every 12 weeks. 
Participants in the M7824 plus N-803 safety cohort who do not have prostate cancer will be exempt 
from bone scans. 
Response and progression will be evaluated in this study using the new international criteria 
proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline 
(version 1.1)[62]. Changes in the largest diameter (unidimensional measurement) of the tumor 
lesions and the shortest diameter in the case of malignant lymph nodes are used in the RECIST 
criteria.  
For exploratory purpose, changes in PSA and measurable lesions will be analyzed for efficacy 
according to the Prostate Cancer Clinical Trials Working Group 2 (PCWG2) recommendations. 
The recommended PSA progressions criteria will not be applied to the study as the criteria are 
arbitrarily proposed and do not necessarily reflect overall disease status. PSA values will be 
captured at each visit and PSA declines and progression will be followed. PSA is not sufficient in 
the evaluation of disease progression in this participant population. This is consistent with the 
recent recommendations by the PCWG2. Progression will be determined by radiographic evidence 
as discussed below or by clinical symptoms (symptomatic clinical progression). 
 


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6.3.1 Disease Parameters 
Measurable disease: Measurable lesions are defined as those that can be accurately measured in at 
least one dimension (longest diameter to be recorded) as:  
 By chest x-ray: >20 mm;  
 By CT scan:  
o Scan slice thickness 5 mm or under: as >10 mm 
o Scan slice thickness >5 mm: double the slice thickness  
 With calipers on clinical exam: >10 mm.   
All tumor measurements must be recorded in millimeters (or decimal fractions of centimeters). 
Note: Tumor lesions that are situated in a previously irradiated area might or might not be 
considered measurable. If the investigator thinks it appropriate to include them, the conditions 
under which such lesions should be considered must be defined in the protocol. 
Malignant lymph nodes. To be considered pathologically enlarged and measurable, a lymph node 
must be >15 mm in short axis when assessed by CT scan (CT scan slice thickness recommended 
to be no greater than 5 mm). At baseline and in follow-up, only the short axis will be measured 
and followed. 
Non-measurable disease. All other lesions (or sites of disease), including small lesions (longest 
diameter <10 mm or pathological lymph nodes with ≥10 to <15 mm short axis), are considered 
non-measurable disease. Bone lesions, leptomeningeal disease, ascites, pleural/pericardial 
effusions, lymphangitis cutis/pulmonitis, inflammatory breast disease, and abdominal masses (not 
followed by CT or MRI), are considered as non-measurable. 
Note: Cystic lesions that meet the criteria for radiographically defined simple cysts should not be 
considered as malignant lesions (neither measurable nor non-measurable) since they are, by 
definition, simple cysts. 
‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable lesions, if 
they meet the definition of measurability described above. However, if non-cystic lesions are 
present in the same participant, these are preferred for selection as target lesions. 
Target lesions. All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in 
total, representative of all involved organs, should be identified as target lesions and recorded and 
measured at baseline. Target lesions should be selected on the basis of their size (lesions with the 
longest diameter), be representative of all involved organs, but in addition should be those that 
lend themselves to reproducible repeated measurements. It may be the case that, on occasion, the 
largest lesion does not lend itself to reproducible measurement in which circumstance the next 
largest lesion which can be measured reproducibly should be selected. A sum of the diameters 
(longest for non-nodal lesions, short axis for nodal lesions) for all target lesions will be calculated 
and reported as the baseline sum diameters. If lymph nodes are to be included in the sum, then 
only the short axis is added into the sum. The baseline sum diameters will be used as reference to 
further characterize any objective tumor regression in the measurable dimension of the disease. 
Non-target lesions. All other lesions (or sites of disease) including any measurable lesions over 
and above the 5 target lesions should be identified as non-target lesions and should also be 


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recorded at baseline. Measurements of these lesions are not required, but the presence, absence, or 
in rare cases unequivocal progression of each should be noted throughout follow-up.  
6.3.2 Methods for Evaluation of Measurable Disease 
All measurements should be taken and recorded in metric notation using a ruler or calipers. All 
baseline evaluations should be performed as closely as possible to the beginning of treatment and 
never more than 4 weeks before the beginning of the treatment. 
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. Imaging-based evaluation is 
preferred to evaluation by clinical examination unless the lesion(s) being followed cannot be 
imaged but are assessable by clinical exam. 
Clinical lesions: Clinical lesions will only be considered measurable when they are superficial 
(e.g., skin nodules and palpable lymph nodes) and 10 mm diameter as assessed using calipers 
(e.g., skin nodules). In the case of skin lesions, documentation by color photography, including a 
ruler to estimate the size of the lesion, is recommended.  
Chest x-ray: Lesions on chest x-ray are acceptable as measurable lesions when they are clearly 
defined and surrounded by aerated lung. However, CT is preferable.  
Conventional CT and MRI: This guideline has defined measurability of lesions on CT scan based 
on the assumption that CT slice thickness is 5 mm or less. If CT scans have slice thickness greater 
than 5 mm, the minimum size for a measurable lesion should be twice the slice thickness. MRI is 
also acceptable in certain situations (e.g. for body scans).  
Use of MRI remains a complex issue. MRI has excellent contrast, spatial, and temporal resolution; 
however, there are many image acquisition variables involved in MRI, which greatly impact image 
quality, lesion conspicuity, and measurement. Furthermore, the availability of MRI is variable 
globally. As with CT, if an MRI is performed, the technical specifications of the scanning 
sequences used should be optimized for the evaluation of the type and site of disease. Furthermore, 
as with CT, the modality used at follow-up should be the same as was used at baseline and the 
lesions should be measured/assessed on the same pulse sequence. It is beyond the scope of the 
RECIST guidelines to prescribe specific MRI pulse sequence parameters for all scanners, body 
parts, and diseases. Ideally, the same type of scanner should be used and the image acquisition 
protocol should be followed as closely as possible to prior scans. Body scans should be performed 
with breath-hold scanning techniques, if possible. 
PET-CT: At present, the low dose or attenuation correction CT portion of a combined PET-CT is 
not always of optimal diagnostic CT quality for use with RECIST measurements. However, if the 
site can document that the CT performed as part of a PET-CT is of identical diagnostic quality to 
a diagnostic CT (with IV and oral contrast), then the CT portion of the PET-CT can be used for 
RECIST measurements and can be used interchangeably with conventional CT in accurately 
measuring cancer lesions over time. Note, however, that the PET portion of the CT introduces 
additional data which may bias an investigator if it is not routinely or serially performed.  
Ultrasound: Ultrasound is not useful in assessment of lesion size and should not be used as a 
method of measurement. Ultrasound examinations cannot be reproduced in their entirety for 
independent review at a later date and, because they are operator dependent, it cannot be 
guaranteed that the same technique and measurements will be taken from one assessment to the 


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next. If new lesions are identified by ultrasound in the course of the study, confirmation by CT or 
MRI is advised. If there is concern about radiation exposure at CT, MRI may be used instead of 
CT in selected instances. 
Endoscopy, Laparoscopy: The utilization of these techniques for objective tumor evaluation is not 
advised. However, such techniques may be useful to confirm complete pathological response when 
biopsies are obtained or to determine relapse in trials where recurrence following complete 
response (CR) or surgical resection is an endpoint. 
Tumor markers: Tumor markers alone cannot be used to assess response. If markers are initially 
above the upper normal limit, they must normalize for a participant to be considered in complete 
clinical response. Specific guidelines for PSA response (in recurrent prostate cancer) have been 
published[63-65].  
Cytology, Histology: These techniques can be used to differentiate between partial responses (PR) 
and complete responses (CR) in rare cases (e.g., residual lesions in tumor types, such as germ cell 
tumors, where known residual benign tumors can remain). 
The cytological confirmation of the neoplastic origin of any effusion that appears or worsens 
during treatment when the measurable tumor has met criteria for response or stable disease is 
mandatory to differentiate between response or stable disease (an effusion may be a side effect of 
the treatment) and progressive disease. 
FDG-PET: While FDG-PET response assessments need additional study, it is sometimes 
reasonable to incorporate the use of FDG-PET scanning to complement CT scanning in assessment 
of progression (particularly possible 'new' disease). New lesions on the basis of FDG-PET imaging 
can be identified according to the following algorithm:  
a. Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of PD 
based on a new lesion. 
b. No FDG-PET at baseline and a positive FDG-PET at follow-up: If the positive FDG-
PET at follow-up corresponds to a new site of disease confirmed by CT, this is PD. If 
the positive FDG-PET at follow-up is not confirmed as a new site of disease on CT, 
additional follow-up CT scans are needed to determine if there is truly progression 
occurring at that site (if so, the date of PD will be the date of the initial abnormal FDG-
PET scan). If the positive FDG-PET at follow-up corresponds to a pre-existing site of 
disease on CT that is not progressing on the basis of the anatomic images, this is not 
PD. 
c. FDG-PET may be used to upgrade a response to a CR in a manner similar to a biopsy 
in cases where a residual radiographic abnormality is thought to represent fibrosis or 
scarring. The use of FDG-PET in this circumstance should be prospectively described 
in the protocol and supported by disease-specific medical literature for the indication. 
However, it must be acknowledged that both approaches may lead to false positive CR 
due to limitations of FDG-PET and biopsy resolution/sensitivity. 
 Note: A ‘positive’ FDG-PET scan lesion means one which is FDG avid with an uptake greater 
than twice that of the surrounding tissue on the attenuation corrected image. 
6.3.3 Response Criteria by RECIST (version 1.1) 
6.3.3.1 Evaluation of Target Lesions 


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Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes 
(whether target or non-target) must have reduction in short axis to <10 mm. 
Partial Response (PR): At least a 30% decrease in the sum of the diameters of target lesions, taking 
as reference the baseline sum of diameters. 
Progressive Disease (PD): At least a 20% increase in the sum of the diameters of target lesions, 
taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest 
on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute 
increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered 
progressions). 
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum of diameters while on study. 
6.3.3.2 Evaluation of Non-Target Lesions 
Complete Response (CR): Disappearance of all non-target lesions and normalization of tumor 
marker level. All lymph nodes must be non-pathological in size (<10 mm short axis). 
Note: If tumor markers are initially above the upper normal limit, they must normalize for a 
participant to be considered in complete clinical response. 
Non-CR/Non-PD: Persistence of one or more non-target lesion(s) and/or maintenance of tumor 
marker level above the normal limits. 
Progressive Disease (PD): Appearance of one or more new lesions and/or unequivocal progression 
of existing non-target lesions. Unequivocal progression should not normally trump target lesion 
status. It must be representative of overall disease status change, not a single lesion increase.  
Although a clear progression of “non-target” lesions only is exceptional, the opinion of the treating 
physician should prevail in such circumstances, and the progression status should be confirmed at 
a later time by the review panel (or Principal Investigator).  
The Investigator may perform scans in addition to a scheduled trial scan for medical reasons or if 
the Investigator suspects PD.  
Treatment may be continued despite progression according to RECIST 1.1 at any time if: 
• 
There are no new or concerning symptoms. 
• 
There is no decrease in ECOG PS. 
• 
The Investigator does not consider it necessary to administer a salvage therapy.  
6.3.3.3 Evaluation of Best Overall Response 
The best overall response is the best response recorded from the start of the treatment until disease 
progression/recurrence (taking as reference for progressive disease the smallest measurements 
recorded since the treatment started). The participant's best response assignment will depend on 
the achievement of both measurement and confirmation criteria. 
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6.3.4 Duration of Response 
Duration of overall response: The duration of overall response is measured from the time 
measurement criteria are met for CR or PR (whichever is first recorded) until the first date that 
recurrent or progressive disease is objectively documented (taking as reference for progressive 
disease the smallest measurements recorded since the treatment started). 
The duration of overall CR is measured from the time measurement criteria are first met for CR 
until the first date that progressive disease is objectively documented. 
 
Duration of stable disease: Stable disease is measured from the start of the treatment until the 
criteria for progression are met, taking as reference the smallest measurements recorded since the 
treatment started, including the baseline measurements.  
6.3.5 Progression-Free Survival 
Measured as the length of time during which the participant is free from new metastatic lesions 
visible on imaging or progression of metastatic lesions from baseline by RECIST 1.1. 
6.4 
TOXICITY CRITERIA 
The following adverse event management guidelines are intended to ensure the safety of each 
participant while on the study. The descriptions and grading scales found in the revised NCI 
Common Terminology Criteria for Adverse Events (CTCAE) version 5 will be utilized for AE 
reporting. All appropriate treatment areas should have access to a copy of the CTCAE version 5. 
A copy of the CTCAE version 5 can be downloaded from the CTEP web site 
(http://ctep.cancer.gov/protocolDevelopment/electronic applications/ctc.htm#ctc ).  
7 
NIH REPORTING REQUIREMENTS/DATA AND SAFETY MONITORING PLAN 
7.1 
DEFINITIONS 
Please refer to definitions provided in Policy 801: Reporting Research Events found here: 
https://irbo.nih.gov/confluence/pages/viewpage.action?pageId=36241835#HRPPPolicies-
800Series-ComplianceandResearchEventReportingRequirements 
7.2 
OHSRP OFFICE OF COMPLIANCE AND TRAINING /IRB REPORTING 
7.2.1 Expedited Reporting 
Please refer to the reporting requirements in Policy 801: Reporting Research Events and Policy 
802 
Non-Compliance 
Human 
Subjects 
Research 
found 
here: 
https://irbo.nih.gov/confluence/pages/viewpage.action?pageId=36241835#HRPPPolicies-
Non-Target Lesions 
New Lesions 
Overall Response 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
* ‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since SD is increasingly used 
as an endpoint for assessment of efficacy in some trials so to assign this category when no lesions can be 
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800Series-ComplianceandResearchEventReportingRequirements. Note: Only IND Safety Reports 
that meet the definition of an unanticipated problem will need to be reported per these policies. 
7.2.2 IRB Requirements for PI Reporting at Continuing Review 
Please refer to the reporting requirements in Policy 801: Reporting Research Events found here: 
https://irbo.nih.gov/confluence/pages/viewpage.action?pageId=36241835#HRPPPolicies-
800Series-ComplianceandResearchEventReportingRequirements.  
7.3 
NCI CLINICAL DIRECTOR REPORTING  
Problems expeditiously reviewed by the OHSRP in the NIH eIRB system will also be reported to 
the NCI Clinical Director/designee; therefore, a separate submission for these reports is not 
necessary.  
In addition to those reports, all deaths that occur within 30 days after receiving a research 
intervention should be reported via email unless they are due to progressive disease.   
To report these deaths, please send an email describing the circumstances of the death to 
NCICCRQA@mail.nih.gov within one business day of learning of the death. 
7.4 
INSTITUTIONAL BIOSAFETY COMMITTEE (IBC) REPORTING CRITERIA 
7.4.1 Serious Adverse Event Reports to IBC 
The Principal Investigator (or delegate) will notify IBC of any unexpected fatal or life-threatening 
experience associated with the use of BN-Brachyury as soon as possible but in no event later than 
7 calendar days of initial receipt of the information. Serious adverse events that are unexpected 
and associated with the use of the BN-Brachyury, but are not fatal or life-threatening, must be 
reported to the NIH IBC as soon as possible, but not later than 15 calendar days after the 
investigator’s initial receipt of the information. Adverse events may be reported by using the FDA 
Form 3500a. 
7.4.2 Annual Reports to IBC 
Within 60 days after the one-year anniversary of the date on which the IBC approved the initial 
protocol, and after each subsequent anniversary until the trial is completed, the Principal 
Investigator (or delegate) shall submit the information described below. Alternatively, the IRB 
continuing review report can be sent to the IBC in lieu of a separate report. Please include the IBC 
protocol number on the report. 
7.4.2.1 Clinical Trial Information  
A brief summary of the status of the trial in progress or completed during the previous year. 
The summary is required to include the following information:  
 the title and purpose of the trial  
 clinical site 
 the Principal Investigator 
 clinical protocol identifiers;  
 participant population (such as disease indication and general age group, e.g., adult or 
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 the total number of participants planned for inclusion in the trial; the number entered into 
the trial to date whose participation in the trial was completed; and the number who 
dropped out of the trial with a brief description of the reasons  
 the status of the trial, e.g., open to accrual of subjects, closed but data collection ongoing, 
or fully completed,  
 if the trial has been completed, a brief description of any study results.  
7.4.2.2 Progress Report and Data Analysis  
Information obtained during the previous year's clinical and non-clinical investigations, 
including:  
 a narrative or tabular summary showing the most frequent and most serious adverse 
experiences by body system 
 a summary of all serious adverse events submitted during the past year 
 a summary of serious adverse events that were expected or considered to have causes not 
associated with the use of the gene transfer product such as disease progression or 
concurrent medications 
 if any deaths have occurred, the number of participants who died during participation in 
the investigation and causes of death 
  a brief description of any information obtained that is pertinent to an understanding of the 
gene transfer product’s actions, including, for example, information about dose-response, 
information from controlled trials, and information about bioavailability. 
7.5 
NIH REQUIRED DATA AND SAFETY MONITORING PLAN 
7.5.1 Principal Investigator/Research Team  
The clinical research team will meet on a regular basis (approximately weekly) when participants 
are being actively treated on the trial to discuss each participant. Decisions about dose level 
enrollment and dose escalation if applicable will be made based on the toxicity data from prior 
participants.  
All data will be collected in a timely manner and reviewed by the principal investigator or a lead 
associate investigator.  
Events meeting requirements for expedited reporting as described in section 7.2.1 will be 
submitted within the appropriate timelines.   
The principal investigator will review adverse event and response data on each participant to 
ensure safety and data accuracy. The principal investigator will personally conduct or supervise 
the investigation and provide appropriate delegation of responsibilities to other members of the 
research staff.  
7.5.2 Data Safety Monitoring Board (DSMB) 
The DSMB is an independent group of at least 3 experts that monitors participant safety and 
advises The Sponsor. DSMB members will be separate and independent of study staff participating 
in this trial and should not have scientific, financial, or other conflicts of interest related to this 


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trial. The DSMB will consist of members with appropriate expertise to contribute to the 
interpretation of data from this trial. A quorum will consist of a simple majority. 
The DSMB will review cumulative safety data from this trial at least annually. 
The DSMB will meet when trial halting criteria (see Section 3.2) are met, or as requested by the 
sponsor or PI. 
The DSMB will have a final review meeting at the end of the study. 
Procedures for DSMB reviews/meetings will be defined in the DSMB charter. The DSMB will 
review applicable data, including, but not limited to, enrollment, demographics, dosing data, 
clinical laboratory data, and safety data, at scheduled timepoints during this trial as defined in the 
DSMB charter. The DSMB will review blinded aggregate data in the open session of the DSMB 
meetings. 
Additional data may be requested by the DSMB, and interim statistical reports may be generated 
as deemed necessary and appropriate by the Sponsor. As an outcome of each review/meeting, the 
DSMB will make a recommendation as to the advisability of proceeding with study product 
administration, and to continue, modify, or terminate this trial.  
8 
SPONSOR PROTOCOL/SAFETY REPORTING 
8.1 
DEFINITIONS 
8.1.1 Adverse Event  
Any untoward medical occurrence in a participant or clinical investigation subject administered a 
pharmaceutical product and which does not necessarily have a causal relationship with this 
treatment. An adverse event (AE) can therefore be any unfavorable and unintended sign (including 
an abnormal laboratory finding), symptom, or disease temporally associated with the use of a 
medicinal (investigational) product, whether or not related to the medicinal (investigational) 
product (ICH E6 (R2)) 
8.1.2 Serious Adverse Event (SAE) 
An adverse event or suspected adverse reaction is considered serious if in the view of the 
investigator or the sponsor, it results in any of the following: 
 
Death, 
 
A life-threatening adverse event (see section 8.1.3) 
 
Inpatient hospitalization or prolongation of existing hospitalization  
o A hospitalization/admission that is pre-planned (i.e., elective or scheduled surgery 
arranged prior to the start of the study), a planned hospitalization for pre-existing 
condition, or a procedure required by the protocol, without a serious deterioration in 
health, is not considered a serious adverse event. 
o A hospitalization/admission that is solely driven by non-medical reasons (e.g., 
hospitalization for patient or subject convenience) is not considered a serious adverse 
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o Emergency room visits or stays in observation units that do not result in admission to 
the hospital would not be considered a serious adverse event. The reason for seeking 
medical care should be evaluated for meeting one of the other serious criteria. 
 
Persistent or significant incapacity or substantial disruption of the ability to conduct normal 
life functions 
 
A congenital anomaly/birth defect 
 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered a serious adverse drug experience when, based upon 
appropriate medical judgment, they may jeopardize the patient or subject and may require 
medical or surgical intervention to prevent one of the outcomes listed in this definition. 
8.1.3 Life-threatening  
An adverse event or suspected adverse reaction is considered "life-threatening" if, in the view of 
either the investigator or sponsor, its occurrence places the patient or subject at immediate risk of 
death. It does not include an adverse event or suspected adverse reaction that, had it occurred in a 
more severe form, might have caused death. (21CFR312.32) 
8.1.4 Severity 
The severity of each Adverse Event will be assessed utilizing the CTCAE version 5.0. 
8.1.5 Relationship to Study Product 
All AEs will have their relationship to study product assessed using the terms:  related or not 
related.   
 Related – There is a reasonable possibility that the study product caused the adverse event. 
Reasonable possibility means that there is evidence to suggest a causal relationship 
between the study product and the adverse event. 
 Not Related – There is not a reasonable possibility that the administration of the study 
product caused the event. 
8.1.6 Adverse Events of Special Interest (AESI) 
An adverse event of special interest (AESI) is one of scientific and medical interest specific to 
understanding of the Investigational Product(s) and may require close monitoring and rapid 
communication by the investigator to the sponsor. An AESI may be serious or non-serious. The 
rapid reporting of AESIs assessed as severe allows ongoing surveillance of these events to 
characterize and understand them in association with the use of these investigational products.  
Only AESIs that match the definition of SAE will be reported as other SAEs within 7 days from 
the knowledge of event. Other non-SAE AESIs should do not need to be reported to OSRO but 
only collected in the clinical database. 
The adverse events related to mucosal bleeding, regardless of site, will be collected as an AESI to 
enable evaluation of potential risk factors, such as site/past radiation/associated infection at 
site/recent instrumentation and other variables such as time to onset, exposure history, grade of 
bleeding, anatomical sites, etc. can be collected. 


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8.2 
ASSESSMENT OF SAFETY EVENTS 
AE information collected will include event description, date of onset, assessment of severity and 
relationship to study product and alternate etiology (if not related to study product), date of 
resolution of the event, seriousness and outcome. The assessment of severity and relationship to 
the study product will be done only by those with the training and authority to make a diagnosis 
and listed on the Form FDA 1572 as the site principal investigator or sub-investigator.  AEs 
occurring during the collection and reporting period will be documented appropriately regardless 
of relationship.  AEs will be followed through resolution. 
SAEs will be: 
 
Assessed for severity and relationship to study product and alternate etiology (if not related 
to study product) by a licensed study physician listed on the Form FDA 1572 as the site 
principal investigator or sub-investigator. 
 
Recorded on the appropriate SAE report form, the medical record and captured in the 
clinical database. 
 
Followed through resolution by a licensed study physician listed on the Form FDA 1572 
as the site principal investigator or sub-investigator. 
For timeframe of recording adverse events, please refer to section 6.1. All serious adverse events 
recorded from the time of first investigational product administration must be reported to the 
sponsor with the exception of any listed in section 8.4.  
8.3 
REPORTING OF SERIOUS ADVERSE EVENTS 
Any AE that meets protocol-defined serious criteria or meets the definition of Adverse Event of 
Special Interest that require expedited reporting must be submitted immediately (within 24 hours 
of awareness) to OSRO Safety using the CCR SAE report form.  Any exceptions to the expedited 
reporting requirements are found in section 8.4. 
All SAE reporting must include the elements described in section 8.2. 
SAE reports will be submitted to the Center for Cancer Research (CCR) at: 
OSROSafety@mail.nih.gov and to the CCR PI and study coordinator.  CCR SAE report form and 
instructions 
can 
be 
found 
at: 
https://ccrod.cancer.gov/confluence/display/CCRCRO/Forms+and+Instructions 
Following the assessment of the SAE by OSRO, other supporting documentation of the event may 
be requested by the OSRO Safety and should be provided as soon as possible. 
8.4 
WAIVER OF EXPEDITED REPORTING TO CCR  
As death due to disease progression is part of the study objectives (PFS), and captured as an 
endpoint in this study, it will not be reported in an expedited manner to the sponsor. However, if 
there is evidence suggesting a causal relationship between the study drug and the event, report 
the event in an expedited manner according to section 8.3. 
 


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8.5 
SAFETY REPORTING CRITERIA TO THE PHARMACEUTICAL COLLABORATORS 
8.5.1 EMD Serono 
To be sent by Office of Sponsor and Regulatory Oversight, CCR, NCI/NIH: 
The following reportable events must be submitted to EMD Serono within 2 business days or 
3 calendar days (whichever comes first) using the applicable safety report form provided.  
 Serious Adverse Events 
 Exposure during Pregnancy or Breastfeeding (even if not associated with an adverse 
event) 
 Occupational exposure (even if not associated with an adverse event) 
 Potential drug-induced liver injury (Hy’s Law cases): These events are considered 
important medical events and should be reported as SAEs. 
 In addition, all aggregated AEs including periodicity will be collected in tabulated 
form and reported to EMD Serono as outlined in the Collaborative Agreement.  
To be sent by study team: 
Reporting of Overdose of M7824 and M9241 
 An overdose is defined as any dose twice the recommended single dose. Any overdose 
must be recorded in the trial medication section of the eCRF. 
 For monitoring purposes, any case of overdose, whether or not associated with an AE 
(serious or non-serious), must be reported to the sponsor. 
 There are no known symptoms of M7824 and M9241 overdose to date. The 
Investigator should monitor closely for AEs should an overdose occur and use his or 
her clinical judgment in providing symptomatic / supportive care as medically 
indicated. There is no known antidote for M7824 and M9241. 
Contact information for submission of reportable events to EMD Serono: 
Fax: +
 
OR 
E-mail: 
 specifying 
 PROTOCOL Number and/or Title 
 EMD Serono assigned Study Number 
 SUBJECT Number 
 SITE Number/PI Name 
 SAE/ONSET DATE 
8.5.2 Immunity Bio 
To be sent by Office of Sponsor and Regulatory Oversight, CCR, NCI/NIH:  
 Serious AEs (SAEs), whether related or not related to study drug, and pregnancies must be 
reported to NantBio (ImmunityBio drug safety affiliate)  Drug Safety (Nant) within  2 
business days with regards to Nant drug use. 


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 In 2 business days, Nant will be receiving notification for not related SAEs and preliminary 
SUSARs not the full assessment of the event (i.e., narrative which would come latter) SAEs 
must be recorded on an OSRO SAE report form or MedWatch form. 
 OSRO will be responsible for reporting of pregnancies unless it became SAE because of 
adverse fetal outcomes.  
 The Sponsor will be responsible for submitting all safety correspondence to the FDA.  Nant 
will be provided with a simultaneous copy of all Serious adverse event submissions filed 
with the FDA. Sponsor will provide NantBio (ImmunityBio’s affiliate for drug safety) a 
copy of the Annual Report concurrently with the submission of the Annual Report to the 
FDA. 
 If only limited information is initially available, follow-up reports are required. (Note: 
Follow-up SAE reports should include the same investigator term(s) initially reported.) If 
an ongoing SAE changes in its intensity or relationship to study drug or if new information 
becomes available, a follow-up SAE notification should be sent within 2 business days to 
Nant using the same procedure used for transmitting the initial SAE report. All SAEs 
should be followed to resolution or stabilization.  
To be sent by study team: 
 The Investigator will ensure that all SAEs in the clinical database are reported to Nant and 
any applicable health authority during the conduct of the study. This reconciliation will 
occur at least quarterly and be initiated by the investigator.  
 Pregnancies on a Pregnancy Surveillance Form (Nant can provide) will be reported by 
study team when it became SAE because of adverse fetal outcomes.  
 Investigator will request a reconciliation report from: 
  During reconciliation, any events found to not be 
reported previously to Nant must be sent to: 
  
Contact information for submission of all SAEs to NantCell: 
All SAEs and any reports submitted to the FDA should simultaneously be faxed or e-mailed to 
NANT at: 
Fax Number: 
 
Email: 
 
 
8.5.3 Bavarian Nordic, Inc. 
To be sent by OSRO: 
 All SAEs and all pregnancy reports must be reported to Bavarian Nordic 
Pharmacovigilance by within 2 business days or 3 calendar days (whichever comes first) 
of the investigator’s knowledge of the event by facsimile, email, or other appropriate 
method using the Medwatch form (or a specific pregnancy report form if applicable). This 
instruction pertains to initial reports as well as any follow-up reports. 
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 At the request of Bavarian Nordic, the investigator may send an email to the address below, 
providing a preliminary notification of an SAE within 24 hours of the investigator’s first 
knowing of the event. 
Contact for SAE reports to BN: 
 
 
 #, PI name/site#, SAE/onset dates 
8.5.4 Incyte 
To be sent by OSRO: 
All suspected unexpected serious adverse events that are considered related to Epacadostat 
treatment and will be reported to the FDA will be reported to Incyte within 2 business days or 3 
calendar days (whichever comes first) of the investigator’s knowledge recorded on the MedWatch 
Form or an OSRO SAE report form and sent to: 
  
8.6 
REPORTING PREGNANCY  
All required pregnancy reports/follow-up to OSRO will be submitted to: 
OSROSafety@mail.nih.gov and to the CCR PI and study coordinator.  Forms and instructions 
can be found here: 
https://ccrod.cancer.gov/confluence/display/CCRCRO/Forms+and+Instructions  
8.6.1 Maternal exposure 
If a participant becomes pregnant during the course of the study, the study treatment should be 
discontinued immediately, and the pregnancy reported to the Sponsor no later than 24 hours of 
when the Investigator becomes aware of it. The Investigator should notify the Sponsor no later 
than 24 hours of when the outcome of the Pregnancy becomes known. 
Pregnancy itself is not regarded as an SAE. However, congenital abnormalities or birth defects 
and spontaneous miscarriages that meet serious criteria (section 8.1.2) should be reported as SAEs.  
The outcome of all pregnancies should be followed up and documented for reporting requirements. 
8.6.2 Paternal exposure 
Male participants should refrain from fathering a child or donating sperm during the study and for 
4 months after the last dose of study therapy. 
Pregnancy of the participant’s partner is not considered to be an AE. The outcome of all 
pregnancies occurring from the date of the first dose until 4 months after the last dose should, if 
possible, be followed up and documented for reporting requirements. Pregnant partners may be 
offered the opportunity to participate in an institutional pregnancy registry protocol (e.g., the NIH 
IRP pregnancy registry study) to provide data about the outcome of the pregnancy for safety 
reporting purposes. 
8.7 
REGULATORY REPORTING FOR STUDIES CONDUCTED UNDER CCR-SPONSORED IND 
Following notification from the investigator, CCR, the IND sponsor, will report any suspected 
adverse reaction that is both serious and unexpected.  CCR will report an AE as a suspected adverse 
reaction only if there is evidence to suggest a causal relationship between the study product and 


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the adverse event.  CCR will notify FDA and all participating investigators (i.e., all investigators 
to whom the sponsor is providing drug under its INDs or under any investigator’s IND) in an IND 
safety report of potential serious risks from clinical trials or any other source, as soon as possible, 
in accordance to 21 CFR Part 312.32.  
All serious events will be reported to the FDA at least annually in a summary format. 
8.8 
SPONSOR PROTOCOL DEVIATION REPORTING 
A Protocol Deviation is defined as any non-compliance with the clinical trial Protocol, Manual 
of Operational Procedures (MOP) and other Sponsor approved study related documents, GCP, or 
protocol-specific procedural requirements on the part of the participant, the Investigator, or the 
study site staff inclusive of site personnel performing procedures or providing services in support 
of the clinical trial. 
It is the responsibility of the study Staff to document any protocol deviation identified by the 
Staff or the site Monitor in the CCR Protocol Deviation Tracking System (PDTS) online 
application. The entries into the PDTS online application should be timely, complete, and 
maintained per CCR PDTS user requirements. In addition, any deviation to the protocol should 
be documented in the participant’s source records and reported to the reviewing IRB per their 
guidelines. OSRO required protocol deviation reporting is consistent with E6(R2) GCP: 
Integrated Addendum to ICH E6(R1): 4.5 Compliance with Protocol; 5.18.3 (a), and 5.20 
Noncompliance; and ICH E3 16.2.2 Protocol deviations. 
9 
CLINICAL MONITORING  
Clinical site monitoring is conducted to ensure: 
 that the rights of the participants are protected; 
 that the study is implemented per the approved protocol, Good Clinical Practice and 
standard operating procedures; and  
 that the quality and integrity of study data and data collection methods are maintained.   
Monitoring for this study will be performed by NCI CCR Office of Sponsor and Regulatory 
Oversight (OSRO) Sponsor and Regulatory Oversight Support (SROS) Services contractor. 
Clinical site monitoring activities will be based on OSRO standards, FDA Guidance E6(R2) Good 
Clinical Practice: Integrated Addendum to ICH E6(R1) March 2018, and applicable regulatory 
requirements. 
Details of clinical site monitoring will be documented in a Clinical Monitoring Plan (CMP) 
developed by OSRO. CMPs will be protocol-specific, risk-based and tailored to address human 
subject protections and integrity of the study data. OSRO will determine the intensity and 
frequency of monitoring based on several factors, including study type, phase, risk, complexity, 
expected enrollment rate, and any unique attributes of the study and the site. The sponsor will 
conduct a periodic review of the CMP to confirm the plan’s continued appropriateness. A change 
to the protocol, significant or pervasive non-compliance with GCP, or the protocol may trigger 
CMP updates.  
OSRO SROS Monitoring visits and related activities will be conducted throughout the life cycle 
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(SAV) (as warranted), followed by a Site Initiation Visit (SIV), Interim Monitoring Visit(s) 
(IMVs), and a study Close-Out Visit (COV). 
Some monitoring activities may be performed remotely, while others will take place at the study 
site(s).  Monitoring visit reports will describe visit activities, observations, and associated action 
items or follow-up required for resolution of any issues, discrepancies, or deviations.  Monitoring 
reports will be distributed to the study PI, NCI CCR QA, CCR Protocol Support Office, 
coordinating center (if applicable) and the Sponsor regulatory file. 
The site Monitor will inform the study team of any deviations observed during monitoring visits. 
If unresolved, the Monitor will request that the site Staff enter the deviations in the CCR Protocol 
Deviation Tracking System (PDTS) for deviation reporting to the Sponsor and as applicable per 
institutional and IRB guidance. 
10 STATISTICAL CONSIDERATIONS  
10.1 STATISTICAL HYPOTHESES 
The primary objective of this trial is to determine if there is clinical benefit to any of a set of 3 
possible treatments for participants with CRPC: 
 BN Brachyury + M7824 
 BN-Brachyury + M7824 + N-803 
 BN-Brachyury + M7824 + N-803 + Epacadostat 
The secondary objectives of this trial are to evaluate and compare the immune response with 
clinical outcomes in participants treated with any of the set of 3 possible treatments with CRPC 
and to characterize the safety profile of the above combinations and M7824 + N-803. Progression 
free survival (PFS) will also be estimated in each arm as a secondary objective. 
10.2 SAMPLE SIZE DETERMINATION 
 
A set of 3 possible treatments will be explored in order to determine if there is any 
substantial benefit to participants using any of these treatments. For each of the 3 arms, the 
trial will aim to determine if there is either an objective clinical response or PSA decline 
of >=30% sustained for a minimum of 21 days. Experiencing any of these would be 
considered a positive outcome (‘efficacy’). 
 
A separate cohort (Cohort 1.1) will enroll up to 18 participants, and function to determine 
safe dosing in N-803 in combination with M7824. See Section 3.1.2 for details.  
 
Phase II data from a trial of PSA-TRICOM vs. placebo in CRPC demonstrated an ORR of 
0% in measurable disease (in placebo and controls) and a PSA decline >=30% in 0% of 
participants receiving placebo[19]. This historic information is the basis for the statistical 
plan below. 
 
In order to establish at least potential utility from each of the regimens, the primary 
objective would be to determine if using the proposed agents would rule out a 10% efficacy 
rate and result in an efficacy rate consistent with 35%. As such, each arm of the trial will 
be conducted using a Simon minimax two-stage phase II trial design (Simon R, Controlled 
Clinical Trials 10:1-10, 1989) in order to rule out an unacceptably low PR+CR or PSA 


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decline of >30% (‘efficacy’) rate of 10% (p0=0.10) in favor of an improved efficacy rate 
of 35% (p1=0.35). There is no multiplicity adjustment for the 3 Simon 2-stage designs. 
With alpha=0.05 (probability of accepting a poor treatment=0.05) and beta = 0.10 
(probability of rejecting a good treatment=0.10), the first stage for each arm will enroll 13 
evaluable participants, and if 0 to 1 of the 13 demonstrate efficacy, then no further 
participants will be accrued in that arm. If 2 or more of the first 13 participants demonstrate 
efficacy, then that arm will continue to accrue participants until a total of 25 evaluable 
participants have been enrolled.  
 
Following this expansion to 25 participants, if there are 2 to 5 participants with efficacy 
out of 25 participants, this would be an uninterestingly low efficacy rate. If there were 6 or 
more of 25 (24.0%) who experienced any efficacy, this would be sufficiently interesting to 
warrant further study in later trials. Under the null hypothesis (10% efficacy rate), the 
probability of early termination is 62.1%. 
 
With 3 arms, the trial will aim to keep enrolling participants by using the following 
algorithm: at first, participants will enroll on arm 2.1 for the initial 13 participants in the 
arm. Then, after these 13 evaluable participants have enrolled, if adequate safety is 
demonstrated in the safety arm 1.1 and in arm 2.1 (<2 of the first 6 participants in the first 
stage of arm 2.1 have a DLT), arm 2.2 will open and enroll participants onto the first stage. 
Then, after the 1st stage of arm 2.2 has completed enrollment of 13 evaluable participants, 
if arm 2.2 is adequately safe (<2 of the first 6 participants in the first stage of arm 2 have a 
DLT), the first stage of arm 2.3 will open and accrue 13 evaluable participants.  
 
After accruing all 39 evaluable participants to the first stages of the three arms, if both arms 
2.1 and 2.2 demonstrate adequate first-stage efficacy, then participants will be randomized 
between the second stages of both arms 2.1 and 2.2. Otherwise, if there is only adequate 
efficacy on one of the first two arms, then participants will begin to enroll directly onto the 
second stage of the arm with adequate efficacy.  
 
Finally, if arm 2.3 also demonstrates adequate efficacy in the first stage, this arm will begin 
to have its second stage participants randomized against participants from one or two other 
arms if there is adequate efficacy from the first stage of at least one of these two arms; 
otherwise it will accrue participants to the second stage without randomization. The 
randomization would continue for all included arms until enrollment of 25 evaluable 
participants in each arm. This may result in some participants never being randomized, but 
rather accrued to the single open available arm if only one arm is available to accrue 
participants. Thus, randomization will take place for the second stage participants during 
the time in which 2 or more arms are available to be randomized, and otherwise accrual 
will take place without randomization to the one open arm. As a result, randomization will 
take place when practical to do so, but not all 2nd stage participants may be randomized. 
By this algorithm, there is no bias in assignment to treatment, and the aim is to randomize 
as many participants as practical while any others are enrolled directly into the only 
available arm.  
 
At the end of the trial, the arms will be evaluated with respect to safety and clinical 
benefit/efficacy. In the absence of appreciably worse toxicity, the arm with the greatest 
fraction and number of participants experiencing efficacy will be considered for evaluation 
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 
It is expected that approximately 1 to 2 participants per month may enroll onto this trial. 
With 3 arms of up to 25 evaluable participants apiece, up to 75 evaluable participants may 
be required. In order to allow for up to 20 inevaluable participants and screen failures, plus 
18 for the safety cohort 1, the accrual ceiling for this trial will be set at 113 participants.  
10.3 POPULATIONS FOR ANALYSIS 
In the M7824 + N-803 safety cohort, all participants who receive at least one dose of both agents 
will be evaluable for safety and toxicity evaluations. All participants will be evaluable for toxicity 
from the time of their first treatment with either agent. 
In each of the phase II arms in the phase II cohort (sequential cohorts) a modified intention to treat 
population will be used. Only those participants who have measurable disease present at baseline 
including a PSA determination, have received at least one cycle of therapy, and have had their 
disease re-evaluated will be considered evaluable for response. (Note: Participants who exhibit 
objective disease progression prior to the end of cycle 1 will also be considered evaluable.) 
10.4 STATISTICAL ANALYSIS 
10.4.1 General approach 
Participants in the M7824 + N-803 safety arm 1.1 will be evaluated with respect to the grades and 
types of toxicities obtained. The results will be presented descriptively, and tabled if appropriate. 
Participants included in the phase II cohort will have their efficacy evaluated as being consistent 
with clinical benefit or not (PR+CR or PSA decline of >30% for 21 days), and appropriate 
confidence intervals will be formed. 
10.4.2 Analysis of the primary endpoints 
Safety will be evaluated in the initial 18 participant safety arm 1.1 by determining the grades and 
types of toxicity experienced by each participant and reporting these findings. Since the objective 
will be to determine the safe combination of agents to use in the phase II cohort, the focus will be 
on reporting the number of DLTs encountered by the participants at the dose levels evaluated and 
how that relates to the use of the agents in phase II. 
In the phase II cohort (sequential cohort), the participants will be scored according to the degree 
of clinical response obtained (CR, PR, SD, PD) as well as whether the participant is able to sustain 
a PSA decline of 30% or more for >21 days (attaining a CR or PR, and/or PSA decline of 30% or 
more for >21 days). The participants who attain these outcomes will be considered to have 
demonstrated efficacy of the agents. The fraction of participants who experience treatment efficacy 
will be reported along with two-sided 80% and 95% confidence intervals.  
10.4.3 Analysis of the secondary endpoints: 
Progression free survival will be estimated in each cohort, from the on study date until progression 
or death without progression. The 6 month PFS probability will be estimated and reported with a 
95% confidence interval. 
Correlation of immunologic outcomes with clinical data and outcomes will be performed  by 
testing the association between the immune outcomes and clinical outcomes, using appropriate 
non-parametric techniques, such as comparing those with and without efficacy (clinical benefit) 
with a Wilcoxon rank sum test, separately within each arm.  


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The participants who are enrolled in the phase II arm (s) will have their grades and types of 
toxicities noted and tabled as appropriate, as a secondary analysis.  
10.4.4 Safety analysis 
In addition to monitoring safety in the initial safety arm 1.1, the participants who are enrolled in 
the phase II arm(s) will have their grades and types of toxicities noted and tabled as appropriate.  
10.4.5 Baseline descriptive statistics 
Baseline demographic data on all participants in the phase II cohort will be reported separately by 
arm. 
10.4.6 Planned interim analysis 
Each of the 3 planned phase II arms will be evaluated for efficacy after the initial stage of the two 
stage Simon optimal designs. 
10.4.7 Exploratory analyses 
Specific analyses may include but are not limited to descriptive evaluation of pre- and post-
treatment samples as well samples taken on treatment for the following:  
 Brachyury-specific T-cell response utilizing intracellular cytokine staining after 
stimulation with 15-mer peptide pools encoding brachyury 
 Immunoscore by analysis of 123 lymphocyte subsets 
 Serum prognostic markers sCD27 and sCD40L 
 TCR clonality 
 PSMA+ and immune cell extracellular vesicles (EVs) 
Each of these measures is a quantitative parameter, and the results will be presented using 
descriptive statistics. 
Additional assays may be performed on an exploratory basis as described in Section 5. Any data 
resulting from these assays will be evaluated using descriptive techniques only. 
11 COLLABORATIVE AGREEMENTS 
11.1 COOPERATIVE RESEARCH AND DEVELOPMENT AGREEMENT (CRADA) 
A CRADA (02666) is in place with EMD Serono for the supply of M7824. 
A CRADA (02561) is in place with Bavarian Nordic, Inc for the supply of BN-Brachyury. 
A CRADA (03058) is in place with Altor Bioscience for the supply of ALT-803 (Note: No 
updated CRADA applicable due to acquisition by Immunity Bio at this time). 
A CRADA (03142) is in place with Incyte for the supply of Epacadostat. 


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12 HUMAN SUBJECTS PROTECTIONS  
12.1 RATIONALE FOR SUBJECT SELECTION 
Subjects from all racial/ethnic groups and both genders are eligible for this study if they meet the 
eligibility criteria. While prostate cancer is the main malignancy being studied and only occurs in 
males, females will be eligible for enrollment in the M7824 + N-803 safety cohort 1. To date, no 
information suggests that differences in drug metabolism, immune response, or disease response 
would be expected in one group compared with another. Efforts will be made to extend accrual to 
a representative population, but in this preliminary study, a balance must be struck between 
participant safety considerations and limitations on the number of individuals exposed to 
potentially toxic and/or ineffective treatments on one hand and the need to explore gender and 
ethnic aspects of clinical research on the other hand. If differences in outcome that correlate with 
ethnic identity are noted, accrual may be expanded or a follow-up study may be written to 
investigate those differences more fully.  
12.2 PARTICIPATION OF CHILDREN 
Because no dosing or adverse event data are currently available on the use of each individual 
agent in participants <18 years of age, children are excluded from this study.  
12.3 PARTICIPATION OF SUBJECTS UNABLE TO GIVE CONSENT 
Adults unable to give consent are excluded from enrolling in the protocol. However, it is possible 
that subjects enrolled in the protocol may permanently lose the capacity to consent for themselves 
during the course of this study. In the event this occurs, because there is a prospect of direct benefit 
from research participation (section 12.5), the subjects will remain in the study. In addition, one 
of the study objectives is progression free survival; taking participants off study would cause loss 
of valuable data. All subjects ≥ age 18 will be offered the opportunity to fill in their wishes for 
research and care, and assign a substitute decision maker on the “NIH Advance Directive for 
Health Care and Medical Research Participation” form so that another person can make decisions 
about their medical care in the event that they become incapacitated or cognitively impaired during 
the course of the study. Note: The PI or AI will contact the NIH Ability to Consent Assessment 
Team (ACAT) for evaluation to assess ongoing capacity of the subjects and to identify LAR, as 
needed. Please see Section 12.6 for consent procedure.  
12.4 PARTICIPATION OF SUBJECTS WHO REFUSE BLOOD TRANSFUSIONS 
Adults who will refuse transfusions are excluded from the protocol. Blood transfusions may be 
necessary to treat known potential risks of bintrafusp alfa and participants who will decline are at 
increased risk.  
12.5 RISKS/BENEFITS ANALYSIS 
12.5.1 Risks 
12.5.1.1 Research Blood Collection Risks 
Risks of blood draws include pain and bruising in the area where the needle is placed, 
lightheadedness, and rarely, fainting. When large amounts of blood are collected, low red blood 
cell count (anemia) can develop.  
12.5.1.2 Risks due to Radiation 


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The study will involve radiation from the following sources: 
 Up to 5 CT scans (C/A/P) per year for disease assessment 
 Up to 5 bone scans (for Prostate Cancer Participants) per year for disease assessment 
Subjects in this study may be exposed up to 7.45 rem maximum annually depending upon how 
much they weigh.  
12.5.1.3 Risks due to contrast dye used in CT scans 
If contrast dye is used, there is a risk for allergic reaction to the dye. Participants who are allergic 
to or sensitive to medications, contrast dye, iodine, or shellfish should notify their physician. 
Participants with kidney failure or other kidney problems should notify their physician. 
12.5.1.4 Risks due to bone scan  
The bone scan carries no greater risk than conventional X-rays. The tracers in the radioactive 
substance used in a bone scan produces very little radiation exposure. The risk of having an allergic 
reaction to the tracers is low. 
12.5.1.5 Risks due to MRI  
People are at risk for injury from the MRI magnet if they have some kinds of metal in their body.  
It may be unsafe to have an MRI scan in participants with pacemakers or other implanted electrical 
devices, brain stimulators, some types of dental implants, aneurysm clips (metal clips on the wall 
of a large artery), metal prostheses (including metal pins and rods, heart valves, and cochlear 
implants), permanent eyeliner, tattoos, an implanted delivery pump, or shrapnel fragments. 
Welders and metal workers may have small metal fragments in the eye. Participants will be 
screened for those conditions before having any MRI scan.   
In addition, all magnetic objects (like watches, coins, jewelry, and credit cards) must be removed 
before entering the MRI scan room. 
Participants with fear of confined spaces may become anxious during an MRI. Those with back 
problems may have back pain or discomfort from lying in the scanner.  The noise from the scanner 
is loud enough to damage hearing, especially in people who already have hearing loss. Everyone 
having a research MRI scan will be fitted with hearing protection.  
There are no known long-term risks of MRI scans. 
12.5.1.6 Risks due to gadolinium enhanced MRI 
The risks of an IV catheter include bleeding, infection, or inflammation of the skin and vein with 
pain and swelling.   
Mild symptoms from gadolinium infusion occur in fewer than 1% of those who receive it and 
usually go away quickly.  Mild symptoms may include coldness in the arm during the injection, a 
metallic taste, headache, and nausea.  In an extremely small number, fewer than one in 300,000 
people, more severe symptoms have been reported including shortness of breath, wheezing, hives, 
and lowering of blood pressure. Participants should not receive gadolinium if they have previously 
had an allergic reaction to it.   
Participants with kidney disease are at risk for a serious reaction to gadolinium contrast called 
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involve the muscles, joints and internal organs.  NSF has resulted in a very small number of deaths.  
Participants will not receive gadolinium for a research MRI scan if your kidney function is below 
the safe level.  
Most of the gadolinium contrast leaves the body in the urine.  However, the FDA has issued a 
safety alert that indicates small amounts of gadolinium may remain in the body for months to years.  
The long-term effects of the retained gadolinium are not known.  Some types of gadolinium 
contrast drugs are less likely to remain in the body than others.  In this study, gadolinium contrast 
drugs that are less likely to remain in the body are used.  
12.5.1.7 Risks due to biopsy 
There are potential risks associated with this procedure including pain or bleeding caused by the 
anesthesia needle as well as the biopsy procedure itself. An allergic reaction to the local anesthetic 
may occur. There may be bruising at the site of biopsy. Continuous bleeding and infection are rare 
and very often is easily controlled.  
12.5.1.8 Risks due to Electrocardiogram (ECG) 
Other than possibly experiencing some minor skin irritation from the electrodes, there are no 
anticipated risks related to complete the electrocardiogram and/or the echocardiogram 
12.5.1.9 Other Risks 
Risks include the possible occurrence of any of a range of side effects which are listed in the 
Consent Document or this protocol document. Frequent monitoring for adverse effects will help 
to minimize the risks associated with administration of the study agents. 
12.5.2 Benefits 
The potential benefit to a participant that goes onto study is a reduction in the bulk of their tumor 
which may or may not have favorable impact on symptoms and/or survival. 
12.6 CONSENT PROCESS AND DOCUMENTATION 
The informed consent document will be provided as a physical or electronic document to the 
participant or consent designee (see section 12.3) for review prior to consenting.  A designated 
study investigator will carefully explain the procedures and tests involved in this study, and the 
associated risks, discomforts and benefits. In order to minimize potential coercion, as much time 
as is needed to review the document will be given, including an opportunity to discuss it with 
friends, family members and/or other advisors, and to ask questions of any designated study 
investigator. A signed informed consent document will be obtained prior to entry onto the study. 
The initial consent process as well as re-consent, when required, may take place in person in a 
private area or remotely (e.g., via telephone or other NIH approved remote platforms used in 
compliance with policy, including HRPP Policy 303) per discretion of the designated study 
investigator and with the agreement of the participant/consent designee(s). 
Whether in person or remote, the privacy of the subject will be maintained. Consenting 
investigators (and participant/consent designee, when in person) will be located in a private area 
(e.g., clinic consult room). When consent is conducted remotely, the participant/consent designee 
will be informed of the private nature of the discussion and will be encouraged to relocate to a 
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Consent will be documented with required signatures on the physical document (which includes 
the printout of an electronic document sent to participant) or as described below, with a manual 
(non-electronic) signature on the electronic document.  When required, witness signature will be 
obtained similarly as described for the investigator and participant. 
Manual (non-electronic) signature on electronic document: 
When a manual signature on an electronic document is used for the documentation of consent 
at the NIH Clinical Center, this study will use the following to obtain the required signatures: 
 
Adobe platform (which is not 21 CFR Part 11 compliant); or,   
 
iMedConsent platform (which is 21 CFR Part 11 compliant) 
During the consent process, participants and investigators will view individual copies of the 
approved consent document on screens at their respective locations (if remote consent); the 
same screen may be used when in the same location, but is not required.   
Both the investigator and the participant will sign the document using a finger, stylus or mouse.  
Note: Refer to the CCR SOP PM-2, Obtaining and Documenting the Informed Consent Process 
for additional information (e.g., verification of participant identity when obtaining consent 
remotely) 
found 
here: 
https://ccrod.cancer.gov/confluence/pages/viewpage.action?pageId=73203825. 
12.6.1 Consent Process for Adults Who Lack Capacity to Consent to Research Participation 
For participants addressed in section 12.3, an LAR will be identified consistent with Policy 403 
and informed consent obtained from the LAR, as described in Section 12.6.  
12.6.2 Request for Waiver of Consent for Screening Activities 
Prior to the subject signing the consent for this study pre-screening activities listed in section 2.2.1 
may be performed.  
We request a waiver of consent for these activities as they involve only minimal risk to the subjects.  
A waiver will not adversely affect the rights and welfare of the subjects given that the activities 
are only intended to determine suitability for screening for participation in research protocols.  
These activities could not practicably be carried out without the wavier as central recruiting 
services, utilized in the NIH Clinical Center, perform pre-screening activities for multiple studies 
and obtaining consent for each one is beyond their resources.  The subjects will be provided with 
additional pertinent information after participation as they will be informed whether or not they 
are eligible to sign a consent for additional screening. 
13 REGULATORY AND OPERATIONAL CONSIDERATIONS  
13.1 STUDY DISCONTINUATION AND CLOSURE 
This study may be temporarily suspended or prematurely terminated if there is sufficient 
reasonable cause.  Written notification, documenting the reason for study suspension or 
termination, will be provided by the suspending, or terminating party to study participants, 
investigator, the Investigational New Drug (IND) sponsor and regulatory authorities.  If the study 
is prematurely terminated or suspended, the Principal Investigator (PI) will promptly inform study 
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the termination or suspension.  Study participants will be contacted, as applicable, and be informed 
of changes to study visit schedule. 
 Circumstances that may warrant termination or suspension include, but are not limited to: 
 Determination of unexpected, significant, or unacceptable risk to participants 
 Demonstration of efficacy that would warrant stopping    
 Insufficient compliance to protocol requirements 
 Data that are not sufficiently complete and/or evaluable 
 Determination that the primary endpoint has been met 
 Determination of futility 
Study may resume once concerns about safety, protocol compliance, and data quality are 
addressed, and satisfy the sponsor, IRB and as applicable, Food and Drug Administration (FDA). 
13.2 QUALITY ASSURANCE AND QUALITY CONTROL 
The clinical site will perform internal quality management of study conduct, data and biological 
specimen collection, documentation and completion.  An individualized quality management plan 
will be developed to describe a site’s quality management. 
Quality control (QC) procedures will be implemented beginning with the data entry system and 
data QC checks that will be run on the database will be generated. Any missing data or data 
anomalies will be communicated to the site(s) for clarification/resolution. 
Following written Standard Operating Procedures (SOPs), the monitors will verify that the clinical 
trial is conducted and data are generated and biological specimens are collected, documented 
(recorded), and reported in compliance with the protocol, International Conference for 
Harmonisation Good Clinical Practice (ICH GCP), and applicable regulatory requirements (e.g., 
Good Laboratory Practices (GLP), Good Manufacturing Practices (GMP)).  
The investigational site will provide direct access to all trial related sites, source data/documents, 
and reports for the purpose of monitoring and auditing by the sponsor, and inspection by local and 
regulatory authorities. 
13.3 CONFLICT OF INTEREST POLICY 
The independence of this study from any actual or perceived influence, such as by the 
pharmaceutical industry, is critical.  Therefore, any actual conflict of interest of persons who have 
a role in the design, conduct, analysis, publication, or any aspect of this trial will be disclosed and 
managed. Furthermore, persons who have a perceived conflict of interest will be required to have 
such conflicts managed in a way that is appropriate to their participation in the design and conduct 
of this trial.  The study leadership in conjunction with the National Cancer Institute (NCI) has 
established policies and procedures for all study group members to disclose all conflicts of interest 
and will establish a mechanism for the management of all reported dualities of interest. 
13.4 CONFIDENTIALITY AND PRIVACY 
Participant confidentiality and privacy is strictly held in trust by the participating investigators, 
their staff, and the sponsor(s). This confidentiality is extended to cover testing of biological 
samples and genetic tests in addition to the clinical information relating to participants. Therefore, 
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confidence. No information concerning the study or the data will be released to any unauthorized 
third party without prior written approval of the sponsor.  
All research activities will be conducted in as private a setting as possible. 
The study monitor, other authorized representatives of the sponsor, representatives of the 
Institutional Review Board (IRB), and/or regulatory agencies may inspect all documents and 
records required to be maintained by the investigator, including but not limited to, medical records 
(office, clinic, or hospital) and pharmacy records for the participants in this study. The clinical 
study site will permit access to such records. 
The study participant’s contact information will be securely stored at the clinical site for internal 
use during the study. At the end of the study, all records will continue to be kept in a secure location 
for as long a period as dictated by the reviewing IRB, Institutional policies, or sponsor 
requirements. 
Study participant research data, which is for purposes of statistical analysis and scientific reporting, 
will be stored at the Center for Cancer Research (CCR). This will not include the participant’s 
contact or identifying information. Rather, individual participants and their research data will be 
identified by a unique study identification number. The study data entry and study management 
systems used by clinical sites and by CCR research staff will be secured and password protected. 
At the end of the study, all study databases will be archived at CCR. 
To further protect the privacy of study participants, a Certificate of Confidentiality has been issued 
by the National Institutes of Health (NIH).  This certificate protects identifiable research 
information from forced disclosure. It allows the investigator and others who have access to 
research records to refuse to disclose identifying information on research participation in any civil, 
criminal, administrative, legislative, or other proceeding, whether at the federal, state, or local 
level. By protecting researchers and institutions from being compelled to disclose information that 
would identify research participants, Certificates of Confidentiality help achieve the research 
objectives and promote participation in studies by helping assure confidentiality and privacy to 
participants. 
14 PHARMACEUTICAL INFORMATION  
14.1 MVA-BN-BRACHYURY (BB-IND 17851) 
14.1.1 Source  
MVA-BN-Brachyury is an active cancer immunotherapy. This phase I study is being conducted 
under an IND held by the Center for Cancer Research (CCR), National Cancer Institute (NCI). 
Bavarian Nordic, Inc. is the manufacturer of MVA-BN-Brachyury-TRICOM and is a CRADA 
partner. 
14.1.2 Toxicity  
MVA-BN-derived vectors that encode heterologous (non-vaccinia virus) antigens are being 
developed for the treatment of cancer. In GLP studies, MVA-BN and MVA-BN-derived vectors 
have been administered to 5 different animal species, including primates. In addition, MVA-BN 
and MVA-BN-derived vectors have been administered in clinical trials to over 10,500 human 
subjects, including immunodeficient individuals. No marked toxicity and no drug-related serious 
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BN and other MVA-BN-derived vaccines include mild to moderate flu-like symptoms such as: 
fever, chills, muscle or joint ache, and tiredness (fatigue). In addition, some localized reactions at 
the site where the vaccine is injected under skin (subcutaneously). These injection site reactions 
may include any or all of the following: swelling, localized pain, hardness of a small area of skin 
around the injection site induration), and redness. The most common side effects from the use of 
fowlpox vaccines are mild and may include the following: fever, tiredness (fatigue), low red blood 
cell count (anemia), low white blood cell count (leucopenia). In addition, some localized reactions 
at the site where the vaccine is injected under skin (subcutaneously). These injection site reactions 
may include any or all of the following: swelling, localized pain, hardness of a small area of skin 
around the injection site induration), and redness. 
A prior study of MVA-BN-Brachyury performed at the NCI demonstrated minimal toxicity related 
to vaccine. The most common adverse events were injection site reaction and transient flu-like 
symptoms.  
Suspected ADR Reported by >1% of Subjects in the Completed MVA-BN Clinical Trialsa 
(N=8992b) 
Preferred Term (PT) 
No. of reports by subjects 
Frequency % 
Injection site pain 
7370 
82.0% 
Injection site erythema 
5875 
65.3% 
Injection site swelling 
4488 
49.9% 
Injection site induration 
3988 
44.4% 
Injection site pruritus 
3573 
39.7% 
Myalgia 
3017 
33.6% 
Fatigue 
2886 
32.1% 
Headache 
2704 
30.1% 
Nausea 
1316 
14.6% 
Rigors/chills 
842 
9.4% 
Body temperature increased 
269 
3.0% 
Pyrexia 
259 
2.9% 
Injection site nodule 
228 
2.5% 
Appetite disorder 
218 
2.4% 
Arthralgia 
209 
2.3% 
Injection site discolouration 
207 
2.3% 
Pain in extremity 
148 
1.7% 
Injection site haematoma 
107 
1.2% 
Axillary pain 
93 
1.0% 
Injection site warmth 
90 
1.0% 
 
a POX-MVA-001, -002, -004, -005, -006, -007, -008, -009, -010, -011, -013, -023, -024, -027, -028, -029, -030, -
031, -036, -037, -03X, HIV-NEF-004 and HIV-POL-002.  
b Eight subjects exposed but not included in analysis. Seven subjects in POX-MVA-009 received Dryvax either on 
the same day or within 7 days after MVA-BN administration and were therefore not included to avoid a potential 
bias in the AE reporting. One subject in POX-MVA-029 was not vaccinated according to the randomization, 
therefore removed from analysis set.  
Source: MVA-BN IB Edition 25 Table 10 


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14.1.3 Formulation and preparation  
MVA-BN-Brachyury is supplied as a frozen aqueous suspension in 2 mL clear borosilicate glass 
vials. The closure is a sterile bromobutyl rubber stopper, crimped with an aluminum cap and 
covered with a polypropylene closure. Each 0.5mL injection will contain a nominal virus titer of 
2.0 x 108 Inf.U.  
MVA-BN-Brachyury is supplied frozen in single-use vials. Each vial must be thawed at room 
temperature for approximately 5 minutes prior to preparation and should not be re-frozen after 
thawing. The thawed suspension will appear milky and may contain clumps or aggregates. To 
ensure homogeneity, the vial should be swirled gently, but not shaken, for approximately 30 
seconds immediately (within 3 minutes) prior to use. The thawed drug product is to be drawn into 
a syringe with an appropriately sized safety-shielded needle suited to patient comfort (e.g., 22- to 
28-gauge). 
14.1.4 Stability and Storage  
MVA-BN-Brachyury should be stored frozen at -80℃ +/- 10℃ and remain frozen until use. Vials 
should not be refrozen once thawed. 
Once drawn into a syringe, the dose should be stored at 2-8℃ or ambient room temperature until 
administration. Vaccine should be administered within 4 hours of completion of dose preparation 
and should be brought to room temperature prior to administration. 
14.1.5 Administration procedures of MVA-BN-Brachyury 
See Section 3.3.1. 
14.2 FPV-BRACHYURY (BB-IND 17851) 
14.2.1 Source 
FPV-Brachyury is an active cancer immunotherapy. This phase I study is being conducted under 
an IND held by the Center for Cancer Research (CCR), National Cancer Institute (NCI). Bavarian 
Nordic, Inc. is the manufacturer of FPV-Brachyury and is a CRADA partner. 
14.2.2 Toxicity 
Fowlpox-derived vectors that encode heterologous (non-vaccinia virus) antigens are being 
developed for the treatment of cancer. In GLP studies, Fowlpox- -derived vectors have been 
administered to 5 different animal species, including primates. In addition, Fowlpox-derived 
vectors have been administered in clinical trials to over 1000 human subjects. No marked toxicity 
and no drug-related serious AEs have occurred in any of these studies. 
14.2.3 Formulation and Preparation 
One vaccine dose has a nominal virus titer of 1 x 109 Inf.U FPV-Brachyury vaccine in 0.5 mL of 
the drug product. This dose will be used for the boost vaccination of subjects receiving FPV-
Brachyury.  
14.2.4 Stability and Storage 
FPV-Brachyury should be stored frozen at -80°C +/- 10°C and remain frozen until use. Vials 
should not be refrozen once thawed. 


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Once drawn into a syringe, the dose should be stored at 2 - 8℃ or ambient room temperature until 
administration. Vaccine should be administered within 4 hours of completion of dose preparation 
and should be brought to room temperature prior to administration. 
14.2.5 Administration Procedures 
See Section 3.3.1. 
14.2.6 Incompatibilities 
There are no known drug interactions associated with the use of Fowlpox-derived vectors. No 
marked toxicities or serious AEs have been noted in clinical trials conducted with Fowlpox-derived 
vectors 
14.3 M7824 (MSB0011359C, BINTRAFUSP ALFA) (BB-IND 17851) 
14.3.1 Source 
M7824 is manufactured and supplied for the trial by EMD Serono Research and Development 
Institute 
14.3.2 Toxicity 
The immunoglobulin portion of M7824 molecule is identical to avelumab (Bavencio). Respective 
warnings and precautions for grade 2 or higher immune-mediated pneumonitis, immune-mediated 
colitis, immune-mediated endocrinopathies, immune-mediated hepatitis) and infusion reactions 
are included in the prescribing for Bavencio (bavencio.com). Patients will be pre-medicated to 
prophylax against infusion reactions. The following additionally significant immune-mediated 
adverse reactions have occurred in less than 1% of 1738 patients treated with BAVENCIO: 
myocarditis with fatal cases, myositis, psoriasis, arthritis, exfoliative dermatitis, erythema 
multiforme, pemphigoid, hypopituitarism, uveitis, Guillain-Barré syndrome, and systemic 
inflammatory response. The above irAEs are all considered an anticipated risk of treatment with 
M7824 and thus will not be considered DLTs. 
In a phase 1, open-label 3+3 dose-escalation study of M7824 in 16 patients, 3 patients experienced 
grade 3 drug-related adverse events including skin infection secondary to grade 2 bullous 
pemphigoid, lipase increased, and colitis with associated anemia. There were no grade 4 – 5 
treatment related adverse events. Please see table below for details: 
Treatment-related TEAE Leading to Permanent Treatment Discontinuation by System 
Organ Class and Preferred Term in ≥ 2 participants in the Pooled Analysis of Dose 
Expansion Cohorts (Source: Investigator Brochure v6)  


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As of the data cutoff of 24 August 2018, 7 deaths (1.1%) were reported as due to treatment-related 
TEAE, however an additional death (primary cause of intra-abdominal hemorrhage, assessed as 
treatment-related) started more than 30 days after the end of treatment and is therefore is not 
included in above count of treatment-related death. In Study EMR200647-001, 3 participants had 
a treatment-related death: 1 participant had dyspnea, hemolysis and thrombocytopenia, 1 
participant had an intracranial tumor hemorrhage and 1 participant had pneumonia. In Study 
MS200647-0008, 4 participants had a treatment-related death: 2 participants died due to ILD, 1 
participant due to sudden death and 1 participant due to septic shock. Please refer to IB v 6.0 


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Section 5.2.2.9 for a summary of the SAEs from the Sponsor’s Global Drug Safety database from 
25 August 2018 to 31 December 2019 for ongoing studies.   
Important identified risks have been identified as IRRs including hypersensitivity, irAEs including 
immune related pneumonitis, hepatitis, colitis, nephritis and renal dysfunction, endocrinopathies, 
rash, myositis, myocarditis, and encephalitis, and skin lesions with hyperkeratosis, 
keratoacanthoma, cutaneous squamous cell carcinoma possibly due to TGFβ inhibition. The 
important identified risks with bintrafusp alfa observed to date were overall manageable. Anemia, 
alterations in wound healing or repair of tissue damage, and embryofetal toxicity remain as 
important potential risks. Mucosal bleeding events of mild to moderate severity were observed in 
participants treated with bintrafusp alfa in ongoing studies and are a potential risk for bintrafusp 
alfa. Events may include epistaxis, hemoptysis, gingival bleeding or hematuria amongst others. In 
general, these reactions resolve without discontinuation of treatment. The iRAEs Guillain-Barré 
Syndrome, uveitis, pancreatitis and myasthenia gravis/myasthenic syndrome are also important 
potential risks.   
In addition, after discussion among NCI investigators on multiple protocols using M7824, multiple 
bleeding events ranging from low grade gingival bleeding and epistaxis to more serious 
hemoptysis, GI bleeding and hematuria have been observed. Some of these events can be attributed 
to bleeding events related to cancer directly and others bleeding events can be attributed to colitis 
or cystitis which is a known toxicity of anti-PD-L1 agents including M7824. However, there 
remains the possibility that M7824 may increase the overall risk of bleeding in ways that may not 
be directly related to direct tumor bleeding or inflammatory bleeding events described with 
checkpoint inhibitors like M7824. It is hypothesized that this possible increased bleeding risk may 
be due to TGF beta inhibition which has an effect on angiogenesis; bleeding has also been observed 
in patients receiving M7824 and may be drug-related (e.g., gum bleeding, nose bleeds, coughing 
up blood, blood in their urine, or blood in the stool).  Accordingly, patients will be notified of the 
same possible risk in the informed consent document for this study. 
Risk of Rapid Progression:  
The experimental drug M7824 is similar to immune check point inhibitors. There are preliminary 
data to suggest that not all patients benefit from immune check point inhibitors nor M7824. 
Additionally, there are preliminary data to suggest that an unexpectedly rapid progression of 
disease occurs in some patients receiving immunotherapy such as immune checkpoint inhibitors. 
14.3.2.1 Risk for cutaneous keratocanthoma/squamous cell carcinoma with administration of 
M7824 
All cases of skin lesions suspicious for the above will be referred to Dermatology at the NIH. 
Patients wills then undergo routine follow-up skin exams and treatment as deemed appropriate 
by the Dermatologist. 
14.3.3 Formulation and Preparation 
M7824 is provided as a sterile liquid formulation and packaged at a 10 mg/mL concentration in 
USP/ Ph Eur type I 50R vials that are filled with drug product solution to allow an extractable 
volume of 60 mL (600 mg/60 mL). The vials are closed with rubber stoppers in serum format 
complying with USP and Ph Eur with an aluminum crimp seal closure. Each single-use vial 
contains 600mg of M7824, formulated as 10mg/mL of active, 6% (w/v) Trehalose, 40 mM NaCl, 
5 mM Methionine, 0.05% (w/v) Tween 20, 10 mM LHistidine at pH 5.5.  


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The liquid formulation is diluted directly with 0.9% sodium chloride solution for injection. The 
estimated volumes of delivery are anticipated to be no more than 250mL. The verified 
concentration range in the infusion solution is 0.16 mg/mL to 9.6 mg/mL.  
14.3.4 Stability and storage 
M7824 must be stored at 2℃ to 8℃ until use. Product stored at room temperature for extended 
periods of time might be subject to degradation. M7824 must not be frozen. Rough shaking of the 
reconstituted solution must be avoided.  
The chemical and physical in-use stability for the infusion solution of M7824 in 0.9% sodium 
chloride for injection has been demonstrated for a total of 72 hours at room temperature; however, 
from a microbiological point of view, the diluted solution should be used immediately and is not 
intended to be stored unless dilution has taken place in controlled and validated aseptic conditions. 
No other drugs should be added to the infusion containers containing M7824. See Manual of 
Preparation of approved ancillary supplies.  
14.3.5 Administration procedures 
See section 3.3.3.  
14.4 N-803, FORMERLY ALT-803 (BB-IND 17851) 
14.4.1 Source 
N 803 is manufactured and supplied by Immunity Bio.  
14.4.2 Toxicity 
The most common toxicities (≥20%) of N-803 include, but may not be limited to, fatigue, fever, 
rigors, headache, hyper- and hypotension, injection-site reactions, laboratory abnormalities – such 
as hypoalbunemia and associated symptoms, and pain (e.g., back pain).  Less common toxicities 
that may be serious include neutropenia and cardiac toxicities (e.g., atrial fibrillation).   
14.4.3 Formulation and preparation 
N-803 is a soluble complex consisting of two protein subunits of a human IL-15 variant associated 
with high affinity to a dimeric human IL-15 receptor α (IL-15Rα) sushi domain/human IgG1 Fc 
fusion protein. The IL-15 variant is a 114 aa polypeptide comprising the mature human IL-15 
cytokine sequence with an Asn to Asp substitution at position 72 of helix C (N72D). The human 
IL-15Rα sushi domain/human IgG1 Fc fusion protein comprises the sushi domain of the human 
IL-15 receptor α subunit (IL-15Rα) (aa 1-65 of the mature human IL-15Rα protein) linked with 
the human IgG1 CH2-CH3 region containing the Fc domain (232 amino acids). Aside from the 
N72D substitution, all of the protein sequences are human. Based on the amino acid sequence of 
the subunits, calculated molecular weight of complex comprising two IL-15N72D polypeptides 
and a disulfide linked homodimeric IL-15RαSu/IgG1 Fc protein is 92.4 kilodaltons (kDa). Each 
IL-15N72D polypeptide has a calculated molecular weight of approximately 12.8 kDa and the IL-
15RαSu/IgG1 Fc fusion protein has a calculated molecular weight of approximately 33.4 kDa. 
Both the IL-15N72D and IL-15RαSu/IgG1 Fc proteins are glycosylated resulting in an apparent 
molecular weight of N-803 as approximately 113 kDa by size exclusion chromatography. The 
isoelectric point (pI) determined for N-803 ranges from approximately 5.5 to 6.5. Thus, the fusion 
protein is negatively charged at pH 7. The calculated molar extinction coefficient at A280 for N-


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803 is 116,540 M-1, or 1.26 OD280 for a 1 mg/mL solution of N-803, or one OD280 is equivalent 
to 0.79 mg/mL solution of N-803.  
The biological drug product, N-803, is formulated in a phosphate buffered saline solution. The 
drug substance is produced by a recombinant mammalian cell line and is manufactured using 
protein-free media. 
14.4.4 N-803 is supplied at a concentration of 2 mg/mL and is administered undiluted 
subcutaneously. Stability and storage 
Study medication is provided in a 2mL vial containing 0.6 mL of ALT 803 at a concentration of 2 
mg/mL. Intact vials are stored at a temperature between 2℃ and 8℃. The duration of time during 
which the product remains stable at room temperature will be obtained from Immunity Bio. 
14.4.5 Administration procedures 
N-803 is administered subcutaneously. See section 3.3.4 
14.5 EPACADOSTAT 
14.5.1 Source 
Epacadostat is manufactured and supplied by Incyte 
14.5.2 Toxicity 
As monotherapy, epacadostat was generally well tolerated in subjects with refractory solid tumors 
at doses of up to 700 mg BID, and there appeared to be no correlation of dose with toxicity. Of the 
52 subjects who were administered epacadostat, the median duration of treatment was 51.5 days. 
Eight subjects (15.4%) had an AE leading to death; of these 8 subjects, the cause of death was 
disease progression for 7 subjects and hypoxia for the remaining subject. Twenty-five subjects 
(48.1%) had an SAE during the study. Serious adverse events were observed in all 8 treatment 
groups. The most frequently reported SAE was disease progression (4 subjects, 7.7%), followed 
by abdominal pain, nausea, and hypoxia (3 subjects each, 5.8%). Treatment-emergent AEs were 
reported in all subjects. Fatigue was the most frequently reported treatment-emergent AE (36 
subjects, 69.2%). In INCB 24360-101, a phase I study of epacadostat, the majority of subjects 
(90.4%) had treatment-related AEs. Fatigue and nausea were the most frequently reported 
treatment-emergent AEs (25 subjects each, 48.1%). The incidence and severity of fatigue were not 
dose related. Thirty subjects (57.7%) had treatment-emergent AEs ≥ Grade 3 in severity and 7 
subjects (13.5%) had a treatment-emergent AE leading to discontinuation of study drug and 
withdrawal from the study. Two DLTs occurred; 1 DLT of radiation pneumonitis at the300 mg 
BID dose level and 1 DLT of fatigue at the 400 mg BID dose level. An MTD was not determined. 
There were no clinically meaningful changes or trends noted in clinical hematology, chemistry, or 
urinalysis results or for vital signs, ECGs, or physical examinations. 
14.5.2.1 Adverse Drug Reactions from Epacadostat IB v 13 
The following  represents Adverse Drug Reactions (ADRs) observed in clinical studies of 
epacadostat as of 29 OCT 2020. There were no suspected SARs that occurred only once or 
fatal/life-threatening. SARs that are considered unexpected and not included in the RSI. Please 
refer to Section 7.5.1 of IB v 13.0 for additional information.  
Adverse drug reactions in participants treated with epacadostat monotherapy (N = 216)  


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 Very common:  nausea and vomiting  
 Common:  rash maculo-papular  
Adverse drug reactions that are new or occurred at a greater frequency or severity than was 
seen in each monotherapy drug in participants treated with epacadostat + pembrolizumab, 
epacadostat + nivolumab, epacadostat + durvalumab, epacadostat + atezolizumab 
(combinations with anti-PD-1/L1 monoclonal antibodies) (N = 1607)  
 Very common:  fatigue, nausea, diarrhea, rash, vomiting, pyrexia, abdominal pain, 
aspartate aminotransferase increased, alanine aminotransferase increased, and asthenia 
 Common:  rash maculo-papular, myalgia, pneumonia, pneumonitis, colitis, and adrenal 
insufficiency 
 Uncommon:  autoimmune hepatitis, drug sensitivity, meningitis aseptic, drug reaction 
with eosinophilia and systemic symptoms, and immune-mediated hepatitis 
Adverse drug reactions that are new or occurred at a greater frequency or severity than was 
seen in each monotherapy drug in participants treated with epacadostat + pembrolizumab 
+ chemotherapy, epacadostat + nivolumab + chemotherapy (combinations with anti-PD-1 
monoclonal antibodies and chemotherapy) (N = 241)  
 Very common:  nausea, vomiting, and rash 
A portion of the M7824 construct is an anti-PD-L1 monoclonal antibody. The table below contains 
a list of AEs considered suspected to be adverse drug reactions observed in patients receiving 
epacadostat in combination with anti−PD-L1 targeted therapy (atezolizumab or durvalumab). 
 


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Serotonin Syndrome 
There is a potential concern that epacadostat could cause an increase in serotonin levels in the brain 
that might trigger serotonin syndrome, when administered alone or in combination with other 
serotonergic agents. This rare syndrome has been associated with some MAOIs and combinations of 
serotonergic drugs[59]. The clinical manifestations of serotonin syndrome range from barely 
perceptible to lethal. Nonclinical data suggest that serotonin syndrome is unlikely following treatment 
with either epacadostat alone or in combination with MAOIs such as linezolid [66].  
As of 29 OCT 2019, 5 participants treated across the epacadostat program have had events reported 
as serotonin syndrome or symptoms of serotonin syndrome; episodes were confounded, mild or 
moderate in severity, and resolved (3 of 5 resolved without further incidents after dose interruption 
while the other 2 resolved following study treatment discontinuation). Two of the 5 participants 
had an event of serotonin syndrome that was reported as a serious event by the investigator. These 
AEs were not clinically substantiated by the sponsor to represent true events of serotonin 
syndrome.  


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The incidence of serotonin syndrome or symptoms of serotonin syndrome is rare. Participants may 
be provided with an informative simplified card describing the potential signs and potential 
symptoms of serotonin syndrome, along with instructions to seek immediate medical care if any 
of these signs or symptoms are observed. A neurology consult is recommended to diagnose or 
confirm serotonin syndrome or to rule out other etiologies.  
The clinical manifestations of SS range from barely perceptible to lethal. Symptom onset is usually 
rapid (within 12 hours of administration) and encompasses a wide range of clinical findings. 
 Mild symptoms may only consist of increased heart rate, shivering, sweating, dilated 
pupils, myoclonus, as well as over-responsive reflexes. 
 Moderate symptoms include additional abnormalities such as hyperactive bowel sounds, 
high blood pressure, and hyperthermia; a temperature as high as 40°C (104°F) is common 
in moderate intoxication. Mental status changes include hypervigilance and agitation. 
 Severe symptoms include severe increases in heart rate and blood pressure that may lead 
to shock. Temperature may rise to above 41.1°C (106.0°F) in life-threatening cases. 
Other abnormalities include metabolic acidosis, rhabdomyolysis, seizures, renal failure, and 
disseminated intravascular coagulation; these effects usually arise as a consequence of 
hyperthermia.  
There is no laboratory test for SS; therefore, diagnosis is by symptom observation. Management 
is based primarily on stopping the usage of the precipitating drugs, the administration of serotonin 
antagonists such as cyproheptadine, and supportive care including the control of agitation, the 
control of autonomic instability, and the control of hyperthermia. Additionally, those who ingest 
large doses of serotonergic agents may benefit from gastrointestinal decontamination with 
activated charcoal if it can be administered within an hour of overdose. The intensity of therapy 
depends on the severity of symptoms. If the symptoms are mild, treatment may only consist of 
discontinuation of the offending medication or medications, offering supportive measures, giving 
benzodiazepines for myoclonus, and waiting for the symptoms to resolve. Moderate cases should 
have all thermal and cardiorespiratory abnormalities corrected and can benefit from serotonin 
antagonists. The serotonin antagonist cyproheptadine is the recommended initial therapy. 
Additional pharmacological treatment for severe cases includes administering atypical 
antipsychotic drugs with serotonin antagonist activity such as olanzapine. Critically ill patients 
should receive the above therapies as well as sedation or neuromuscular paralysis. Patients who 
have autonomic instability such as low blood pressure require treatment with direct-acting 
sympathomimetics such as epinephrine, norepinephrine, or phenylephrine. Conversely, 
hypertension or tachycardia can be treated with short-acting antihypertensive drugs such as 
nitroprusside or esmolol; longer acting drugs such as propranolol should be avoided as they may 
lead to hypotension and shock. Based on preliminary studies in the rat, concentrations of 
epacadostat in the cerebrospinal fluid were below the quantifiable limit of detection (2 nM) after 
IV administration, and total brain homogenate concentrations were approximately 15% of 
corresponding plasma concentrations. Therefore, epacadostat exhibits apparent limited penetration 
across the blood brain barrier and is likely not associated with significant effects on Trp 
metabolism in the brain that might impact brain serotonin levels. Although this represents a 
theoretical risk only, use of MAO inhibitors will be prohibited in patients receiving epacadostat. 


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14.5.3 Formulation and preparation 
The chemical name of epacadostat is (Z)-N-(3-bromo-4-fluorophenyl)-N'-hydroxy-4-(2-
(sulfamoylamino)ethylamino)-1,2,5-oxadiazole-3-carboximidamide. Epacadostat has a molecular 
formula of C11H13BrFN7O4S and a molecular weight of 438.23  
Epacadostat is formulated as an immediate release tablet in 25mg, 100mg  and 300mg. However, 
only the 100mg and 300mg tablets are anticipated to be used in this trial. The tablets contain the 
active drug (epacadostat) along with commonly used compendial excipients (lactose monohydrate, 
microcrystalline cellulose, povidone, croscarmellose sodium, colloidal silicon dioxide, magnesium 
stearate). 
14.5.4 Storage 
Epacadostat drug product should be stored at ambient conditions (15°C- 30°C). 
14.5.5 Administration procedures 
Epacadostat is to be administered by mouth. See section 3.3.5. 
 
 


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15.2 APPENDIX B: N-803 INJECTION SITE REACTION DIARY 
 
 
 


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15.3 APPENDIX C PATIENT’S MEDICATION DIARY ________________________ 
Cycle___________________ 
Participant’s ID ___________________ 
INSTRUCTIONS TO THE PARTICIPANT: 
 
Complete one form for each cycle of treatment 
 
You will take Epacadostat _________mg twice a day. You should take the tablets with food at 
approximately the same time each day. 
 
Dose: ____________ 
 
Record the date, the number of tablets that you took, and when you took them. 
 
If you have any comments or notice any side effects, please record them in the comments column. 
 
Please bring this form and your bottles of Epacadostat when you come for your clinic visits. 
Day 
Date 
Time of 
AM 
Dose 
# of Tablets 
Taken 
 
Time of 
PM 
Dose 
# of Tablets 
Taken  
Comments 
1 
 
 
 
 
 
 
 
 
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3 
 
 
 
 
 
 
 
 
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5 
 
 
 
 
 
 
 
 
6 
 
 
 
 
 
 
 
 
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Participant’s signature:  ___________________________________________________


Abbreviated Title: QuEST1 
Version Date:05/17/2024 
 
101 
15.4 APPENDIX D: UDP GLUCURONOSYLTRANSFERASE (UGT1A9) INHIBITORS 
Below is a list of known UDP-glucuronosyltransferase UGT1A9 inhibitors that are prohibited 
during the concurrent use of epacadostat at doses > 300mg BID. UGT1A9 inhibitors not on the 
list below should be discussed with the medical monitor before use. 
acitretin, amitriptyline, androsterone, cyclosporine, dasatinib, diclofenac, diflunisal, efavirenz, 
erlotinib, flutamide, gefitinib, gemfibrozil, glycyrrhetinic acid glycyrrhizin, imatinib, 
imipramine, ketoconazole (systemic), mycophenolic acid, niflumic acid, nilotinib, phenobarbital, 
phenylbutazone, phenytoin, probenecid, quinidine, ritonavir, sorafenib, sulfinpyrazone, valproic 
acid, and verapamil. 
 
 
 
 
 
 
 
 
 


Abbreviated Title: QuEST1 
Version Date:05/17/2024 
 
102 
15.5 APPENDIX E: OATP1BI & 1B3 TRANSPORTERS AND CYP1A2, CYP2C8 AND CYP2C19 
SUBSTRATES 
Due to the potential concern for epacadostat metabolite inhibition of CYP1A2, CYP2C8 
and CYP2C19, OATP1B1 and OATP1B3 transporters with doses of epacadostat greater 
than 300 mg BID (eg 400 mg BID or 600 mg BID), the below medications will be 
prohibited immediately for concomitant use. 
 
Participants should seek alternatives that are not in the class. If alternatives cannot be found you 
may contact the medical monitor to discuss if enrollment is appropriate. 
 
OATP1B1 & 
1B3 
Transporters
CYP1A2 
Substrates 
CYP2C8 
Substrates 
CYP2C19 
Substrates 
 atorvastatin 
 bosentan 
 cerivastatin 
 danoprevir 
 docetaxelb 
 fexofenadine 
 glyburide 
 nateglinide 
 
paclitaxelb 
 repaglinide 
 pitavastatin 
 pravastatin 
 rosuvastatin 
 simvastatin acid
 fimasartan 
 glecaprevir 
 maraviroc 
 tacrolimus 
 voxilaprevir 
Sensitive: 
 alosetron 
 caffeinea 
 duloxetine 
 melatonin 
 pirfenidone 
 ramelteon 
 selegiline 
 tacrine 
 tasimelteon 
 theophylline 
 tizanidine 
 
Sensitive: 
 repaglinide 
 daprodustat 
 dasabuvir 
 montelukast 
 pioglitazone 
 rosiglitazone 
Sensitive: 
 s-mephenytoin 
 lansoprazole 
 omeprazole 
 tilidine 
 pantoprazole 
 hexobarbital 
 diazepam 
 gliclazide 
 rabeprazole 
 voriconazole 
 proguanil 
 
a An epacadostat metabolite is a moderate in vitro inhibitor of CYP1A2, thus it is recommended 
to avoid or limit caffeine consumption (e.g., no more than 1 cup of coffee or 2-3 soft drinks 
per day) 
b Docetaxel and paclitaxel as part of combination therapy with epacadostat at doses < 600 
mg BID are permitted. 
 
 
 

ICF_001.pdf: 


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date:  05/17/2024 
Page 2 of 21
CC ICF template v. 09.27.19
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
BN-brachyury, M7824, N-803 and Epacadostat are all investigational (have not been approved by 
the FDA) immunotherapy drugs. 
Generally, these treatments are all thought to help the body’s immune system fight cancer in 
different ways. 
M7824 can attach to many different types of cells in the body.  When it is attached to cancer, it 
can make it easier for your immune system to destroy the cancer. When attached to immune cells, 
it can increase the body’s immune response. M7824 has not been used to treat your type of cancer 
before, therefore we do not know whether or not it will work. M7824 has been tried in other types 
cancers. Recently, the manufacturer of the drug closed 3 large studies because the drug was shown 
not to help those patients more than standard therapies. In addition, in some cases it seemed like 
the drug might make the cancer grow faster. However, the type of cancer treated in those studies 
was not the same as your cancer.
N-803 can supercharge different types of immune cells that kill tumor cells. It can also increase 
the numbers of these cancer-fighting cells.
BN-Brachyury is cancer vaccine designed to create immune cells that can recognize and kill 
certain types of cancer.
Cancer can create chemicals within the body that make it more difficult for the immune system to 
attack cancer. Epacadostat is a drug that blocks production of those chemicals. 
In this study, we will investigate the safety of using BN-brachyury, M7824, N-803 and Epacadostat 
given in different combinations and whether this combined treatment will cause your tumors to 
shrink. 
This study has two parts: a phase I and a phase II. In phase I, we are going to evaluate the safety 
of using M7824 in combination with N-803. Increasing doses of N-803 will be given to patients 
in the study to find the highest dose of N-803 that people can tolerate when given in combination 
with M7824. 
In phase II we will first evaluate safety of different combination of drugs: BN-brachyury + M7824, 
BN-brachyury + M7824 + N-803, BN-brachyury + M7824 + N-803 + Epacadostat. If safe, these 
combinations will be further evaluated to find a combination which will be the most effective in 
making your tumors shrink.
WHY ARE YOU BEING ASKED TO TAKE PART IN THIS STUDY?
You are being asked to take part in this research study because your prostate cancer has spread to 
other parts of your body, and your disease is no longer responding to hormonal therapy or you 
have a different type of cancer that has metastasized to other parts of your body.
HOW MANY PEOPLE WILL TAKE PART IN THIS STUDY? 
Up to 113 subjects will take part in this study. Approximately 18 participants will be enrolled in 
the phase I part and approximately 75 participants will be enrolled in the phase II part. 
IRB NUMBER: 18C0078
IRB EFFECTIVE DATE: 6/25/2024


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date:  05/17/2024 
Page 3 of 21
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MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
DESCRIPTION OF RESEARCH STUDY
For your safety, some medications and therapies are not allowed during the study. You should tell 
the study doctor before you take any new medications (includes prescription, herbal, and over-the-
counter remedies) or start a new therapy during the study. Please notify the study doctor if you are 
not willing to have a blood transfusion or receive blood products. 
If you agree to take part and have signed the informed consent form, you will undergo screening 
tests and procedures to see if you qualify for the study. This is known as the Screening Period.  
These tests and procedures may be done prior to signing this consent.   Not everyone who wants 
to be in the study will be able to join. 
Before you begin the study
Before you begin this study, you will need to have the following exams and tests during the 
screening period to make sure you are eligible for this study. The exams and tests are part of regular 
cancer care. If you have had some of the tests recently, they may not need to be repeated. If you 
are not eligible, you will not be able to participate in the study. 

A review of any past or current medical conditions, medicines you are taking and cancer 
history.

Physical examination, including height, weight, and vital signs.

Review of your symptoms and your ability to perform your normal activities.

Imaging Assessments – either a CT (a series of x-ray images taken of parts of your body) 
or if you cannot have a CT scan, MRI (magnetic testing, which does not involve any 
radiation).. These will be used to examine your chest, abdomen and pelvis. If your doctor 
thinks this is needed, you might have additional imaging of your bones. A bone scan is an 
imaging test that helps detect cancer that has spread (metastasized) to the bone.  
o
Magnetic resonance imaging (MRI) is an alternative to CT scan that is used in some 
situations. MRI is safe and does not cause any side effects. MRI uses a strong 
magnetic field and radio waves to take pictures of your body. The MRI scanner is 
a metal cylinder surrounded by a strong magnetic field. During the MRI, you will 
lie on a table that can slide in and out of the cylinder. We will place soft padding or 
a coil around your head. You will be in the scanner about 30 minutes. You may be 
asked to lie still for up to 30 minutes at a time. While in the scanner you will hear 
loud knocking noises, and you will be fitted with earplugs or earmuffs to muffle 
the sound. You will be able to communicate with the MRI staff at all times during 
your scan, and you may ask to be moved out of the machine at any time. 

You will have about 1 tablespoon of blood drawn for:
o
routine blood tests to find out if you have low blood counts, and if your liver, kidneys, 
and other organs are working well
o
tests for HIV, Hepatitis B and Hepatitis C
IRB NUMBER: 18C0078
IRB EFFECTIVE DATE: 6/25/2024


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date:  05/17/2024 
Page 4 of 21
CC ICF template v. 09.27.19
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
o
PSA and Testosterone level 

Routine urinalysis

You will be asked to provide confirmation of your diagnosis. 

EKG: a test that is performed while you lie still for about 5 minutes.  It involves placing 
electrodes (small stickers that are attached to wires that go to the machine) on the chest and 
arms/legs and recording the electrical activity of your heart 
HIV, Hepatitis B, and Hepatitis C Testing
As part of this study, we will test you for infection with the human immunodeficiency virus (HIV), 
the virus that causes AIDS and Hepatitis B and C.  If you are infected with HIV, Hepatitis B or C 
you will not be able to participate in this study.  We will tell you what the results mean, how to 
find care, how to avoid infecting others, how we report HIV infection, and the importance of 
informing your partners at possible risk because of your infection.
During the study
Depending on time when you are entering the study, you will have treatment combination of two, 
three or four drugs: M7824 + N-803, BN-brachyury + M7824, BN-brachyury + M7824 + N-803 
or BN-brachyury + M7824 + N-803 + Epacadostat.
You will be treated with combination of drugs until your disease gets worse. The treatment might 
be interrupted prematurely if you have unacceptable side effects or if in the opinion of the 
Investigator your disease worsened to the point when these drugs do not help you anymore.
If you cannot tolerate treatment of combination you receive, or if your disease gets worse, you will 
not get another combination and will be taken off all treatments on this protocol. 
For all Participants:
M7824 will be administered to you through an IV (intravenous catheter, a small plastic tube that 
is put into a vein, usually in your arm) once every 2 weeks (2 weeks = 1 Cycle).  This is given to 
you as an outpatient. 
N-803 will be administered to you as a single subcutaneous injection once every 2 weeks (2 weeks 
= 1 Cycle). You will be given an Injection Site Reaction Diary to complete for each cycle. In the 
diary, you will be asked to record any skin changes at the injection site. Please bring the diary with 
you at every study visit.
BN-brachyury will be administered to you as four subcutaneous injections to different limbs. Two 
priming doses will be administered 2 weeks apart, Day 1 of Cycle 1 and Day 1 of Cycle 2 (2 weeks 
= 1 Cycle). Two weeks later, the first booster dose will be administered, then every 4 weeks for 6 
months, then every 3 months until reaching 2 years. After 2 years you will receive the injections 
every 6 months. 
Only for Participants who will receive Epacadostat:
Epacadostat is a pill that you will take by mouth every 12 hours. You do not need to take it with 
food, but you can if you want to.  If you need to take your Epacadostat earlier than scheduled or 
IRB NUMBER: 18C0078
IRB EFFECTIVE DATE: 6/25/2024


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date:  05/17/2024 
Page 5 of 21
CC ICF template v. 09.27.19
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
you missed the dose, you can take it up to 4 hours before or after the scheduled time. If more than 
4 hours have passed, skip the dose and take your next scheduled dose. You will be given a Patient’s 
Diary to complete for each cycle. In the diary, you will be asked to record the date, time you took 
the dose and any doses you may have missed. Please bring the diary with you at every study visit. 
Since the drug Epacadostat can interact with other medicines, we will check what other 
medications you are taking. Rarely and if it is safe, you will be asked by your doctor to stop a 
medicine that may interact with Epacadostat. 
Tests that you will have before you start the treatment

Electrocardiogram (EKG – a record of your heartbeat) to evaluate your heart

CT scan of bones if necessary 

Blood tests (about 3 teaspoons):
o
Blood test to check your HLA status (only if you do not have results of this test 
performed any time before this treatment) 
o
Blood test to check your endocrine organs (organs that make hormones). These 
tests will be done in the morning hours (7-9 am) and after fasting for at least 8 
hours. 
Ongoing Procedures before treatment on the first day of each cycle 

Physical exam and vital signs 

Review of your symptoms and your ability to perform your normal activities

Blood Tests (about 1 tablespoon at any visit):
o
Routine blood tests to find out if you have low blood counts, the status of your 
immune system, and if your liver, thyroid, kidneys, and other organs are working 
well. 
o
PSA and testosterone blood test – (every 4 weeks)
o
Blood test to check your organs that make hormones (every 4 weeks starting at 
cycle 4). These tests will be done in the morning hours (7-9 am) and after fasting 
for at least 8 hours. If your test was positive before you started the treatment, you 
will not be tested again. 

Routine urinalysis
Additional Procedures and Visits

During cycles 1 and 2 you will need to come for additional safety visits on day 8 for:
Physical exam and vital signs 
Review of your symptoms and your ability to perform your normal activities
Routine blood tests (about 1.5 teaspoons) to find out if you have low blood counts, the 
status of your immune system, and if your liver, thyroid, kidneys, and other organs are 
working well.
IRB NUMBER: 18C0078
IRB EFFECTIVE DATE: 6/25/2024


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date:  05/17/2024 
Page 6 of 21
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MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
EKG every 12 weeks to check your heart if you are receiving Epacadostat.

Imaging Assessments – a CT scan or if you cannot have a CT scan, an MRI, of chest, 
abdomen and pelvis and a bone scan– every 12 weeks depending on your response to the 
treatment). 
Additional Research tests
In addition to the tests that we will conduct to determine whether you are having side effects or if 
you are responding to the study therapy, we will also collect blood samples from you for purposes 
of research only. About 6-8 tablespoons of blood may be collected at any visit. Some of your 
samples will be sent outside of the NIH for testing, but any information that can be used to identify 
you will be removed before we send them. 

To measure drug level in your blood, we will collect samples before and immediately after 
M7824 infusion on Day 1 of cycles 1 and 3. We will also collect a sample before the 
infusion on Day 1 of cycles 2, 6, and at the time you finish taking the drugs. Additional 
samples may be collected every 12 weeks after cycle 6. 

To study the effects of therapy on your immune system we will collect samples before 
treatment on Day 1 of cycles 1, 2, 3, 6, 12 and at the time you finish taking the drugs. 
Additional samples may be collected every 12 weeks after cycle 12. 

If you are treated with Epacadostat, we will collect blood samples before Epacadostat on 
Day 1 of cycle 1 and before and 2 hours after Epacadostat treatment on Day 8 of Cycle 2. 
We will ask you to fast for 8 hours before these samplings. 
When you are finished taking the drugs
About 4 – 5 weeks after you have finished taking the study drug, you will be asked to return for a 
safety follow up visit. At this visit, you will be asked questions about your health, get a physical 
exam, and undergo blood tests. 
If your disease did not get worse, but you finished taking drugs for any other reasons, we will 
invite you for imaging studies every 3 months. If you are unable to return for these visits, we will 
call you to ask about your health and any side effects you may have. You will not be scanned if 
you start new study therapy.
BIRTH CONTROL
If you are the partner of a woman who can become pregnant, you or your partner will need to 
practice an effective form of birth control before you start study treatment, during study treatment, 
and for 4 months after the last drug infusion. If you think that your partner is pregnant, you should 
tell your study doctor or nurse at once. 
Effective forms of birth control include: 
•
abstinence 

intrauterine device (IUD)
IRB NUMBER: 18C0078
IRB EFFECTIVE DATE: 6/25/2024


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date:  05/17/2024 
Page 7 of 21
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MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
•
hormonal [birth control pills, injections, or implants]
•
tubal ligation
•
condoms
•
vasectomy
RISKS OR DISCOMFORTS OF PARTICIPATION
If you choose to take part in this study, there is a risk that:

You may lose time at work or home and spend more time in the hospital or doctor’s office 
than usual

You may be asked sensitive or private questions which you normally do not discuss
Drugs used in this study may affect how different parts of your body work such as your liver, 
kidneys, heart, and blood. The study doctor will be testing your blood and will let you know if 
changes occur that may affect your health.
There is also a risk that you could have side effects from the study drugs. 
Here are important points about side effects:

The study doctors do not know who will or will not have side effects.

Some side effects may go away soon, some may last a long time, or some may never go 
away.

Some side effects may interfere with your ability to have children.

Some side effects may be serious and may even result in death.
Here are important points about how you and the study doctor can make side effects less of a 
problem:

Tell the study doctor if you notice or feel anything different so they can see if you are 
having any symptoms.

The study doctor may be able to treat some side effects.

The study doctor may adjust the study drugs to try to reduce side effects.
Late side effects of the investigational agents may affect your ability to tolerate subsequent 
regimens of standard of care chemotherapy.
Below we show the most common and the most serious side effects that researchers know about. 
There might be other side effects that researchers do not yet know about. If important new side 
effects are found, the study doctor will discuss these with you.
Risks from study therapy
Note: There are treatments for the side effects listed below, and these treatments can often ease 
side effects. If you experience any of these side effects, treatment will be provided for you.
IRB NUMBER: 18C0078
IRB EFFECTIVE DATE: 6/25/2024


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date:  05/17/2024 
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MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
As a side effect of this experimental therapy, the immune system may target normal tissue. Normal 
endocrine organs (organs that make hormones) may not work as well leading to tiredness (from 
low thyroid hormones or adrenal hormones). This may need to be treated by replacement hormones 
(pills). We will monitor the hormone levels in your blood during the treatment.
M7824
Likely
Less Likely

Fatigue (tiredness or lack of energy) 

Nausea 

Diarrhea

Constipation

Vomiting

Swelling of your lower legs or hands

Fever

Decreased appetite

Loss of body fluids (dehydration)

Skin growths called keratoacanthomas. 
These appear as small bumps and have 
the potential to turn into squamous cell 
carcinoma skin cancer gradually over 
time. We work with a dermatologist at 
the 
NIH. 
If 
you 
develop 
a 
keratoacanthoma while on this study, 
we will make every attempt to prevent 
progression to skin cancer. The 
dermatologist 
will 
monitor 
you 
regularly and can remove these lesions 
if indicated.

Rash, blisters, skin discoloration and 
other skin abnormalities

Bleeding from various organs. This can 
include nosebleeds, bleeding from your 
gums, blood in your urine, stool, etc. 
This bleeding can be life threatening 
and require you to receive a blood 
transfusion. If you experience any 
bleeding please tell the study team 
immediately.  Tell your doctor if 

Chills (feeling cold)

Blood clots that form throughout the 
body, blocking small blood vessels. 
Symptoms may include chest pain, 
shortness of breath, leg pain, problems 
speaking, or problems moving parts of 
the body

Easy bruising

Reaction to other drugs such as rash, 
anaphylaxis, and changes in blood

Infusion-related reaction, including 
dizziness or fainting (low blood 
pressure), 
flushing, 
rash, 
fever, 
shortness of breath or sick to your 
stomach, or pain at the site of infusion

Back pain

Cancerous growth on the skin that can 
be removed

Stroke

Slow wound healing. If you are having 
surgery, please discuss with your 
doctor.

Thickening of the skin, nails 
IRB NUMBER: 18C0078
IRB EFFECTIVE DATE: 6/25/2024


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date:  05/17/2024 
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MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
you've had a life-long problem of 
frequent or excessive bleeding or 
bruising, or if you take aspirin or 
prescription medication to thin your 
blood.

Shortness of breath

Cough

Anemia- low number of red blood cells 
that can cause tiredness and shortness 
of breath. May require a transfusion

Abdominal pain

Headache

Itching
Allergic reactions or reactions in the context with the infusions might occur during treatment. 
Although M7824 is a fully human protein the risk cannot be completely excluded. In general, these 
reactions are mild to moderate and can be handled with appropriate drugs, but in very rare cases 
severe to life-threatening and even fatal reactions might occur, which require advanced cardiac life 
support. 
In addition to the above, we have seen a few cases of nodular regenerative hyperplasia. This is 
when small growths, or nodules, occur in the liver. These usually do not cause symptoms, but can 
occasionally be associated with high blood pressure in the vein to the liver which could over time 
lead to liver damage.
In addition, immune-mediated side effects might be possible. These side effects are caused by over 
activity of your body’s immune system. The immune system normally works to protect you from 
things that are harmful such as infections, foreign substances, and sometimes from cancer. If the 
immune system is overactive, it can attack normal parts of the body because it mistakenly 
recognizes them as foreign/harmful.
Examples of these side effects are listed below. In rare cases, immune-related side effects can be 
life-threatening or fatal.

joint pain

arthritis (inflammatory disease of the joint)

pneumonitis (inflammatory disease of the lung): symptoms may include but are not limited 
to a new or worsening cough, shortness of breath possibly with fever. Preliminary data 
suggested that there may be the tendency of higher frequency and severity in Japanese 
patients compared with non-Japanese patients: tell your study doctor right away if you have 
any of these symptoms as it may need to be treated urgently

hypothyroidism (decreased function of the thyroid gland)

hyperthyroidism (increased function of thyroid gland)
IRB NUMBER: 18C0078
IRB EFFECTIVE DATE: 6/25/2024


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
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CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY

thyroiditis (inflammatory disease of the thyroid gland)

autoimmune hepatitis (inflammatory disease of the liver caused by the body’s immune 
system): Signs and symptoms of this include yellowing of the skin or whites of the eyes, 
dark urine, severe nausea and vomiting, pain in the upper right side of your abdomen, skin 
itchiness, not feeling hungry and bleeding or bruising more easily than normal

thrombocytopenia (decrease of the blood platelets)

inflammatory eye disease (Uveitis)

diabetes mellitus (high blood sugar levels)

decreased function of the adrenal glands or other glands that produce important hormones. 
This may cause stomach pains, vomiting, muscle weakness and fatigue, depression, low 
blood pressure, weight loss, kidney problems, and changes in mood and personality. These 
complications may be permanent and may require hormone replacement. If this occurs, 
medication can effectively treat this.
o
Since this  condition could occur months after receiving immunotherapy, it is 
important that you tell your outside doctor that  you were on an  immunotherapy if 
you experience decreased energy, headaches, persistent nausea/vomiting, or 
dizziness after you are done with your NIH follow up  period.

inflammatory disease of muscles characterized by pain and tenderness

colitis (inflammatory disease of the large intestine): It may cause abdominal pain and 
diarrhea with or without blood. Fever may be present. It may require you to receive 
additional fluids. If left untreated, in rare occasions this may lead to a tear in the wall of 
the intestine which can be serious and life threatening

impairment of the brain function

nerve irritation that can result in pain, numbness and/or weakness in any part of the body. 
In rare situations, there is the potential for the nervous system to be severe. 

skin rash with blisters that can be itchy

myocarditis (inflammation of the heart muscle)

kidney problems: you may have an increase of creatinine levels in a blood test (creatinine 
is a protein marker that measures kidney function) but not have any symptoms or feel 
unwell. Uncommonly a patient may experience nephritis which is an inflammation of the 
kidneys that stops the kidneys from working properly

problems with the pituitary gland (hypopituitarism): Hypopituitarism refers to decreased 
output of hormones from the pituitary gland in the brain and may be caused by 
inflammation of the pituitary gland (hypophysitis). Symptoms may include headaches, 
thirstiness, and trouble seeing or double vision, leakage of breast milk or irregular periods 
in women. These complications may be permanent and may require hormone replacement

pancreatitis (inflammation of the pancreas)

liver problems: Increases in the blood level of substances called enzymes found within 
your liver cells. The enzyme changes are unlikely to make you feel unwell, however, if 
IRB NUMBER: 18C0078
IRB EFFECTIVE DATE: 6/25/2024


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these blood enzyme levels become very high, your study doctor may need to stop the study 
medication

Nervous system problems: symptoms can include unusual weakness of legs, arms, or face, 
numbness, or tingling in hands or feet. In rare situations, there is the potential for the 
inflammation of the nervous system to be severe.
If any of these side effects occur, you must inform your study doctor immediately.
BN-brachyury vaccine
Likely
Less Likely
Rare 
but 
Serious
•
Injection-site 
reaction (pain 
or discomfort, 
itching, 
redness, 
firmness, 
swelling, skin 
thickening, or 
bumps) 
•
Acute fever 
•
Chills 
•
Flu-like symptoms (fatigue, soreness, general 
body pain, abdominal pain, cough, fever, 
headache) 
•
Chest tightness 
•
Shortness of breath 
•
Leg pain and/or swelling 
•
Headache 
•
Loss of appetite 
•
Weight loss 
•
Diarrhea 
•
Constipation 
•
Rash 
•
Nausea 
•
Dizziness 
•
Mild inflammation of tissue lining the lungs 
•
Chronic inflammation of the skin 
•
Difficulty sleeping
•
Open sores (ulcers) at the injection site 
•
Enlarged lymph nodes 
•
Low blood levels of sodium 
•
Inflammation of the testicles
•
Inflammation of thyroid tissue
•
Difficulty 
breathing 
•
Low blood 
pressure 
•
Wheezing 
•
Clots in the 
lung 
•
Clots in the leg 
•
Kidney 
damage
•
Decreased 
blood oxygen 
levels
•
Fluid around 
the lining of 
the lungs
•
Fluid around 
the lining of 
the heart
IRB NUMBER: 18C0078
IRB EFFECTIVE DATE: 6/25/2024


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N-803 (previously known as ALT-803)
Common (out of 100 people who receive N-803, 20 or more people may have):

Feeling tired

Fever and chills

Flu-like symptoms 

Headache

High blood pressure

Low blood pressure

Large red rash and/or swelling at the site of injection that fades over 1-2 weeks (out of 100 
people, 50 or more people may have this)

Abdominal pain

Low albumin, which may cause fluid build-up, yellowing of your skin, rapid heart beat, 
nausea and vomiting, itchy skin or appetite changes

Back pain
One or more of these side effects may begin 1-2 days after receiving N-803 and go away a few 
days later.
Uncommon (out of 100 people who receive N-803, 1 or less people may have): 

Low white blood cell counts

Atrial fibrillation, a quivering or irregular heartbeat (arrhythmia), that can lead to blood 
clots, stroke, heart failure and other heart-related complication and may require the addition 
of a blood thinner
Epacadostat 
Likely
Less Likely
Rare but Serious

Diarrhea

Nausea

Vomiting

Fatigue/general 
weakness

Rash 

Abnormal liver 
tests

Joint pains

Itching

Decreased thyroid 
function

Adrenal insufficiency, a condition in which the 
glands on top of the kidneys do not make 
enough of a hormone. This can cause tiredness, 
weakness, feeling faint, salt craving, and in 
severe cases require hospitalization or be life 
threatening if not treated promptly.

Serotonin syndrome (SS) is a rare condition 
associated with certain types of medications. 
SS can be mild or life-threatening. People with 
Serotonin Syndrome may experience a feeling 
IRB NUMBER: 18C0078
IRB EFFECTIVE DATE: 6/25/2024


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Likely
Less Likely
Rare but Serious
that their heart is racing, confusion, fever, 
chills, sweats, muscle spasms, stomach upset, 
or seizures. Rarely, patients taking Epacadostat 
have experienced mild or moderate symptoms 
that might have been Serotonin Syndrome. A 
patient card discussing the SS will be provided 
to you by the study doctor.
Risks of Epacadostat when combined with M7824
Likely
Less Likely
Rare but Serious

 Fatigue

 Nausea 

Diarrhea

 Rash

 Vomiting

 Fever, Abdominal pain

 Aspartate 
aminotransferase and 
Alanine aminotransferase 
increased (Liver enzymes 
increased)

 Weakness

Muscle pain

 Pneumonia

Inflammatory 
disease of the 
lung/intestine

Adrenal 
insufficiency
(Hormonal 
disorder)

Drug sensitivity

Inflammation of the brain

 Drug reaction with eosinophilia (increased 
number of these blood cells) 

Systemic symptoms, and immune-mediated 
hepatitis
More than one of these side effects may happen at the same time. If you experience any of these 
symptoms, follow the instructions provided by your study doctor.
Risks from Blood Collection 
Side effects of blood draws include pain and bruising in the area where the needle was placed, 
lightheadedness, and rarely, fainting. When large amounts of blood are collected, low red blood 
cell count (anemia) can develop.
What are the risks of radiation from being in the study?
During your participation in this research study, you will be exposed to radiation from up to 5 CT 
scans (chest/abdomen/pelvis) and up to 5 bone scans annually. The amount of radiation exposure 
you will receive from these procedures is equal to approximately 7 rem (or 7.45 rem if you weigh 
more than 265 lb). A rem is a unit of absorbed radiation.  
Every day, people are exposed to low levels of radiation that come from the sun and the 
environment around them.  The average person in the United States receives a radiation exposure 
IRB NUMBER: 18C0078
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of 0.3 rem per year from these sources.  This type of radiation is called “background radiation.”  
No one knows for sure whether exposure to these low amounts of radiation is harmful to your 
body. 
The CT and bone scans that you get in this study will expose you to the roughly the same amount 
of radiation as 23years (or 24.8years if you weigh more than 265 lb) of background radiation.  
Being exposed to too much radiation can cause harmful side effects such as an increase in the risk 
of cancer. The risk depends on how much radiation you are exposed to.  Please be aware that about 
40 out of 100 people (40%) will get cancer during their lifetime, and 20 out of 100 (20%) will die 
from cancer. The risk of getting cancer from the radiation exposure in this study is 0.7 out of 100 
(0.7%) and of getting a fatal cancer is 0.4 out of 100 (0.4%).
Risks due to Contrast dye used in CT scans
If contrast dye is used, there is a risk for allergic reaction to the dye. If you are allergic to or 
sensitive to medications, contrast dye, iodine, or shellfish, you should notify it to the Study team. 
If you have had kidney problems/failure in the past, please notify it to your study doctor. 
Risks of Bone Scan
The bone scan carries no greater risk than conventional X-rays. The tracers in the radioactive 
substance used in a bone scan produces very little radiation exposure. The risk of having an allergic 
reaction to the tracers is low.
Risks of MRI
MRI is safe and there are no side effects. People who have some kinds of metal in their body are 
at risk for injury from the MRI magnet. You will be questioned about having metal in your body 
before your MRI and you will not have the MRI if it is determined that is not safe to do so. It may 
be unsafe for you to have an MRI scan if you have pacemakers or other implanted electrical 
devices, brain stimulators, some types of dental implants, aneurysm clips (metal clips on the wall 
of a large artery), metal prostheses (including metal pins and rods, heart valves, and cochlear 
implants), permanent eyeliner, tattoos, an implanted delivery pump, or shrapnel fragments. 
Welders and metal workers may have small metal fragments in the eye. You will be screened for 
these conditions before having any MRI scan.  If you have a question about metal in your body, 
you should inform the staff. You will be asked to complete an MRI screening form before each 
MRI scan you have. 
In addition, all magnetic objects (like watches, coins, jewelry, and credit cards) must be removed 
before entering the MRI scan room.
People with fear of confined spaces may become anxious during an MRI. Those with back 
problems may have back pain or discomfort from lying in the scanner.  The noise from the scanner 
is loud enough to damage hearing, especially in people who already have hearing loss. Everyone 
having a research MRI scan will be fitted with hearing protection. If the hearing protection comes 
loose during the scan, you should let us know right away.
There are no known long-term risks of MRI scans.
IRB NUMBER: 18C0078
IRB EFFECTIVE DATE: 6/25/2024


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Risks of Gadolinium- a contrast dye used in MRIs
The risks of an IV catheter include bleeding, infection, or inflammation of the skin and vein with 
pain and swelling.  
Mild symptoms from gadolinium infusion occur in fewer than 1% of those who receive it and 
usually go away quickly.  Mild symptoms may include coldness in the arm during the injection, a 
metallic taste, headache, and nausea.  In an extremely small number, fewer than one in 300,000 
people, more severe symptoms have been reported including shortness of breath, wheezing, hives, 
and lowering of blood pressure. You should not receive gadolinium if you previously had an 
allergic reaction to it.  You will be asked about such allergic reactions before gadolinium is given.   
People with kidney disease are at risk for a serious reaction to gadolinium contrast called 
“nephrogenic systemic fibrosis (NSF)”.  This condition always involves the skin and can also 
involve the muscles, joints and internal organs.  NSF has resulted in a very small number of deaths.  
A blood test of your kidney function may be done within the month before an MRI scan with 
gadolinium contrast. You will not receive gadolinium for a research MRI scan if your kidney 
function is below the safe level. 
Most of the gadolinium contrast leaves the body in the urine.  However, the FDA has issued a 
safety alert that indicates small amounts of gadolinium may remain in the body for months to years.  
The long-term effects of the retained gadolinium are unknown.  Some types of gadolinium contrast 
drugs are less likely to remain in the body than others.  In this study, we will use the gadolinium 
contrast drugs that are less likely to remain in the body.
Risks of Biopsy
There are potential risks associated with this procedure including pain or bleeding caused by the 
anesthesia needle as well as the biopsy procedure itself. An allergic reaction to the local anesthetic 
may occur. There may be bruising at the site of biopsy. Continuous bleeding and infection are rare 
and very often is easily controlled. 
Risks due to Electrocardiogram (EKG)
Other than possibly experiencing some minor skin irritation from the electrodes, there are no 
anticipated risks related to complete the electrocardiogram and/or the echocardiogram. 
POTENTIAL BENEFITS OF PARTICIPATION
Are there benefits to taking part in this study? 
The aim of this study is to find out whether the experimental treatment will cause your tumors to 
shrink. We do not know if you will receive personal, medical benefit from taking part in this study. 
Potential benefits could include shrinking of your tumor or lessening of your symptoms, such as 
pain, that are caused by the cancer. Because there is not much information about the drug’s effect 
on your cancer, we do not know if you will benefit from taking part in this study, although the 
knowledge gained from this study may help others in the future who have cancer. 
IRB NUMBER: 18C0078
IRB EFFECTIVE DATE: 6/25/2024


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ALTERNATIVE APPROACHES OR TREATMENTS
Instead of being in this study, you have these options:

Getting treatment or care for your cancer without being in a study 
If you have prostate cancer, enzalutamide, abiraterone acetate and docetaxel are three 
other types of treatments that can make men with CRPC live longer.
If you have another type of cancer, ask your doctor if an alternative treatment is 
appropriate for you.

Taking part in another study

Getting comfort care, also called palliative care. This type of care helps reduce pain, 
tiredness, appetite problems and other problems caused by the cancer. It does not treat the 
cancer directly. Instead, it tries to improve how you feel. Comfort care tries to keep you as 
active and comfortable as possible.
Please talk to your doctor about these and other options.
STOPPING THERAPY
Your doctor may decide to stop your therapy for the following reasons:

if he/she believes that it is in your best interest

if your disease comes back during treatment

if you need to take medication that is not allowed on the study

if you have side effects from the treatment that your doctor thinks are too severe

if new information shows that another treatment would be better for you

if the investigator decides to end the study
In this case, you will be informed of the reason therapy is being stopped.
You can stop taking part in the study at any time. However, if you decide to stop taking part in the 
study, we would like you to talk to the study doctor and your regular doctor first.
If you decide at any time to withdraw your consent to participate in the trial, we will not collect 
any additional medical information about you. However, according to FDA guidelines, 
information collected on you up to that point may still be provided to EMD Serono, Bavarian 
Nordic, Inc., Immunity Bio, Incyte or designated representatives. If you withdraw your consent 
and leave the trial, any samples of yours that have been obtained for the study and stored at the 
NCI can be destroyed upon request. However, any samples and data generated from the samples 
that have already been distributed to other researchers or placed in the research databases cannot 
be recalled and destroyed.
IRB NUMBER: 18C0078
IRB EFFECTIVE DATE: 6/25/2024


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CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
CONFLICT OF INTEREST
The National Institutes of Health (NIH) reviews NIH staff researchers at least yearly for conflicts 
of interest.  This process is detailed in a COI Guide. You may ask your research team for a copy 
of the COI Guide or for more information.  Members of the research team who do not work for 
NIH are expected to follow these guidelines or the guidelines of their home institution, but they 
do not need to report their personal finances to the NIH.
The National Institutes of Health and the research team for this study are using therapies developed 
by EMD Serono, Immunity Bio, Bavarian Nordic, Inc, and Incyte through a joint study with your 
researchers and the companies. The company also provides financial support for this study. 
USE OF SPECIMENS AND DATA FOR FUTURE RESEARCH
To advance science, it is helpful for researchers to share information they get from studying human 
samples. They do this by putting it into one or more scientific databases, where it is stored along 
with information from other studies. A researcher who wants to study the information must apply 
to the database and be approved. Researchers use specimens and data stored in scientific databases 
to advance science and learn about health and disease. 
These specimens and data will be used for future research and shared with other researchers. We 
will not contact you to ask about each of these future uses. These specimens and data will be 
stripped of identifiers such as name, address or account number, so that they may be used for future 
research on any topic and shared broadly for research purposes. Your specimens and data will be 
used for research purposes only and will not benefit you. It is also possible that the stored 
specimens and data may never be used. Results of research done on your specimens and data will 
not be available to you or your doctor. It might help people who have cancer and other diseases in 
the future. 
If you do not want your stored specimens and data used for future research, please contact us in 
writing and let us know that you do not want us to use your specimens and/or data. Then any 
specimens that have not already been used or shared will be destroyed and your data will not be 
used for future research. However, it may not be possible to withdraw or delete materials or data 
once they have been shared with other researchers.
COMPENSATION, REIMBURSEMENT, AND PAYMENT
Will you receive compensation for participation in the study?
Some NIH Clinical Center studies offer compensation for participation in research. The amount 
of compensation, if any, is guided by NIH policies and guidelines.
You will not receive compensation for participation in this study. 
Will you receive reimbursement or direct payment by NIH as part of your participation?
Some NIH Clinical Center studies offer reimbursement or payment for travel, lodging or meals 
while participating in the research. The amount, if any, is guided by NIH policies and guidelines.
IRB NUMBER: 18C0078
IRB EFFECTIVE DATE: 6/25/2024


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CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
On this study, the NCI will cover the cost for some of your expenses.  Some of these costs may be 
paid directly by the NIH and some may be reimbursed after you have paid.  Someone will work 
with you to provide more information.
Will taking part in this research study cost you anything? 
NIH does not bill health insurance companies or participants for any research or related clinical 
care that you receive at the NIH Clinical Center. 

If some tests and procedures performed outside the NIH Clinical Center, you 
may have to pay for these costs if they are not covered by your insurance 
company.

Medicines that are not part of the study treatment will not be provided or paid 
for by the NIH Clinical Center.

Once you have completed taking part in the study, medical care will no longer be 
provided by the NIH Clinical Center.
CLINICAL TRIAL REGISTRATION AND RESULTS REPORTING 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required 
by U.S. Law. This Web site will not include information that can identify you. At most, the Web 
site will include a summary of the results. You can search this Web site at any time.
CONFIDENTIALITY PROTECTIONS PROVIDED IN THIS STUDY  
Will your medical information be kept private? 
We will do our best to make sure that the personal information in your medical record will be kept 
private.  However, we cannot guarantee total privacy.  Organizations that may look at and/or copy 
your medical records for research, quality assurance, and data analysis include:

The NIH and other government agencies, like the Food and Drug Administration (FDA), 
which are involved in keeping research safe for people.

National Institutes of Health Intramural Institutional Review Board

Qualified representatives from the pharmaceutical companies, producing drugs: EMD 
Serono (M7824), Immunity Bio (N-803), Bavarian Nordic, Inc (BN-Brachyury), Incyte 
(Epacadostat).
The researchers conducting this study and the NIH follow applicable laws and policies to keep 
your identifying information private to the extent possible.  However, there is always a chance 
that, despite our best efforts, your identity and/or information about your participation in this 
research may be inadvertently released or improperly accessed by unauthorized persons.
In most cases, the NIH will not release any identifiable information collected about you without 
your written permission.  However, your information may be shared as described in the section of 
this document on sharing of specimens and data, and as further outlined in the following sections.  
Further, the information collected for this study is protected by NIH under a Certificate of 
Confidentiality and the Privacy Act. 
IRB NUMBER: 18C0078
IRB EFFECTIVE DATE: 6/25/2024


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CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
Certificate of Confidentiality
To help us protect your privacy, the NIH Intramural Program has received a Certificate of 
Confidentiality (Certificate). With this certificate, researchers may not release or use data or 
information about you except in certain circumstances.  
NIH researchers must not share information that may identify you in any federal, state, or local 
civil, criminal, administrative, legislative, or other proceedings, for example, if requested by a 
court.  
The Certificate does not protect your information when it:  
1. is disclosed to people connected with the research, for example, information may be used 
for auditing or program evaluation internally by the NIH; or 
2. is required to be disclosed by Federal, State, or local laws, for example, when information 
must be disclosed to meet the legal requirements of the federal Food and Drug 
Administration (FDA); 
3. is for other research;
4. is disclosed with your consent. 
The Certificate does not prevent you from voluntarily releasing information about yourself or your 
involvement in this research. 
The Certificate will not be used to prevent disclosure to state or local authorities of harm to self or 
others including, for example, child abuse and neglect, and by signing below you consent to those 
disclosures. Other permissions for release may be made by signing NIH forms, such as the Notice 
and Acknowledgement of Information Practices consent.
Privacy Act
The Federal Privacy Act generally protects the confidentiality of your NIH medical records we 
collect under the authority of the Public Health Service Act.  In some cases, the Privacy Act 
protections differ from the Certificate of Confidentiality.  For example, sometimes the Privacy Act 
allows release of information from your medical record without your permission, for example, if 
it is requested by Congress. Information may also be released for certain research purposes with 
due consideration and protection, to those engaged by the agency for research purposes, to certain 
federal and state agencies, for HIV partner notification, for infectious disease or abuse or neglect 
reporting, to tumor registries, for quality assessment and medical audits, or when the NIH is 
involved in a lawsuit.  However, NIH will only release information from your medical record if it 
is permitted by both the Certificate of Confidentiality and the Privacy Act.
RESEARCH-RELATED INJURIES  
The NIH Clinical Center will provide short-term medical care for any injury resulting from your 
participation in research here. In general, no long-term medical care or financial compensation for 
research-related injuries will be provided by the NIH, the NIH Clinical Center, or the Federal 
Government. However, you have the right to pursue legal remedy if you believe that your injury 
justifies such action.
IRB NUMBER: 18C0078
IRB EFFECTIVE DATE: 6/25/2024


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CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
PROBLEMS OR QUESTIONS
If you have any problems or questions about this study, or about your rights as a research 
participant, or about any research-related injury, contact the Principal Investigator, James Gulley, 
MD, PhD, Phone: 301-480-7164, Email: gulleyj@mail.nih.gov. You may also call the NIH 
Clinical Center Patient Representative at 301-496-2626, or the NIH Office of IRB Operations at 
301-402-3713, if you have a research-related complaint or concern.
CONSENT DOCUMENT 
Please keep a copy of this document in case you want to read it again.
IRB NUMBER: 18C0078
IRB EFFECTIVE DATE: 6/25/2024


PATIENT IDENTIFICATION
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MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
Adult Research Participant: I have read the explanation about this study and have been given the opportunity 
to discuss it and to ask questions. I consent to participate in this study.
Signature of Research Participant
Print Name of Research Participant
Date
Legally Authorized Representative (LAR) for an Adult Unable to Consent: I have read the explanation 
about this study and have been given the opportunity to discuss it and to ask questions. I am legally authorized 
to make research decisions on behalf of the adult participant unable to consent and have the authority to 
provide consent to this study. As applicable, the information in the above consent was described to the adult 
participant unable to consent who agrees to participate in the study.
Signature of LAR
Print Name of LAR
Date
Investigator:
Signature of Investigator
Print Name of Investigator
Date
Witness should sign below if either:
1. A short form consent process has been used to enroll a non-English speaking subject or
2.
An oral presentation of the full consent has been used to enroll a blind or illiterate subject:
Signature of Witness*
Print Name of Witness
Date
*NIH ADMINISTRATIVE SECTION TO BE COMPLETED REGARDING THE USE OF AN 
INTERPRETER:
An interpreter, or other individual, who speaks English and the participant’s preferred language facilitated
the administration of informed consent and served as a witness. The investigator obtaining consent may not 
also serve as the witness.
An interpreter, or other individual, who speaks English and the participant’s preferred language facilitated
the administration of informed consent but did not serve as a witness. The name or ID code of the person 
providing interpretive support is:
.
IRB NUMBER: 18C0078
IRB EFFECTIVE DATE: 6/25/2024