Conditions: Small Bowel Cancers Colorectal Cancers
Keywords: CEA MUC1 Vaccine CV301 M7824 N-803 NHS-IL12 Bintrafusp alfa M9241
Allocation: NON_RANDOMIZED | Intervention model: SEQUENTIAL
Enrollment: 32
Healthy volunteers: no

Brief summary:
Background:

Metastatic or refractory/recurrent small bowel and colorectal cancers cannot be cured and are often not helped by standard treatments. Researchers want to find better treatments by testing a combination of drugs.

Objective:

To learn if a new combination of immunotherapy drugs can shrink tumors in people with advanced small bowel and colorectal cancers.

Eligibility:

People ages 18 and older who have advanced metastatic or refractory/recurrent small bowel and/or colorectal cancer.

Design:

Participants will be screened on a separate protocol. They will have a physical exam and medical history. They will have imaging scans. They will have blood and urine tests. Their heart function will be measured. They may have a tumor biopsy.

Participants will repeat some of the screening tests during the study.

Participants will be put into study groups. Each group will get a combination of the following drugs: CV301 vaccine (modified vaccinia Ankara (MVA)-BN-CV301 and Fowlpox (FPV)-CV301), M7824 (MSB0011359C), and N-803 (Anktiva). Some will also get NHS-IL12 (M9241).

Participants will get the CV301 vaccines by injection under the skin. They will get M7824 by intravenous infusion every 2 weeks. They will get N-803 by injection under the skin every 2 or 4 weeks. They may get NHS-IL12 by injection under the skin every 4 weeks. They will take the study drugs for up to 1 year. They will visit the National Institutes of Health (NIH) every 2 weeks.

After treatment ends, participants will go to the clinic for a 28-day follow-up visit or have a telephone call. They will be contacted every 3 months for 1 year, and then every 6 months after that for the rest of their life.

Detailed description:
Background:

* Metastatic or refractory/recurrent small bowel and colorectal cancers are incurable and poorly palliated by standard therapies. There is an unmet need for active treatments for these tumors.
* To date immunotherapies including anti programmed cell death protein 1 (PD-1) or anti programmed death-ligand 1 (PD-L1) inhibitors have proven largely ineffective for the vast majority of these cancers.

  * In microsatellite stable (MSS) colorectal cancer (\>95% of these cancers) the response rate to checkpoint inhibitors has been \<5%.
  * Preclinical studies suggest that the use of different combinations of multiple immunotherapy agents may improve anti-tumor efficacy. These studies have employed (1) a vaccine targeting a tumor associated antigen, (2) an IL-15 superagonist (N-803, also known as ALT-803), (3) an anti-PD-L1 MAb or a bifunctional fusion protein targeting PD-L1 and TGF beta (M7824 (MSB0011359C), and (4) a tumor targeted immunocytokine (NHS-IL12 (M9241).

Objectives:

To evaluate the objective response rate (ORR) according to Response Evaluation Criteria (Response Evaluation Criteria in Solid Tumors (RECIST) 1.1) of the combination of (1) CV301, a poxviral based vaccine targeting carcinoembryonic antigen (CEA) and mucin-1 (MUC1), (2) N-803 and (3) M7824; and of the combination of (1) CV301, (2) N-803, (3) M7824 and (4) NHS-IL12 (M9241) in subjects with advanced checkpoint naive microsatellite stable (MSS) small bowel and colorectal cancers.

Eligibility:

* Age \>= 18 years old
* Subjects with cytologically or histologically confirmed locally advanced or metastatic small bowel or colorectal adenocarcinomas.
* Prior first line systemic therapy is required unless the patient declines standard treatment after appropriate counseling has been provided.
* Subjects must have measurable disease.

Design:

* This is a phase II trial of combination immunotherapy, with a brief dose escalation portion for Arm 2.
* The trial will be conducted using a Simon optimal two-stage design in each Phase II Arm.
* Patients will be enrolled on the following arms in sequential order: (1) Arm 1: CV301 + M7824 + N-803, (2) Arm 2A and Arm 2B: CV301 + M7824 + N-803 + NHS-IL12; N-803 dose level will be evaluated in Arm 2A prior to further enrollment in Arm 2B.
* The first six patients on arm 1 will be evaluable for dose limiting toxicities (DLTs) and accrual will only continue to 9 patients on that arm if less than 2 out of the first 6 patients experience a DLT.
* In Arm 2B, patients will receive 4 drug treatments (CV301 + M7824 + N-803 + NHSIL12), but the dose level of N-803 will first be determined during a 3-level dose escalation portion, Arm 2A. Following determination of the maximum tolerated dose (MTD) or highest safe dose evaluated, the 6 patients at that dose level will be included among the initial 9 patients for the first stage of that arm.
* If two or more out of nine patients have objective responses on a given arm that arm will be expanded to enroll 20 evaluable patients.

Arms:
arm 1: CEA/ MUC1 Vaccines + M7824 + N-803 (Triple Therapy). arm 2: CEA/ MUC1 Vaccines + M7824 + N-803 + NHSIL12 (Quadruple Therapy); dose escalation of NHS-IL12. arm 3: CEA/ MUC1 Vaccines + M7824 + N-803 + NHSIL12 (Quadruple Therapy); fixed dose of NHS-IL12.

Interventions: intervention 1: CV301 intervention 2: MSB0011359C intervention 3: N-803 intervention 4: NHS-IL12
Intervention descriptions: intervention 1: CV301 vaccine consists of MVA-BN-CV301 and FPV-CV301. MVA-BN-CV301 (4 x 10\^8 infectious units/0.5 mL each) will be administered as four subcutaneous injections on D1 and D15. Starting on D29, FPV-CV301 (1 x 10\^9 infectious units/ 0.5mL) will be administered as a single subcutaneous injection every 4 weeks on Arm 1 or every 6 weeks on Arm 2A and 2B for up to one year. intervention 2: 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 or 300 mg independent of body weight. M7824 is administered as an intravenous infusion with a mandatory 0.2 micron in-line filter. intervention 3: N-803 will be given via subcutaneous injection at a dose of 15 mcg/kg every four weeks on Arm 1. N-803 will be administered at as dose of 10 (Micro)g/kg by SC injection every 4 weeks on Arm 2A and Arm 2B. intervention 4: NHS-IL12 will be given via subcutaneous injection at a dose of 8 mcg/kg every 4 weeks or 16 mcg/kg for the first 4 injections and 8 mcg/kg thereafter on Arms 2A and 2B.

Protocol document:
Prot_SAP_003.pdf: 
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Abbreviated Title: QuICC Trial
Version Date: 03.25.2025
Abbreviated Title: QuICC Trial
NIH Protocol #: 20C0138
Version Date: March 25, 2025
IBC Registration Number: RD-19-IX-01
NCT Number: NCT04491955
Title: Phase II Trial of Combination Immunotherapy in Subjects with Advanced Small Bowel 
and Colorectal Cancers
NCI Principal Investigator: Hoyoung Maeng, MD 
Center for Immuno-Oncology (CIO)
Center for Cancer Research (CCR)
National Cancer Institute (NCI)
10 Center Drive 
Room 3B37
Bethesda, MD 20892 
Phone: 240-781-3253 
Email: hoyoung.maeng@nih.gov 
Drug Name:
MSB0011359C
(M7824)
N-803
NHS-IL12
(M9241)
CV301
IND Number: 19660
Sponsor:
Center for Cancer Research, NCI
Manufacturer: EMD Serono, Inc. ImmunityBio, Inc. EMD Serono, Inc. Bavarian Nordic, Inc.
Supplier: 
EMD Serono, Inc. ImmunityBio, Inc. EMD Serono, Inc. Bavarian Nordic, Inc.
Commercial Agents: None


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PRÉCIS
Background:
•
Metastatic or refractory/recurrent small bowel and colorectal cancers are incurable and 
poorly palliated by standard therapies. There is an unmet need for active treatments for 
these tumors.
•
To date immunotherapies including anti PD-1 or anti PD-L1 inhibitors have proven 
largely ineffective for the vast majority of these cancers. 
o
In microsatellite stable (MSS) colorectal cancer (>95% of these cancers) the 
response rate to checkpoint inhibitors has been <5%.
o
Preclinical studies suggest that the use of different combinations of multiple 
immunotherapy agents may improve anti-tumor efficacy. These studies have 
employed (1) a vaccine targeting a tumor associated antigen, (2) an IL-15 
superagonist (N-803, also known as ALT-803), (3) an anti-PD-L1 MAb or a 
bifunctional fusion protein targeting PD-L1 and TGFβ (M7824), and (4) a tumor 
targeted immunocytokine (NHS-IL12).
Objectives:
•
To evaluate the objective response rate (ORR) according to Response Evaluation Criteria 
(RECIST 1.1) of the combination of (1) CV301, a poxviral based vaccine targeting CEA 
and MUC1, (2) N-803 and (3) M7824; and of the combination of (1) CV301, (2) N-803, 
(3) M7824 and (4) NHS-IL12 (M9241) in subjects with advanced checkpoint naïve MSS 
small bowel and colorectal cancers. 
Eligibility:
•
Age > 18 years old
•
Subjects with cytologically or histologically confirmed locally advanced or metastatic 
small bowel or colorectal adenocarcinomas. 
•
Prior first line systemic therapy is required unless the participant declines standard 
treatment after appropriate counseling has been provided.
•
Subjects must have measurable disease.
Design:
•
This is a phase II trial of combination immunotherapy, with a brief dose escalation 
portion for Arm 2.
•
The trial will be conducted using a Simon optimal two-stage design in each Phase II Arm.
•
Participants will be enrolled on the following arms in sequential order: (1) Arm 1: CV301 
+ M7824 + N-803, (2) Arm 2A and Arm 2B: CV301 + M7824 + N-803 + NHS-IL12; 
NHS-IL12 dose level will be evaluated in Arm 2A prior to further enrollment in Arm 2B.
•
The first six participants on arm 1 will be evaluable for dose limiting toxicities (DLTs) 
and accrual will only continue to 9 participants on that arm if less than 2 out of the first 6 
participants experience a DLT.  
•
In Arm 2B, participants will receive 4 drug treatments (CV301 + M7824 + N-803 + 
NHS-IL12), but the dose level of NHS-IL12 will first be determined during a dose 
escalation portion, Arm 2A. Following determination of the MTD or highest safe dose 


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evaluated, the 6 participants at that dose level will be included among the initial 9 
participants for the first stage of that arm.
•
If two or more out of nine participants have objective responses on a given arm that arm 
will be expanded to enroll 20 evaluable participants.
  


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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 .......................................................29
2.1
Eligibility Criteria ...........................................................................................................29
2.2
Screening Evaluation ......................................................................................................32
2.3
Participant Registration and Status Update Procedures..................................................33
2.4
Baseline Evaluation.........................................................................................................34
3
STUDY IMPLEMENTATION .............................................................................................34
3.1
Study Design...................................................................................................................34
3.2
Drug Administration .......................................................................................................38
3.3
Study Intervention Compliance ......................................................................................39
3.4
Dose Modifications.........................................................................................................39
3.5
Study Calendar................................................................................................................50
3.6
Cost and Compensation ..................................................................................................52
3.7
Criteria for Removal from Protocol Therapy and Off Study Criteria.............................52
4
CONCOMITANT MEDICATIONS/MEASURES...............................................................53
4.1
The Following Treatments Should Not Be Administered During the Trial: ..................53
4.2
N-803 ..............................................................................................................................54
5
CORRELATIVE STUDIES FOR RESEARCH / PHARMACOKINETICS STUDIES......54
5.1
Biospecimen Collection ..................................................................................................54
5.2
Samples for Genetic/Genomic Analysis .........................................................................56
5.3
Sample Storage, Tracking and Disposition.....................................................................56
6
DATA COLLECTION AND EVALUATION .....................................................................58
6.1
Data Collection ...............................................................................................................58
6.2
Data Sharing Plans..........................................................................................................59
6.3
Response Criteria ............................................................................................................60
6.4
Toxicity Criteria..............................................................................................................66


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7
NIH REPORTING REQUIREMENTS / DATA AND SAFETY MONITORING PLAN...66
7.1
Definitions.......................................................................................................................66
7.2
OHSRP Office of Compliance and Training / IRB Reporting........................................66
7.3
NCI Clinical Director Reporting.....................................................................................67
7.4
Institutional Biosafety Committee (IBC) Reporting Criteria..........................................67
7.5
NIH Required Data and Safety Monitoring Plan............................................................68
8
SPONSOR/PROTOCOL SAFETY REPORTING................................................................69
8.1
Definitions.......................................................................................................................69
8.2
Assessment of Safety Events ..........................................................................................70
8.3
Reporting of Serious Adverse Events .............................................................................71
8.4
Waiver of Expedited Reporting to CCR .........................................................................71
8.5
Safety Reporting Criteria to the Pharmaceutical Collaborators......................................71
8.6
Reporting Pregnancy.......................................................................................................71
8.7
Regulatory Reporting for Studies Conducted Under CCR-Sponsored IND...................72
8.8
Sponsor Protocol Deviation Reporting ...........................................................................72
9
CLINICAL MONITORING PLAN ......................................................................................72
10
STATISTICAL CONSIDERATIONS ...............................................................................73
10.1
Statistical Hypothesis ..................................................................................................73
10.2
Sample Size Determination.........................................................................................73
10.3
Populations for Analyses.............................................................................................74
10.4
Statistical Analyses......................................................................................................75
11
COLLABORATIVE AGREEMENTS...............................................................................77
11.1
Cooperative Research and Development Agreement (CRADA)................................77
12
HUMAN SUBJECTS PROTECTIONS.............................................................................77
12.1
Rationale For Subject Selection ..................................................................................77
12.2
Participation of Children .............................................................................................77
12.3
Participation of Subjects Unable to Give Consent ......................................................77
12.4
Risk/Benefit Assessment.............................................................................................78
12.5
Consent Process and Documentation ..........................................................................79
13
REGULATORY AND OPERATIONAL CONSIDERATIONS.......................................81
13.1
Study Discontinuation and Closure.............................................................................81
13.2
Quality Assurance and Quality Control ......................................................................81


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13.3
Conflict of Interest Policy ...........................................................................................82
13.4
Confidentiality and Privacy.........................................................................................82
14
PHARMACEUTICAL INFORMATION ..........................................................................83
14.1
CV301 (IND # 19660).................................................................................................83
14.2
M7824 (MSB0011359C) (IND # 19660)....................................................................85
14.3
N-803 (IND # 19660)..................................................................................................88
14.4
NHS-IL12 (IND # 19660) ...........................................................................................89
15
REFERENCES ...................................................................................................................92
16
APPENDICES ....................................................................................................................97
16.1
Appendix A: Performance Status Criteria...................................................................97


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STATEMENT OF COMPLIANCE
The trial will be carried out in accordance with International Conference on 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 evaluate the objective response rate (ORR) according to Response Evaluation Criteria 
(RECIST 1.1) of the combination of (1) CV301, a poxviral based vaccine targeting CEA 
and MUC1, (2) N-803 and (3) M7824; and of the combination of (1) CV301, (2) N-803, 
(3) M7824 and (4) NHS-IL12 in subjects with advanced checkpoint naïve MSS small 
bowel and colorectal cancers. 
1.1.2
Secondary Objectives
•
To evaluate the safety of the combination of (1) CV301, (2) N-803 and (3) M7824 in 
subjects with advanced small bowel and colorectal cancers.
•
To evaluate the safety of the combination of (1) CV301, (2) N-803, (3) M7824 and (4) 
NHS-IL12 in subjects with advanced small bowel and colorectal cancers.
•
To assess progression-free survival time (PFS) according to RECIST 1.1 per treatment 
assignment (three or four drug combination).
•
To assess overall survival (OS) per treatment assignment (three or four drug 
combination).
•
To assess duration of response per treatment assignment (three or four drug 
combination).
•
To assess ratio of participants that are hospitalized because of adverse events attributed to 
disease progression
1.1.3
Exploratory Objectives
•
To conduct exploratory immunologic studies to understand and improve the administered 
treatment, including:


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o
peripheral immune subset analysis before and on treatment;
o
soluble factors circulation (e.g., sCD27 and sCD40 ligand) before and on treatment;
o
tumor tissue PD-L1 expression and immune infiltration before and after treatment.
•
To assess responses to therapy using iRECIST per treatment assignment (three or four 
drug combination). 
•
To assess response to therapy using RECIST and iRECIST in checkpoint refractory 
participants (including participants with MSI disease)
•
To assess responses to therapy by RAS mutation status
1.2
BACKGROUND AND RATIONALE
1.2.1
Colorectal Cancers
Metastatic colorectal cancer is characterized by poor outcomes. The statistics are discussed below 
and highlight the unmet need for effective treatments in this populations. In the face of the failures 
of the many tested treatment strategies for these patients, it is clear that innovative and bold 
approaches will be needed in order to develop treatment regimens that positively affect this 
population’s prognoses. 
1.2.1.1
Metastatic Colon Cancer
Each year, approximately 300,000 new cases of colon cancer are diagnosed in the United States 
and Europe. Following first-line treatment with 5-fluorouracil-based combination chemotherapy 
plus targeted therapy, median overall survival is approximately 2 years. Once a patient progresses 
on first-line treatment, overall survival is further diminished to 10-12 months. Oral salvage 
chemotherapy agents have received regulatory approval in recent years. However, the overall 
survival benefit seen in phase III studies with these agents is an additional 1-2 months [1-3]. With 
the exception of microsatellite unstable cases of mCRC, activity of ICI monotherapy is rare [4-6].
1.2.2
Rationale for Combination of Immunotherapy Agents
The vast majority of human carcinomas are characterized as “cold” tumors in that they do not 
respond to checkpoint MAb therapy. Preclinical studies are now revealing that an effective 
immuno-oncology strategy for so-called “cold” tumors such as colon carcinoma (MSS) is the use 
of multiple immune-mediating agents, each targeting different components of the immune system. 
These include: (a) induction of an immune response via vaccination directed against tumor-
associated antigens, (b) potentiation of the systemic immune response by the use of 
immunocytokines (such as the N-803, an IL-15 superagonist fusion protein) to enhance both NK 
and CD8+ T-cell responses, (c) potentiation of the immune response in the tumor 
microenvironment (TME) by the use of the tumor targeting NHS-IL12 immunocytokine, and (d) 
reduction of immunosuppressive entities in the TME by the use of anti-PD1/PDL1 MAb 
checkpoint inhibitors, and/or reduction of immunosuppressive cytokines such as TGF-β with the 
use of a bifunctional anti-PDL1/TGF-β2 “Trap” designated M7824.
The LTIB, in collaboration with the GMB, has been able to develop and/or co-develop these agents 
via a series of CRADAs. Each has been interrogated in a series of preclinical studies and in Phase 
I/II clinical studies in the CCR as well as by other investigators. Preclinical studies and early 
clinical studies are demonstrating the relative lack of additional toxicities with enhanced clinical 
benefit employing combinations of 2 of these agents. Preclinical studies are now demonstrating 


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that the combined use of agents from each of the immune-mediating categories described above 
elicits the most immune-mediated anti-tumor activities.
Avelumab (anti-PD-L1) and M7824 (anti-PD-L1/TGF- βR2)
Studies in the LITB were the first to describe [7, 8] avelumab, a fully human anti-PD-L1 IgG1 
MAb, and its ability to mediate ADCC for a range of human carcinoma cells employing NK cells 
as effectors. Avelumab (Bavencio) has since been approved by the FDA for the therapy of Merkel 
cell carcinoma (the first drug approved for this indication) and second line urothelial carcinomas. 
We have also shown that endogenous IL-12 will enhance avelumab-mediated NK lysis, thus 
forming the basis for the combined use of avelumab or M7824 with NHS-IL12. The first-in-human 
clinical study of avelumab with over 1,700 patients was led by Gulley with the dose escalation and 
initial PK and PD done entirely within the CCR [8]. Because of the activity this study was amended 
to include multiple expansion cohorts internationally. Because PD-L1 is also expressed on some 
immune cell subsets, and because avelumab can mediate ADCC there was initial concern that 
Avelumab may lead to depletion of PD-L1 expressing immune cells. Our finding [9] that there 
were no adverse events in the patients treated with avelumab above that seen with other anti-PD-
L/PD-L1 MAbs (which did not mediate ADCC) was important for planning further studies with 
avelumab or M7824. 
TGF-β is a well-known inhibitor of immune cell function, especially in the TME [10-15]. Prior 
studies have indicated the advantage in the use of a TGF-β inhibitor in combination with 
checkpoint therapy [16, 17] In collaboration with our CRADA partner EMD Serono, we have co-
developed a bifunctional fusion protein aimed at bringing a TGF-β TRAP to tumor cells via 
binding to PD-L1. M7824 is a novel fusion protein consisting of avelumab linked to the 
extracellular domain of two TGF-βR2 (serving as a TGF-β TRAP) (Figure 1). We were the first 
to report [18, 19] that M7824 (a) mediates ADCC, (b) increases tumor cell gene expression of 
molecules involved in T-cell trafficking to the tumor, (c) enhances TRAIL- and antigen-specific 
CD8+ T-cell lysis of tumor cells, and (d) reduces TGF-β‒induced immunosuppressive activity. 
We have also recently demonstrated [20] in in vivo preclinical murine carcinoma models 
(Figure 2A and B) that M7824 has the ability to decrease TGF-β‒ induced signaling in the 
TME.


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Figure 1 M7824 (anti-PD-L1/TGFβR2): “TRAP”.
Specifically, phosphorylation of SMAD2 was significantly decreased in tumors following M7824 
treatment, and not with an M7824(mut) molecule, devoid of the PD-L1 binding site (Figure 2C). 
In both breast and colon carcinoma murine models, M7824 decreased tumor burden and increased 
survival, which required both CD8+ and NK cell activity (Figure 2D). Two recent studies [21, 22] 
demonstrated the advantage in anti-tumor activity in the use of the bifunctional agent vs. the use 
of a PD-1/PD-L1 checkpoint in combination with a systemic TGF-β inhibitor. TGFβ is also known 
to alter human carcinoma cells from a more epithelial to a more mesenchymal phenotype and such 
tumor cells are more resistant to a range of therapies (Figure 3). In LTIB studies, TGF-β‒induced 
mesenchymalization of carcinoma cells was shown [23] to be reversed by M7824, rendering tumor 
cells more susceptible to chemotherapy and immune-mediated killing [18, 20, 23].


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Figure 2 (A) Comparison of anti-tumor activity of M7824, and M7824(mut) devoid of PD-L1 
binding site in the EMT6 breast cancer model. (B) Accumulation of M7824 in the TME resulting 
in reduction of SMAD2 signaling (C) and increased T- and NK-cell activation (D) [20]. 
Figure 3 Functions of M7824 [18, 23] 
The first-in-human trial of M7824 (anti-PD-L1/TGF-βR2) was conducted at the CCR. Nineteen 
heavily pretreated patients with solid tumors (non-melanoma) were treated; the MTD was not 
reached. M7824 was shown to saturate peripheral PD-L1 and sequester all released (acid released) 
plasma TGFβ1, -β2, and -β3 throughout the dosing period at >1 mg/kg (recommended phase 2 


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dose is 1200 mg or about 10 mg/kg). There were signs of clinical efficacy across all dose levels 
(Figure 4, Figure 5), including one ongoing CR (cervical cancer), two durable PRs (pancreatic 
and anal cancers), one near PR (cervical) and two cases of prolonged stable disease [24]. In the 
Phase I study and a subsequent Phase II study, greater than 30‒40% of patients with HPV+ 
malignancies showed evidence of clinical response to M7824 therapy. Prior studies by others have 
shown approximately 15-20% patient responses in this population employing checkpoint 
inhibition therapy. 
Figure 4 (A), (B) Phase I Trial of  M7824 [24]


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Figure 5: Phase I Trial of M7824 [24] 
N-803 (IL-15 Superagonist)
IL-15 is a well-studied Th1 cytokine. Prior studies by others [25-28] have shown, in both 
preclinical and clinical studies, the ability of prokaryotic rec. IL-15 protein to enhance the level of 
both NK and CD8+ T cells. Limitations in the use of rec. IL-15 center around issues of 
pharmacokinetics and toxicity, and the lack of the IL-15/IL-15R complex for optimal activity. Our 
interest in IL-15 was also piqued by the ability of avelumab and M7824 to mediate ADCC. N-803 
is an IL-15/IL-15Rα-Fc superagonist fusion protein developed by our CRADA partner 
ImmunityBio, Inc. (formerly Altor Bioscience and NantCell, Inc.). In a series of studies, we have 
shown [19, 29, 30] that N-803 can (a) significantly increase cytotoxic NK cells, showing enhanced 
NK lysis of tumor cells on a per-cell basis, (b) increase memory CD8+ T cells, (c) elicit anti-tumor 
effects in metastatic models of breast and colon carcinoma, and (d) inhibit TGF-β‒mediated 
reduced NK function, leading to increased NK lysis of a range of human carcinoma cell types.  
It has now been reported [31] that N-803 can re-induce objective responses to anti-PD-1 
immunotherapy after treatment relapse or failure. Historically, about 8% of patients with NSCLC 
treated past progression had partial responses with continued PD-1 monoclonal antibodies 
treatment. The objective responses to N-803-nivolumab combination treatment after PD-1 
treatment failure coincided directly with initiation of N-803 after progression in patients with 
relapsed disease treated with uninterrupted nivolumab [31]. Moreover, partial responses were seen 
in 3 out of 10 (30%) patients whose tumor lacked PD-L1 expression and in 3 out of 11 (27%) 
patients who had relapsed or refractory disease after previous anti-PD-1 immunotherapy. The level 
of toxicity observed in the combination was similar to (and perhaps less than) that observed with 
PD-1/PD-L1 monotherapy. These data suggest that N-803 represents a novel immunotherapeutic 


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agent that could augment the anti-tumor activity of checkpoint inhibitors in several treatment 
settings.
Vaccines
Both CEA and MUC-1 have been reported as relevant immunologic targets in colon cancer.  
Earlier efforts to generate efficient cancer immunotherapy were directed towards the 
development of PANVAC, a prime and boost approach based on the administration of a 
replicating-competent Vaccinia-based delivery vector followed by a Fowlpox vector. Both 
vectors encoded the transgenes for B7.1, ICAM-1 and LFA-3, together with the CEA and MUC-
1. In order to establish its therapeutic potential, several preclinical studies were performed, 
showing that PANVAC activates antigen-specific human T cells in vitro [32], elicits antibody 
and cellular immune responses in vivo, and shows significant antitumor efficacy against tumors 
expressing either human CEA or MUC-1 in mice, resulting in programmed death ligand 1 (PD-
L1) up-regulation within the tumor microenvironment. Subsequently, the clinical development 
program continued with the design of several clinical trials to further confirm the efficacy and 
safety of this intervention. Overall, the results of Phase I and II clinical trials in different cancer 
populations employing PANVAC monotherapy or in combination with GM-CSF or docetaxel 
demonstrate a good safety profile accompanied by some hints of clinical benefits [33, 34].
A second generation cancer immunotherapy strategy was developed, giving rise to CV301 
involving a modified vaccinia. CV301 is a recombinant non-replicating poxvirus based 
immunotherapy encoding the same 5 transgenes used in PANVAC (B7.1, ICAM-1, LFA-3, CEA 
and MUC-1) and thus designed to activate an antigen-specific response.  Therefore, tumors 
expressing these antigens, including colon cancer, qualify as a potential indication for CV301. 
Given the potential risks associated with the replicating capacity of the vaccinia-based PANVAC-
V construct, the next generation cancer immunotherapeutic candidate MVA-BN-CV301 was 
generated by Bavarian Nordic as part of a CRADA with the NCI (LTIB). It constitutes a 
recombinant non-replicating poxvirus- based immunotherapy derived from the MVA-BN 
construct. This novel viral vector was developed from the highly attenuated vaccinia virus known 
as MVA, which after more than 500 serial passages in chicken embryo fibroblasts lost 
approximately 15% of the original vaccinia genome. Furthermore, MVA-BN differs from other 
MVA strains in its extensive plaque purification and propagation in serum-free conditions, and has 
already undergone extensive investigation as a new smallpox vaccine. Within this comprehensive 
clinical development program, MVA-BN has been administered to more than 7,700 subjects 
without major safety concerns, hence exhibiting a robust safety profile. Accordingly, besides 
decreasing the risk of cardiac adverse events associated with earlier generation vaccinia-based 
strategies, the improved MVA-BN enables previously excluded segments of the general 
population, such as immunocompromised individuals and persons diagnosed with atopic 
dermatitis, to receive the potential benefits offered by this novel approach. Therefore, it embodies 
a highly novel approach and offers a reliable technological platform that enables the safe delivery 
of different transgenes to produce a tailored immune response against specific antigens.
The new CV301 strategy encodes the same 5 transgenes expressed by the previous PANVAC 
vector: CEA, MUC-1, B7.1, ICAM-1 and LFA-3. However, these inserts encode each of the 
transgenes with amino acid sequences that are slightly different from the original vectors. In fact, 
MUC-1 has been modified with additional agonistic epitopes. Consequently, the CV301 construct 
is expected to promote an antigen-specific targeted immune response for tumors expressing these 


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antigens. In addition, a change in biosafety also characterizes the new CV301 construct. Thus, 
whereas vaccinia possesses a BSL-2, MVA has been categorized as BSL1 in Europe. As well, 
similarly to the earlier PANVAC concept, CV301 also encompasses a heterologous prime-boost 
regimen employing an MVA-BN-CV301 priming dose followed by a Fowlpox-based FPV-CV301 
boosting dose, thus replacing the former PANVAC-V and PANVAC-F components. Given the 
existing correspondences between the CV301 and PANVAC vectors, the clinical development 
program designed for CV301 will rely on the extensive nonclinical and clinical data currently 
available from PANVAC.
Clinical Safety Data
Analysis of safety data from a Phase 1/1b clinical trial of CV301 in 24 subjects showed no dose 
limiting toxicities at a dosage up to 1.6 × 109 Inf.U of MVA-BN-CV301. 
In both Phase 1b cohorts (CV301 plus nivolumab and CV301 plus pembrolizumab) the safety of 
the combination regimen was established. There was only one case of DLT reported due to 
immune mediated events in the nivolumab combination: one case of pneumonitis that further 
developed into a vasculitis, DIC and ultimately multi organ failure (fatal outcome). Overall, DLT 
and IMAE were below the pre-specified threshold to continue the trial based on the now 
established safety profile. In conclusion, there was no increased toxicity of the combination 
regimens CV301 plus pembrolizumab or nivolumab as compared to ICIs alone (per ICI 
prescribing information). 
The clinical safety data for the MVA-BN backbone vector and its recombinant products tested 
clinically to date are provided in Section 5.2 of CV301 IB v 5. In summary, no safety concerns, 
in particular no cardiac concerns have arisen from the development program of the MVA-BN 
platform, involving more than 51,000 subjects who have received MVA-BN and MVA-BN 
based recombinant products in completed and ongoing clinical trials. 
Six of the seven clinical trials with CV301’s predecessor product PANVAC with data available 
have demonstrated an acceptable safety profile for the vaccines. Across these clinical trials, the 
most common treatment-related AEs were injection site reaction (including injection site 
erythema, injection site pain, and injection site swelling), myalgia, fatigue, vomiting, nausea, and 
abdominal pain. Most treatment-related AEs were Grade 1 or 2 in severity. SAEs related to study 
treatment, discontinuations due to AE, and deaths related to study treatment were rare (only 1 
death due to Grade 5 pulmonary infiltrate was assessed as possibly related to study drug).
Cardiac toxicity: 
A detailed analysis of the TEAEs reported under the cardiac disorders SOC in clinical trial TBC-
PAN-003 and CTEP No 6977 were performed due to an imbalance of cardiovascular events 
reported in the PANVAC treatment arms. This detailed analysis concluded that for all reported 
cardiac SAEs and cases of pericardial effusion, alternative risk factors were present and causality 
with regard to PANVAC is unlikely. Importantly, there have been no reported observations of 
myocarditis or pericarditis in any of the PANVAC clinical trials. 
Based upon these data and the total clinical experience with poxvirus vectors for anticancer 
vaccines, including CV301’s predecessor product PANVAC, a causal relationship of cardio-
toxicity following treatment with CV301 and/or PANVAC is unlikely. Nonetheless, a proactive 
approach in pharmacovigilance will be applied prospectively, requesting from the investigators a 


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deeper characterization of every case with a cardiac AE with the working hypothesis that 
myocarditis/pericarditis may be the underlying cause. 
Further toxicities monitored during clinical trials: 
Immune-Mediated Adverse Events: Autoimmune diseases and immune-mediated clinical 
syndromes, emerging since the initiation of trial product, will be reported as potential IMAEs. So 
far, no signal has emerged from the diverse poxvirus constructs studied in the clinic, but the 
theoretical possibility exists that breaking the immune tolerance to self-antigens may induce 
autoimmune phenomena. This possibility deserves close monitoring.
CV-301 Phase I Experience
A phase I study was just completed at the NCI [35]. As expected, there were no grade 3 or 
greater toxicities reported in the study. There were no dose-limiting toxicities. Twelve patients 
enrolled on trial [dose level (DL) 1 = 3, DL2 = 3, DL3 = 6). Most side effects were seen with the 
prime doses and lessened with subsequent boosters. All treatment-related adverse events were 
temporary, self-limiting, grade 1/2, and included injection-site reactions and flu-like symptoms. 
Antigen-specific T cells to MUC1 and CEA, as well as to a cascade antigen, brachyury, were 
generated in most patients. Single-agent BN-CV301 produced a confirmed partial response (PR) 
in 1 patient and prolonged stable disease (SD) in multiple patients, most notably in KRAS-mutant 
gastrointestinal tumors. Furthermore, 2 patients with KRAS-mutant colorectal cancer had 


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prolonged SD when treated with an anti-PD-L1 antibody following BN-CV301. 
Figure 6 NHS-IL12 Immunocytokine. (A) NHS76 is a fully human 2nd generation TNT antibody 
bound to 2 murine IL-12 (p70) molecules. (B) a: Specific tumor targeting of transplanted lung 
carcinoma by the MAb NHS-IL12(mu). Control MAb BC1-IL12(mu). b: NHS-IL12 tumor 
targeting of nuclear DNA histones.
NHS-IL12 Immunocytokine (M9241)
NHS-IL12 is a tumor targeting immunocytokine that binds to DNA-histone in necrotic areas of 
tumor. Studies by others have shown the ability of radiolabeled NHS-IL12 to target murine and 
human tumors (Figure 6). Prior studies in the LTIB have shown the ability of this agent to elicit 
anti-tumor activity in multiple murine models, and in combination with anti-PD-L1 and with 
radiation and chemotherapy [36]. J. Strauss (LTIB), in collaboration with J. Gulley (GMB, 
CCR), conducted the Phase I dose escalation trial of the NHS-IL12 immunocytokine [36]. Due to 
known prior toxicities using a rec. IL-12 protein, multiple ascending dose levels were employed 
and the agent was administered every 4 weeks. Time-dependent increase in serum IFN-γ and 
subsequent rise in IL-10 increased with dose and varied greatly among patients (Figure 7A). 
Increases in TCR diversity and TIL density in the TME following NHS-IL12 dosing were 
observed in those patients with elevated IFN-γ serum levels (Figure 7B). Toxicity was 
acceptable with an MTD of 16.8 mcg/kg. Although no objective tumor responses were seen, of 


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30 patients with measurable disease, 15 had stable disease, with some durable (from 6‒30+ 
months).
Figure 7 (A) Diversity of IFN-γ spikes in sera among patients 3 days post-NHS-IL12 treatment 
for cycles 1 (C1) and 2 (C2): as examples, 2 patients with high (pts 1 and 2, red and blue) and 
low (pts 3 and 4, green and orange) levels are shown. (B) Changes in TCR clonal diversity in 
the tumor biopsy correlate with serum IFN-g responses post-NHS-IL12 treatment. (C) # of 
clones in tumor comprising the top 25% of the repertoire of patient 1 pre- and post-NHS-IL12, 
demonstrating an increase in TCR diversity in a high IFN-g responder after therapy.
Our recent preclinical studies (Figure 8) have also shown that there is enhanced anti-tumor effect 
of avelumab when used in combination with NHS-IL12 (Figure 8) and that this effect is mediated 
via an IFN-γ‒dependent mechanism. Studies in NSG-β2m‒/‒ mice bearing a human carcinoma and 
reconstituted with human PBMC also showed the enhanced anti-tumor effect of the combination 
that coincided with increased NK and CD8+ in the TME. This further provided the rationale for an 
ongoing CCR led clinical study of avelumab in combination with NHS-IL12 (NCT02994953), 
currently evaluating safety and efficacy of the combination. In addition to the combination being 
found to be safe and well-tolerated, evidence of clinical responses has been observed. As an 
example, a patient with checkpoint refractory metastatic urothelial cancer with a large sacral mass 
and retroperitoneal adenopathy at enrollment has had an ongoing complete response for 21+ 
months and a patient with rapidly progressive small cell bladder cancer with metastases to liver 
who progressed on standard therapy has an ongoing partial response for 15+ months. 
Combination Immunotherapies
As a consequence of the potential multi-functionality of M7824, we have conducted several 
combination studies employing this agent. We have previously shown [20] enhanced anti-tumor 
activity when M7824 is combined with vaccine in a metastatic carcinoma murine model (Figure 
9). While M7824 can mediate ADCC for a range of human carcinoma cells, it is not as potent as 
avelumab in this mechanism; the addition of N-803, however, enhanced the ADCC activity of both 


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avelumab and M7824, but more importantly, increased the tumor lytic ability of M7824 to that 
equivalent of avelumab with N-803 [29] (Figure 10). 
A series of preclinical studies have been carried out employing combinations of vaccine, M7824, 
N-803, and NHS-IL12. Combining M7824 with the NHS-IL12 molecule greatly enhanced anti-
tumor activity (Figure 11). Tumor challenge studies showed the presence of immune memory. 
This was shown in 3 different murine carcinoma models.
Figure 8 Anti-tumor Activity of Immunocytokine NHS-IL12 + anti-PD-L1. (A) [37, 38] (B) 
Ongoing Trial: Avelumab + NHS-IL12 (Strauss et al, unpublished).


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Figure 9 Combined effect of Ad-Twist vaccine and M7824 in EMT6 carcinoma model [20].
Figure 10 N-803 enhances the NK-mediated lysis of avelumab and M7824 [29].


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Figure 11 SG51: Anti-tumor effect of M7824 + NHS-IL12 combination treatment in EMT6 
murine carcinoma tumors.
Multimodal therapies were also carried out. Employing NSG-β2m‒/‒ mice bearing human 
carcinomas and reconstituted with human PBMC, the combination of vaccine, N-803, and M7824 
resulted in the greatest level of anti-tumor activity compared to the use of individual agents (Figure 
12). Employing the MC38 syngeneic murine colon carcinoma model the combination of vaccine, 
N-803, anti-PD-L1, and NHS-IL12 resulted in precipitous reduction of large tumors not seen with 
combinations of 3 of these agents (Figure 13). The use of all 4 agents also resulted in an intense 
influx of CD8+ T cells in tumors not seen with lesser combinations (Figure 14). Tumor challenge 
studies showed the presence of immune memory.


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Figure 12 Multimodal therapy in mice reconstituted with PBMCs from patients.
Figure 13 The ability of a neoantigen vaccine to enhance combinatorial anti-tumor activity 
(Unpublished data).


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Figure 14 Neoantigen Vaccination in Combination Therapies: Tumor-infiltrating CD8 T Cells. 
(Unpublished data)
1.2.3
Safety and Efficacy of Immunotherapy Combinations in Humans
As detailed below (Figure 15), evidence of clinical activity has been observed in MSS CRC 
patients who received anti-tumor vaccine, followed by ICI. These observations are particularly 
intriguing in the MSS colon cancer population, a group in which ICI activity has been rare [39]. 
Evidence of clinical activity has also been seen in a MSS, CRC patient who received the 
combination of M7824 and N-803 following a CEA/ MUC1 based vaccine regimen (Figure 16). 


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Figure 15 (A) CEA (mcg/L) of a patient with KRAS mutant, MSS colorectal cancer. This patient enrolled 
on the phase 1 CV301 trial, had an unconfirmed partial response at the first retagging (6 weeks), then 
developed new mediastinal adenopathy at the 12-week restaging. Patient was then enrolled on a PD-L1 trial 
and experienced a subsequent decrease in her tumor markers as well as a radiographic response to treatment. 
Blue dotted line represents baseline CEA. (B) Unconfirmed PR on CV301 at 6 weeks on study. (C) 
Developed new mediastinal adenopathy (red arrows) at week 12 on CV301 trial, resulting in patient coming 
off trial for progressive disease. Patient was then started on another trial with a PD-L1 agent. After 3 months 
on the PD-L1 trial, mediastinal adenopathy had necrosed and tumor markers declined.


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Figure 16 (A) CEA (mcg/L) of a patient with NRAS mutant, MSS colorectal cancer (B) Presence 
of large right sided hilar mass prior to starting M7824 + N-803 (C) Substantial tumor reduction at 
first restaging following starting M7824 + N-803.
This patient enrolled on the phase 1 trial of a CEA/MUC1based vaccine regimen, had evidence of 
disease progression, and switched over to another trial of M7824 plus N-803. Shortly after starting 
M7824 plus N-803 his tumor marker was found to drop precipitously. In addition, his first 
restaging scan showed a substantial partial response which was confirmed on his next scan.  
Many of these novel immunotherapy agents have been tested clinically in combination with other 
immunotherapy agents and demonstrated an acceptable safety profile (Table 1).


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Table 1
Nivolumab + N-803 [40]
NCT02523469
Avelumab (anti-PD-L1) + NHS-IL12
NCT02994953
CV301 (Poxviral vaccine) + M7824
NCT03315871
N-803 + M7824
NCT03493945 
Poxviral vaccine + N-803 + M7824 
NCT03493945
Safety data with the combination of Nivolumab and N-803 has been reported [31]. Twenty-three 
patients were enrolled and 21 patients treated at four dose levels of N-803 (6,10,15, and 20 mcg/kg) 
in combination with nivolumab at standard FDA approved dosing. No dose limiting toxicities were 
observed. And the maximum tolerated dose was not reached. The most common adverse events 
were injection site reactions (in 19 [90%] of 21 patients) and flu-like symptoms (in 15 [71%] of 
21 patients). The most common grade 3 adverse events, occurring in two patients each were 
lymphopenia and fatigue. A grade 3 myocardial infarction occurred in one patient (only case of 
treatment discontinuation due to AE). No grade 4 or 5 adverse events were recorded. One case of 
grade 2 pneumonitis occurred which resolved without steroids. Otherwise no other notable 
autoimmune toxicity was observed. 
Thirty-three patients have been treated with the combination of avelumab (anti PD-L1) and NHS-
IL12. 26 patients in four dose levels of NHS-IL12 (4, 8, 12, or 16.8 mcg/kg) in combination with 
standard dosing of avelumab 10 mg/kg IV every 2 weeks and 7 additional patients in a fifth dose 
level which received NHS-IL12 at 16.8 mcg/kg in combination with avelumab 800 mg flat dosing 
weekly. One dose limiting toxicity occurred at DL3 (grade 3 autoimmune hepatitis). No dose 
limiting toxicities were observed at any other dose level.  No grade 4 or 5 adverse events were 
recorded. The one case of grade 3 autoimmune hepatitis was the only notable autoimmune toxicity 
observed. 
Six patients have been treated with the combination of CV301, a poxviral vaccine, and M7824. 
No dose limiting toxicities have been observed. One patient did have a transient asymptomatic 
grade 3 lipase elevation which did not require treatment hold and self-resolved. No grade 4 or 5 
adverse events were recorded. Aside from the one case of transient asymptomatic lipase elevation 
no other notable autoimmune toxicities were observed.
Thirteen patients have been treated with the combination of two dose levels of N-803 (10 and 15 
mcg/kg) and M7824 at 1200 mg flat dose. No dose limiting toxicities have been observed. One 
patient had grade 3 enterocolitis which resolved with steroid taper. No grade 4 or 5 adverse events 
were recorded. Aside from the one case of enterocolitis no other notable autoimmune toxicities 
were observed.
Nine patients have been treated with the combination of the same poxviral vaccine vector 
employed in CV301 composed of an MVA component as four injections (4x108 IU/0.5 mL) each 
on day 1 and 15 followed by an FPV component (1x109 IU/0.5 mL), in addition to N-803 at 15 
mcg and M7824 at 1200 mg flat dose. No dose limiting toxicities have been observed. 


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The level of toxicity observed with all of these combinations were similar to (and perhaps less 
than) that observed with PD-1/PD-L1 monotherapy. 
1.2.4
Clinical Rationale for using M7824 over other anti PD-L1 agents in Immunotherapy 
Combinations
M7824 is being chosen over other anti PD-1/L1 agents as M7824 has been well tested in the CCR 
having had the first in human phase I trial done here and also having shown early promising 
efficacy in a number of tumor types often beyond the efficacy observed with avelumab or other 
anti PD-L1 agents. As an example in a subset analysis of patients treated within the dose-escalation 
cohort with human papillomavirus (HPV)-associated disease (n = 17), including patients with anal, 
cervical, and squamous cell carcinoma of the head and neck, there was an ORR of 35.3%, and an 
ORR of 41.7% in patients with known HPV-positive disease (n = 12) which exceeded the expected 
ORR of 15-20% expected with single agent PD-L1 inhibition [41]. In another cohort of patients 
with advanced NSCLC and PD-L1 expressing tumors the confirmed ORR was 40.7% in patients 
treated at the recommended phase II dose (1200 mg every 2 weeks) which also compared favorably 
to the 15-20% expected response rate with single agent PD-L1 inhibition.  In patients with high-
PD-L1 expressing tumors, the ORR was 71.4% (n = 7) [42]. Based upon its potentially enhanced 
efficacy, M7824 is being used as the anti PD-1/L1 agent of choice in a number of combination 
trials either ongoing or planned in the CCR. In addition, once the safety profile of M6903 is well 
defined in combination with M7824 we plan to further expand on this combination by evaluating 
it in the context of additional IO agents such as vaccine therapies.   
1.2.5
Dose Rationale
In the phase I dose escalation trial of combination N-803 and M7824, escalating doses of N-803 
were evaluated at 10 and 15 mcg/kg given with a standard flat RP2D of M7824 at 1200 mg.  No 
DLTs were observed. Therefore, a dose of 15 mcg/kg of N-803 is being chosen for this trial for 
Arm 1 in combination with standard RP2D of M7824 at 1200 mg. In the phase I dose escalation 
trial of combination Avelumab (anti-PD-L1) + NHS-IL12, escalating doses of NHS-IL12 were 
evaluated at 8,12, and 16.8 mcg/kg given every 4 weeks in combination with standard dosing of 
Avelumab. The combination including NHS-IL12 at the highest dose evaluated (16.8 mcg/kg 
given every 4 weeks) was found to be well tolerated. The only DLT observed on the trial was a 
transient grade 3 AST/ALT elevation at NHS-IL12 at 12 mcg/kg but otherwise no other DLT was 
observed and the MTD was not reached. On another trial (20C0045) evaluating the combination 
of a therapeutic cancer vaccine plus NHS-IL12 at 16.8 mcg/kg and M7824 no DLTs were observed 
in the six participant lead in safety cohort, although the majority of original participants (11/19; 
57.9%) treated on that trial needed dose reductions of NHS-IL12 when given in combination with 
the therapeutic cancer vaccine and M7824 due to grade 2 fever or flu like symptoms. After further 
evaluation a dose of NHS-IL12 at 8 mcg/kg was found to be very tolerable when combined with a 
therapeutic cancer vaccine and M7824 on that other trial. Therefore, based on that data we 
evaluated NHS-IL12 at a dose of 8 mcg/kg on both this study and the 20C0045 study. However, 
after evaluating a total of 39 patients on the 20C0045 study including 21 patients with starting dose 
of 16.8 mcg/kg and 18 patients with starting dose of 8 mcg/kg we observed what looks to be 
reduced efficacy in patients receiving 8 mcg/kg as a starting dose with only 3/18 patients 
responding with the 8 mcg/kg starting dose as compared to 11/21 with the 16.8 mcg/kg starting 
dose. Therefore, based on this observation that the possibility that a lowering starting dose of NHS-


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IL12 may reduce efficacy in combination with vaccine and M7824, we are amending to allow 
treatment (effective with Protocol Amendment Version 10.20.2021) with a limited number of 
doses of NHS-IL12 at 16.8 mcg/kg (four doses total) before reducing NHS-IL12 to 8 mcg/kg on 
both this study and the 20C0045 study. This is based upon responding patients in the first 21 
patients on the 20C0045 study which received anywhere between 1-4 doses of NHS-IL12 at 16.8 
mcg/kg before dose reductions were made. 
Although N-803 and NHS-IL12 have potential overlapping toxicities (e.g., grade 1-2 flu like 
symptoms), it should be noted that no DLTs were observed in the six patient safety lead in 
combination of NHS-IL12 at 8 mcg/kg and N-803 at 10 mcg/kg.  The NHS-IL12 and N-803 doses 
are being given on alternating schedules to minimize overlapping toxicities. Additionally, it was 
noted that 3/6 patients on this dose level (NHS-IL12 at 8 mcg/kg + N-803 10 mcg/kg in 
combination with vaccine and M7824) had bleeding events which did not meet DLT criteria but 
nonetheless limited patients’ ability to receive further treatment with M7824 as part of this 
combination. Therefore, we are planning to dose reduce M7824 to 300 mg when evaluating the 
next and highest dose level on Arm 2A which also includes NHS-IL12 at 16.8 mcg/kg (for up to 
a total of 4 doses before reducing to 8 mcg/kg) + N-803 at 10 mcg/kg. A dose of M7824 at 300 
mg has been found to be clinically active and anecdotally result in less bleeding.
1.2.6
Immune Assays
Multiple immune assays have been developed in the LTIB to better define the mechanism(s) 
involved in the use of specific novel agents, as monotherapy or in combination therapies, both for 
preclinical and clinical studies (Section 5.1). In addition to analyses of biopsies, analyses of the 
peripheral immunome can provide valuable information in that multiple samples can be analyzed 
over the course of a given therapy vs. pre-therapy. The LTIB has now developed and employed 
[8, 9, 24, 43] a flow cytometry‒based assay that can analyze 123 immune cell subsets in human 
PBMC from one vial of processed PBMC (approximately 10^7 cells). This assay will be used in 
this clinical trial to detect multiple subsets of CD4+ T cells (n=32), CD8+ T cells (n=29), Tregs 
(n=7), B cells (n=5), NK (n=20), NKT (n=4), DC (n=10), and MDSC (n=16) to better understand 
the role of each agent. We also plan to evaluate changes in TCR clonal diversity both in biopsies 
and the periphery. One example involves an ongoing first-in-human trial of the NHS-IL12 tumor-
targeting immunocytokine. TCR diversity increased 6-14‒fold in biopsies of patients with a high 
or intermediate IFN-γ response but were unchanged or decreased with a low IFN-γ response. These 
findings also correlated with TIL in biopsies. We are also currently employing NanoString 
analyses to identify a gene signature in biopsies and PBMC, pre- and post-treatment. The GMB 
will conduct multiplexed, multispectral imaging of FFPE tissue to evaluate multiple immune 
parameters within the TME before and after treatment in patients with available tissue.
1.2.7
Summary
•
We are proposing a novel immunotherapy combination to help overcome multiple 
barriers in an effective anti-tumor immune response. 
o
(1) vaccines targeting tumor associated antigens to prime an anti-tumor immune 
response
o
(2) N-803 to expand the response and activate T effector cells and NKs
o
(3) NHS-IL12 and M7824 to enable activated immune cells to work better in the 
TME


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•
Preclinical studies have shown that the addition of M7824 to vaccine therapy improves 
anti-tumor activity
•
Preclinical studies have shown that the addition of N-803 to vaccine therapy and M7824 
further improves anti-tumor activity
•
Preclinical studies have shown that the addition of NHS-IL12 to vaccine therapy, N-803 
and checkpoint therapy still further improves anti-tumor activity
•
Clinical data suggests that M7824 is at least as effective if not more effective at 
producing anti-tumor responses than other standard anti PD-L1 agents in a number of 
tumor types
•
Clinical data evaluating the safety of combination immunotherapy has shown multiple 
combinations of these agents to be safe and overall well tolerated including:
o
Vaccine + M7824
o
NHS-IL12 + Checkpoint therapy
o
N-803+ M7824
o
Vaccine + N-803 + M7824
•
There has been anecdotal evidence of clinical activity with combination immunotherapy 
o
Vaccine + anti PD-L1
o
Vaccine + M7824 + N-803
2
ELIGIBILITY ASSESSMENT AND ENROLLMENT 
2.1
ELIGIBILITY CRITERIA
2.1.1
Inclusion Criteria
2.1.1.1
Subjects with cytologically or histologically confirmed locally advanced or metastatic 
small bowel or colorectal adenocarcinoma
2.1.1.2
Subjects must have received two prior lines of systemic therapy unless the subject is not 
eligible to receive standard therapy or declines standard treatment
2.1.1.3
Subjects must have measurable disease  
2.1.1.4
ECOG performance status < 2 (Appendix A: Performance Status Criteria)
2.1.1.5
Adequate hematologic function at screening, as follows:
•
Absolute neutrophil count (ANC) ≥1 x 109/L 
•
Hemoglobin ≥ 9 g/dL 
•
Platelets ≥ 75,000/microliter 
2.1.1.6
Adequate renal and hepatic function at screening, as follows:
•
Serum creatinine ≤ 1.5 x upper limit of normal (ULN) OR 
Measured or calculated creatinine clearance ≥ 40 mL/min for participant with 
creatinine levels > 1.5 X institutional ULN (GFR can also be used in place of 
creatinine or CrCl);
•
Bilirubin ≤ 1.5 x ULN OR in subjects with Gilbert’s syndrome, a total bilirubin ≤ 3.0 
x ULN
•
Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 x ULN, 
unless liver metastases are present, then values must be ≤ 3 x ULN)


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2.1.1.7
The effects of the immunotherapies on the developing human fetus are unknown; thus, 
women of childbearing potential and men must agree to use highly effective 
contraception (hormonal or barrier method of birth control; abstinence) prior to study 
entry, for the duration of study treatment and up to two months after the last dose of study 
drug. Should a woman become pregnant or suspect she is pregnant while she or her 
partner is participating in this study, she should inform her treating physician 
immediately.
2.1.1.8
Participants serologically positive for HIV, Hep B, Hep C are eligible as long as the viral 
loads are undetectable by quantitative PCR. HIV positive participants must have CD4 
count ≥ 200 cells per cubic millimeter at enrollment, be on stable antiretroviral therapy 
for at least 4 weeks and have no reported opportunistic infections or Castleman’s disease 
within 12 months prior to enrollment.
2.1.1.9
Ability of subject to understand and the willingness to sign a written informed consent 
document.
2.1.2
Exclusion Criteria
2.1.2.1
Participants with prior investigational drug, chemotherapy, immunotherapy or any prior 
radiotherapy (except for palliative bone directed therapy) within the past 28 days prior to 
the first drug administration 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. Additionally, current therapies (e.g., maintenance 
capecitabine) may be continued where in the opinion of the investigator stopping such 
therapies may increase the risk of disease progression. Also, participants may continue 
adjuvant hormonal therapy in the setting of a definitively treated cancer (e.g., breast).
2.1.2.2
Participants with microsatellite unstable or mismatch repair deficient disease.
2.1.2.3
Major surgery within 28 days prior to the first drug administration (minimally invasive 
procedures such as diagnostic biopsies are permitted).
2.1.2.4
Known life-threatening side effects resulting from prior checkpoint inhibitor therapy (e.g., 
colitis, pneumonitis, fulminant hepatitis which led to permanent discontinuation of prior 
checkpoint therapy). Autoimmune toxicity which was not life threatening (e.g., arthritis) 
or did not lead to discontinuation of prior checkpoint therapy is allowed.
2.1.2.5
Known active brain or central nervous system metastasis (less than a month out from 
definitive radiotherapy or surgery), seizures requiring anticonvulsant treatment (<3 
months) or clinically significant cerebrovascular accident (<3 months). In order to be 
eligible participants must have repeat CNS imaging at least a month after definitive 
treatment showing stable CNS disease. Participants with evidence of intratumoral or 
peritumoral hemorrhage on baseline imaging are also excluded unless the hemorrhage is 
grade ≤ 1 and has been shown to be stable on two consecutive imaging scans.    
2.1.2.6
Pregnant women are excluded from this study because these drugs have not been tested 
in pregnant women and there is potential for teratogenic or abortifacient effects.  Because 
there is an unknown but potential risk for adverse events in nursing infants secondary to 


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treatment of the mother with these immunotherapies, breastfeeding should be 
discontinued if the mother is treated on this protocol.
2.1.2.7
Active autoimmune disease that might deteriorate when receiving an immunostimulatory 
agent with exception of: 
•
Diabetes type I, eczema, vitiligo, alopecia, psoriasis, hypo- or hyperthyroid disease or 
other mild autoimmune disorders not requiring immunosuppressive treatment; 
•
Subjects requiring hormone replacement with corticosteroids are eligible if the 
steroids are administered only for the purpose of hormonal replacement and at doses 
≤ 10 mg of prednisone or equivalent per day;
•
Administration of steroids for other conditions through a route known to result in a 
minimal systemic exposure (topical, intranasal, intro-ocular, or inhalation) is 
acceptable;
•
Subjects on systemic intravenous or oral corticosteroid therapy with the exception of 
physiologic doses of corticosteroids (≤ the equivalent of prednisone 10 mg/day) or 
other immunosuppressive agents such as azathioprine or cyclosporin A are excluded 
on the basis of potential immune suppression. For these subjects these excluded 
treatments must be discontinued at least 1 weeks prior to enrollment for recent short 
course use (≤ 14 days) or discontinued at least 4 weeks prior to enrollment for long 
term use (> 14 days). In addition, the use of corticosteroids as premedication for 
contrast-enhanced studies is allowed prior to enrollment and on study.
2.1.2.8
Subjects with a history of serious intercurrent chronic or acute illness, such as cardiac or 
pulmonary disease, hepatic disease, bleeding diathesis or recent (within 3 months) 
clinically significant bleeding events or other illness considered by the Investigator as 
high risk for investigational drug treatment. 
2.1.2.9
Subjects unwilling to accept blood products as medically indicated.
2.1.2.10 History of second malignancy within 3 years of enrollment except for the following: 
adequately treated localized skin cancer, cervical carcinoma in situ, superficial bladder 
cancer, or other localized malignancy which has been adequately treated or malignancy 
which does not require active systemic treatment (e.g., low risk CLL). 
2.1.2.11 Subjects with a known severe hypersensitivity reaction to a monoclonal antibody (grade 
≥ 3 NCI-CTCAE v5) will be evaluated by the allergy/immunology team prior to 
enrollment.
2.1.2.12 Receipt of any organ transplantation requiring ongoing immunosuppression. 
2.1.2.13 Receipt of prior lymphodepleting chemotherapy (e.g., cyclophosphamide or fludarabine 
at standard lymphodepleting doses).
2.1.3
Recruitment Strategies
This study will be listed on www.clinicaltrials.gov. This study will be posted on NIH websites and 
on NIH social media forums. Participants will be recruited from the current participant population 
at NIH. Any recruitment materials will be submitted to the IRB for approval prior to distribution.


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2.2
SCREENING EVALUATION
2.2.1
Screening activities prior to the 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
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 # 01C0129 (provided the procedures are permitted on that study) on which 
screening activities will be performed within 28 days prior to enrollment. Assessments performed 
at outside facilities or on another NIH protocol within the timeframes listed may also be used to 
determine eligibility once a participant has signed the consent.
•
Complete medical history and physical examination (including height, weight, vital signs, 
and ECOG performance status).
•
CT of chest, abdomen and pelvis or MRI, if clinically indicated.
•
A brain CT scan in participants with known CNS disease as described in Section 2.1.2.5 
/ MRI scan if clinically indicated.
•
EKG.
•
Clinical laboratory tests (within 16 days prior to enrollment).

Chemistry: sodium, potassium, chloride, bicarbonate, calcium, glucose, BUN, 
creatinine, ALT, AST, alkaline phosphatase, total protein, albumin, and total and 
direct bilirubin.

Hematology: complete blood count (CBC) with differential.

CD4 (if HIV positive).
•
Coagulation panel: PT, INR, and PTT.
•
Urine or serum pregnancy test (β-HCG) for females of childbearing-potential and women 
< 12 months since the onset of menopause (within 16 days prior to enrollment). 
•
Urinalysis.
•
HBV, HCV, HIV testing including viral load in positive participants (within 3 months 
prior to enrollment).
•
Histologic confirmation (at any time point prior to enrollment). If there is no available 
tumor sample or pathology report, a biopsy will be performed to confirm the diagnosis.


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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 
at: 
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 
transient lab abnormality may be rescreened. 
2.3.2
Treatment Assignment Procedures
Cohorts
Number
Name
Description
1
Cohort 1 
Subjects with small bowel or colon adenocarcinoma 
receiving fixed doses of treatment.
2
Cohort 2
Subjects with small bowel or colon adenocarcinoma 
receiving quadruple therapy during dose escalation of 
NHS-IL12.
Arms
Number
Name
Description
1
Arm 1
CEA/ MUC1 Vaccines + M7824 + N-803 (Triple 
Therapy).
2
Arm 2A
CEA/ MUC1 Vaccines + M7824 + N-803 + NHS-IL12 
(Quadruple Therapy); dose escalation of NHS-IL12
3
Arm 2 B
CEA/ MUC1 Vaccines + M7824 + N-803 + NHS-IL12 
(Quadruple Therapy); fixed dose of NHS-IL12
Arm Assignment
Assignment of participants will be sequentially to arm 1, then 2A, then 2B as follows:
Participants in Cohort 1 will be assigned to Arm 1 first.


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Then participants in Cohort 2 will be assigned to Arm 2A until the MTD or maximum safe dose 
of NHSIL12 has been determined in the quadruple combination.
Then, following completion of Arm 2A, participants in Cohort 1 will be assigned to Arm 2B.
If there is a pause in accrual to Arm 1 after the first Simon II stage step (due to pending clinical 
outcomes needed for the determination to expand Arm 1) accrual may continue to Arm 2A and 2B 
in the interim and be switched back to Arm 1 if and when the decision is made to expand Arm1. 
2.4
BASELINE EVALUATION
All subjects are required to complete baseline evaluations within one week 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. 
•
Concomitant Medications and Baseline Signs and Symptoms evaluation.
•
Urine or serum pregnancy test (β-HCG) for females of childbearing-potential and women 
< 12 months since the onset of menopause.
•
Chemistry: sodium, potassium, chloride, bicarbonate, calcium, glucose, BUN, creatinine, 
ALT, AST, alkaline phosphatase, total protein, albumin, and total and direct bilirubin.
•
ACTH, TSH, free T4, lipase, amylase, CRP.
•
Hematology: CBC with differential.
3
STUDY IMPLEMENTATION
3.1
STUDY DESIGN
•
This is a phase II trial of combination immunotherapy, with a brief dose escalation portion 
for Arm 2.  
•
The trial will be conducted using a Simon optimal two-stage design in each Phase II Arm.
•
Participants will be enrolled on the following two arms in sequential order: (1) CV301+ 
M7824 + N-803, (2) CV301 + M7824 + N-803 + NHS-IL12 (Figure 17).
•
Given the known overlapping toxicities of NHS-IL12 and N-803 (e.g., flu like symptoms), 
as of the amendment dated 10.20.2021 the second arm will evaluate the safety of the 
combination of standard dosing of vaccines and M7824 with N-803 at 10 mcg/kg and 
escalating doses of NHS-IL12 at 8 and 16.8 mcg/kg using a modified 3+3 design (six 
patients per dose level; if < 2/6 patients with DLTs may move up to higher dose level; if > 
1/6 patients with DLTs may move to lower dose level). Dose level 1 on Arm 2A (including 
N-803 at 10 mcg/kg and NHS-IL12 at 8 mcg/kg) was found to be safe without any DLTs. 
Therefore, we plan to escalate to dose level 2 on Arm 2A evaluating the combination of N-
803 at 10 mcg/kg and NHS-IL12 at 16.8 mcg/kg (for up to 4 consecutive doses followed 
by 8 mcg/kg thereafter) with standard dosed vaccine + M7824 at 300 mg). The maximum 
tolerated dose level deemed safe on Arm 2Awill be expanded to nine evaluable patients 
and used for the Simon optimal two-stage design. If dose level 2 on Arm 2A is determined 
to be the maximum tolerated dose and expanded to nine evaluable patients in Arm 2B as 


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part of the Simon two stage design then dose level 1 on Arm 2A may also be expanded up 
to nine evaluable patients for further immune correlative assessments. 
•
The first six participants on arm 1 will be evaluable for dose limiting toxicities (DLTs) and 
accrual will only continue to 9 participants on that arm if less than 2 out of the first 6 pts 
experience a DLT. 
•
In Arm 2A, participants will receive the combination of 4 treatments, but the dose level of 
NHS-IL12will be determined during a dose escalation using a modified 3+3 design (six 
patients per dose level; if < 2/6 patients with DLTs may move up to higher dose level; if > 
1/6 patients with DLTs may move to lower dose level). Following determination of the 
MTD or highest safe dose evaluated, the 6 participants at that MTD or highest safe dose 
level will be included among the initial 9 participants for the first stage of Arm 2B.
•
There will be a minimum of 28 days between the sixth participant (last participant for 
determining safety) enrolled to Cohort 1 and assigned to Arm1 and the first participant 
enrolled on cohort 2 and assigned to Arm 2A
•
There will be a minimum of one week between the first three subjects enrolled in Arm 1 
and for each dose level of Arm 2A. The fourth through sixth participant of Arm 1 or each 
dose level of Arm 2A may enroll no sooner than 48 hours after the most recent enrollee. 
Once a dosage combination has been determined to be safe in six participants further 
participants may enroll at any time to that dosage combination.  
•
In the second stage of the Simon optimal two-stage design, if two or more out of nine 
participants have objective responses on a given arm that arm will be expanded to enroll 
20 evaluable participants 
•
It is possible that the response rates observed with combination immunotherapy will be 
less in participants who have previously received checkpoint therapy and not be truly 
reflective of a population of participants who have not had prior checkpoint therapy. While 
checkpoint experienced participants will not be excluded from enrollment, the primary 
efficacy analyses will be limited to checkpoint naïve participants with MSS colon cancer 
and efficacy analyses in the checkpoint refractory participants will be only exploratory.
•
Participants with small bowel cancers are being evaluated in this trial as well as participants 
with colorectal cancer but if efficacy is not observed in the first stage of the Simon II step 
design for either Arm 1 or Arm 2B than participants with small bowel cancer may be 
replaced with participants with colorectal cancer at the discretion of the investigator.


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Of note each Day # in the figure above has a corresponding Week # in the Study Calendar 
(D1 = W1, D15 = W3, D29 = W5, etc.). 
*Note: ALT803 is also known as N-803 
Dose Escalation Schedule
Dose Level
N-803
M7824
NHS-IL12
Arm 1
15 mcg/kg
1200 mg
n/a
Arm 2A, Dose Level 1
10 mcg/kg
1200 mg
8 mcg
Arm 2A, Dose Level 2
10 mcg/kg
300 mg
16.8 mcg
Arm 2B
MVA as 4 
injections 4 x 
108 IU/0.5 
mL each) on 
D1 and D15, 
followed by 
FPV (1 x 109 
IU/ 0.5mL)
10 mcg/kg
300 mg
MTD
Figure 17
3.1.1
Dose Limiting Toxicity
Dose limiting toxicities (DLT) (For first 6 participants in Arm 1, and all participants during 
dose escalation in Arm 2A): 


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Dose-limiting toxicity (DLT) will be defined as any one of the following adverse events, possibly 
attributable to study drugs, that occur within 28 days of the start of therapy:
•
Any Grade 3 or greater adverse drug reactions (ADRs) as defined by CTCAE v5.0 and 
assessed as possibly attributed to an agent except for any of the following:
o
Grade 3 flu-like symptoms or fever, as well as associated symptoms of fatigue, 
headaches, nausea, emesis which can be controlled with conservative medical 
management.  
o
Tumor flare phenomenon defined as local pain, irritation, or rash localized at sites 
of known or suspected tumor.
o
Grade 3 Hgb decrease (< 8.0 g/dL) not attributed to grade 3 or greater bleeding 
events that is clinically manageable with blood transfusions or erythroid growth 
factor use does not require treatment discontinuation. 
o
Grade 3 laboratory values laboratory values that are asymptomatic or resolve to 
Grade ≤ 1 or baseline grade within 14 days.
o
Grade 4 laboratory values that are asymptomatic and have no clinical correlate (e.g., 
lymphopenia). 
o
Keratoacanthoma and squamous cell carcinoma of the skin. 
o
Any endocrinopathy that can be medically managed with hormone replacement
o
Any grade 3 adverse drug reaction which can be medically managed with minimal 
risk to the participant (e.g., placement of a pleural catheter for recurrent 
inflammatory pleural effusions) and resolves to at least grade one or baseline grade 
within 14 days.
Criteria are based on the NCI Common Terminology Criteria for Adverse Events, Version 5.
Where clinically appropriate subjects on all arms will receive one year of treatment during which 
subjects will be followed with surveillance scans. On a case by case basis treatment beyond a year 
is allowed per investigator discretion. Subjects with evidence of disease progression after 
completing a year of treatment will be allowed retreatment on the same arm.
Patents might be taken off treatment for disease progression prior to completing one year of 
treatment, but where clinically appropriate, treatment beyond radiographic progression is allowed 
if in the opinion of the investigator the subject is benefiting from treatment.
Subjects will be taken off treatment if unacceptable toxicity.
Both arms of this trial will be conducted using a Simon two-stage phase II trial design in which 9 
evaluable participants will enroll and if 2 or more of the 9 have an objective response, then accrual 
would continue until a total of 20 evaluable participants have been treated on a given arm. If there 
are 5 or more of 20 (25.0%) who experience a response in a given arm, this would be sufficiently 
interesting to warrant further study. 
In the event that a participant develops a response (>30% decrease in target lesions as compared 
with baseline scan) following initial progression or “pseudo-progression”, this response will be 
considered as an objective response in the determination to expand accrual.


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3.2
DRUG ADMINISTRATION
3.2.1
General Rule 
A window of +/- 14 days for a scheduled treatment is allowed in the event of scheduling issues 
(i.e., holiday, bad weather or other scheduling issues). The minimum time between administrations 
of a similar agent is 11 days.
3.2.2
CV301
The CV301 vaccine regimen consists of MVA-BN-CV301 (priming vaccine) and FPV-CV301 
(booster vaccine).
MVA-BN-CV301 is administered as four subcutaneous injections (4 x 108 infectious units/0.5 mL 
each) on D1 and D15. Starting on D29, FPV-CV301 (1 x 109 infectious units/ 0.5mL) is 
administered every 4 weeks on Arm 1 or every 6 weeks on Arm 2A and 2B for up to one year. 
MVA-BN-CV301 is administered as one injection in each of the following locations: upper left 
arm, upper right arm, upper left thigh and upper right thigh (i.e., four injection sites per dose). 
Alternate subcutaneous sites may be used with approval of the principle investigator.
FPV-CV301 is administered as a subcutaneous injection preferably in the upper arm (i.e., one 
injection site per dose). An alternate subcutaneous site may be used with approval of the principle 
investigator.
3.2.3
M7824
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 either 300 
mg or 1,200 mg independent of body weight depending on dose level. M7824 is administered as 
an intravenous infusion with a mandatory 0.2 micron in-line filter.
In order to mitigate potential infusion-related reactions, premedication with 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 optional and at the discretion 
of the Investigator.
3.2.4
N-803
N-803 will be given via subcutaneous injection at a dose of 15 mcg/kg every four weeks on Arm 
1 and 10 mcg/kg every four weeks on Arm 2A and Arm 2B.    
N-803 dosing will be calculated using a weight obtained within one week 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. 


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3.2.5
NHS-IL12
NHS-IL12 will be administered at a dose of 8 or 16.8 mcg/kg by SC injection every 4 weeks on 
Arm 2A and Arm 2B depending on dose level assignment. The SC injection may be given in the 
upper arm, anterolateral thigh or abdomen and should preferably be at least 5 cm away from any 
other subcutaneous injection. The dose of NHS-IL12 will be calculated based on the weight of the 
subject determined within 72 hours prior to the day of drug administration. The dose of NHS-IL12 
used for the previous administration can be repeated if the change in the subject’s weight is 10% 
or less than the weight used for the last dose calculation. 
Note: Vital signs will be obtained prior to treatment and 30 minutes after administration of the last 
study drug. Participants should be observed for 30 minutes after the administration of the last study 
drug. 
3.3
STUDY INTERVENTION COMPLIANCE
All study drug administration will be given at NIH and documented in the electronic medical 
record.
3.4
DOSE MODIFICATIONS
3.4.1
Discontinuation
Treatment with individual agents will be discontinued in the case of:
•
Any Grade 4 or higher adverse drug reactions (ADRs) as defined by CTCAE v5.0 and 
assessed as possibly related to that agent by the Investigator, except for laboratory values 
that are asymptomatic or resolve to Grade ≤ 1 or baseline grade within 7 days without 
medical intervention”. 
•
Any Grade 3 ADRs possibly attributed to an agent except for any of the following:
o
Grade 3 flu-like symptoms or fever, as well as associated symptoms of fatigue, 
headaches, nausea, emesis which can be controlled with conservative medical 
management.  
o
Tumor flare phenomenon defined as local pain, irritation, or rash localized at sites of 
known or suspected tumor.
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
Grade 3 laboratory values that are asymptomatic or resolve to Grade ≤ 1 or baseline 
grade within 14 days. 
o
Keratoacanthoma and squamous cell carcinoma of the skin. 
o
Any endocrinopathy that can be medically managed with hormone replacement
o
Any grade 3 adverse drug reaction which can be medically managed with minimal risk 
to the participant (e.g., placement of a pleural catheter for recurrent inflammatory pleural 
effusions) and resolves to at least grade one or baseline grade within 14 days. 
3.4.2
Dose Delay
Individual agents should be withheld for any Grade 2 or 3 ADR possibly attributed to that agent 
until resolution to Grade ≤ 1 unless the ADR in the opinion of the investigator is not clinically 
relevant or can be medically managed with minimal risk to the participant. Should a clinically 


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relevant grade 2 or 3 ADR persist for more than 4 weeks, consideration should be given to 
discontinuing treatment with that individual agent at the discretion of the investigator. 
For non-medical logistical reasons, unrelated acute illnesses, or palliative radiation, scheduled 
assessments and dosing can be delayed up to 2 months. Where at all possible, dosing should be 
restarted to keep in line with the original treatment schedule.     
N-803 may be held or delayed 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; 
•
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.
3.4.3
Dose Modification 
Participants with dose modifications or skipped doses within DLT period (for first 6 participants 
in Arm 1 and all participants during dose escalation in Arm 2A) for reasons other than a DLT (e.g., 
logistical reasons) who do not experience a DLT within the DLT window will not be evaluable for 
DLTs and will be replaced for the DLT assessment.  Participants who have dose modifications or 
skipped doses within the DLT period for logistical reasons and nevertheless experience a DLT 
within the DLT period will be considered DLT evaluable. 
CEA/ MUC1 vaccines: Vaccine doses will not be modified but doses may be skipped per 
investigator discretion. 
N-803: Doses may be reduced to 4, 6 or 8 mcg/kg dose or doses may be skipped. On Arm1, if 
participants do not tolerate N-803 at 15 mcg/kg every 4 weeks, N-803 may be given on an 
alternative treatment schedule at lower doses every 2 weeks per investigator discretion.  
M7824: Doses may be reduced to a 200 or 300 mg flat dose or doses may be skipped.
NHS-IL12: Doses may be reduced to a 4,6, 8 or 12 mcg/kg dose or doses may be skipped.
Stopping Rule: Any death at least possibly related to study regimen will prompt a suspension of 
accrual and reassessment of available safety information prior to reopening study to accrual.
As a general rule consideration should be given to holding doses of drugs when a toxicity greater 
than grade 1 at least possibly attributed to a given drug occurs until resolution of that toxicity to at 
least grade 1 or better. If this occurs with N-803 or NHS-IL12 than consideration should be given 
to restarting at a reduced dose when restarting treatment with those agents. On Arm1, N-803 may 
be restarted at any scheduled visit as long as there is at least 14 days between doses of this agent. 
Dose reductions for vaccine and M7824 are not allowed. If repeated grade 2 adverse events occur 
than consideration should be given to permanently discontinuing a given agent. 


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3.4.4
Guidelines for Management of Infusion Reactions
(In addition to the below guidelines, investigators may also use NCCN, ASCO, SITC or FDA 
guidelines for Immune Related Adverse Events) 
NCI-CTCAE Grade
Treatment Modification for Infused Agent 
(M7824)
Grade 1 – mild
Mild transient reaction; infusion interruption not 
indicated; intervention not indicated.
Consider decreasing the infusion rate of the 
particular agent by 50% and monitoring closely 
for any worsening.
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 infusion of 
the particular agent.
Consider resuming infusion of the particular agent 
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.
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 infusion immediately and disconnect 
infusion tubing from the subject.
For grade 3 events:  Consider withdrawing 
immediately from treatment with that particular 
agent and not offering any further treatment with 
that agent based upon if the clinical condition can 
be safely managed.
For grade 4 events: Withdraw immediately from 
treatment and do not offer further treatment with 
that agent. 
If the infusion rate of M7824 has been decreased by 50% or interrupted due to an infusion reaction, 
keep it decreased for the next scheduled infusion. If no infusion reaction is observed in the next 
scheduled infusion, the infusion rate may be returned to baseline at the subsequent infusions based 
on investigator’s medical judgment. 
If hypersensitivity reaction occurs, the subject should be treated according to the best available 
medical practice.


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3.4.5
Guidelines for Management of Immune-Mediated Adverse Reactions
Gastrointestinal irAEs
Severity of Diarrhea/Colitis
(NCI-CTCAE v5)
Initial Management
Follow-up Management
Grade 1
Diarrhea: < 4 stools/day over Baseline
Colitis: asymptomatic 
Consider continuing M7824 
Symptomatic treatment (e.g. 
loperamide)
Consider close monitoring for 
worsening symptoms
Consider educating subject to 
report worsening immediately
If worsens:
Treat as Grade 2, 3 or 4. 
Grade 2 
Diarrhea: 4 to 6 stools per day over 
Baseline; IV fluids indicated < 24 
hours; not interfering with ADL
Colitis: abdominal pain; blood in stool 
Consider withholding M7824 
Symptomatic treatment
If improves to Grade ≤ 1: 
Consider resuming therapy
If persists > 7 days or recurs:
Consider treating as Grade 3 or 4.
Grade 3 to 4
Diarrhea (Grade 3): ≥ 7 stools per day 
over Baseline; incontinence; IV fluids 
≥ 24 h; interfering with ADL
Colitis (Grade 3): severe abdominal 
pain, medical intervention indicated, 
peritoneal signs
Grade 4: life-threatening, perforation
Consider withholding or permanently 
discontinuing M7824 for Grade 3 
events based upon if the clinical 
condition can be safely managed. For 
grade 4 events permanently 
discontinue treatment.
Consider 1.0 to 2.0 mg/kg/day 
prednisone IV or equivalent
Consider adding prophylactic 
antibiotics for opportunistic 
infections 
Consider lower endoscopy 
If improves: 
Consider continuing steroids 
until Grade ≤ 1, then tapering 
over at least 1 month; consider 
resuming therapy following 
steroids taper (for initial Grade 
3). 
If worsens, persists > 7 days, or 
recurs after improvement:
Consider adding infliximab 
5mg/kg (if no contraindication). 
Note: infliximab should not be 
used in cases of perforation or 
sepsis. 


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Dermatological irAEs
Grade of Rash
(NCI-CTCAE v5)
Initial Management
Follow-up Management
Grade 1 to 2 
Covering ≤ 30% body surface area 
Consider continuing M7824 
Consider symptomatic therapy (for 
example, antihistamines, topical 
steroids) 
If persists > 1 to 2 weeks or 
recurs: 
Consider withholding M7824 and 
OX40 therapy 
Consider skin biopsy 
Consider 0.5-1.0 mg/kg/day 
prednisone or equivalent. Once 
improving, consider tapering 
steroids over at least 1 month, 
consider prophylactic antibiotics 
for opportunistic infections, and 
consider resuming M7824 
therapy following steroids taper.
If worsens: 
Consider treating as Grade 3 to 4. 
Grade 3 to 4
Grade 3: Covering > 30% body 
surface area; 
Grade 4: Life threatening 
consequences 
Consider withholding or permanently 
discontinuing M7824 for Grade 3 
events based upon if the clinical 
condition can be safely managed. For 
grade 4 events permanently 
discontinue treatment.
Consider skin biopsy 
Consider dermatology consult 
Consider 1.0 to 2.0 mg/kg/day 
prednisone or equivalent
Consider adding prophylactic 
antibiotics for opportunistic 
infections 
If improves to Grade ≤ 1: 
Consider tapering steroids over at 
least 1 month; consider resuming 
therapy following steroids taper 
(for initial Grade 3).
Pulmonary irAEs
Grade of Pneumonitis
(NCI-CTCAE v5)
Initial Management
Follow-up Management
Grade 1
Radiographic changes only 
Consider withholding M7824 
Consider Pulmonary and Infectious 
Disease consults 
Consider re-assessing at least 
every 3 weeks
If worsens: 
Consider treating as Grade 2 or 
Grade 3 to 4. 
Grade 2
Mild to moderate new symptoms 
Consider withholding M7824 
Consider pulmonary and Infectious 
Disease consults
If improves: 


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Consider monitoring symptoms 
daily; consider hospitalization 
Consider 1.0 to 2.0 mg/kg/day 
prednisone or equivalent
Consider adding prophylactic 
antibiotics for opportunistic 
infections 
Consider bronchoscopy, lung biopsy 
When symptoms return to Grade 
≤ 1, consider tapering steroids 
over at least 1 month, and then 
consider resuming therapy 
following steroids taper 
If not improving after 2 weeks or 
worsening: 
Consider treating as Grade 3 to 4. 
Grade 3 to 4
Grade 3: Severe new symptoms; 
New/worsening hypoxia;
Grade 4: Life-threatening 
Consider withholding or permanently 
discontinuing M7824 for Grade 3 
events based upon if the clinical 
condition can be safely managed. For 
grade 4 events permanently 
discontinue treatment.
Consider hospitalization.
Consider pulmonary and Infectious 
Disease consults.
Consider 1.0 to 2.0 mg/kg/day 
prednisone or equivalent 
Consider adding prophylactic 
antibiotics for opportunistic 
infections 
Consider bronchoscopy, lung biopsy 
If improves to Grade ≤ 1: 
Consider tapering steroids over at 
least 1 month 
If not improving after 48 hours or 
worsening: 
Consider adding additional 
immunosuppression (for 
example, infliximab, 
cyclophosphamide, IV 
immunoglobulin, or 
mycophenolate mofetil) 
Hepatic irAEs
Grade of Liver Test Elevation
(NCI-CTCAE v5)
Initial Management
Follow-up Management
Grade 1
Grade 1 AST or ALT > ULN to 3.0 x 
ULN and/or Total bilirubin > ULN to 
1.5 x ULN 
Consider continuing M7824 
Consider continued liver function 
monitoring 
If worsens: 
 Consider treating as Grade 2 or 3 
to 4. 
Grade 2
AST or ALT > 3.0 to ≤ 5 x ULN 
and/or total bilirubin > 1.5 to ≤ 3 x 
ULN 
Consider withholding M7824 
If returns to Grade ≤ 1:
Consider resuming therapy.
If elevation persists > 7 days or 
worsens: 
Consider treating as Grade 3 to 4.
Grade 3 to 4
AST or ALT > 5 x ULN and/or total 
bilirubin > 3 x ULN 
Consider withholding or permanently 
discontinuing M7824 for Grade 3 
events based upon if the clinical 
condition can be safely managed. For 
grade 4 events permanently 
discontinue treatment. 
Consider 1.0 to 2.0 mg/kg/day 
prednisone or equivalent
If returns to Grade ≤ 1: 
Consider tapering steroids over at 
least 1 month 
If does not improve in > 7 days, 
worsens or rebounds: 
Consider adding mycophenolate 
mofetil 1 gram (g) twice daily 


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Consider adding prophylactic 
antibiotics for opportunistic 
infections 
Consider consulting 
gastroenterologist/ hepatologist
Consider obtaining MRI/CT scan of 
liver and liver biopsy if clinically 
warranted 
If no response within an 
additional 7 days, consider other 
immunosuppressants per local 
guidelines.
Renal irAEs
Grade of Creatinine Increased 
(NCI-CTCAE v5)
Initial Management
Follow-up Management
Grade 1
Creatinine increased > ULN to 1.5 x 
ULN
Consider continuing M7824 
Continue renal function monitoring
If worsens:
Consider treating as Grade 2 to 3 or 
4.
Grade 2 
Creatinine increased > 1.5 and ≤ 6 x 
ULN
Consider withholding M7824 
Consider 1.0 to 2.0 mg/kg/day 
prednisone or equivalent.
Consider adding prophylactic 
antibiotics for opportunistic infections
Consider renal biopsy
If returns to Grade ≤1:
Consider tapering steroids over at 
least 1 month, and consider 
resuming therapy following 
steroids taper.
If worsens: 
Treat as Grade 4.
Grade 3-4
Creatinine increased > 6 x ULN
Consider withholding or permanently 
discontinuing M7824 for Grade 3 
events based upon if the clinical 
condition can be safely managed. For 
grade 4 events permanently 
discontinue treatment.
Consider 1.0 to 2.0 mg/kg/day 
prednisone or equivalent.
Consider adding prophylactic 
antibiotics for opportunistic infections
Consider renal biopsy
Consider Nephrology consult
If returns to Grade ≤1:
Consider tapering steroids over at 
least 1 month.
Cardiac irAEs
Myocarditis
Initial Management
Follow-up Management
New onset of cardiac signs or 
symptoms and / or new laboratory 
cardiac biomarker elevations (e.g. 
troponin, CK-MB, BNP) or cardiac 
imaging abnormalities suggestive of 
myocarditis. 
Consider withholding or permanently 
discontinuing M7824 based upon if 
the clinical condition can be safely 
managed.
Consider hospitalization
If symptoms improve and 
immune-mediated etiology is 
ruled out, consider re-starting 
therapy.


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In the presence of life threatening 
cardiac decompensation, consider 
transfer to a facility experienced in 
advanced heart failure and 
arrhythmia management.
Consider cardiology consult to 
establish etiology and rule-out 
immune-mediated myocarditis. 
Consider myocardial biopsy if 
recommended per cardiology consult.
If symptoms do not 
improve/worsen, viral 
myocarditis is excluded, and 
immune-mediated etiology is 
suspected or confirmed following 
cardiology consult, consider 
managing as immune-mediated 
myocarditis.
Immune-mediated myocarditis
Consider withholding or permanently 
discontinuing M7824 based upon if 
the clinical condition can be safely 
managed.
Consider guideline based supportive 
treatment as appropriate as per 
cardiology consult.
Consider 1.0 to 2.0 mg/kg/day 
prednisone or equivalent
Consider adding prophylactic 
antibiotics for opportunistic 
infections.
Once improving, consider 
tapering steroids over at least 1 
month.
If no improvement or worsening, 
consider additional 
immunosuppressants (e.g. 
azathioprine, cyclosporine A).
*Local guidelines, or eg. ESC or AHA guidelines 
ESC guidelines website: https://www.escardio.org/Guidelines/Clinical-Practice-Guidelines
AHA guidelines website: 
http://professional.heart.org/professional/GuidelinesStatements/searchresults.jsp?q=&y=&t=1001
Endocrine irAEs
Endocrine Disorder
Initial Management
Follow-up Management
Grade 1 or Grade 2 
endocrinopathies (hypothyroidism, 
hyperthyroidism, adrenal 
insufficiency, type I diabetes 
mellitus)
Consider continuing M7824 
Consider endocrinology consult if 
needed
Consider starting thyroid hormone 
replacement therapy (for 
hypothyroidism), anti-thyroid 
treatment (for hyperthyroidism), 
corticosteroids (for adrenal 
insufficiency) or insulin (for Type I 
diabetes mellitus) as appropriate. 
Consider ruling-out secondary 
endocrinopathies (i.e. 
hypopituitarism / hypophysitis)
Consider continuing hormone 
replacement/suppression and 
monitoring of endocrine function 
as appropriate.
Grade 3 or Grade 4 
endocrinopathies (hypothyroidism, 
hyperthyroidism, adrenal 
insufficiency, type I diabetes 
mellitus)
Consider withholding or 
permanently discontinuing M7824 
for Grade 3-4 events based upon if 
the clinical condition can be safely 
managed. 
Consider resuming therapy once 
symptoms and/or laboratory tests 
improve to Grade ≤ 1 (with or 
without hormone 
replacement/suppression).


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Consider hospitalization
Consider endocrinology consult
Consider starting thyroid hormone 
replacement therapy (for 
hypothyroidism), anti-thyroid 
treatment (for hyperthyroidism), 
corticosteroids (for adrenal 
insufficiency) or insulin (for type I 
diabetes mellitus) as appropriate. 
Consider ruling-out secondary 
endocrinopathies (i.e. 
hypopituitarism / hypophysitis)
Consider continuing hormone 
replacement/suppression and 
monitoring of endocrine function 
as appropriate. 
Hypopituitarism/Hypophysitis 
(secondary endocrinopathies)
If secondary thyroid and/or adrenal 
insufficiency is confirmed (i.e. 
subnormal serum FT4 with 
inappropriately low TSH and/or low 
serum cortisol with inappropriately 
low ACTH):
•
Consider referring to 
endocrinologist for dynamic 
testing as indicated and 
measurement of other hormones 
(FSH, LH, GH/IGF-1, PRL, 
testosterone in men, estrogens 
in women) 
•
Consider hormone 
replacement/suppressive therapy 
as appropriate 
•
Consider performing pituitary 
MRI and visual field 
examination as indicated
If hypophysitis confirmed:
•
Continue M7824 if mild 
symptoms 
•
Consider withholding M7824 
and if moderate, severe or life-
threatening symptoms of 
hypophysitis. Consider 
hospitalization. Consider 
initiating corticosteroids (1 to 2 
mg/kg/day prednisone or 
equivalent) followed by 
corticosteroids taper during at 
least 1 month.
•
Consider adding prophylactic 
antibiotics for opportunistic 
infections.
Consider resuming therapy once 
symptoms and hormone tests 
improve to Grade ≤ 1 (with or 
without hormone replacement).
In addition, for hypophysitis 
with abnormal MRI, consider 
resuming M7824 only once 
shrinkage of the pituitary gland 
on MRI/CT scan is documented. 
Consider continuing hormone 
replacement/suppression therapy 
as appropriate.


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Other irAEs (not described above)
Grade of other irAEs 
(NCI-CTCAE v5)
Initial Management
Follow-up Management
Grade 2 or Grade 3 clinical signs or 
symptoms suggestive of a potential 
irAE
Consider withholding M7824 
pending clinical investigation
If irAE is ruled out, consider 
managing as appropriate 
according to the diagnosis and 
consider re-starting therapy
If irAE is confirmed, consider 
treating as Grade 2 or 3 irAE.
Grade 2 irAE or first occurrence of 
Grade 3 irAE
Consider withholding M7824 based 
upon if the clinical condition can be 
safely managed.
Consider 1.0 to 2.0 mg/kg/day 
prednisone or equivalent 
Consider adding prophylactic 
antibiotics for opportunistic 
infections 
Specialty consult as appropriate
If improves to Grade ≤ 1: 
Consider tapering steroids over 
at least 1 month and resuming 
therapy following steroids taper.
Recurrence of same Grade 3 irAEs
Consider permanently discontinuing 
M7824 based upon if the clinical 
condition can be safely managed; 
Consider
1.0 to 2.0 mg/kg/day
prednisone or equivalent
Consider adding prophylactic 
antibiotics for opportunistic 
infections 
Specialty consult as appropriate
If improves to Grade ≤ 1: 
Consider tapering steroids over 
at least 1 month.
Grade 4 
Permanently discontinue M7824 
Consider to 2.0 mg/kg/day
prednisone or equivalent and/or 
other immunosuppressant as needed
Consider adding prophylactic 
antibiotics for opportunistic 
infections 
Consider specialty consult as 
appropriate
If improves to Grade ≤ 1: 
Consider tapering steroids over 
at least 1 month
Requirement for 10 mg per day or 
greater prednisone or equivalent 
for more than 12 weeks for reasons 
other than hormonal replacement 
for adrenal insufficiency
Persistent Grade 2 or 3 irAE 
lasting 12 weeks or longer
Consider permanently discontinuing 
M7824 
Consider specialty consult as 
appropriate 


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Abbreviations: ACTH=adrenocorticotropic hormone; ADL=activities of daily living; 
ALT=alanine aminotransferase; AST=aspartate aminotransferase; BNP=B-type natriuretic 
peptide; CK-MB=creatine kinase MB; CT= computed tomography; FSH=follicle-stimulating 
hormone; GH=growth hormone; IGF-1=insulin-like growth factor 1; irAE=immune related 
adverse event; IV=intravenous; LH=luteinizing hormone; MRI=magnetic resonance imaging; 
NCI CTCAE=National Cancer Institute Common Terminology Criteria for Adverse Events; 
PRL=prolactin;T4=thyroxine; TSH=thyroid stimulating hormone; ULN=upper limit of normal


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3.5
STUDY CALENDAR
Procedure
Screening1 Baseline / 
Week 12
Week 
(2N+1)3
EOT4
Safety 
follow 
up5
Long Term 
follow up6
Treatment3 
X
X
NIH Advance Directives Form7
X
Medical History
X
Height
X
History (e.g., bleeding history) and 
physical exam, weight, vital signs, 
ECOG 
X
X
X
X
X
HIV, HCV, HepB
X
EKG
X
X
X
X
CBC with differential
X
X
X
X
X
Biochemical profile8
X
X
X
X
X
Tumor Markers9
X
X
X
CD410
X
X
X10
X
ACTH, TSH, Free T4, lipase, 
amylase, CRP
X
X11
Urinalysis 
X
Urine or serum pregnancy testing in 
women of childbearing potential (see 
Section 2.2) 
X
X
X
PT, INR, aPTT
X
X
X
X
X
Tumor Evaluation (CT Scan / 
MRI)12
X
X
X
Brain CT / MRI 13
X
Concomitant Medications
X
X
X
X
Adverse Events
X
X
X
X
Optional biopsy for immune 
analysis14
X
X
Research Blood15
X
X
X
Telephone Follow Up
X
X


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1. Screening evaluations performed within 28 days prior to the first drug administration, unless specified in Section 
2.2.
2. Baseline evaluations performed within 1 week prior to the first drug administration.
3. Schedule of therapeutic agents administered will be as outlined in Section 3.2, Figure 17, depending upon the arm 
of study participant has been assigned to. Of note each week in the study calendar above has a corresponding day # in 
Figure 17 (W1 = D1, W3 = D15, W5 = D29, etc.). CV301 will be given every 2 weeks for the first 3 doses followed 
by every 4 weeks on Arm 1 and every 6 weeks on Arm 2A and 2B thereafter. M7824 infusion will be every two weeks 
for both arms. Subjects assigned to Arm 1 will receive N-803 every 4 weeks. Subjects assigned to Arm 2 will receive 
N-803 or NHS-IL12 on an alternating schedule every 2 weeks (each of these agents will be given individually every 
4 weeks). Administration of study agents and indicated evaluations can be done up to 14 days earlier or delayed up to 
14 days due to holidays, inclement weather, conflicts, or similar reasons. The timing of subsequent administrations is 
adjusted to maintain a minimum of 11 days between treatments of similar agents. 
Note: Vital signs will be obtained prior to treatment and 30 minutes after administration of the last study drug. 
Participants should be observed for 30 minutes after the administration of the last study drug.
4. EOT – End of treatment visit: Where feasible, on the day of or within 7 days of the decision to discontinue treatment 
prematurely before completion of one year of treatment. Does not need to be completed if drug is withheld after one 
year of treatment.
5. 28 days (+/- 7 days) after last treatment. If subjects are not willing to come to NIH for FU visit, they will be contacted 
by phone to assess adverse events. 
6. Participants who have come off treatment for disease progression will be followed by phone annually for survival. 
Participants who have not progressed on treatment will continue to be followed and scanned per investigator discretion 
until progression. Those that completed one year of treatment will be invited for an additional year of treatment at the 
time of progression. Initial and follow up courses of treatment may extend beyond a year per investigator discretion. 
7. As indicated in Section 12.3, all subjects will be offered the opportunity to complete an NIH advanced 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
8. Biochemical profile: sodium, potassium, chloride, bicarbonate, calcium, glucose, BUN, creatinine, ALT, AST, 
alkaline phosphatase, total protein, albumin, and total and direct bilirubin. Serial Troponins and echocardiogram may 
also be added as clinically indicated if there is evidence or concern for myopericarditis. 
9. Evaluate CEA, CA19-9, CA125 and CA15-3 at baseline and follow elevated values thereafter.
10. In HIV positive participants; Every 8 weeks
11. Every 8 weeks.
12. Every 8 weeks. In the event of a PR or CR tumor imaging assessments may be performed every 3 months (+/- 2 
weeks) at the discretion of the investigator. Tumor assessment should be continued beyond end of treatment in 
participants who have not experienced PD until they experience PD in order to assess PFS. MRI will be used when 
CT scan is not an option to follow the disease clinically. Gadolinium will be used only for clinically indicated MRIs. 
Bone scans and other imaging assessments may also be performed as clinically indicated.
13. In participants with known CNS disease as described in Section 2.1.2.5. MRIs may be performed as clinically 
indicated in this population.
14. Optional biopsies at baseline and as close as possible to first imaging restaging.
15. Where feasible, research blood for all study assessments (see Section 4.2) will be collected at weeks 1, 3, 5, 7 and 
every 6 weeks thereafter in selected participants per PI discretion.


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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
There will be no compensation provided 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
Regardless of reason for removal from study therapy, participants will be asked to have a 28 day 
follow up safety visit. Participants who refuse to return for this visit will be asked to review any 
safety concerns by phone within this time period.  
3.7.1
Criteria for Removal from Protocol Therapy
•
Clinical or radiographic progression of disease except when the investigator feels the 
subject is still benefiting from treatment. (It is generally preferable for participants to 
remain on treatment past initial radiographic progression in case there is pseudo -
progression, except when the investigator feels that the clinical picture warrants 
changing therapy at initial progression).
•
Unacceptable toxicity possibly attributed to all active therapies. 
•
Participant requests to be withdrawn from active therapy.
•
Start of another systemic anticancer treatment (with the exception of continuation of 
maintenance therapy) or participation in another investigational therapeutic trial. Focal 
palliative radiotherapy, ablation, or surgery to a site of disease will not necessitate 
removal from protocol therapy. Investigator discretion.
•
Positive pregnancy test.
3.7.2
Off-Study Criteria
•
Screen failure.
•
PI decision to end the study.
•
Participant requests to be withdrawn from study. 
•
Participant lost to follow up.
•
Investigator discretion. 


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•
Death.
3.7.3
Lost to Follow-up
A participant will be considered lost to follow-up if he or she fails to return for 4 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 the 
next two 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
Any medications (other than those excluded by the clinical trial protocol) that are considered 
necessary to protect subject welfare or alleviate symptoms and will not interfere with the trial 
medication may be given at the Investigator’s discretion.
Palliative radiotherapy delivered in a normal organ-spearing technique may be administered during 
the trial. The assessment of PD will not be based on the necessity for palliative radiotherapy.
4.1
THE FOLLOWING TREATMENTS SHOULD NOT BE ADMINISTERED DURING THE TRIAL: 
•
Other immunotherapies or immunosuppressive drugs (for example, chemotherapy or 
systemic corticosteroids except for prophylaxis or treatment of allergic reactions, 
endocrine replacement therapy at low dose prednisone [≤ 10 mg daily] or equivalent, for 
the treatment of irAEs, or for short courses (≤ 14 days) as appropriate medical therapy for 
unrelated medical conditions (e.g., asthma).  Steroids with no or minimal systemic effect 
(topical, inhalation) are allowed.
•
Prophylactic use of corticosteroids for infusion related reactions. Corticosteroid 
administration prior to CT scans in participants with intravenous contrast allergy is 
allowed.
•
Any live vaccine therapies for the prevention of infectious disease. Administration of 
inactivated vaccines is allowed (for example, inactivated influenza vaccines or locally 
approved COVID vaccines).
•
Systemic anticancer treatment.


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4.2
N-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.
5
CORRELATIVE STUDIES FOR RESEARCH / PHARMACOKINETICS STUDIES 
5.1
BIOSPECIMEN COLLECTION 
Test/assay
Volume 
(approx.) per 
Timepoint
Type of tube a
Collection point
Location of specimen 
analysis*
Standard and 123 
immune cell subsets 
by FACS
LTIB
Functional Analysis 
of immune cell 
subsets by FACS
LTIB
Antigen Specific 
Immune Response 
by cytokine staining 
assay
LTIB
T cell clonality by 
immunseq platform
LTIB and NCI 
Frederick Genomic 
Core Facility
RNA expression 
level of 770 genes
60-80 mL 
blood for 
PBMCs
Sodium 
heparin (green 
top) tubes
LTIB and NCI 
Frederick Genomic 
Core Facility
8 mL blood for 
serum
SST
Soluble Factors (to 
include sCD27 and 
sCD40 ligand) by 
ELISA 
10 mL blood 
for plasma
EDTA tube
See study calendar 
3.5
LTIB


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Test/assay
Volume 
(approx.) per 
Timepoint
Type of tube a
Collection point
Location of specimen 
analysis*
Immune Markers 
by IHC
Tumor samples
N/A
GMB TIME Lab
RNA expression 
level of 770 genes
Tumor samples
N/A
LTIB and NCI 
Frederick Genomic 
Core Facility
T cell clonality by 
immunseq platform
Tumor samples
N/A
LTIB and NCI 
Frederick Genomic 
Core Facility
*Research blood samples will be sent to the Clinical Services Program – Leidos Biomedical 
Research, Inc. (CSP) (Section 5.3.1) for barcoding, initial processing and storage. Tissue will be 
sent to the Laboratory of Pathology as described in Section 5.3.2. From these facilities, coded, 
linked samples will be sent to the designated labs for analysis upon request.
a Please note that tubes and media may be substituted based on availability with the permission of 
the PI or laboratory investigator.
5.1.1
Immune Phenotyping
Exploratory immunologic studies will be conducted to evaluate the study drug’s effect on the 
immune response before and after treatment, to gain insight into potential biomarkers, and help 
improve the administered therapy. Blood will be collected as per Study Calendar 3.5. The 
following immune assays may be performed at the Laboratory of Tumor Immunology and Biology 
(LTIB) at the NCI’s Center for Cancer Research (CCR) in select participants where adequate 
samples are available:
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, using multi-color flow 
cytometry.
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 using flow-based 
assays.
3. PBMCs may be analyzed for tumor antigen-specific immune responses using an 
intracellular cytokine staining assay. PBMCs will be stimulated in vitro with overlapping 
15-mer peptide pools encoding the tumor-associated antigens such as CEA, MUC-1 and 
Brachyury; 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. 


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5.1.2
Soluble Factors
Samples for soluble factor analysis will be collected as per Study Calendar 3.5. 
-Sera and/or plasma may be analyzed pre- and post-therapy for the following soluble factors: 
sCD27, sCD40 ligand using commercial ELISA kits.
-Sera and/or plasma 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).
5.1.3
Analyses of Tumor Tissue for Immune Markers
Study of immune infiltration as well as PD-L1 status within the tumor microenvironment pre vs. 
post treatment by IHC and/or multiplex immunofluorescence may be performed by the GMB 
TIME Lab. Where available, archival tumor samples will be requested. For participants with 
lesions amenable to biopsy, two optional biopsies may be performed at baseline and at first 
restaging. Tumor samples will be sent to the Laboratory of Pathology for disease evaluation; 
remaining samples will be used for research. Tissue samples for research may also be stored in 
CSP as described in Section 5.3.1.  
5.2
SAMPLES FOR GENETIC/GENOMIC ANALYSIS
5.2.1
Description of the Scope of Genetic/Genomic Analysis
5.2.1.1
RNA and T-cell Receptor Clonality Analysis of Blood and Tumor Tissue
Where possible, RNA expression and T-cell receptor clonality analysis will be done on the 
peripheral blood as well as archived tumor tissue or optional biopsies to help further evaluate 
changes in immune response and RNA expression levels with treatment as well as to determine 
tumor and infiltrating lymphocyte characteristics which may be predictive of response to 
treatment. In addition, these analyses will also be used to gauge resistance mechanisms and 
additional targets for future therapy. Coded, linked samples may be analyzed for RNA expression 
levels using the Nanostring platform and T-cell receptor clonality using the ImmunoSeq platform 
(LTIB and NCI Frederick Genomic Core Facility).
NCI Fredrick Genomic Core Facility:
Leidos Biomedical Research, Inc:
Dr. Xiaolin Wu 
ATRF, Rm C3016
8560 Progress Drive
Frederick, MD 21701
Ph. 301-846-7677
5.2.2
Description of How Privacy and Confidentiality of Medical Information/Biological 
Specimens will be Maximized
Confidentiality for genetic samples will be maintained as described (Section 5.3.1 and 5.3.2).
5.3
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 


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will not be sent outside the National Institutes for Health (NIH) without appropriate approvals 
and/or agreements, if required.
The PI will record any loss or unanticipated destruction of samples as a deviation. Reporting will 
be per the requirements of Section 7.2
5.3.1
Sample Management and Storage at Clinical Services Program – Leidos Biomedical 
Research, Inc. (CSP)
Clinical Services Program - Leidos Biomedical Research, Inc.
Attn: Theresa Burks 
1050 Boyles Street
Bldg. 496/Room 121
Frederick, MD 21702
On days samples are drawn, Jen Bangh at CSP (part of NCI Frederick Central Repositories) should 
be notified (phone: [301] 846-5893; fax [301] 846-6222). 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. 
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, 


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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. 
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.
5.3.2
Procedures for Storage of Tissue Specimens in the Laboratory of Pathology
Tissues designated for clinical diagnostics are transported to the Laboratory of Pathology (LP) 
where they are examined grossly and relevant portions are fixed, embedded in paraffin and 
sectioned and stained for diagnostic interpretation. Unutilized excess tissues are stored for up to 
three months, in accordance with College of American Pathologists/Joint Commission on 
Accreditation of Healthcare Organizations (CAP/JCAHO) guidelines, and then discarded. 
Following completion of the diagnostic workup, the slides and tissue blocks are stored indefinitely 
in the LP’s clinical archives. All specimens are catalogued and retrieved utilizing the clinical 
laboratory information systems, in accordance with CAP/JCAHO regulations. The use of any 
stored specimens for research purposes is only allowed when the appropriate IRB approval has 
been obtained. In some cases, this approval has been obtained via the original protocol on which 
the participant was enrolled.
5.3.3
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 
subjects will be stored until they are no longer of scientific value or if a subject withdraws consent 
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.
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. 


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Document AEs from the time the study consent is signed through 28 days after removal from study 
treatment or until off-study, whichever comes first. Adverse events that are serious need to be 
recorded through 28 days after the last intervention. Beyond 28 days after the last intervention and 
through long term follow up (survival of subject), only adverse events which are serious and related 
to the study intervention 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. 
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.
How and where will the data be shared? 
Data will be shared through:
•
An NIH-funded or approved public repository: clinicaltirals.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.


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6.2.2
Genomic Data Sharing Plan
Unlinked genomic data will be deposited in public genomic databases such as dbGaP in 
compliance with the NIH Genomic Data Sharing Policy. 
6.3
RESPONSE CRITERIA
6.3.1
Antitumor Response
Tumor assessments may include the following evaluations: physical examination (with photograph 
and measurement of skin lesions, as applicable); cross-sectional imaging using computed 
tomography (CT) or magnetic resonance imaging (MRI) scan of the chest, abdomen, and pelvis 
(pelvis scan is optional unless known pelvic disease is present at baseline); nuclear bone scan for 
subjects with known/suspected bone lesions; and CT or MRI scan of the brain (only as clinically 
warranted based on symptoms/findings). The preferred method of disease assessment is CT with 
contrast. If CT with contrast is contraindicated, CT of the chest without contrast and MRI scan of 
the abdomen/pelvis is preferred. 
At baseline, tumor lesions will be selected and categorized as target or non-target lesions. Target 
lesions include those lesions that can be accurately measured in at least 1 dimension as ≥ 20 mm 
with conventional techniques or ≥ 10 mm with CT scan. Malignant lymph nodes with a short axis 
diameter ≥ 15 mm can be considered target lesions. Up to a maximum of 2 target lesions per organ 
and 5 target lesions in total will be identified at baseline. These lesions should be representative of 
all involved organs and selected based on their size (those with the longest diameter) and their 
suitability for accurate repeated measurements. A sum of the longest lesion diameter (LLD) for all 
target lesions will be calculated and reported as the baseline sum LLD. For malignant lymph nodes 
identified as target lesions, the short axis diameter will be used in the sum of LLD calculation. All 
other lesions (or sites of disease) should be identified as non-target lesions (including bone 
lesions).
All post-baseline response assessments should follow the same lesions identified at baseline. The 
same mode of assessment (e.g., CT) used to identify/evaluate lesions at baseline should be used 
throughout the course of the study unless subject safety necessitates a change (e.g., allergic 
reaction to contrast media).
For the primary endpoint antitumor activity will be evaluated with target and/or non-target lesions 
according to RECIST Version 1.1.
6.3.2
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.
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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 
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. 
6.3.3
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. 


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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.
6.3.4
Response Criteria
All the scans performed at Baseline and other imaging performed as clinically required (other 
supportive imaging) need to be repeated at subsequent visits. In general, lesions detected at 
Baseline need to be followed using the same imaging methodology and preferably the same 
imaging equipment at subsequent tumor evaluation visits.
Brain CT / MRI scan should be performed, if clinically indicated by development of new specific 
symptoms or on the discretion of the Principal Investigator. For each subject, the Investigator will 
designate 1 or more of the following measures of tumor status to follow for determining response: 
CT or MRI images of primary and / or metastatic tumor masses, physical examination findings, 
and the results of other assessments. All available images collected during the trial period will be 
considered. The most appropriate measures to evaluate the tumor status of a subject should be 
used. The measure(s) to be chosen for sequential evaluation during the trial have to correspond to 
the measures used to document the progressive tumor status that qualifies the subject for 
enrollment. The tumor response assessment will be assessed and listed according to the Study 
Calendar 3.5.
The foreseen treatment duration is until disease progression verified by a scan subsequent to the 
initial documentation of PD, unacceptable toxicity, or any criterion for withdrawal from the trial 
occurs (see Section 6.3). Before stopping the treatment, progressive disease should be confirmed 
by imaging 4 to 6 weeks (preferably 6 weeks, but not later) after progression has been diagnosed 
according to RECIST 1.1 [44, 45]. If progression is based on the occurrence of a new lesion in an 
area not scanned at Baseline, a further on-study scan 6 weeks later should be considered before 
performing the 28-Day Safety Follow-up visit. 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.


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•
The Investigator does not consider it necessary to administer a salvage therapy. 
The treatment should be stopped immediately, if the subject does not tolerate M7824 or if 
therapeutic failure occurs, which requires urgent treatment with an additional drug or results in 
clinically significant progression / deterioration. 
Tumor responses to treatment will be assigned based on the evaluation of the response of target, 
non-target, and new lesions according to RECIST 1.1 (all measurements should be recorded in 
metric notation).
•
To assess objective response, the tumor burden at baseline will be estimated and used for 
comparison with subsequent measurements. At baseline, tumor lesions will be categorized in target 
and non-target lesions according to RECIST 1.1.
Results for these evaluations will be recorded with as much specificity as possible so that pre  and 
post-treatment results will provide the best opportunity for evaluating tumor response. 
Any CR or PR should be confirmed according to RECIST 1.1. In the case of a PR or CR, a 
confirmatory CT or MRI scan should be done no sooner than 4 weeks (preferably at the scheduled 
6-week interval). 
The Investigator may perform scans in addition to a scheduled trial scan for medical reasons or if 
the Investigator suspects PD.
As an exploratory endpoint antitumor activity will also be evaluated according to iRECIST
Using iRECIST criteria the following will be incorporated into assessment:
1. An increase in the sum of target lesions of more than 20%, unequivocal increase in non-
target lesions or new lesions result in iUPD (unconfirmed progressive disease); iUPD can 
be assigned multiple times as long as iCPD (confirmed progressive disease) is not confirmed 
at the next assessment.
2. Progression is confirmed in the target lesion category if the next imaging assessment after 
iUPD (4–8 weeks later) confirms a further increase in sum of measures of target disease 
from iUPD, with an increase of at least 5 mm. Progression is confirmed in the non-target 
lesion category if subsequent imaging, done 4–8 weeks after iUPD, shows a further 
unequivocal increase in non-target lesions. Progression is confirmed in the new lesions 
category if at next assessment additional new lesions appear or an increase in size of 
previously seen new lesions is seen (≥5 mm for sum of new lesion target).
3. However, the criteria for iCPD (after iUPD) are not considered to have been met if 
complete response, partial response, or stable disease criteria (compared with baseline and 
as defined by RECIST 1.1) are met at the next assessment after iUPD. The status is reset 
(unlike RECIST 1.1, in which any progression precludes later complete response, partial 
response, or stable disease). iCR, iPR, or iSD should then be assigned; and if no change is 
detected, then the timepoint response is iUPD.
6.3.5
Response Criteria by RECIST 1.1
6.3.5.1
Evaluation of Target Lesions
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.


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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.
6.3.5.2
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).
6.3.5.3
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.
For Participants with Measurable Disease (i.e., Target Disease)
Target 
Lesions
Non-Target 
Lesions
New 
Lesions
Overall 
Response
Best Overall Response when 
Confirmation is Required*
CR
CR
No
CR
>4 wks. Confirmation**
CR
Non-
CR/Non-PD
No
PR
CR
Not 
evaluated
No
PR
>4 wks. Confirmation**


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Target 
Lesions
Non-Target 
Lesions
New 
Lesions
Overall 
Response
Best Overall Response when 
Confirmation is Required*
PR
Non-
CR/Non-
PD/not 
evaluated
No
PR
SD
Non-
CR/Non-
PD/not 
evaluated
No
SD
Documented at least once >4 
wks. from baseline**
PD
Any
Yes or 
No
PD
Any
PD***
Yes or 
No
PD
Any
Any
Yes
PD
no prior SD, PR or CR
*
See RECIST 1.1 manuscript for further details on what is evidence of a 
new lesion.
**
Only for non-randomized trials with response as primary endpoint.
***
In exceptional circumstances, unequivocal progression in non-target 
lesions may be accepted as disease progression.
Note: Participants with a global deterioration of health status requiring 
discontinuation of treatment without objective evidence of disease 
progression at that time should be reported as “symptomatic 
deterioration.” Every effort should be made to document the objective 
progression even after discontinuation of treatment.
For Participants with Non-Measurable Disease (i.e., Non-Target Disease)
Non-Target Lesions
New Lesions
Overall Response
CR
No
CR
Non-CR/non-PD
No
Non-CR/non-PD*
Not all evaluated
No
not evaluated
Unequivocal PD
Yes or No
PD


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Non-Target Lesions
New Lesions
Overall Response
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 measured is not advised
6.3.5.4
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. 
6.3.5.5
Progression-Free Survival
PFS is defined as the duration of time from start of treatment to time of progression or death, 
whichever occurs first.
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 5.0 will be utilized for AE 
reporting. All appropriate treatment areas should have access to a copy of the CTCAE version 5.0. 
A copy of the CTCAE version 5.0 can be downloaded from the CTEP web site 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm). 
7
NIH REPORTING REQUIREMENTS / DATA AND SAFETY MONITORING PLAN
7.1
DEFINITIONS
Please refer to definitions provided in Policy 801: Reporting Research Events found at: 
https://irbo.nih.gov/confluence/pages/viewpage.action?pageId=36241835#Policies&Guidance-
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 
at: 


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https://irbo.nih.gov/confluence/pages/viewpage.action?pageId=36241835#Policies&Guidance-
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 at: 
https://irbo.nih.gov/confluence/pages/viewpage.action?pageId=36241835#Policies&Guidance-
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 CV301 vaccine 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 CV301 vaccine but are not fatal or life-threatening, much 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; 


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•
participant population (such as disease indication and general age group, e.g., adult or 
pediatric); 
•
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; and
•
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; and 
•
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 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) – Sponsor (OSRO)
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 3.4.3) 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
Adverse Event of Special Interest (AESI)
Mucosal bleeding events which are at least possibly related to study drug (M7824) will be 
captured as AESIs. These events will not require expedited reporting to the study sponsor unless 
they also meet SAE criteria. 
8.1.3
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 8.1.4);
•
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 
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o
A hospitalization/admission that is solely driven by non-medical reasons (e.g., 
hospitalization for participant convenience) is not considered a serious adverse event. 
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 participant or subject and may 
require medical or surgical intervention to prevent one of the outcomes listed in this 
definition.
8.1.4
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 participant 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).
8.1.5
Severity
The severity of each Adverse Event will be assessed utilizing the CTCAE version 5.0.
8.1.6
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.
8.2
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 


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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 must be reported to the sponsor 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 overall survival, which includes death due to disease progression and hospitalization due to 
disease progression are part of the study objectives, and captured as an endpoint in this study, 
death/hospitalization due to disease progression will not be reported in 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.
8.5
SAFETY REPORTING CRITERIA TO THE PHARMACEUTICAL COLLABORATORS
Reporting will be per the collaborative agreement. 
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. 


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Pregnancy itself is not regarded as an SAE. However, congenital abnormalities or birth defects 
and spontaneous miscarriages that meet serious criteria (Section 8.1.3) should be reported as SAEs. 
The outcome of all pregnancies should be followed up and documented.
8.6.2
Paternal Exposure
Male participant should refrain from fathering a child or donating sperm during the study and for 
2 months after the last dose of M7824.
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 2 months after the last dose should, if 
possible, be followed up and documented.
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 in expedited manner to the FDA in accordance 
to 21 CFR 31.2.32. 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 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 PLAN
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 
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•
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 
of each protocol. The first activity is before the study starts to conduct a Site Assessment Visit 
(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 occur at the study site. 
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 HYPOTHESIS
The primary objectives of this trial are to determine the objective response rate of combination 
immunotherapy in two separate arms evaluating triple or quadruple therapy in participants with 
checkpoint naïve MSS small bowel or colorectal cancer. A secondary hypothesis (objective) will 
be to obtain preliminary data on duration of response, PFS, OS and ratio of participants that are 
hospitalized because of adverse events attributed to disease progression for each of these arms. An 
exploratory hypothesis (objective) will be to evaluate exploratory immunologic studies to 
understand and improve the administered treatment. 
10.2 SAMPLE SIZE DETERMINATION
Initially, Arm 1 will be conducted using the phase II design described below. Upon its completion, 
a dose level escalation of NHS-IL12 will be conducted, called Arm 2A. This arm will enroll up to 
18 participants in the three dose levels and the participants at the highest safe dose level (or MTD) 


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will be included in the first stage of the phase II evaluation of the quadruple therapy (Arm 2B) as 
described below. 
In participants with microsatellite stable small bowel or colon cancer, the clinical response rate to 
current single agent therapies is very low (<5%). It would be desirable if by using a combination 
of multiple agents, the response rate would be improved. To establish the efficacy of each of the 
proposed combinations (triple or quadruple therapy), the primary objective would be to determine 
if the proposed combination would rule out a 10% response rate and result in a response rate 
consistent with 40%. As such, participants on each arm (Arm 1 or 2B) will be treated in a trial 
conducted using a Simon optimal two-stage phase II trial design (Simon R, Controlled Clinical 
Trials 10:1-10, 1989) to rule out an unacceptably low PR+CR rate of 10% (p0=0.10) in favor of 
an improved response rate of 40% (p1=0.40). 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 9 evaluable participants, and if 0 to 1 of the 9 have a clinical response, 
then no further participants will be accrued in that cohort. For evaluation of the quadruple therapy, 
the first 6 participants may include those at the MTD from Arm 2A, assuming they are fully 
evaluable for response. For simplicity, once these participants are included in the Phase II 
evaluation, they will be considered as if they were in Arm 2B in the descriptions below. If 2 or 
more of the first 9 participants have a response, then accrual would continue until a total of 20 
evaluable participants have been treated on that arm. As it may take up to several months to 
determine if a participant has experienced a response, a temporary pause in the accrual may be 
necessary to ensure that enrollment to the second stage is warranted. If there are 2 to 4 participants 
with a response out of 20 participants in a given arm, this would be an uninterestingly low response 
rate. If there were 5 or more of 20 (25.0%) who experienced a response, this would be sufficiently 
interesting to warrant further study in later trials in this disease type. Under the null hypothesis 
(10% response rate), the probability of early termination is 77.5%.
It is anticipated that 2-3 participants per month may enroll onto this trial. Thus, it is expected that 
the trial can enroll up to 46 evaluable participants (up to 12 for safety evaluation during dose 
escalation in Arm 2A, 40 for primary efficacy analyses in Arm 1 and Arm 2B together, minus 6 
included from the dose escalation Arm 2A) in approximately two years. To allow for a small 
number of screen failures and participants who will be inevaluable for the primary objective 
analysis (e.g., checkpoint refractory), the accrual ceiling will be set at 80 participants.   
10.3 POPULATIONS FOR ANALYSES
All participants who receive any investigational treatment will be evaluable for safety and toxicity 
evaluations. All participants will be evaluable for toxicity from the time of their first treatment 
with any agent. 
For efficacy, a modified intention to treat population will be used. Only those participants who 
have measurable disease present at baseline and have had their disease re-evaluated will be 
considered evaluable for response. (Note: Participants who discontinue treatment before the first 
scan due to treatment related toxicity or exhibit objective disease progression prior to first 
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10.4 STATISTICAL ANALYSES
10.4.1 General Approach
The fraction of participants with response to the triple or quadruple therapy will be reported. For 
those enrolled during the first 6 participants on Arm 1 or during the dose escalation for NHS-IL12 
(Arm 2A), the participants will be evaluated with respect to the grades and types of toxicities 
obtained. The results will be presented descriptively and tabled if appropriate.
10.4.2 Analysis of the Primary Endpoints
The percentage of subjects that achieve an objective confirmed complete or partial overall tumor 
response using RECIST Version 1.1 will be evaluated per arm (Arm 1 and 2B). If anti-tumor 
responses are observed, the 95% confidence interval of the response rate will be evaluated.  
It is possible that the response rates observed with combination immunotherapy will be less in 
participants whom have previously received checkpoint therapy and not be truly reflective of a 
population of participants whom have not had prior checkpoint therapy. While checkpoint 
experienced participants will not be excluded from enrollment, the primary efficacy analyses will 
be limited to checkpoint naïve participants with MSS colon cancer and efficacy analyses in the 
checkpoint refractory. 
10.4.3 Analysis of the Secondary Endpoints
Data will be obtained on duration of response, PFS, OS and ratio of participants that are 
hospitalized because of adverse events attributed to disease progression.
10.4.3.1 Duration of Response
The duration of overall response will be evaluated by arm for those with a PR or greater in Arm 1 
and Arm 2B. 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 PD is objectively documented 
and is evaluated using the Kaplan-Meier method.
10.4.3.2 Progression-Free Survival
PFS will be evaluated by arm using Kaplan-Meier methods. PFS will be defined as the time from 
the date of first treatment to the date of disease progression or death (any cause) whichever occurs 
first. Subjects who do not have disease progression or have not died at the end of follow up will 
be censored at the last known date the subject was progression free.
10.4.3.3 Objective Response
Objective response is a complete or partial radiographic response as defined by RECIST 1.1 
(Section 6.3.5).
10.4.3.4 Overall Survival
OS will be evaluated using Kaplan-Meier methods. OS will be defined as the time from the date 
of first treatment to the date of death (any cause). Subjects who are alive at the end of follow up 
will be censored at the last known date alive.
10.4.4 Safety Analyses
Safety endpoints will be analyzed as summary statistics during treatment and/or as change scores 
from baseline assessments.  AEs will be coded as defined in the Medical Dictionary for Regulatory 
Activities (MedDRA). All AEs will be recorded and tabulated following each treatment. AEs will 


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be recorded by severity, frequency, and relationship to the study intervention and will be presented 
by System Organ Class (SOC) designations and preferred term groupings. Information on each 
AE will include start date, stop date, severity, relationship, expectedness, outcome, and duration. 
Adverse events leading to premature discontinuation from the study intervention and serious 
treatment-emergent AEs will be presented either in a Table or a Listing. 
In addition, overall safety will be assessed by descriptive analyses using tabulated frequencies of 
AEs by grade using CTCAE Version 5 within dose cohorts and for the overall study population in 
terms of treatment-emergent AEs, SAEs, and clinically significant changes in safety laboratory 
tests, physical examinations, ECGs, and vital signs. 
10.4.5 Baseline Descriptive Statistics
Baseline Characteristics will be described. 
10.4.6 Planned Interim Analyses
Interim assessment of efficacy will be made according to the Simon two stage Phase II designs of 
each arm described.
10.4.7 Tabulation of Individual Participant Data
Individual responses in a cohort may be depicted within a larger group using a waterfall plot or 
spider diagram. 
10.4.8 Exploratory Analyses
The following are the planned exploratory objectives and endpoints:
To conduct exploratory immunologic studies to understand and improve the administered 
treatment, including:
•
peripheral immune subset analysis before and on treatment;
•
soluble factors circulation (e.g., sCD27 and sCD40 ligand) before and on treatment;
•
tumor tissue PD-L1 expression and immune infiltration before and after treatment.
Where feasible, exploratory immune analyses will be conducted to evaluate anti-tumor immune 
responses. Immune response will be assessed among all subjects treated in each phase II cohort. 
The magnitude of immune responses will be described. A subject will be considered evaluable for 
immune response if they receive at least one dose of treatment. The percentage of subjects with a 
positive immune response will be evaluated separately by arm. For flow cytometry analyses on 
PBMC samples, Student t-tests or Wilcoxon rank sum tests as appropriate will be performed on 
percentages of TNF- and/or IFN- expressing cells among the different cohorts to determine any 
significant differences in cell populations between arms For antigen specific T cell responses, a 
positive immune response is defined by CMI reactivity in ex vivo stimulation using a flow 
cytometric readout (cytokine production or CD107 expression). Antigen-specific peptide 
challenge assays require a readout of >250 reactive T-cells/million cells above the background 
[46]. In general, evaluations of soluble factors and tumor tissue immune infiltration will be 
compared before vs. after treatment using appropriate paired tests. Any statistical analyses 
performed on these exploratory endpoints will be done without formal adjustment for multiple 
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To assess responses to therapy using iRECIST per treatment assignment (three or four drug 
combination). 
To assess response to therapy using RECIST and iRECIST in checkpoint refractory participants 
(including participants with MSI disease).
To assess responses to therapy by RAS mutation status.
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 and NHS-IL12.
A CRADA (02561) is in place with Bavarian Nordic for the supply of CV301 (MVA-BN-CV301 
and FPV-CV-301). 
A CRADA (03058) is in place with ImmunityBio, Inc. for the supply of N-803.
12 HUMAN SUBJECTS PROTECTIONS  
12.1 RATIONALE FOR SUBJECT SELECTION
Subjects from all racial/ethnic groups are eligible for this study if they meet the eligibility criteria. 
Efforts will be made to extend accrual to a representative population. Due to impaired cellular 
immunity which may affect the efficacy of treatment, participants with poorly controlled HIV as 
well as patents with detectable viral loads of hepatitis B and C will be excluded. 
As there is a risk of severe bleeding with this study drug, participants must be willing to receive 
blood transfusions if medically necessary for their own safety. Participants must be able to receive 
blood transfusions in order to minimize the risks of receiving M7824.
12.2 PARTICIPATION OF CHILDREN
Individuals under the age of 18 will not be eligible to participate in this study because of unknown 
toxicities in pediatric participants.
12.3 PARTICIPATION OF SUBJECTS UNABLE TO GIVE CONSENT
Adults unable to provide 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, the subjects will remain in 
the study because there is a prospect of direct benefit from research participation. 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 an LAR, as needed.
Please see Section 12.5.1 for consent procedure. 


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12.4 RISK/BENEFIT ASSESSMENT
12.4.1 Known Potential Risks
Some of the procedures performed on this study are not known to be associated with risk. These 
include urine tests and EKGs. Below are a list of procedures and study interventions that are 
associated with risk.
12.4.1.1 Study Drug Risks 
Risks include the possible occurrence of any of a range of side effects which are listed in  
Sections 14.1.2, 14.2.2, 14.3.2 and 14.4.2.
Participants may be harmed from being in this study by toxicity due to the drug or combination 
of drugs given during this study. 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. 
12.4.1.2 Risk of Optional Biopsies
All care will be taken to minimize risks that may be incurred by tumor sampling. However, there 
are procedure-related risks (such as bleeding, infection and visceral injury) that will be explained 
fully during informed consent.
12.4.1.3 Risks of Exposure to Ionizing Radiation
This research study involves: 7 possible additional CT CAP scans, 1 brain CT scan, and 2 CT 
guided biopsies collected for research purposes. 
Subjects undergoing these scans and biopsies will be exposed to 9.4 rem. The CT scans and CT 
guided biopsies in this study will expose the research participant to 31.3 years’ worth of 
background radiation. This level of exposure results in an increased risk of cancer. 
12.4.1.4 CT Scan Risk 
CT scans create low levels of radiation, which has a small potential to cause cancer and other 
defects. However, the risk associated with scan is small. 
12.4.1.5 Risks Due to Contrast Agents for CT 
Contrast agents can cause allergic reactions and kidney damage. Allergic reactions can include 
mild itching associated with hives but can also result in a serious life-threatening emergency from 
difficulty breathing. If this occurs, it is treatable. 
12.4.1.6 Risk of MRI
People are at risk for injury from the MRI magnet if they have some kinds of metal in their body. 
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. 
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12.4.1.7 Risk of Gadolinium Enhanced MRI
The gadolinium infusion may cause mild symptoms such as coldness in the arm during the 
injection, a metallic taste, headache, and nausea. There are risks of an IV catheter include bleeding, 
infection, or inflammation of the skin and vein with pain and swelling.  
Procedure-related risks from MRI and gadolinium enhanced MRI will be explained fully during 
informed consent.
12.4.1.8 Risks of Blood Collection
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. 
The amount of blood that may be drawn from adult participants for research purposes shall not 
exceed 10.5 mL/kg or 550 mL, whichever is smaller, over any eight-week period. Specific volumes 
are also listed in table in Section 5.1.
12.4.1.9 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.
12.4.2 Known Potential 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.
12.4.3 Assessment of Potential Risks and Benefits
Advanced small bowel and colorectal cancers are in need of improved therapy options. Preclinical 
studies suggest that the use of a combination of multiple immunotherapy agents may have 
improved anti-tumor efficacy. 
A number of clinically appropriate strategies to minimize risks to participants have been built into 
the protocol through the means of inclusion/exclusion criteria, monitoring strategies, and 
management guidelines. Overall, the potential benefits of the combination of a vaccine targeting  
tumor associated antigens (CV301), a bifunctional fusion protein targeting PD-L1 and TGF beta 
(M7824), an IL-15 superagonist (N-803), and a tumor targeted immunocytokine (NHS-IL12) in 
subjects with advanced small bowel and colorectal malignancies for participants retaining the 
ability to consent and those who lose capacity to consent during the course of the trial outweigh 
the risks associated with this combination immunotherapy proposed in this study.
12.5 CONSENT PROCESS AND DOCUMENTATION
The informed consent document will be provided as a physical or electronic document to the 
participant or consent designee(s) as applicable 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.


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The initial consent process as well as re-consent, when required, may take place in person 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 more private setting if needed.  
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 as described below.
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 at the same location but is not required.
Both the investigator and the subject 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 at 
https://ccrod.cancer.gov/confluence/pages/viewpage.action?pageId=73203825.
As there is an optional biopsy for research in this protocol, the participant will be asked to sign a 
separate consent at the time of the procedure. If the participant refuses the optional biopsy at that 
time, the refusal will be documented in the medical record and in the research record.
12.5.1 Consent Process for Participants Who Decline Other Treatment Options
Participants who are eligible because they decline the treatment options described in the 
eligibility criteria (see Section 2.1) will have consent obtained in the presence of an independent 
consent monitor from the Bioethics department or Human Subjects Protection Unit (HSPU).
12.5.2 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 12.5. 


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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 
participants, the Institutional Review Board (IRB), and sponsor and will provide the reason(s) for 
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
•
Participant death at least possibly attributed to study treatment
•
A higher than expected rate (>15-20%) of grade 3 or greater bleeding events due to study 
treatment or the occurrence of a grade 5 bleeding event due to study treatment.
Study may resume once concerns about safety, protocol compliance, and data quality are 
addressed, and satisfy the sponsor, IRB andas 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 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 on 
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 
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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 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, the study protocol, documentation, data, and all other information generated will be 
held in strict 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/each 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 transmitted to and stored at the NCI 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 the clinical site and by NCI CCR research staff will be secured and 
password protected. At the end of the study, all study databases will be archived at the NIH.
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 
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14 PHARMACEUTICAL INFORMATION
14.1 CV301 (IND # 19660)
14.1.1 Source 
CV301 (MVA-BN-CV301 and FPV-CV-301) will be supplied by the manufacturer, Bavarian 
Nordic.
14.1.2 Toxicity 
A phase I study was just completed at the NCI with no dose limiting toxicities (unpublished).  As 
expected, CV-301 was well tolerated in all 12 participants with no DLT noted.  The only 
attributable toxicities were grade 1 and 2, and primarily injections site reactions and flu-like 
symptoms, with other rare toxicities such as headache and nausea (also grade 2 or less) also 
reported.  There were no grade 3 or greater toxicities reported in the study. 
Initial safety data show that the most frequently occurring treatment-related AEs were temporary 
and self-limiting, grade 1 or 2 in severity and included injection site reactions (injection site 
erythema, pruritus, pain, induration and swelling) and general symptoms including fever/chills, 
flu-like symptoms, headache, fatigue/weakness, nausea/vomiting, myalgia and arthralgia. There 
was no occurrence of any of the pre-specified adverse events of special interest (immune-related 
events and cardiac events). There were no related SAEs. There were no dose limiting toxicities.
MVA-BN-CV301 (Prime Vaccine)
The most common side effects associated with MVA-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.  
FPV-CV301 (Boost Vaccine)
The most common side effects from the use of fowlpox vaccines are mild and may include the 
following: fever, tiredness (fatigue), muscle or joint ache, headache, and flu-like symptoms.  
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.  
Pooled ADR data of all completed MVA-BN trials
The following two tables from the CV301 Investigator Brochure (IB) v5 summarize the pooled 
ADR data of all completed MVA-BN trials. The safety profile of each of the trials with 
recombinant MVA-BN based vaccines is comparable to the safety profile as displayed in the table, 
as the occurrence of the ADRs is considered to be a reaction to the vector rather than the insert 
based on previous experience with recombinant
Suspected Adverse Drug Reactions Reported by ≥ 1% of Subjects in the Completed MVA-BN 
Clinical Trials* (N=7863**)
Preferred Term (PT)
No. of reports by 
subjects
Frequency
%


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Injection site pain
6385
81.2
Injection site erythema
5049
64.2
Injection site swelling
3804
48.4
Injection site induration
3315
42.2
Injection site pruritus
2935
37.3
Myalgia
2524
32.1
Fatigue
2425
30.8
Headache
2274
28.9
Nausea
1102
14.0
Rigors/chills
684
8.7
Body temperature increased
269
3.4
Appetite disorder
218
2.8
Arthralgia
206
2.6
Injection site nodule
195
2.5
Injection site discolouration
191
2.4
Pain in extremity
147
1.9
Injection site haematoma
107
1.4
Pyrexia
99
1.3
Axillary pain
91
1.2
Injection site warmth
85
1.1
* POX-MVA-001, -002, -004, -005, -006, -007, -008, -009, -010, -011, -013, -023, -024, -027, -028, -029, -030, -
036, -037, -03X, HIV-NEF-004 and HIV-POL-002. 
** 8 subjects exposed but not included in analysis. 7 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 
adverse event reporting. 1 subject in POX-MVA-029 was not vaccinated according to the randomization, therefore 
removed from analysis set. Source: MVA-BN IB Ed. 24.0
ADRs for FPV (Originating from the PROSTVAC program)
Additional safety information on vaccinia and FPV can be found in the PROSTVAC 
Investigator’s Brochures.
14.1.3 Formulation and Preparation 
MVA-BN-CV301 and FPV-CV301 encode the human MUC-1 and the human CEA gene in 
combination with human TRICOM. No marker gene is present in both recombinant viruses.
MVA-BN-CV301 is a liquid-frozen, highly attenuated, live recombinant virus based on the viral 
vector MVA-BN. It is administered as s.c. injection. Packaging and vials will be labeled according 
to the respective product specifications. 


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One MVA-BN-CV301 vaccine vial has a nominal titer of 4 x 108 infectious units (Inf.U) in 0.5 
mL of the drug product.
FPV-CV301 is a liquid-frozen, highly attenuated, live recombinant virus. It is administered as s.c. 
injection. The packages and vials will be labeled according to the respective product specifications. 
One FPV-CV301 vaccine vial has a nominal virus titer of 1 x 109 Inf.U in 0.5 mL of the drug 
product.
MVA-BN-CV301 and FPV-CV301 are each supplied in 2 mL type I borosilicate glass vials closed 
with sterile bromobutyl rubber stoppers, crimped with aluminum caps and covered with 
polypropylene closures.
14.1.4 Stability and Storage 
Supplies of both the MVA-BN-CV301 and the FPV-CV301 vaccines will be shipped temperature 
controlled and monitored to the clinical trial site. Once at the site, the package should be handed 
over to personnel in charge of vaccine preparation (e.g., the pharmacist or representative). Site 
personnel are responsible for proper storage of vaccine upon receipt.
Both the MVA-BN-CV301 and the FPV-CV301 vaccines must be shipped to site and stored at a 
temperature of -20℃ +/- 5℃) or -80℃ +/- 5℃, avoiding direct light. A vial must not be re-frozen 
once it has been thawed. A provisional shelf life of 2 years at -80°C ± 10°C has been given. Expiry 
date may be extended due to real time stability data. Storage at -20°C ± 5°C is limited to 12 months 
after moving from -80°C ± 10°C to -20°C ± 5°C.
14.1.5 Administration Procedures
Each dose of MVA-BN-CV301 consists of 4 injections administered subcutaneously (one in each 
arm and one in each leg). 
Each dose of FPV-CV301 consists of 1 injection administered subcutaneously (preferably in the 
non-dominant arm).
14.1.6 Incompatibilities
Not available.
14.2 M7824 (MSB0011359C) (IND # 19660)
14.2.1 Source / Acquisition and Accountability
M7824 is manufactured and supplied for the trial by EMD Serono Research and Development 
Institute. 
M7824 will be provided to the clinical trial site by the manufacturer. The investigator or designee 
(e.g., pharmacist) will maintain an ongoing inventory of the investigational product supply 
according to standard site procedures. The investigational product will be dispensed at the 
direction of an investigator for administration to a study participant enrolled on the clinical trial. 
Disposal of expired or unused product will be returned to the manufacturer or disposed of 
according to standard site procedures based on agreement between the manufacturer and the site.
14.2.2 Toxicity 
The immunoglobulin portion of M7824 molecule is identical to avelumab (Bavencio). Respective 
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colitis, immune-mediated endocrinopathies, immune-mediated hepatitis) and infusion reactions 
are included in the prescribing for Bavencio (bavencio.com). Participants will be pre-medicated to 
prophylax against infusions reactions. The following additionally significant immune-mediated 
adverse reactions have occurred in less than 1% of 1738 participants 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 participants, 3 participants 
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 adverse events
3 mg/kg (n = 
3)
10 mg/kg (n = 3)
20 mg/kg (n = 7)
Total (n = 16)
Any 
Grade
Grade 
3
Any 
Grade
Grade 
3
Any 
Grade
Grade 
3
Any 
Grade
Grade 
3
Participants with 
any event**
2 
(66.7)
1 
(33.3)
1 
(33.3)
0 (0.0)
4 
(57.1)
2 
(28.6)
7 
(43.8)
3 
(18.8)
Anemia
1 
(14.3)
1 
(14.3)
1 (6.3)
1 (6.3)
Bullous 
pemphigoid 
1 
(33.3)
1 (6.3)
Colitis
1 
(14.3)
1 
(14.3)
1 (6.3)
1 (6.3)
Dermatitis 
acneiform
1 
(33.3)
1 (6.3)
Dyspnea 
exertional***
1 
(14.3)
1 (6.3)
Hyperthyroidism
1 
(14.3)
1 (6.3)
Hypophosphatemia
1 
(14.3)
1 (6.3)
Hypothyroidism
1 
(33.3)
1 
(14.3)
2 
(12.5)
Infusion-related 
reaction
1 
(14.3)
1 (6.3)
Keratoacanthoma
1 
(14.3)
1 (6.3)
Lipase increase
1 
(14.3)
1 
(14.3)
1 (6.3)
1 (6.3)
Nausea
1 
(33.3)
1 (6.3)


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3 mg/kg (n = 
3)
10 mg/kg (n = 3)
20 mg/kg (n = 7)
Total (n = 16)
Pruritus
1 
(33.3)
1 (6.3)
Rash maculo-
papular
1 
(33.3)
1 
(33.3)
2 
(12.5)
Skin infection
1 
(33.3)
1 
(33.3)
1 (6.3)
1 (6.3)
Vomiting
1 
(33.3)
1 (6.3)
**There were no treatment-related AEs in the 3 participants treated with 1 mg/kg M7824.
***The differential for this dyspnea was pneumonitis vs. lymphangitic spread of disease (disease 
progression).
As of August 2017, > 500 participants have been treated with M7824 across multiple solid tumor 
expansion cohorts. The safety profile is consistent with other monotherapy checkpoint inhibitors, 
with the exception of keratoacanthomas and cutaneous squamous cell carcinomas which have 
occurred in approximately 3-5% of participants, and are well managed with surgical excision. 
These lesions have not been a criterion for treatment discontinuation, but thus far have all 
spontaneously regressed following treatment discontinuation.
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 participants 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, participants will be 
notified of the same possible risk in the informed consent document for this study (e.g., gum 
bleeding, nose bleeds, coughing up blood, blood in their urine, or blood in the stool). 
At least 2 instances of nodular regenerative hyperplasia have been observed with the use of this 
agent.
14.2.3 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. 
14.2.4 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. 
14.2.5 Administration Procedures
See Section 3.2. 
14.2.6 Incompatibilities
Not available. 
14.3 N-803 (IND # 19660)
14.3.1 Source / Acquisition and Accountability
N-803 is manufactured and supplied by ImmunityBio, Inc. 
N-803 will be provided to the clinical trial site by the manufacturer. The investigator or designee 
(e.g., pharmacist) will maintain an ongoing inventory of the investigational product supply 
according to standard site procedures. The investigational product will be dispensed at the 
direction of an investigator for administration to a study participant enrolled on the clinical trial. 
Disposal of expired or unused product will be returned to the manufacturer or disposed of 
according to standard site procedures based on agreement between the manufacturer and the site.
14.3.2 Toxicity 
In participants receiving the 10 mcg/kg subcutaneous injection, the following were reported grade 
1 and 2 toxicities: worsening anemia, nausea/vomiting, constipation, fatigue, fever, peripheral IV 
infiltration, injection site reactions, pain/aches, sinusitis, hypoalbuminemia, hypocalcemia, 
hypophosphatemia, decreased iron, headaches, dysgeusia, and cough. Grade 3 hypertension and 
decreased lymphocyte count were also reported. Atrial fibrillation, neutropenia and febrile 
neutropenia have also been reported as potential risks of N-803.
N-803 has been tested in combination with the anti-PD-1 agent, nivolumab at a dose of 240 mg 
i.v. every 4 weeks, in a phase 1 dose expansion study (n=21) with N-803 given weekly for 5 weeks 
on, 1 week off, for up to 5-6 months for pre-treated, advanced/metastatic NSCLC (NCT02523469). 
Fifteen participants received higher N-803 dosing: 15 mcg/kg (n=6) and 20 mcg/kg (n=9). Among 
all doses, there were no DLTs and no Grade 4 or 5 adverse events. Grade 3 adverse events were 
fever (n=1), flu-like illness (n=2), lymphopenia (n=2), fatigue (n=2), back pain (n=1), and 
dizziness (n=1). Grade 1 or 2 large injection site reactions were observed in 14 participants.


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14.3.3 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-
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.
N-803 is supplied at a concentration of 2 mg/mL and lot FG-16-0182-2 is administered undiluted. 
For lots other than FG-16-0182-2, the manufacturer will provide additional preparation 
instructions. 
14.3.4 Stability and Storage 
Study medication is provided in a 2mL vial containing 0.6 mL of N-803 at a concentration of 2 
mg/mL. Study medication must be maintained at a temperature between 2℃ and 8℃. The duration 
of time during which the product remains stable at room temperature will be obtained from Altor.
14.3.5 Administration Procedures
N-803 is administered subcutaneously. 
14.3.6 Incompatibilities
Not available.
14.4 NHS-IL12 (IND # 19660)
14.4.1 Source / Acquisition and Accountability
NHS-IL12 is manufactured and supplied by EMD Serono.
NHS-IL12 will be provided to the clinical trial site by the manufacturer. The investigator or 
designee (e.g., pharmacist) will maintain an ongoing inventory of the investigational product 
supply according to standard site procedures. The investigational product will be dispensed at the 
direction of an investigator for administration to a study participant enrolled on the clinical trial. 


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Disposal of expired or unused product will be returned to the manufacturer or disposed of 
according to standard site procedures based on agreement between the manufacturer and the site.
14.4.2 Toxicity 
Subjects (n=59) were treated subcutaneously with NHS-IL12 in a single ascending dose cohort 
followed by a multiple ascending dose cohort (n=37 with every 4-week dosing). The primary 
objective of this trial was to determine MTD as defined by the number of DLTs. None of the 
subjects treated with single or multiple doses up to 12.0 µg/kg experienced a DLT. At 16.8 µg/kg, 
1/6 subjects had a DLT (grade 3 increase in alanine transaminase [ALT]). At 21.8 µg/kg, 2/6 
subjects had a DLT (grade 3 increase in aspartate transaminase [AST] and ALT; grade 3 increase 
in lipase without clinical signs of pancreatitis). MTD was 16.8 µg/kg. The most frequently 
observed treatment-related adverse event (TRAE) was decreased lymphocyte count (27/59 
subjects; 45.8%). Other TRAEs included decreased white blood cells (WBCs) (24/59; 40.7%), 
fever and elevated AST (21 each; 35.6%), elevated ALT (20; 3.9%), and anemia and flu-like 
symptoms (18 each; 30.5%) (Tab. Among the cohort receiving 16.8 µg/kg, the most frequently 
reported TRAEs were elevated AST (75%), decreased WBCs and elevated ALT (68.8% each), 
and decreased lymphocyte count and fever (62.5% each). At least one grade ≥ 3 TRAE was seen 
in 12/59 subjects (20.3%). These included decreased lymphocyte count (5; 8.5%), decreased 
neutrophil count (4; 6.8%), elevated ALT (3; 5.1%), decreased WBCs (2; 3.4%), and hypokalemia, 
hyperhidrosis, elevated alkaline phosphatase, AST, and lipase (1 each; 1.7%). All grade ≥ 3 
TRAEs were transient; only hyperhidrosis was symptomatic. One grade 4 TRAE was observed 
(asymptomatic decreased lymphocyte count); no grade 5 TRAE was observed. 
14.4.3 Formulation and Preparation 
NHS-IL12 is formulated as a 1.5 mg/mL solution and is supplied by the Sponsor in single-use 
glass vials with a rubber stopper and sealed with an aluminum Flip Off® crimp seal closure. 
The contents of the NHS-IL12 vials are sterile and nonpyrogenic, and do not contain bacteriostatic 
preservatives. Any spills that occur should be cleaned up using the facility’s standard cleanup 
procedures for biologic products. 
Rough shaking of the solution must be avoided. 
NHS-IL12 drug product is ready-to-use. However, for doses below 300 g, NHS-IL12 drug 
product must be diluted with 0.9% saline solution (sodium chloride injection). Detailed 
information on medical devices to be used for the preparation and administration of NHS-IL12 
will be provided in the Manual of Operations. 
Any unused portion of the solution should be discarded in biohazard waste disposal with final 
disposal by accepted local and national standards of incineration.
14.4.4 Stability and Storage 
NHS-IL12 drug product must be stored at 2°C to 8°C until use, with a temperature log maintained 
daily. All medication boxes supplied to the study site must be stored carefully, safely, and 
separately from other drugs. 
The chemical and physical in-use stability of NHS-IL12 diluted and undiluted solution in syringes 
has been demonstrated for 24hours at 25°C. However, to reduce the risk of microbial 
contamination, the solution should be used immediately unless medication preparation has been 


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performed in controlled and validated aseptic conditions. Rough shaking of the solution must be 
avoided. 
14.4.5 Administration Procedures
NHS-IL12 is administered subcutaneously. 
14.4.6 Incompatibilities
Not available. 


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Immunol Res 2015, 3(11):1248-1256.


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16 APPENDICES
16.1 APPENDIX A: PERFORMANCE STATUS CRITERIA
ECOG Performance Status Scale
Karnofsky Performance Scale
Grade
Descriptions
Percent
Description
100
Normal, no complaints, no 
evidence of disease.
0
Normal activity.  Fully active, 
able to carry on all pre-disease 
performance without restriction.
90
Able to carry on normal activity; 
minor signs or symptoms of 
disease.
80
Normal activity with effort; 
some signs or symptoms of 
disease.
1
Symptoms, but ambulatory.  
Restricted in physically strenuous 
activity, but ambulatory and able 
to carry out work of a light or 
sedentary nature (e.g., light 
housework, office work).
70
Cares for self, unable to carry on 
normal activity or to do active 
work.
60
Requires occasional assistance, 
but is able to care for most of 
his/her needs.
2
In bed <50% of the time.  
Ambulatory and capable of all 
self-care, but unable to carry out 
any work activities.  Up and 
about more than 50% of waking 
hours.
50
Requires considerable assistance 
and frequent medical care.
40
Disabled, requires special care 
and assistance.
3
In bed >50% of the time.  
Capable of only limited self-care, 
confined to bed or chair more 
than 50% of waking hours.
30
Severely disabled, 
hospitalization indicated.  Death 
not imminent.
20
Very sick, hospitalization 
indicated. Death not imminent.
4
100% bedridden.  Completely 
disabled.  Cannot carry on any 
self-care.  Totally confined to bed 
or chair.
10
Moribund, fatal processes 
progressing rapidly.
5
Dead.
0
Dead.

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: 11/19//2021
Page 1 of 22
CC ICF template v. 05.05.20
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
PRINCIPAL INVESTIGATOR: Julius Strauss, MD
STUDY TITLE: Phase II Trial of Combination Immunotherapy in Subjects with Advanced Small 
Bowel and Colorectal Cancers
STUDY SITE: NIH Clinical Center
Cohort: Affected Participants
Consent Version:  11/19/2021 
WHO DO YOU CONTACT ABOUT THIS STUDY? 
Principal Investigator:  Julius Strauss, MD
Phone: 240-858-3999
Email: julius.strauss@nih.gov
KEY INFORMATION ABOUT THIS RESEARCH 
This consent form describes a research study and is designed to help you decide if you would 
like to be a part of the research study.  
You are being asked to take part in a research study at the National Institutes of Health (NIH). 
This section provides the information we believe is most helpful and important to you in making 
your decision about participating in this study. Additional information that may help you decide 
can be found in other sections of the document. Taking part in research at the NIH is your choice.
You are being asked to take part in this study because you have been diagnosed with advanced 
metastatic or refractory/recurrent small bowel and/or colorectal cancer.
The purpose of this research study is to determine if a new combination of immunotherapy drugs 
is effective in participants with advanced small bowel and colorectal cancers. These 
immunotherapy drugs are designed to help the immune system fight cancer.
The CV301 vaccines (MVA-BN-CV301 and FPV-CV301), M7824, N-803, and NHS-IL12 are 
considered investigational, which means that the use of this combination has not been approved 
by the U.S. Food and Drug Administration (FDA) to treat advanced small bowel and colorectal 
cancers. However, the FDA has given us permission to use this combination in this study.
M7824 has been tried in other types cancers. Recently, the manufacturer of the drug closed 3 
large studies because the drug was not shown 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.
There are other drugs that may be used to treat your disease, and these can be prescribed/given 
by your regular cancer doctor, even if you are not in this study. 
IRB NUMBER: 20C0138
IRB APPROVAL DATE: 12/16/2021


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 11/19//2021
Page 2 of 22
CC ICF template v. 05.05.20
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
If you decide to join this study, here are some of the most important things that you should know 
that will happen:
•
We will first perform some tests and procedures to find out if you meet the study 
requirements. We will also confirm the status of your disease. You must have already 
received treatment for this cancer unless you are not eligible to receive standard therapy 
or you decline standard treatment.
•
You will receive a combination of the following drugs: CV301 (MVA-BN-CV301 and 
FPV-CV301), M7824, and N-803 for up to one year. Depending on when you enroll on 
the study, you will also receive NHS-IL12 along with the other drugs. Each treatment 
will be given in the Oncology Outpatient Center and will take approximately 2-4 hours. 
This allows time to give the treatment and monitor you before and after.
o
CV301 will be given by injection under the skin. On Day 1 and Day 15 MVA-BN-
CV301 will be given. FPV-CV301 will be given on Day 29 and every 4 weeks on 
Arm 1 and every 6 weeks on Arm 2A and 2B. 
o
M7824 will be given by intravenous infusion (a needle inserted into a vein allowing 
the solution to be administered over a period of time) every two weeks. The infusion 
will take approximately one hour, but could take more or less time. 
o
N-803 will be given by injection under the skin every two weeks or every four weeks 
depending on the group you are assigned to. 
o
NHS-IL12 will be given by injection under the skin every four weeks. 
•
You may experience side effects from taking part in this study. Some can be mild or very 
serious, temporary, long-lasting, or permanent, and may include death. Examples of 
some of the side effects that you may have include: fatigue, nausea, vomiting, diarrhea, 
chills, anemia, increased blood sugar, flu-like symptoms, and poor oral intake in 
combination, which must be treated with increased intake of fluids to prevent 
dehydration. It is possible that anemia and/or bleeding may be so severe that you require 
a blood transfusion. You cannot join this study if you are not willing to have a blood 
transfusion. A more complete list of possible side effects is described later in this 
consent. It is important that you read and understand the possible risks. Call your study 
doctor right away if you experience this. 
•
You will be seen regularly during the study. You will have clinical, laboratory, and 
imaging tests to see how you are doing and to see if your disease is responding to 
treatment. We will also collect required samples from you (such as blood and tumor 
biopsies) for both clinical and research purposes.
•
After the study treatment has ended, we will contact you for long term follow-up every 
3 months for one year and then every 6 months after the first year to ask about any 
adverse events, further treatment of your tumor, and your survival for the rest of your 
life. 
Just as we do not know what side effects you might have, we cannot know if you may benefit 
from taking part in this study. If you do not benefit, this study and the results from our research 
will help others in the future.
IRB NUMBER: 20C0138
IRB APPROVAL DATE: 12/16/2021


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 11/19//2021
Page 3 of 22
CC ICF template v. 05.05.20
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
You are free to stop participating in the trial at any time. If you decide to stop, the study doctor 
may ask you to agree to certain tests to make sure it is safe for you to stop.
The remaining document will now describe the research study in more detail. This information 
should be considered before you make your choice. Members of the study team will talk with you 
about the information in this document. Some people have personal, religious, or ethical beliefs 
that may limit the kinds of medical or research interventions in which they would want to 
participate. Take the time you need to ask any questions and discuss this study with NIH staff, and 
with your family, friends, and personal health care providers.
If the individual being asked to participate in this research study is not able to give consent for 
themselves, you, as the Legally Authorized Representative, will be their decision-maker and you 
are being asked to give permission for this person to be in this study. For the remainder of this 
document, the term “you” refers to you as the decision-maker and/or the individual being asked to 
participate in this research.
IT IS YOUR CHOICE TO TAKE PART IN THE STUDY
You may choose not to take part in this study for any reason. If you join this study, you may change 
your mind and stop participating in the study at any time and for any reason. In either case, you 
will not lose any benefits to which you are otherwise entitled. However, to be seen at the NIH, you 
must be taking part in a study or are being considered for a study. If you do choose to leave the 
study, please inform your study team to ensure a safe withdrawal from the research.  
WHY IS THIS STUDY BEING DONE?
The purpose of this research study is to determine if a new combination immunotherapy is effective 
in shrinking tumors in participants with advanced small bowel and colorectal cancers.
We are asking you to join this research study because you have been diagnosed with advanced 
metastatic or refractory/recurrent small bowel and/or colorectal cancer. 
The CV301 vaccines (MVA-BN-CV30 and FPV-CV301), M7824, N-803, and NHS-IL12 are 
considered investigational, which means that the use of this combination has not been approved 
by the U.S. Food and Drug Administration (FDA) to treat advanced small bowel and colorectal 
cancers. 
WHAT WILL HAPPEN DURING THE STUDY?
Below is a description of what will be asked of you and what will occur if you decide to take part 
in this study.
Before you begin the study
To determine if you can be a part of this study, you will need to have the following tests and 
procedures. These will be done under a separate protocol:

Medical history and physical examination including height, weight, and vital signs; 

CT scan of the chest, abdomen and pelvis and/or MRI;
IRB NUMBER: 20C0138
IRB APPROVAL DATE: 12/16/2021


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
Brain CT/MRI;

Routine blood tests; 

Pregnancy test for women who are able to have children; 

Hepatitis B and C screening tests; 

As part of this study, we will test you for infection with HIV, the virus that causes AIDS. 
If you are infected with HIV and have a detectable viral load, you will not be able to take 
part in this study. We will tell you what the results mean, how to find care, how to avoid 
infecting others, how we report HIV infections, and the importance of informing your 
partners at possible risk because of your HIV infection; 

Urine tests;

Confirmation of your disease. If there is no available tumor sample or pathology report, 
a biopsy will be performed to confirm the diagnosis.
Structural MRI
Magnetic resonance imaging (MRI) uses a strong magnetic field and radio waves to take pictures 
of the body. If you have a history of metastases to your brain or if we are concerned that you may 
have metastases to your brain, we will obtain pictures of your brain for this study. 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 anytime. 
It is very important for the experiment that you do not move your head or body inside the scanner. 
We will use padding around your head to help keep it in place.
We may place a bar in your mouth to help keep your head still.
During the study
Once we know that you are eligible and you sign the consent document agreeing to participate in 
the study, you may need to have some of the tests that were done at screening repeated depending 
on how much time has passed. Your study team will let you know if any of the above tests need to 
be repeated.
During your participation you will receive a combination of the following drugs: CV301 vaccine 
(MVA-BN-CV301 and FPV-CV301), M7824, and N-803. Depending on when you enroll on the 
study, you will also receive NHS-IL12 along with the other drugs. Your specific combination 
depends on the group you are assigned to and may be different from other participants on this 
study. Your specific combination of these drugs will depend on the group you are assigned to as 
described above in Key Information About This Research.

You will receive the CV301 vaccines by injection under the skin. On Day 1 and Day 15 
MVA-BN-CV301 will be given. FPV-CV301 will be given on Day 29 and every 4 weeks 
on Arm 1 and every 6 weeks on Arm 2A and 2B. 
IRB NUMBER: 20C0138
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
You will receive M7824 by IV infusion every two weeks. The infusion will take 
approximately one hour, but could take more or less time. Before your M7824 infusion you 
may receive standard pre-medication of an antihistamine and acetaminophen (Tylenol). 

You will receive N-803 by injection under the skin every two weeks or every four weeks 
depending on the group you are assigned to. 

You may receive NHS-IL12 by injection under the skin every four weeks. 
Please let us know about any herbal and over-the-counter medications that you are taking as there 
may be interactions between these and the study drugs. We can prevent side effects and other 
negative outcomes only if you let us know.  
We will continue to take standard assessments, such as physical exam, weight, vital signs, EKG, 
collection of blood for testing, pregnancy test for women of childbearing age, and scans for the 
evaluation of your tumor, during your participation. 
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 samples from you for purposes of 
research only. The samples are being tested to look at the effects of therapy on your immune system 
and markers of tumor activity, including collecting and testing tumor cells. 
The samples included for these studies include:

Blood Tests: collected before you have taken any study drug, weeks 1, 3, 5, 7, and every 6 
weeks thereafter and at some restaging visits if your study doctor thinks your blood needs 
to be tested. The total amount of blood we will draw for research in this study will be less 
than 550ml (about 2 cups and 5 tablespoons).

Tumor Biopsy (optional): collected before you have taken any study drug and at first 
restaging.

CT Scans: every 8 weeks.
In this study we will perform genetic testing on your DNA and RNA. DNA (also called 
deoxyribonucleic acid) in the cells carries genetic information and passes it from one generation 
of cells to the next – like an instruction manual. RNA (ribonucleic acid) carries instructions from 
your DNA to the parts of the cells that makes proteins. We will perform limited genetic testing on 
certain immune cells in your blood and tumor samples to characterize changes in the DNA of a 
particular molecule located on the immune cell. We will perform further genetic testing on your 
blood samples, looking at how much RNA you have for certain panels genes. This helps us to learn 
how active the genes are.
When you are finished with treatment 
End of Treatment Visit
If you stop participation in the study before the completion of one year of treatment, then you will 
be asked to come into the clinic on the day of or within 7 days of the decision to stop treatment for 
the following tests and procedures: physical examination including weight and vital signs; EKG; 
routine blood tests to measure blood chemistry and complete blood count; pregnancy test if you 
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are a woman who can have children; and scans if you stop study therapy before your disease 
worsens.
Safety Visit
After your treatment ends or if you stop participation in the study for any reason you will be asked 
to come into the clinic for a 28 day follow-up visit or telephone call following your last dose of 
study drug(s).
During the visit the following tests and procedures will be given: physical examination including 
weight and vital signs; EKG; and routine blood tests; and pregnancy test if you are a woman who 
can have children. 
Long Term Follow-up
If your disease has progressed while being treated then you will be followed by phone or email for 
your survival, any adverse events, and further treatment of your tumor. 
If your disease did not progress while being treated then you will receive tumor scans until 
progression of your disease and will be followed by phone or email for your survival, any adverse 
events, and further treatment. If you completed one year of treatment then you may be asked to 
complete an additional year of treatment at the time of your disease progression. 
HOW LONG WILL THE STUDY TAKE?
If you agree to take part in this study, the treatment portion is expected to last for approximately 
one year.
You will be seen multiple times during treatment. You will be asked to come to the NIH every two 
weeks. Visits usually take about 5-6 hours, but will take no longer than 8 hours.
HOW MANY PEOPLE WILL PARTICIPATE IN THIS STUDY?
We plan to have approximately 80 people participate in this study at the NIH. 
WHAT ARE THE RISKS AND DISCOMFORTS OF BEING IN THE STUDY?
Risks from Study Therapy
Side effects of CV301 (MVA-BN-CV301 and FPV-CV301)
MVA-BN-CV301 (Prime Vaccine)
The most common side effects associated with MVA-BN and other MVA-BN-derived vaccines 
that you may experience include mild to moderate flu-like symptoms such as:

Fever

Chills

Muscle or joint ache

Tiredness (Fatigue)

Headache
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
Nausea

Increased body temperature

Changes in appetite
In addition, you may experience some localized reactions at the site where the vaccine is injected 
under your 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)

Redness

Itching
FPV-CV301 (Boost Vaccine)
The most common side effects that you may experience from the use of fowlpox vaccines are mild 
and may include the following:

Fever

Tiredness (Fatigue)

Muscle or joint ache

Headache

Flu-like symptoms

Nausea

Dizziness 
In addition, you may experience some localized reactions at the site where the boosting vaccine is 
injected under your 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)

Redness

Itching
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Side effects of M7824
Common side effects (occurring in more than 5% of patients):

Fatigue (tiredness and lack of energy)

Nausea

Diarrhea

Constipation

Vomiting

Swelling of you lower legs or hands

Fever 

Decreased appetite

Loss of body fluids (dehydration)

Skin growths called keratoacanthomas that resemble skin cancer. These usually go away 
after treatment and can leave a scar. 

Rash, blisters, skin discoloration and other skin abnormalities.

Bleeding has been frequently observed in patients receiving M7824. Patients may 
experience bleeding in different organs such as gums, nose, ears, eyes, vagina, breasts, 
blood in the urine, stool, or bleeding in the internal organs or skull, coughing up or 
vomiting blood. Occasionally, this bleeding can be serious and potentially life threatening 
and require you to receive a blood transfusion. If you experience any bleeding on this 
trial, please tell the study team immediately. Tell your doctor if 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
Occasional side effects (occurring in less than 5% of patients):

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
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
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. 
Although usually reversible with treatment, it can be severe or life threatening. 

Back pain

Cancerous growth on the skin that can be removed

Stroke

Slow wound healing

Thickening of the skin, nails
There is a risk of tumor lysis syndrome due to tumor shrinkage. This complication is caused by 
the breakdown products of dying cells and includes elevated blood potassium, elevated blood 
phosphorus, elevated blood uric acid and elevated urine uric acid, low blood calcium, and 
consequent acute kidney failure. This might happen in any tumor type although some tumors are 
more prone than others. 
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.
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, 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 protects 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.
Types of immune related side effects:

Inflammation of the lungs (pneumonitis): 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)
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
Thyroiditis (inflammatory disease of the thyroid gland)

You may develop inflammation of the liver called hepatitis. 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)

Uveitis (inflammation in the eye) 

Diabetes mellitus (high blood sugar levels)

Problems with your adrenal glands (Adrenal Insufficiency): 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.

Myositis (inflammation of the muscles characterized by pain and tenderness)

Myasthenia gravis (weakness in the skeletal muscles)

Inflammation of the intestine (colitis). 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. 

Autoimmune encephalitis is a type of brain inflammation where the body's immune 
system attacks healthy cells and tissues in the brain or spinal cord.

Myocarditis (inflammation of the heart muscle)

Pemphigoid (fluid-filled blisters that can be itchy)

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 
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.
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Side effects of N-803
Not many studies have been done with ALT-803 in humans. However, some reported side effects, 
which were mostly not serious, have included:

Fast heart rate
•
Dry eyes
•
Nausea
•
Vomiting
•
Fever
•
Fatigue
•
Abnormal liver enzymes
•
Flushing
•
Itching rash
•
Stomach pain
•
Joint pain
•
Headache
•
Blood in the urine
•
Muscle pains
•
Altered taste
•
Redness, soreness, or swelling at the injection site 2 to 3 days after injection 
•
Shortness of breath
•
Constipation
•
Chills
•
Leg swelling
•
Low blood pressure
•
Cough
•
Sweats
•
Muscle twitching
•
Diarrhea
•
Hypertension
•
Anorexia
•
Atrial Fibrillation
•
Neutropenia / Febrile Neutropenia
Side effects of NHS-IL12 
NHS-IL12 is in the early stages of development and the potential side effects are not completely 
known.  
Common side effects (occurring in more than 10% of patients):

Decreased white blood cells (including lymphocytes and neutrophils)

Hyperglycemia (increased blood sugar)

Increased aspartate aminotransferase and alanine aminotransferase (liver enzymes)
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
Anemia (decreased red blood cells)

Fever 

Flu-like symptoms

Increased alkaline phosphatase (an enzyme found in the blood)

Thrombocytopenia (decreased platelets)

Fatigue (tiredness) 

Hypoalbuminemia (decreased albumin levels in the blood) 

Hypophosphatemia (decreased phosphate levels in the blood)
If you suffer any of these side effects (or any others not listed) or you think you are experiencing 
a side effect during this study, you must tell your study doctor immediately.  
Any side effects or other health issues occurring during the study will be followed up by the 
study doctor.
It is possible that the symptoms of your condition will not improve during the study or may even 
worsen. Treatment with this study drug may also involve risks to your future health that we 
currently do not know about. 
Other Risks
Risk from Blood Collection
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. 
Risks from Biopsy 
Care will be taken to minimize risks that may happen during collection of a tumor sample. This 
procedure usually causes only brief discomfort at the site from which the biopsy is taken. You may 
experience some bruising around the biopsy site. Rarely, infection or bleeding may occur at the 
needle site. 
Tumor biopsies will be done by a specialist using the CT scanner or ultrasound machine to guide 
the biopsy needle into the tumor to ensure accuracy. To collect the optional research biopsies, you 
may be exposed to 2 CT scans. Your radiation exposure from this procedure is below the guidelines 
allowed for research subjects at the NIH. See What are the risks of radiation from being in the 
study? below for more details. 
CT Scan Risk 
CT scans create low levels of radiation, which has a small potential to cause cancer and other 
defects. However, the risk associated with one scan is small.
Risks Due to Contrast Agents for CT 
You may receive a contrast agent as part of your CT scan. Contrast agents can cause allergic 
reactions and kidney damage. Allergic reactions can include mild itching associated with hives but 
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can also result in a serious life-threatening emergency from difficulty breathing. If this occurs, it 
is treatable. 
Risks for 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 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.
Risks of Gadolinium enhanced MRI
During part of the MRI you will receive gadolinium, a contrast agent, through an intravenous (iv) 
catheter. It will be done for research and medical purposes. 
It is not known if MRI with contrast is completely safe for a developing fetus. Therefore, all 
women of childbearing potential will have a pregnancy test performed no more than 24 hours 
before each MRI scan with contrast. The scan will not be done if the pregnancy test is positive. 
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 
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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 
effects of the retained gadolinium are not clear. At this time, retained gadolinium has not been 
linked to health risks in people whose kidneys work well. 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. We will also give you additional information called 
a “Medication Guide.” Upon request, we will give you individual information about retained 
gadolinium we see on your studies.
What are the risks related to pregnancy?
If you are able to become pregnant, we will ask you to have a pregnancy test before starting this 
study. You will need to practice an effective form of birth control before starting study treatment, 
during study treatment, and for 2 months after you finish study treatment (the restricted period).
If you become pregnant, there may be unknown risks to the fetus or unborn child, or risks that we 
did not anticipate. There may be long-term effects of the treatment being studied that could 
increase the risk of harm to a fetus. You must tell the study doctor if your birth control method 
fails during the restricted period. If you think or know you have become pregnant during the 
restricted period, please contact the study team as soon as possible. 
If you are a sexually active person with a partner able to become pregnant, it is important that your 
partner not become pregnant during the restricted period. There may be unknown risks to a fetus 
or risks we did not anticipate. You and your partner must agree to use birth control if you want to 
take part in this study. If you think your partner has become pregnant during the restricted period, 
please contact the study  team as soon as possible. If you and your partner plan for your partner to 
become pregnant after the restricted period, please discuss this with the study team.
Acceptable birth control options for you and your partner include:

abstinence;

hormonal contraceptives or therapies (such as birth control pills, injections, or implants);

barrier methods (such as a condom or diaphragm) used with a spermicide;

an intrauterine device (IUD);

surgical sterilization (tubal ligation or vasectomy).
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 CT scans 
and CT guided biopsies (optional). The amount of radiation exposure you will receive from these 
procedures is equal to approximately 9.4 rem. A rem is a unit of absorbed radiation. 
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MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
Note: The 2 CT guided biopsies are optional and depend on your decision to agree to the biopsies 
and their location with your study doctor. Of the 9.4 rem, you will receive around 1.6 rems from 
the optional CT guided biopsies. 
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 
of 0.3 rem per year from these sources.  This type of radiation is called “background radiation.”  
This study will expose you to more radiation than you get from everyday background radiation. 
No one knows for sure whether exposure to these low amounts of radiation is harmful to your 
body. 
The CT scans and CT guided biopsies that you get in this study will expose you to the roughly the 
same amount of radiation as 31.3 years’ worth 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 0.9 out of 100 (0.9%) and of getting a 
fatal cancer is 0.5 out of 100 (0.5%).
You may not participate in this study if you are pregnant. If you are capable of becoming pregnant, 
we will perform a pregnancy test before exposing you to radiation. You must tell us if you may 
have become pregnant within the previous 14 days because the pregnancy test is unreliable during 
that time.
WHAT ARE THE BENEFITS OF BEING IN THE STUDY?
You might not benefit from being in this study. 
However, the potential benefit to you might be a reduction in the bulk of your tumor which may 
or may not have favorable impact on symptoms and/or survival. 
Are there any potential benefits to others that might result from the study?
There is a need for beneficial treatments in patients with metastatic or refractory/recurrent small 
bowel and colorectal cancers as they are incurable and standard therapies often do not work. In the 
future, other people might benefit from this study because of the knowledge gained from the 
outcome of this trial. 
WHAT OTHER OPTIONS ARE THERE FOR YOU?
Before you decide whether or not to be in this study, we will discuss other options that are 
available to you. Instead of being in this study, you could: 

choose to be treated with surgery, radiation or with drugs already approved by the FDA for 
your disease;

choose to take part in a different study, if one is available;

choose not to be treated for cancer but you may want to receive comfort care to relieve 
symptoms.
IRB NUMBER: 20C0138
IRB APPROVAL DATE: 12/16/2021


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 11/19//2021
Page 16 of 22
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MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
You should discuss with your doctor your other choices and their risks and benefits.
DISCUSSION OF FINDINGS
New information about the study
If we find out any new information that may affect your choice to participate in this study, we 
will get in touch with you to explain what we have learned. This may be information we have 
learned while doing this study here at the NIH or information we have learned from other 
scientists doing similar research in other places.
EARLY WITHDRAWAL FROM THE STUDY 
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 worsens or comes back during treatment

if you have side effects from the treatment that your doctor thinks are too severe

if you become pregnant

if MVA-BN-CV301, FPV-CV301, M7824, N-803, and/or NHS-IL12 becomes 
unavailable

if new information shows that another treatment would be better for you

if you do not follow the study rules

if the study is stopped for any reason
In this case, you will be informed of the reason therapy is being stopped.  
After therapy is stopped we would like to see you for a safety visit 28 days after your last dose.
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 Bavarian Nordic, Inc., EMD 
Serono, Inc., ImmunityBio, Inc., or designated representatives.
STORAGE, SHARING AND FUTURE RESEARCH USING YOUR SPECIMENS AND 
DATA
Will Your Specimens or Data Be Saved for Use in Other Research Studies?
As part of this study, we are obtaining specimens and data from you. We will remove all the 
identifiers, such as your name, date of birth, address, or medical record number and label your 
specimens and data with a code so that you cannot easily be identified. However, the code will 
be linked through a key to information that can identify you. We plan to store and use these 
specimens and data for studies other than the ones described in this consent form that are going 
on right now, as well as studies that may be conducted in the future. These studies may provide 
additional information that will be helpful in understanding bowel and colorectal cancers or other 
IRB NUMBER: 20C0138
IRB APPROVAL DATE: 12/16/2021


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 11/19//2021
Page 17 of 22
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MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
diseases or conditions. This could include studies to develop other research tests, treatments, 
drugs, or devices, that may lead to the development of a commercial product by the NIH and/or 
its research or commercial partners. There are no plans to provide financial compensation to you 
if this happens. Also, it is unlikely that we will learn anything from these studies that may directly 
benefit you. 
I give permission for my coded specimens and data to be stored and used for future research as 
described above.
_____ Yes
_____ No
Initials
Initials
Will Your Specimens or Data Be Shared for Use in Other Research Studies?
We may share your coded specimens and data with other researchers. If we do, while we will 
maintain the code key, we will not share it, so the other researchers will not be able to identify 
you.  They may be doing research in areas that are similar to this study or in other unrelated areas. 
These researchers may be at NIH, other research centers and institutions, or commercial entities.
I give permission for my coded specimens and data to be shared with other researchers and used 
by these researchers for future research as described above.
_____ Yes 
_____ No
Initials
Initials
If you change your mind and do not want us to store and use your specimens and data for future 
research, you should contact the research team member identified at the top of this document. 
We will do our best to comply with your request but cannot guarantee that we will always be 
able to destroy your specimens and data. For example, if some research with your specimens and 
data has already been completed, the information from that research may still be used. Also, for 
example, if the specimens and data have been shared already with other researchers, it might not 
be possible to withdraw them. 
In addition to the planned use and sharing described above, we might remove all identifiers and 
codes from your specimens and data and use or share them with other researchers for future 
research at the NIH or other places. When we or the other researchers access your anonymized 
data, there will be no way to link the specimens or data back to you. We will not contact you to 
ask your permission or otherwise inform you before we do this. We might do this even if you 
answered "no" to the above questions. If we do this, we would not be able to remove your 
specimens or data to prevent their use in future research studies, even if you asked, because we 
will not be able to tell which are your specimens or data.
NIH policies require that your clinical and other study data be placed in an internal NIH database 
that is accessible to other NIH researchers for future research. Usually, these researchers will not 
have access to any of your identifiers, such as your name, date of birth, address, or medical 
IRB NUMBER: 20C0138
IRB APPROVAL DATE: 12/16/2021


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 11/19//2021
Page 18 of 22
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MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
record number; and your data will be labeled with only a code. We cannot offer you a choice of 
whether your data to be placed in this database or not. If you do not wish to have your data placed 
in this database, you should not enroll in this study.  
Will Your Genomic Data Be Shared Outside of This Study?
As part of this research study, we will put your genomic data in a large database for broad sharing 
with the research community. These databases are commonly called data repositories. The 
information in this database will include but is not limited to genetic information, race and 
ethnicity, and sex.  If your individual data are placed in one of these repositories, they will be 
labeled with a code and not with your name or other information that could be used to easily 
identify you, and only qualified researchers will be able to access them. These researchers must 
receive prior approval from individuals or committees with authority to determine whether these 
researchers can access the data.
Summary information about all of the participants included in this study (including you) is being 
placed in a database and will be available through open access. That means that  researchers and 
non-researchers will be able to access summary information about all the participants included 
in the study, or summary information combined from multiple studies, without applying for 
permission. The risk of anyone identifying you with this information is very low.
NIH policies require that genomic data be placed in a repository for sharing. Therefore, we 
cannot offer you a choice of whether your data will be shared.  If you do not wish to have your 
data placed in a repository, you should not enroll in this study.  
How Long Will Your Specimens and Data be Stored by the NIH?
Your specimens and data may be stored by the NIH until they are no longer of scientific value 
or if you withdraw consent for their continued use, at which time they will be destroyed. Your 
specimens and data may be stored by the NIH indefinitely.
Risks of Storage and Sharing of Specimens and Data
When we store your specimens and data, we take precautions to protect your information from 
others that should not have access to it. When we share your specimens and data, we will do 
everything we can to protect your identity, for example, when appropriate, we remove information 
that can identify you. Even with the safeguards we put in place, we cannot guarantee that your 
identity will never become known or someone may gain unauthorized access to your information. 
New methods may be created in the future that could make it possible to re-identify your data or 
samples.
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. 
IRB NUMBER: 20C0138
IRB APPROVAL DATE: 12/16/2021


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 11/19//2021
Page 19 of 22
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MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
Will you receive reimbursement or direct payment by NIH as part of you 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.
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. The amount and form 
of these payments are determined by the NCI Travel and Lodging Reimbursement Policy. You 
will be given a summary of the policy which provides 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 are 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.
CONFLICT OF INTEREST (COI) 
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 NIH and the research team for this study are using:

MVA-BN-CV301 and FPV-CV301 developed by Bavarian Nordic, Inc.,

M7824 and NHS-IL12 developed by EMD Serono, Inc.

N-803 developed by ImmunityBio, Inc.
through a joint study with your study team and these companies. These companies also provide 
financial support for this study.
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  
Some of your health information, and/or information about your specimen, from this study will 
be kept in a central database for research. Your name or contact information will not be put in 
IRB NUMBER: 20C0138
IRB APPROVAL DATE: 12/16/2021


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 11/19//2021
Page 20 of 22
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MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
the database. Your test results will be identified by a unique code and the list that links the code 
to your name will be kept separate from your sample and health information. Your information 
may be given out if required by law. For example, certain states require doctors to report to health 
boards if they find a disease like tuberculosis. However, the researchers will do their best to 
make sure that any information that is released will not identify you.
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 National Cancer Institute 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.

The study Sponsor (NCI Center for Cancer Research) or their agent(s).

Qualified representatives from Bavarian Nordic, Inc., the pharmaceutical company who 
produces MVA-BN-CV301 and FPV-CV301, or their agent(s).

Qualified representatives from EMD Serono, Inc., the pharmaceutical company who 
produces M7824 and NHS-IL12, or their agent(s).

Qualified representatives from ImmunityBio, Inc., the pharmaceutical company who 
produces N-803, or their agent(s).
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.
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 the 
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 
IRB NUMBER: 20C0138
IRB APPROVAL DATE: 12/16/2021


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 11/19//2021
Page 21 of 22
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MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
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); or
3. is for other research; or
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.
Policy Regarding 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.
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, Julius Strauss, 
MD, julius.strauss@nih.gov, 240-858-3999. 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: 20C0138
IRB APPROVAL DATE: 12/16/2021


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 11/19//2021
Page 22 of 22
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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: 20C0138
IRB APPROVAL DATE: 12/16/2021