Conditions: Histologically or Cytologically Confirmed Pancreatic Cancer Unresectable or Borderline Resectable Pancreatic Cancer Pancreatic Neoplasms Pancreatic Cancer Metastatic Pancreatic Cancer
Keywords: Neoadjuvant therapy Anti-Tumor Activity Synergistic Anti-cancer Activity Combining Immunotherapy and Radiation Therapy
Allocation: NON_RANDOMIZED | Intervention model: SEQUENTIAL
Enrollment: 3
Healthy volunteers: no

Brief summary:
Background:

Fewer than 10 percent of people with pancreas cancer can have surgery. Surgery gives the best outcome. Radiation therapy is usually used to make surgery possible. But it does not work for most people. Adding immunotherapy might help.

Objective:

To find a safe combined dose of Bintrafusp Alfa (M7824), NHS-IL12 (M9241, and radiation and to see if it causes pancreas cancer tumors to shrink.

Eligibility:

People ages 18 and older who have pancreas cancer and cannot have curative surgery

Design:

Participants will be screened under protocol 01-C-0129 with:

Medical history

Physical exam

Heart, urine, and blood tests

Scans. For this, participants will lie in a machine that takes pictures of the body. They may receive a contrast agent by vein.

Possible tumor biopsy

Participants will take the study drugs either alone or with radiation. They will get M7824 by vein every 2 weeks. They will get M9241 injected under the skin every 4 weeks. Participants who get radiation will get it 5 days in a row the first month.

Participants will have visits every 2 weeks. They will repeat screening tests.

If participants tumors shrink, they will have surgery. If their whole tumor is removed, they will stop treatment. They will otherwise continue treatment as long as they can tolerate it and it is helping them.

Participants will have visits 1 week and 1 month after they stop treatment. Then they will be contacted by phone or email for life. If they stop treatment for a reason other than their disease getting worse, they will have scans every 12 weeks.

Detailed description:
Background:

* At time of diagnosis, fewer than 10% of newly diagnosed pancreatic cancer patients present with resectable disease (patients who can undergo surgery) and patients able to undergo a margin-negative surgical resection (R0) are reported to have the most favorable outcome.
* Locally advanced, non-metastatic pancreas cancer (LAPC) is observed in up to 30% of all pancreas cancer patients at time of diagnosis (including both borderline resectable and non-resectable disease).
* The primary goal of neoadjuvant therapy in LAPC is, among tumor control and extension of survival, the conversion to resectable disease achieving a R0 resection.
* Radiation therapy (RT) is commonly used as neoadjuvant treatment for LAPC.
* However, currently used RT neoadjuvant treatment regimens result in only about 40%-60% of patients with borderline resectable pancreas cancer to undergo surgical resection, in initially unresectable LAPC patient conversion are even lower, with only 7% - 19% able to undergo resection.
* Combining immunotherapy and radiation therapy could synergistically improve anti-cancer activity.
* Bintrafusp alfa (M7824) is a bifunctional fusion protein consisting of an anti-programmed death ligand 1 (PD-L1) antibody functioning as an immune checkpoint inhibitor and the extracellular domain of transforming growth factor beta (TGF-beta) receptor type 2, a TGF-beta trap.
* The NHS-IL12 (M9241) immunocytokine is composed of 2 interleukin-12 (IL-12) heterodimers, each fused to one of the H-chains of the NHS76 antibody, which has affinity for both single- and double-stranded deoxyribonucleic acid (DNA). M9241 targets delivery of IL12, a proinflammatory cytokine that has been shown anti-tumor activity including objective responses in phase I clinical trials, to regions of tumor necrosis where DNA has become exposed, e.g., after radiation therapy.
* We hypothesize that released neo-epitopes upon increased DNA damage induced by radiation therapy together with the local proinflammatory action of M9241 will complement the anti-tumor activity of M7824 in locally advanced pancreas cancer.

Objectives:

* To determine the safety and tolerability and the recommended phase 2 dose (RP2D) of M7824 and M9241 in combination with stereotactic body radiotherapy (SBRT) as neoadjuvant/perioperative treatment in subjects with pancreas cancer.
* To determine a preliminary estimate of efficacy as best overall response (BOR) according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 of M7824 and M9241 in combination with SBRT as neoadjuvant/perioperative treatment in subjects with locally advanced pancreas cancer.

Eligibility:

* Histologically or cytologically proven pancreatic adenocarcinoma.
* Patient must be eligible to undergo stereotactic body radiation therapy (SBRT) (Cohorts 2-3).
* Patients must have measurable disease.
* Age greater than or equal to 18 years

Design:

* This is an open label Phase I/II trial. During phase I the safety and tolerability of M7824 and M9241 will be evaluated and recommended Phase II dose (RP2D) of M7824 and M9241 in combination with SBRT will be estimated. During phase II efficacy of the M7824 and M9241 in combination with SBRT will be examined.
* Patients will receive treatment in cycles consisting of 28 days (with exception of additional administer of M7824 alone in Phase IA).
* Treatment will continue until unacceptable toxicity or disease progression.
* If during treatment patient become candidate for curative surgery, treatment will be stopped and can be restarted after surgery in case if surgical exploration does not result in the successful removal of the tumor.

Arms:
arm 1: De-escalating doses of NHS-IL12 (M9241) in combination with bintrafusp alfa (M7824) arm 2: De-escalating doses of NHS-IL12 (M9241) in combination with bintrafusp alfa (M7824) and stereotactic body radiotherapy (SBRT) arm 3: Recommended phase 2 dose (RP2D) of bintrafusp alfa (M7824) and NHS-IL12 (M9241) in combination with stereotactic body radiotherapy (SBRT)

Interventions: intervention 1: M7824 intervention 2: M9241 intervention 3: SBRT
Intervention descriptions: intervention 1: Intravenous (IV) on Days 1 and 15 of every cycle intervention 2: Subcutaneous injection on Day 1 of every cycle intervention 3: Radiation therapy will be starting on Day 17 (+5 days) of Cycle 1 and continue for 5 consecutive business days.

Protocol document:
Prot_SAP_000.pdf: 
Abbreviated Title: M7824, M9241 and SBRT
Version date: 11/10/2021
1
Abbreviated Title: M7824, M9241 and SBRT
NIH Protocol # 20C0074 
Version Date: 11/10/2021
NCT Number: NCT04327986
Title: A Phase I/II Study of the Immune Checkpoint Inhibitor M7824 and the Immunocytokine 
M9241 in Combination with Stereotactic Body Radiation Therapy (SBRT) in Adults with 
Advanced Pancreas Cancer.
NCI Principal Investigator
Udo Rudloff, MD, PhD 
Rare Tumor Initiative, POB, NCI
Building 10, Room 2B-38D
Bethesda, MD 20892
Phone: 240-760-6238 
E-Mail: rudloffu@mail.nih.gov
Investigational Agents: 
Drug Name:
M7824
M9241
IND Number:
146972
146972
Sponsor:
CCR
CCR
Manufacturer:
EMD Serono 
EMD Serono
Supplier:
EMD Serono 
EMD Serono
Commercial Device: Stereotactic Body Radiation Therapy


Abbreviated Title: M7824, M9241 and SBRT
Version date: 11/10/2021
2
PRÉCIS 
Background:

At time of diagnosis, fewer than 10% of newly diagnosed pancreatic cancer patients present 
with resectable disease (patients who can undergo surgery) and patients able to undergo a 
margin-negative surgical resection (R0) are reported to have the most favorable outcome.

Locally advanced, non-metastatic pancreas cancer (LAPC) is observed in up to 30% of all 
pancreas cancer patients at time of diagnosis (including both borderline resectable and non-
resectable disease).

The primary goal of neoadjuvant therapy in LAPC is, among tumor control and extension of 
survival, the conversion to resectable disease achieving a R0 resection. 

Radiation therapy (RT) is commonly used as neoadjuvant treatment for LAPC.

However, currently used RT neoadjuvant treatment regimens result in only about 40%-60% of 
patients with borderline resectable pancreas cancer to undergo surgical resection, in initially 
unresectable LAPC patient conversion are even lower, with only 7% - 19% able to undergo 
resection. 

Combining immunotherapy and radiation therapy could synergistically improve anti-cancer 
activity. 

M7824 is a bifunctional fusion protein consisting of an anti-programmed death ligand 1 (PD-
L1) antibody functioning as an immune checkpoint inhibitor and the extracellular domain of 
transforming growth factor beta (TGF-β) receptor type 2, a TGF-β trap.

The M9241 immunocytokine is composed of 2 IL-12 heterodimers, each fused to one of the 
H-chains of the NHS76 antibody, which has affinity for both single- and double-stranded 
DNA. M9241 targets delivery of IL12, a proinflammatory cytokine that has been shown anti-
tumor activity including objective responses in phase I clinical trials, to regions of tumor 
necrosis where DNA has become exposed, e.g. after radiation therapy.

We hypothesize that released neo-epitopes upon increased DNA damage induced by radiation 
therapy together with the local proinflammatory action of M9241 will complement the anti-
tumor activity of M7824 in locally advanced pancreas cancer.
Objectives:

To determine the safety and tolerability and the recommended phase 2 dose (RP2D) of M7824 
and M9241 in combination with SBRT as neoadjuvant / perioperative treatment in subjects 
with pancreas cancer. 

To determine a preliminary estimate of efficacy as best overall response (BOR) according to 
RECIST 1.1 of M7824 and M9241 in combination with SBRT as neoadjuvant / perioperative 
treatment in subjects with locally advanced pancreas cancer.
Eligibility:

Histologically or cytologically proven pancreatic adenocarcinoma. 

Patient must be eligible to undergo stereotactic body radiation therapy (SBRT) (Cohorts 2-3).


Abbreviated Title: M7824, M9241 and SBRT
Version date: 11/10/2021
3

Patients must have measurable disease.

Age ≥18 years 
Design:

This is an open label Phase I/II trial. During phase I the safety and tolerability of M7824 
and M9241 will be evaluated and recommended Phase II dose (RP2D) of M7824 and 
M9241 in combination with SBRT will be estimated. During phase II efficacy of the 
M7824 and M9241 in combination with SBRT will be examined.

Patients will receive treatment in cycles consisting of 28 days (with exception of additional 
administer of M7824 alone in Phase IA).

Treatment will continue until unacceptable toxicity or disease progression.

If during treatment patient become candidate for curative surgery, treatment will be stopped 
and can be restarted after surgery in case if surgical exploration does not result in the 
successful removal of the tumor.


Abbreviated Title: M7824, M9241 and SBRT
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4
TABLE OF CONTENTS 
PRÉCIS
2
TABLE OF CONTENTS
4
STATEMENT OF COMPLIANCE
10
1
INTRODUCTION
10
1.1
Study Objectives:
10
1.1.1
Primary Objectives:
10
1.1.2
Secondary Objectives:
10
1.1.3
Exploratory Objectives:
10
1.2
Background and Rationale
11
1.2.1
Neoadjuvant therapy for locally advanced pancreas cancer (LAPC)
11
1.2.2
Radiation and immunotherapy: a synergistic combination
15
1.2.3
Radiation therapy counters immune evasion
16
1.2.4
Current progress in immunotherapy for pancreas cancer
16
1.2.5
M7824 (bintrafusp alfa; bifunctional fusion protein targeting PD-L1 and TGF-β)
24
1.2.6
M9241
25
1.2.7
Neoadjuvant RT for pancreas cancer – SBRT with Simultaneous Integrated Boost 
(SIB)
27
1.2.8
Health-related quality of life
32
1.2.9
Rationale for this clinical trial
32
2
ELIGBILITY ASSESSMENT AND ENROLLMENT
33
2.1
Eligibility Criteria
33
2.1.1
Inclusion Criteria
33
2.1.2
Exclusion Criteria
35
2.1.3
Recruitment Strategies
36
2.2
Screening Evaluation
36
2.2.1
Screening activities performed prior to obtaining informed consent
36
2.2.2
Screening activities performed after a consent for screening has been signed
36
2.3
Participant Registration and Status Update Procedures
37
2.3.1
Treatment assignment procedures (For registration purposes only):
37
2.4
Baseline Evaluation
38
3
STUDY IMPLEMENTATION
39
3.1
Study Design
39


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3.1.1
Dose Limiting Toxicity
41
3.1.2
Phase IA/IB:
42
3.1.3
Phase II, Cohort 3, Arm 2
44
3.2
Study Stopping Rules
44
3.3
Drug Administration
44
3.3.1
M7824
44
3.3.2
M9241
45
3.3.3
SBRT
45
3.4
Dose Modifications:
46
3.4.1
M7824
46
3.4.2
M9241
51
3.4.3
SBRT
53
3.5
Assessments On Treatment
54
3.5.1
Study assessments
54
3.5.2
End-of-Treatment Visit and Follow UP
54
3.5.3
Treatment pauses for surgery
54
3.6
Questionnaires
55
3.7
Research Imaging
56
3.8
Study Calendar
57
3.9
Cost and Compensation
62
3.9.1
Costs
62
3.9.2
Compensation
62
3.10
Reimbursement
62
3.11
Criteria for Removal from Protocol Therapy and Off Study Criteria
62
3.11.1
Criteria for Removal from Protocol Therapy
62
3.11.2
Off -Study Criteria
62
3.11.3
Lost to Follow-up
63
4
CONCOMITANT MEDICATIONS / MEASURES
63
4.1
Permitted Medicines
63
4.2
Prohibited Medicines
63
5
BIOSPECIMEN COLLECTION
64
5.1.
Correlative Studies For Research/Pharmacokinetic Studies
64
5.1.3
Pharmacokinetic analysis
65


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5.1.4
ADA
65
5.1.5
Serum cytokines and serum TNF levels
66
5.1.6
Changes in systemic and intratumoral immunogenicity of M7824 and /or M9241 in 
combination with SBRT (Immune marker panel evaluation by IHC)
66
5.2
Samples for Genetic/Genomic Analysis
66
5.2.1
Description of the scope of genetic/genomic analysis
66
5.2.2
Circulating free tumor DNA measures:
66
5.2.3
Management of Results
67
5.2.4
Genetic counseling
67
5.3
Sample Storage, Tracking and Disposition
67
5.3.1
Protocol Completion/Sample Destruction
68
6
DATA COLLECTION AND EVALUATION
68
6.1
Data Collection
68
6.1.1
PK Data
69
6.1.2
Tumor data
69
6.1.3
Concomitant Medications and Therapies
69
6.2
Data Sharing Plans
69
6.2.1
Human Data Sharing Plan
69
6.2.2
Genomic Data Sharing Plan
70
6.3
Response Criteria
70
6.3.1
Disease Parameters
70
6.3.2
Methods for Evaluation of Measurable Disease
71
6.3.3
Response Criteria
72
6.3.4
Responses
74
6.4
Immune-Related Response Criteria (irRECIST)
74
6.5
Toxicity Criteria
74
7
NIH REPORTING REQUIREMENTS / DATA AND SAFETY MONITORING 
PLAN
74
7.1
Definitions
74
7.2
OHSRP Office Of Compliance and Training / IRB Reporting
74
7.2.1
Expedited Reporting
74
7.2.2
IRB Requirements for PI Reporting at Continuing Review
74
7.3
NCI Clinical Director Reporting
75


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7.4
NIH Required Data and Safety Monitoring Plan
75
7.4.1
Principal Investigator/Research Team
75
8
SPONSOR PROTOCOL/SAFETY REPORTING
75
8.1
Definitions
75
8.1.1
Adverse Event
75
8.1.2
Serious Adverse Event (SAE)
75
8.1.3
Life-threatening
76
8.1.4
Severity
76
8.1.5
Relationship to Study Product
76
8.1.6
Adverse Events of Special Interest (AESI)
76
8.2
Assessment of Safety Events
77
8.3
Reporting of Serious Adverse Events
77
8.4
Waiver of Expedited Reporting to CCR
77
8.5
Safety Reporting Criteria to the Pharmaceutical Collaborators
78
8.6
Reporting Pregnancy
78
8.6.1
Maternal exposure
78
8.6.2
Paternal exposure
78
8.7
Regulatory Reporting for Studies Conducted Under CCR-Sponsored IND
78
8.8
Sponsor Protocol Non-Adherence Reporting
78
9
CLINICAL MONITORING
79
10
STATISTICAL CONSIDERATIONS
79
10.1
Statistical Hypothesis
79
10.1.1
Primary endpoints:
79
10.1.2
Secondary endpoints
80
10.2
Sample Size Determination
80
10.3
Populations For Analysis
81
10.4
Statistical Analyses
82
10.4.1
General Approach
82
10.4.2
Analysis of the primary endpoints
82
10.4.3
Analysis of the secondary endpoints
82
10.4.4
Safety analyses
83
10.4.5
Baseline descriptive statistics
83
10.4.6
Planned interim analyses:
83


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10.4.7
Exploratory analyses
83
11
COLLABORATIVE AGREEMENT
84
11.1
Cooperative Research And Development Agreement (CRADA)
84
12
HUMAN SUBJECTS PROTECTIONS
84
12.1
Rationale for Subject Selection
84
12.2
Participation of Children
84
12.3
Participation of Subjects Unable to Give Consent
84
12.4
Risk/Benefit Assessment For All Participants
84
12.4.1
Known Potential Risks
84
12.4.2
Known Potential Benefits
86
12.4.3
Assessment of Potential Risks and Benefits
86
12.5
Consent Process And Documentation
86
12.5.1
Consent Process for Adults Who Lack Capacity to Consent to Research 
Participation
87
13
REGULATORY AND OPERATIONAL CONSIDERATIONS
87
13.1
Study Discontinuation And Closure
87
13.2
Quality Assurance And Quality Control
88
13.3
Conflict Of Interest Policy
88
13.4
Confidentiality and Privacy
88
14
PHARMACEUTICAL AND INVESTIGATIONAL DEVICE INFORMATION
89
14.1
M7824 (146972)
89
14.1.1
Acquisition and Accountability
89
14.1.2
Administration.
89
14.1.3
Formulation and Preparation
89
14.1.4
Storage and Stability:
90
14.1.1
Toxicity
90
14.2
M9241 (146972)
90
14.2.1
Administration.
90
14.2.2
Formulation and Preparation
90
14.2.3
Storage and Stability:
90
14.2.1
Toxicity
90
14.3
Stereotactic Body Radiation Therapy
91
14.3.1
Toxicity
91


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9
15
REFERENCES
92
16
APENDICES
97
16.1
Appendix A: Diagnostic criteria of borderline resectable pancreas cancer
97
16.2
Appendix B: M9241 Multiple Dose PK Profile in Humans and M9241-Induced 
Alterations in Plasma Cytokine Profiles and Peripheral Blood Immune Cell 
Phenotype.
99
16.3
Appendix C: Fact-Hep Version 4
102
16.4
Appendix D:Performance Status Criteria
105
16.5
Appendix E:Modified Immune-related Response Criteria (irRECIST)
106


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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 Objectives:

To determine the safety and tolerability and the recommended phase 2 dose (RP2D) of 
M7824 and M9241 in combination with SBRT as neoadjuvant / perioperative treatment in 
subjects with pancreas cancer. 

To determine a preliminary estimate of efficacy as best overall response (BOR) according 
to RECIST 1.1 of M7824 and M9241 in combination with SBRT as neoadjuvant / 
perioperative treatment in subjects with locally advanced pancreas cancer. 
1.1.2
Secondary Objectives:

To assess overall survival (OS) in patients after completion of RT in combination with 
M9241 and M7824. 

To assess progression-free survival (PFS) for all participants.

To assess progression-free survival (PFS) for participants who did not undergo surgical 
resection.

To determine fraction of patients with LAPC who are able to undergo surgical resection 
after M7824 and M9241 in combination with SBRT treatment.

For patients who underwent surgical resection after M7824 and M9241 in combination 
with SBRT treatment:
To determine time-to-recurrence of the disease
To determine complete pathological response rate(s) 
1.1.3
Exploratory Objectives:

To determine ADA profile of M7824 in combination with M9241.


Abbreviated Title: M7824, M9241 and SBRT
Version date: 11/10/2021
11

To determine the PK of M7824 in combination with M9241. 

To evaluate serum cytokines and tumor necrosis factor (TNF) levels pre-treatment and on-
treatment.

To correlate the tumoral immune infiltrate via IHC with clinical outcome.

To evaluate impact of genomic profile of advanced pancreatic cancers on clinical response 
to M7824 and M9241 in combination with SBRT.

To correlate circulating free tumor DNA (ctDNA) levels with clinical course of pancreatic 
cancer patients treated with M7824 and M9241 in combination with SBRT.

To measure subjective Health-related Quality of Life (HRQoL) affecting disease-specific 
symptoms and treatment-related concerns pre-treatment and on-study and compare 
HRQoL scores with historical controls of other Quality of Life (QoL) interventions in 
advanced pancreas cancer patients.

To evaluate the impact of M7824 in combination with M9241 on tumoral perfusion 
measured by perfusion-weight Dynamic Contrast-enhanced (DCE) Magnetic Resonance 
Imaging (DCE-MRI).
1.2
BACKGROUND AND RATIONALE
Rationale for this study is provided by available preclinical and clinical evidence of the individual 
mono-immunotherapy components: 
-
TGFβ blockade and PD-L1 inhibition, --- by M7824
-
local increase in IL-12 function, --- by M9241, and 
-
enhanced anti-tumor immunogenicity, --- by radiation therapy (RT) 
which synergize / cooperate treatment effect when combined:
-
cooperation of PD-L1 checkpoint inhibition with RT
-
cooperation of TGFβ blockade with RT 
-
IL-12 immunotherapy (M9241) in combination with RT
-
IL-12 immunocytokine therapy (M9241) in combination with TGFβ- and PD-L1 inhibition 
(M7824).
1.2.1
Neoadjuvant therapy for locally advanced pancreas cancer (LAPC)
Pancreatic cancer is a life-threatening disease with a dismal outcome. In 2016, about 48,960 people 
(24,840 men and 24,120 women) were diagnosed with pancreatic cancer, and 40,560 people 
(20,710 men and 19,850 women) are estimated to have died of pancreatic cancer.[1] AACR 
estimates deaths due to pancreas cancer to rank 2nd among all cancer-related deaths in the U.S. by 
2030.[2] At time of diagnosis, fewer than 10% of newly diagnosed pancreatic cancer patients 
present with resectable disease (patients who can undergo surgery; stage I - IIA) and patients able 
to undergo a margin-negative surgical resection (R0) are reported to have the most favorable 
outcome achieving 5-year survival rates of 25 – 30% (Figure 1). 


Abbreviated Title: M7824, M9241 and SBRT
Version date: 11/10/2021
12
Figure 1: Percent patients at different AJCC stages at time of initial diagnosis of pancreas cancer. Left: per 7th 
edition of American Joint Commission of Cancer, AJCC more than 6,000 pancreas cancer patients presenting between 
2000 and 2005 to Memorial Sloan-Kettering Cancer Center, NY, and their corresponding 5-year survival rates (right) 
from MSKCC Pancreatic Cancer Registry.
Approximately 50 to 60 % of patients at time of diagnosis have metastatic disease (stage IV).[3] 
The rest (one third) of all patients with pancreas cancer have disease that is locally advanced 
because of local interface or invasion of adjacent structures.[4-6] While ultimately a continuum of 
disease progression LAPC is subdivided into borderline resectable pancreas cancer characterized 
by a higher risk of a margin positive surgical resection due to one, or more, interface(s) of the 
tumor with a mesenteric structure and unresectable, locally invasive disease.[5, 7] There are no 
commonly agreed criteria of borderline resectable pancreas cancer, different organizations have 
published slight variations of primarily radiographic criteria which are listed in Appendix A. 
The primary goal of neoadjuvant therapy in LAPC is, among tumor control and extension of 
survival, the conversion to resectable disease achieving a R0 resection.[4] Some series have 
reported for patients with initially borderline resectable pancreas cancer who after neoadjuvant 
therapy were able to undergo a margin-negative surgical resection of their tumor similar outcomes 
like for patients with initially resectable disease.[4, 6, 8, 9] However, even after multimodality 
therapy that includes surgical resection, 5-year overall survival only reached 25 – 30% with an 
ongoing risk of systemic and locoregional disease recurrence speaking to the systemic nature of 
the disease and making pancreas cancer, even in its early stages, a near incurable condition.[4, 7, 
9] 
Patients unable to undergo margin-negative resection have a poor outcome frequently similar to 
patients with stage IV disease and have poor quality of life indices due to challenging palliation of 
gastric outlet, biliary duct obstruction, or neuropathic pain due to local tumor progression.[4] 
Currently used neoadjuvant RT treatment regimens result in only about 40 – 60% of patients with 
borderline resectable pancreas cancer to undergo surgical resection and in unresectable LAPC 
patient conversion are even lower, with only 7% - 19% being able to undergo resection which is 
increased to 29% with the use of the most involved and toxic combination of triple FOLFIRINOX 
chemotherapy in combination with RT in highly selected patients.[5, 6, 10] Figure 2 shows the 
flow diagram and outcome differences between all locally advanced pancreas cancer patients 
(intent-to-treat), outcome of patients who were able to undergo surgical resection, and patients 
who could not undergo surgery of one of the first sentinel series on the use of neoadjuvant therapy 
using gemcitabine-based chemoradiation therapy.[9]


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Figure 2: MDACC experience of preoperative gemcitabine-based chemoradiation (EBRT) for patients with 
potentially resectable (borderline) adenocarcinoma of the pancreatic head. Flowchart of all 86 patients on the 
left, survival curve for all 86 patients and survival curves for the patients who underwent pancreaticoduodenectomy 
(PD; n=64) versus those who did not undergo PD (n=22). The median overall survival for all patients (intent-to-treat) 
was 22.7 months, for the resected patients 34 months, and for patients not taken to surgery 7 months.[9]
Thus, the primary goal of neoadjuvant therapy in LAPC is, among tumor control and extension of 
survival, the conversion to resectable disease achieving a R0 resection. Neoadjuvant therapy 
provides the theoretical advantages over standard adjuvant therapy including 
-
treatment of distant micro metastasis
-
assessment of tumor response to treatment, and 
-
better triaging and selection of patients for surgical resection (summarized in [11]).
2016 American Society of Clinical Oncology (ASCO) Clinical Practice Guidelines on locally 
advanced pancreas cancer (LAPC) recommend ‘Initial systemic therapy with combination 
regimens is recommended for most patients who meet the following criteria: Eastern Cooperative 
Oncology Group performance status (ECOG PS) 0 or 1, a favorable comorbidity profile, and 
patient preference and a support system for aggressive medical therapy.[5] There is no clear 
evidence to support one regimen over another, and physicians may offer therapy on the basis of 
extrapolation from data derived from studies in the metastatic setting. For many patients, induction 
chemotherapy may be offered up front, followed by radiation therapy (CRT), on the basis of patient 
and physician preference.[5, 12]
If there is an insufficient response to initial induction chemotherapy, which is not uncommonly 
difficult to judge due to the inability of current radiologic criteria to confidently discriminate 
between tumor tissue, fibrous tissue without tumor, or fibrous tissue with tumor nests, or if there 


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is local tumor extension without the development of metastasis after induction chemotherapy, RT 
may be offered to patients who meet criteria with regard to their performance status, organ 
function, and preference.[4, 5] Overall, patients with locally advanced pancreas who receive 
neoadjuvant therapy receive in 98% of cases some form of systemic chemotherapy and in up to 
94% RT although the rates for RT administration have recently dropped due to the introduction of 
oxaliplatin and gem/abraxane-containing chemotherapy regimens into the neoadjuvant setting.[4] 
RT, like in the proposed study, is generally given either as 
-
external beam radiation therapy (EBRT) delivering a total dose of 50 – 54 Gy in daily 
fractions of 1.7 – 3Gy over 4 to 8 weeks, or less frequently with less data available, as
-
stereotactic radiation therapy (SBRT) using an abbreviated schedule delivering 5 – 6.6 
Gy in 5 session.[5, 6, 12]) (please see Section 1.2.7.)
RT is combined with a chemo sensitizing agent which is either oral capecitabine (oral 5-FU pro-
drug; 830mg/m2 PO twice daily) or gemcitabine (300mg/m2 weekly; therapeutic dose 
1,000mg/m2) with despite direct comparison in a radio-chemotherapy (RCT) no clear superiority 
in efficacy of one over the other.[13] For this study on the days of SBRT 830mg/m2 capecitabine 
twice daily by mouth is given.
Figure 3 provides a flow chart of summary of treatment algorithm of pancreas cancer aligned with 
ASCO 2016 Practice Guidelines. While the algorithm lists specific chemotherapy regimens in the 
management of LAPC patients who undergo neoadjuvant treatment, there is currently no 
consensus that one is superior to the other (FOLFIRINOX vs gemcitabine-based regimens 
including gem/abraxane) and ASCO Guidelines suggest an individual-based decision making. 


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Figure 3: Overview of currently practiced treatment algorithm for patients diagnosed with pancreas cancer. 
Please note that there is currently no level I recommendation of type of 1st vs 2nd line chemotherapy in the metastatic 
setting, or chemotherapy regimens used in the neoadjuvant treatment of LAPC.
Overall, there is a medical need to improve current neoadjuvant treatment of LAPC, ideally with 
a combination of agents which improves both local response rates as well as long term control of 
undetected micro metastasis, the to-date most common cause of death in LAPC and pancreas 
cancer patients in general.
1.2.2
Radiation and immunotherapy: a synergistic combination
Pancreatic cancer is highly chemotherapy and radiation therapy-resistant, making treatment 
options very limited. Contrary to immune-active tumors with an abundant infiltration of CD8+ T 
cells like melanoma, non-small cell lung carcinoma (NSCLC), or microsatellite high (MSI high) 
gastrointestinal (GI) tumors, pancreas cancer is an immune quiescent cancer which lacks 
infiltration of effector T cells and is resistant to single agent checkpoint inhibition treatment.[14-
16] Whether the recent discovery of a molecular immunogenic subtype based on gene expression 
profiling conducted within the Cancer Genome Atlas (TCGA) effort changes this paradigm 
remains to be seen.[17]
During the process of tumorigenesis, tumor antigens, originating in large from somatic gene 
variants in the tumor (referred to as neoantigens), arise and are recognized by the host’s immune 
system as foreign.[18] However, and in particular pancreatic tumors, cancers select effective 
immune evasive mechanism within the educated and reprogrammed tumor microenvironment to 
curb recognition of such tumor antigen recognition and T cell responses.[16, 19] Through myriad 


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immune suppressive stimuli, the T cell phenotype in the stroma mimics T cell exhaustion seen 
normally upon repeat and chronic antigen stimulation which include, but are not limited the 
upregulation of PD-L1 (B7-H1), indoleamine 2,3-dioxygenase (IDO), IL-10, lymphocyte 
activation gene 3 (LAG3), transforming growth factor-β (TGF-β), the education of CD4+ T 
regulatory cells from a naïve towards an effector/memory phenotype, or the attraction of a variety 
of cellular elements like MDSCs or M2 tumor-associated macrophages within the tumor 
microenvironment.[20] 
1.2.3
Radiation therapy counters immune evasion
There are a variety of known molecular and immunologic mechanisms regarding how RT 
augments, both at the site of irradiation as well as at distant sites not included into the radiation 
field (abscopal effect), tumor responses which are not only under intense clinical evaluation but 
where early clinical efficacy signals of synergistic radiation and immunotherapy combinations 
have already emerged. In brief, mechanisms how RT induces, and augments anti-tumor responses 
include
-
Radiation therapy mitigates evasion of antigen presentation of tumors: Expression of 
MHC-I molecules, critical for antigen recognition by cognate CD8+ T-cell receptors 
(TCR)s, is diminished in tumors as tumors can also lose the ability to process antigens 
intracellularly or can select for less antigenic clones. Radiation, on the other hand, 
augments MHC-I expression via HMGB-1/toll-like receptor 4 (TLR4) interaction[20-22]
-
RT causes dying tumor cells to release high mobility group box 1 (HMGB-1), a well-
described “danger signal” that binds and activates TLR4. Activation of TLR4 establishes 
a mechanistic link between an innate and adaptive immune response that may overcome 
the failure of the intrinsic immune system, or immunotherapy, to establish a link between 
the two[23]
-
radiation-induced DNA damage or loss of ataxia-telangiectasia mutated (ATM, a protein 
involved in DNA repair) leads to the release of nuclear DNA in the cytoplasm (cytosolic 
DNA). After sensing cytosolic DNA, STING (stimulator of interferon genes) adaptor 
protein will bind to Tank-binding kinase 1 (TBK1), which will be followed by the 
activation of the transcription of IFN regulatory factor 3 (IFN3) to induce type I interferon 
(IFN) providing another connection between innate and adaptive immunity[24, 25]
-
RT can also generate tumor-specific cytotoxic T cells. Cytotoxic T cells are more easily 
recruited to the irradiated tumor site due to the release of chemokines such as CXCL16; 
irradiated tumors also upregulate death receptors (e.g., FAS), promoting the cytotoxic 
effect of T cells at the tumor site[26]
-
The destruction of tumor cells by RT releases usually intracellularly contained antigens 
which, upon release, gene generate T cell responses[20]
1.2.4
Current progress in immunotherapy for pancreas cancer
Considering the pleiotropy of anti-immunogenic cues in tumors, synergistic combinations of 
immunotherapy and RT are not limited to one immune pathway but can, and should, involve the 
targeting of a combination of immune suppressive cues to tip the anti-tumor responses towards 
tumor elimination [20]. Such a combinational approach, targeting several avenues of immune 
escape is also supported by clinical observations of immunotherapy in pancreas cancer to date: 


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while single-agent checkpoint blockade or single therapeutic vaccine therapy failed to elicit any 
anti-tumor activity, the triple combination of the GVAX vaccine, the anti-mesothelin vaccine 
CRS-207, a recombinant live-attenuated, double-deleted Listeria monocytogenes engineered 
vaccine secreting tumor antigens into the cytosol of antigen presenting cells, and mnetromonic 
cyclophosphamide chemotherapy (administered to reduce T regulatory cells), yielded improved 
overall survival compared to cyclophosphamide and GVAX [27]. Enhanced mesothelin-specific 
CD8 T-cell responses were associated with longer OS, regardless of treatment arm. In a follow-up 
randomized phase II study, the combination of cyclophosphamide, GVAX, and CRS-207 did not 
show a survival benefit over chemotherapy in patients with previously-treated metastatic 
pancreatic ductal adenocarcinoma (mPDA). These efforts are now extended, and complemented, 
by the addition of e.g. anti-PD-L1 checkpoint blockade to improve outcome of combination 
immunotherapy.[16]
Thus, based on the promise of combination immunotherapy and the pleiotropy of immunological 
anti-tumor effects of RT this study aims to exploit synergies of RT and immunotherapy using the 
dual checkpoint inhibitor M7824 targeting the immune checkpoints PD-1/PD-L1 and TGFβ and 
locally increased levels of IL-12 through the immunocytokine M9241 in combination with RT to 
improve outcome in locally advanced pancreas cancer. Examples of preclinical and clinical 
cooperativity/synergy for these individual immunotherapy combinations are as follows:
1.2.4.1
Cooperation of PD-L1 checkpoint inhibition and RT
The dual immune checkpoint inhibitor M7824 used in this trial has two components: one is the 
recombinant extracellular domain of the human TGFβ receptor, the other is a humanized 
monoclonal antibody fragment against PD-L1, which is identical to avelumab, the PD-L1 
checkpoint inhibitor recently approved for advanced metastatic Merkel cell carcinoma and 
urothelial cancer and currently in a number of large phase III studies and in combination studies 
with radiation therapy [28].
Examples of cooperative/synergistic clinical efficacy of immune checkpoint blockade and RT 
include combining palliative RT with the anti-CTLA-4 checkpoint inhibitor ipilimumab in 
metastatic melanoma, the combination of the PD-1 inhibitor nivolumab or the CTLA-4 inhibitor 
ipilimumab with RT therapy for the treatment of brain metastasis in melanoma, or from early and 
ongoing clinical trials the combination of radiation and immune checkpoint therapy in 
(oligo)metastatic lung cancer patients treated with thoracic RT and immune checkpoint inhibitors 
or from the combination in patients with breast cancer [29-31]. Another strong signal for immune-
editing of RT comes from the recently released PACIFIC study, a randomized, double-blind, phase 
3 study comparing consolidation therapy with durvalumab versus placebo in patients with stage 
III, locally advanced, unresectable NSCLC that had not progressed after the standard treatment for 
stage III NSCLC (platinum-based chemotherapy/RT). Patients were randomized to durvalumab (n 
= 473) or placebo (n = 236). The median PFS was 16.8 months (95% CI, 13.0-18.1) with 
durvalumab compared with 5.6 months (95% CI, 4.6-7.8) for placebo (HR, 0.52; 95% CI, 0.42-
0.65; P <.001). The objective response rates were 28.4% versus 16%.0, respectively (P <.001).
Within this line, PD-L1 inhibition, as part of the dual checkpoint inhibitor M7824 in this clinical 
protocol, does synergize with radiation therapy in the syngeneic, immune competent pancreas KPC 
and Panc02 (data not shown from Panc02 mice) preclinical mouse models [32]. Figure 4 shows 
that addition of anti-PD-L1 to high (12, 5 × 3, 20 Gy) but not low (6, 5 × 2 Gy) RT doses 
significantly improved tumor response in KPC allografts. Radio sensitization after PD-L1 


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blockade was associated with reduced CD11b+Gr1+ myeloid cell infiltration and enhanced 
CD45+CD8+ T-cell infiltration with concomitant upregulation of T-cell activation markers and 
increased CD8:Treg ratio. Depletion of CD8+ T cells abrogated radio sensitization by anti-PD-L1. 
Of note the triple combination of gemcitabine‐based chemo irradiation, the addition of gemcitabine 
as a radiation sensitizer as suggested in the clinical trial, showed the largest anti-tumor impact in 
the KPC tumors (Figure 5).
Figure 4: Synergistic effect of RT and PD-L1 inhibition in the syngeneic murine pancreas cancer KPC model. 
A. Fractionated RT synergizes with PD-L1 blockade to inhibit tumor growth. Synergistic effect is dependent on CD8 
T cells. B. Simultaneous PD-L1 administration is superior to sequential administration (from [32])
Figure 5: Triple combination of gemcitabine‐based chemo irradiation with anti‐PD‐L1 shows superior efficacy 
compared to irradiation and PD-L1 blockade without chemo sensitization in KPC pancreas cancer allograft. 
Tumor growth of indicated regimens over time shown on left, time for tumors to reach 400m2 on the right (from [32])
Thus, PD-L1 blockade enhances anti-tumor efficacy of RT in preclinical models of pancreas 
cancer. The cooperative effect is further improved through the addition of gemcitabine-based radio 
sensitization (CRT) as in the proposed trial.
1.2.4.2
Preclinical and clinical cooperation of TGFβ blockade in combination with RT
The TGF beta receptor small molecule inhibitor LY2157299 (galunisertib) is currently undergoing 
phase II clinical testing in combination with neoadjuvant chemoradiation in patients with rectal 


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adenocarcinoma (ExIST study - NCT02688712) and the mAb TGF beta inhibitor fresolimumab, 
an anti-transforming growth factor beta (TGFB) antibody, as part of the SABR-ATAC trial 
(Stereotactic Ablative Radiotherapy and anti-TGFB Antibody Combination - NCT02581787) in 
combination with RT for the treatment of NSCLC. TGF beta inhibitors are also combined with 
SBRT for glioblastoma.
These clinical trials are based on a plethora of preclinical data showing that TGFβ inhibition 
augments the effects of RT. 
To show that above findings of 
- cooperativity of PD-L1 inhibition and RT
- cooperativity of TGFβ inhibition and RT (the two components of M7824)
are indeed reproducible with the use of M7824, the dual PD-L1 and TGFβ inhibitor used in the 
proposed clinical trial, M7824 was tested in combination with RT in the syngeneic, immune 
competent MC38 cancer model:
Figure 6 shows the significant synergy between M7824 and RT, both at the local tumor site as 
well as at distant tumor sites (abscopal effect) leading (1) to significant tumor regression in the 
combination group in this model, and (2) significant induction of anti-tumor activity as shown by 
enhanced interferon gamma release of CD8+ T cell isolated from these tumors and co-cultured 
with cancer cells (EliSpot assay) [28]. M7824 and the first fraction of RT was given at the same 
time. Thus, both PD-L1 and TGFβ inhibition individually synergize with RT, with early clinical 
data in favor of immune checkpoint inhibition and radiation therapy emerging, and dual inhibition 
of PD-L1 and TGFβ signaling with M7824, as proposed in this study, in combination with RT 
causes tumor regression in preclinical syngeneic cancer models.


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Figure 6: Low dose radiation combined with a single low dose of M7824 induced tumor regression that is 
associated with a strong T cell response in MC38 tumors. A. Tumor volume of MC38 mice treated with vehicle, 
low-dose irradiation, M7824, and the combination of RT and M7824. B. Tumor weights at 14 days. C. Intratumoral 
CD8+ T cell activity of four cohorts. D-F. Local irradiation in combination with M7824 induces anti-tumor responses 
at sites distant from irradiated tumors (from [28])
1.2.4.3
IL-12 immunotherapy in combination with RT
Interleukin-12 (IL-12) is a proinflammatory cytokine produced by activated phagocytes and 
dendritic cells (DCs) that plays a critical role in regulating the transition from innate to adaptive 
immunity. IL-12 acts directly on cytotoxic immune effector cells, namely natural killer (NK) cells, 
NKT cells, and CD8+ T cells, to stimulate their proliferation and increase their cytotoxic 
functions.[33] Furthermore, IL-12 drives differentiation of helper T cells down the Th1 pathway, 
thereby promoting the production of cytokines, most notably IFN-γ, that favor cell-mediated 
immunity.[34] There is also evidence that IL-12 acts directly on DCs to further stimulate IL-12 
production 
and 
enhance 
antigen 
presentation.[35] 
By 
amplifying 
these 
positive 
immunostimulatory effects, therapeutic administration of exogenous IL-12 has the potential to 
promote effective anti-tumor immune responses.
Despite this therapeutic rationale, recombinant (r) IL-12 has yet to be approved for any indication, 
due to previously reported toxic side effects of systemic administration, which may have limited 
its ability to induce objective response rates, and delaying further clinical development.[36, 37] In 
a phase I study of rIL-12, dose levels tolerated during repeated administrations proved to be toxic 
in a subsequent phase II trial. 


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Nevertheless, IL-12 has shown some promising clinical activity in phase I trials, including 
stabilization of disease in renal cancer patients, with partial regression of a metastatic lesion.[38] 
This is a clear example of rIL-12’s ability to create anti-tumor immune responses when applied at 
maximum tolerated dose (MTD) over an extended period of time.[39] Furthermore, higher 
objective response rates with rIL-12 have been reported in certain neoplastic diseases, including 
T-cell lymphoma (56%), non-Hodgkin’s lymphoma (21%), and AIDS-related Kaposi’s sarcoma 
(50-71%).[40-42] 
The M9241 concept is one strategy to reduce the toxicity associated with systemic administration 
of recombinant human IL-12, by altering pharmacokinetics and selectively targeting delivery of 
IL-12 to tumors.[43] The NHS antibody component has been shown to selectively target human 
lung carcinomas as a radiolabeled monoclonal antibody. The M9241 immunocytokine is 
composed of two IL-12 heterodimers, each fused to one of the H-chains of the NHS76 antibody 
that has affinity for both single- and double-stranded DNA which are abundant in areas of tumor 
necrosis.[44] This antibody targets IL-12’s delivery to regions of tumor necrosis where DNA has 
become exposed, like post-radiation therapy, thus increasing intratumoral exposure and reducing 
systemic exposure.[43] That pancreatic cancer is a solid organ malignancy with per se 
heterogenous and poor perfusion and high rate of necrosis is shown in Figure 7. 
Figure 7: Example of dense human pancreatic cancer stroma. Masson trichrome, collagen I with poor 
vascularization (by anti-CD34 staining) (top) and large areas of poor perfusion (Dextran perfusion; upper right) with 
intratumoral necrosis (by hydroxy probe detection) in autochthonous murine pancreatic tumors (bottom).
Thus, not only does this targeted strategy have the potential to reduce systemic toxicity, but it also 
has the potential to increase immune infiltration and activity locally within the tumor 
microenvironment, as well as systemically (abscopal effect), and is ideally suited to be combined 
with RT.[45, 46] With the other anti-tumor immunogenic effects of RT this in turn has the potential 


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to optimal prime otherwise non-immunogenic tumors like pancreas cancer to checkpoint inhibition 
and increase the spectrum of cancers which may respond to these agents. That administration of 
IL-12 limited by local intratumoral injection of an adenovirus (Ad) encoding interleukin-12 gene 
already can mediate improved anti-tumor immunogenicity has been shown by a previous phase I 
study of repeat intratumoral injections of Ad-IL-12 into primary liver, and secondary colon and 
pancreas cancer liver lesions.[47] In four of 10 assessible patients who received more than 4 
injections a significant increase in tumor infiltration by effector immune cells including CD8+ T 
cells was note with some stable diseases and one objective tumor regression (in HCC).[47]
Figure 8 shows the significant synergy of M9241. 
Figure 8: M9241 cooperatives with both radiation therapy. A. Effect of vehicle, M9241 monotherapy, low-dose 
radiation, and the combination of M9241 and RT in the Lewis lung cancer model. (from [44])
Additionally, the two investigational agents M7824 and M9241 do cooperate in syngeneic murine 
models of cancer inducing tumor regressions and extension of survival (Figure 9). Immune 
profiling of both tumor and splenic immune subsets as well as T cell activity measures via EliSpot 
assays suggest cooperativity of two independent, non-overlapping immune strategies funneling 
into enhanced tumor antigen recognition and anti-tumor immunogenicity (data not shown).


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Figure 9: M7824 in combination with M9241 improves anti-tumor activity compared to M7824 and M9241 
monotherapy. A. Anti-tumor activity, and B. Overall survival of mice with syngeneic MC38 tumors treated vehicle 
(black), M7824 alone (blue), M9241 (green), and the combination of M7824 and M9241 (purple). C. Anti-tumor 
activity of the same treatment regimens in the EMT-6 orthotopic breast cancer model in Balb/c mice.
In summary, the above data suggest that both of the investigational agents – the immunocytokine 
M9241 and the dual PD-L1 - TGFβ inhibitor M7824 – cooperate / exert synergistic activities with 
RT. Furthermore, the agents themselves, M7824 and M9241, independently cooperative in 
immune competent preclinical models of cancer. Thus, this trial derives its rationale of multiple 
synergies of combination immunotherapy and RT to improve outcome in LAPC. 


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1.2.5
M7824 (bintrafusp alfa; bifunctional fusion protein targeting PD-L1 and TGF-β)
To date, M7824 has been given to more than 600 patients at the 1,200 mg dose levels (please refer 
to Investigator Brochure, 04/2019). The important potential risks of M7824 include infusion-
related reactions including hypersensitivity, immune related adverse event (irAE)s /autoimmune 
disorders, anemia, rash with hyperkeratosis/ keratoacanthomas/ squamous cell carcinoma (SCC) 
of the skin, possible embryo-fetal toxicity, and alterations in wound healing or repair of tissue 
damage [28]. All of these are considered important potential risks. 
In line with early clinical experience of similar anti-TGFβ agents, the toxicity profile of M7824 is 
described as predominantly benign; in the recently released results of the phase I study 
NCT02517398 - ‘Phase 1 Trial of M7824, a Bifunctional Fusion Protein Targeting PD-L1 and 
TGFβ, in Advanced Solid Tumors’ with dose escalation cohorts of 1, 3, 10, and 20mg/kg (+ 1,200 
mg flat starting dose in this study). M7824 given 2-weekly, the MTD was not reached: data 
suggested overall good tolerance. One out of 16 patients developed a keratoacanthoma which could 
be related to the TGFβ inhibition mechanism of M7824. There was no grade 4-5 adverse events 
(AEs). The only DLT observed was colitis. Overall, the MTD was not exceeded at doses up to 20 
mg/kg. The overall safety profile of M7824 in Phase I was considered well tolerated, can be 
adequately managed, and was consistent across various tumor types.
Further updated information on these risks (e.g. presenting symptoms) can be found in the current 
version of the M7824 Investigator Brochure 
Currently no clinical data exists for the combination of M9241 and M7824. Preclinical data has 
demonstrated potential synergy between PD-L1 blockade and muNHS-IL12 (M9241) which has 
led to the clinical evaluation of the combination of avelumab (anti-PD-L1) and M9241 in a phase 
Ib open-label, dose-finding trial in subjects with locally advanced, unresectable, or metastatic solid 
tumors (NCT02994953). At present, 16.8 mcg/kg Q4W via subcutaneous injection (dose level 8) 
is the current recommended phase II dose (RPD2) of M9241 without concerning safety signals in 
this trial.
1.2.5.1
Summary of Clinical Findings of M7824 including Adverse Events (AEs) in Pancreas 
Cancer Patients to date:
As of December 2017, at least N=36 patients with a diagnosis of advanced pancreas cancer have 
received at least one, or more, doses of 1,200 mg of M7824. Overall, the drug was well tolerated 
at the 1,200 mg dose level with a typical AE profile for an advanced cancer patient cohort. Of note, 
anemia was (6 out 36; 16.7%) was the most common grade 3 or greater toxicity. The only other 
grade 3 toxicities occurring in more than 10 percent of study subjects were fatigue (4 out of 36; 
11.1%) and abdominal discomfort (4 out 36; 11.1%). There were 5 subjects with ≥grade 3 events 
listed as related to M7824. These include G4: lipase increased (1 event), and G3: anemia (2), colitis 
(1), diarrhea (1), ALT increase (1).
Preliminary clinical efficacy signal of the N=36 pancreatic cancer M7824 monotherapy cohort 
(provided by EMD Serono): while PD-1/PD-L1 monotherapy in unselected patients has not shown 
any activity preliminarily, clinical activity has been seen with objective responses and a prolonged 
disease stabilization rate of 16.7%. The cohort is being actively reviewed and remains dynamic.
At least 2 instances of nodular regenerative hyperplasia have been observed with the use of this 
agent.


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1.2.6
M9241
M9241 was evaluated in a phase I study on safety, tolerability, pharmacokinetics, biological and 
clinical activity, as well as the effects on immune cell subsets and TCR clonality in patients with 
metastatic or locally advanced solid epithelial or mesenchymal tumors at the National Institute of 
Health (NIH) Clinical Center.[48]
A total of 59 patients were enrolled and treated with M9241. The single ascending dose cohort 
included a total of 22 patients who received one single dose administration of M9241 on day 1 and 
completed the study after 28 days of safety observation. In the multiple ascending dose escalation 
and expansion cohorts, a total of 37 patients were enrolled and treated every four weeks. 
The primary objective of this trial was to determine the MTD as defined by the number of DLTs. 
None of the subjects treated with single or multiple doses up to and including 12.0 µg/kg 
experienced a DLT. At the 16.8 µg/kg dose level, one out of six subjects had a DLT (Grade 3 
increase in ALT). At the 21.8 µg/kg dose level, two out of six subjects had a DLT (Grade 3 increase 
in AST and ALT; Grade 3 increase in lipase without clinical signs of a pancreatitis) and the MTD 
was determined to be 16.8 µg/kg administered subcutaneously every four weeks, per formal 
protocol criteria. 
1.2.6.1
Treatment-related adverse events
The most frequently observed treatment-related adverse event was a decrease in lymphocyte count 
in 27 subjects (45.8%), followed by a decrease in WBCs in 24 subjects (40.7%), fever and an 
increase in AST, each in 21 subjects (35.6%), an increase in ALT in 20 subjects (33.9%), and 
anemia and flu-like symptoms, each in 18 subjects (30.5%) (Table 1). 
Twelve of the overall 59 subjects (20.3%) experienced at least one ≥ Grade 3 treatment-related 
adverse event. These included events of a decrease in lymphocyte count in five subjects (8.5%), a 
decrease in neutrophil count in four subjects (6.8%), an increase in ALT in three subjects (5.1%), 
a decrease in WBCs in two subjects (3.4%), and hypokalemia, hyperhidrosis, an increase in 
alkaline phosphatase, an increase in AST, and an increase in lipase, each in one patient (1.7%). Of 
these subjects who had Grade ≥ 3 treatment-related AEs, all were transient and only one event 
(Grade 3 hyperhidrosis) was symptomatic. Only one Grade 4 event (asymptomatic decrease in 
lymphocyte count) was observed and no Grade 5 treatment-related AE was observed. 
Table 1: Adverse Events of M9241
Grade 1/2
n (%)
Grade 3
n (%)
Grade 4
n (%)
Decrease in lymphocyte count
21 (35.6%)
5 (8.5%)
1 (1.7%)
Decrease in neutrophil count
6 (10.2%)
4 (6.8%)
0
Thrombocytopenia
12 (20.3%)
0
0
Decrease in WBCs
22 (37.3%)
2 (3.4%)
0
Hyperglycemia
10 (16.9%)
0
0


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Grade 1/2
n (%)
Grade 3
n (%)
Grade 4
n (%)
Hypoalbuminemia
6 (10.2%)
0
0
Hypokalemia
0
1 (1.7%)
0
Hypophosphatemia 
6 (10.2%)
0
0
Hyperhidrosis 
0
1 (1.7%)
0
Anemia
18 (30.5%)
0
0
Fatigue
10 (16.9%)
0
0
Fever
21 (35.6%)
0
0
Flu-like symptoms
18 (30.5%)
0
0
Increase in ALT
17 (28.8%)
3 (5.1%)
0
Increase 
in 
alkaline 
phosphatase
12 (20.3%)
1 (1.7%)
0
Increase in AST
20 (33.9%)
1 (1.7%)
0
Increase in lipase 
0
1 (1.7%)
0
Nine subjects (15.5%) experienced serious AEs, two of which (3.4%) were assessed as related to 
M9241 treatment. Generally, similar incidences of AEs and serious AEs were observed between 
the single dose and multiple dose groups despite different observation periods. In the latter, the 
rate of AEs ≥ Grade 3 and AEs related to M9241 was slightly higher. In the single dose group, no 
subject experienced an AE leading to permanent discontinuation of treatment and no subject had 
any serious AEs assessed as related to M9241 (Table 1). 
Table 2 below summarizes Treatment Emergent Adverse Events of M9241 from phase I clinical 
testing.
Table 2. Overview of known Treatment Emergent Adverse Events of M9241
Further updated information on these risks (e.g. presenting symptoms) can be found in the current 
version of the M9241 Investigator Brochure


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1.2.6.2
Response to Therapy
No objective tumor responses were observed according to the modified RECIST criteria in the 
phase I study with M9241. Out of 30 subjects with measurable disease, 15 had stable disease and 
15 had progressive disease as Best Overall Response (BOR). Five patients (prostate x2, colorectal, 
breast, chordoma) stayed on study treatment for ≥182 days. More specifically, two patients, one 
with prostate cancer and one with chordoma, had prolonged stable disease for 30+ months 
(ongoing) and 13 months, respectively. 
1.2.6.3
Pharmacokinetics and Pharmacodynamics Data
PK data from the single dose and multiple dose cohorts show a dose dependent increase in T1/2, 
Cmax, and AUC for M9241. PD data from this trial demonstrates a time-dependent rise in plasma 
IFN-γ levels after administration and a subsequent rise of IL-10. These correspond to a rise in IL-
12 similar to what is seen with the PK data, peaking around 36 hours, and then falling to near 
baseline levels around day 8. Looking only at the multiple dose patients, in most cases, despite a 
similar rise in the serum IL-12, a diminished rise in IFN-γ and IL-10 is observed after the second 
dose. The pharmacokinetic and pharmacodynamic parameters for M9241 dosed at the MTD of 
16.8 µg/kg every four weeks are shown in Appendix B. A time-dependent rise in IFN-γ was noted 
after administration and a subsequent rise of IL-10. These corresponded to a rise in IL-12 similar 
to what was seen with the PK values, peaking around 36 hours, and then falling to near baseline 
levels around day 8. When patients were re-dosed at four weeks, in most cases, despite a similar 
rise in the serum IL-12, a diminished rise was noted in IFN-γ and IL-10 with the second dose. The 
frequencies of five refined immune cell subsets changed significantly one week post‒cycle 1 vs. 
pre‒M9241 (NHS-IL-12) treatment for 10 patients at dose level 8 (16.8 µg/kg) (Appendix B). 
The frequencies of five refined immune cell subsets changed significantly one-week post‒cycle 1 
vs. pre‒M9241 (NHS-IL-12) treatment for 10 patients at dose level 8 (16.8 µg/kg). 
Overall, PD data from this trial (Appendix B) demonstrated a time-dependent rise in IFN-γ after 
administration and a subsequent rise of IL-10 about 36 to 48 hours after administration. Looking 
only at multiple dose patients, we observe, in most cases, despite a similar rise in the serum IL-12, 
a diminished rise in IFN-γ and IL-10 on the second dose. Overall, M9241 is well-tolerated with a 
benign safety profile which has, with the exception of lympho- and leukocytopenia, limited to no 
overlap with the toxicity profile known from RT.
1.2.7
Neoadjuvant RT for pancreas cancer – SBRT with Simultaneous Integrated Boost 
(SIB)
Both EBRT and stereotactic regimens are described in ASCO’s 2016 Practice Guidelines on 
management of locally advanced, unresectable and potentially curable (borderline resectable) 
pancreas cancer as acceptable treatment modalities.[5, 6] The Eastern Cooperative Oncology 
Group trial as one of the few randomized studies provided hereby one of the strongest rationales 
for the inclusion of RT regimens into treatment algorithms of LAPC; the study compared 
gemcitabine chemotherapy with gemcitabine plus RT, and while it did not complete accrual and 
terminate early, it identified a signal for improved local control and survival for the combination 
group. [49]
Stereotactic body radiation therapy (SBRT) is a method of external beam radiotherapy which 
delivers higher doses compressed into fewer fractions. Due to its increased risk of toxicity to 
surrounding, not involved structures it is dependent robust target definition and respiratory motion 


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control.[50] These pre-requests are particularly important in SBRT of pancreatic head and body 
lesions which are surrounded by a complex GI and vascular structures.[51] Over the last decade 
there have been several series of SBRT treatment for LAPC emerged which attest to the safety of 
this approach overcoming the challenges of gross tumor volume delineation (GTV) and reduction 
of internal motion. Table 3 provides an updated and extended review of studies on SBRT for the 
management of LAPC reflecting the recent increase in the use of SBRT for LAPC. Additional 
literature corroborating the safety and above outcomes of SBRT in LAPC include the large 
experience on 167 patients published by the Stanford group or a recent systematic review analyzing 
outcome with special focus on toxicity of 16 studies (572 pancreatic cancer patients) treated with 
SBRT.[52, 53] Overall, following neoadjuvant therapy, approximately up to one third of patients 
initially felt to be unresectable were converted to resectable status.[51, 54]
Table 3: Series of studies on the use of SBRT in LAPC.[55-65] 
Overall these studies consistently describe a median overall survival in LAPC of about 1 year, a 
grade 3 and higher toxicity rate of ~10-15%, primarily acute GI toxicity in the form of radiation 
enteritis with symptoms of nausea, vomiting, and abdominal pain, and less frequently bone marrow 


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depression with leukopenia and lymphopenia, as well as generalized symptoms of fatigue. There 
is an urgent medical need to improve these outcomes.
Since in the majority of patients, tumor motion exceeded the predicted range by 10% when using 
motion management planning strategies like four-dimensional computed tomography (4D CT), in 
order to improve accuracy and reduce damage to surrounding areas for regimens exceeding 5 Gy 
x 5 fractions the use of fiducial markers is recommended. Thus, the “current practice / standard of 
care" in leading medical centers is to use fiducials, along with respiratory motion management 
during treatment and doses in the order of 6.6 Gy x 5 to the tumor or greater.
Since borderline resectable patients are, in theory, potentially curable, if the tumor can be resected, 
the primary purpose of the radiation is to reduce the size of the tumor and to sterilize what would 
be the margins of resection, so that the resection can have the best odds of being part of a curative 
management plan. In the absence of surgery, a biologically equivalent dose (BED) of ~100 Gy 
should be delivered to achieve maximum ablative effect within the tumor. However, tumor control 
and reduction in tumor size (conversion from unresectable to resectable) is achieved with treatment 
strategies with a BED. Table 4 of listing converting BED of different SBRT regimens shows that 
5 Gy x 5 (25 Gy total) is likely to improve resect ability. This study will deliver 5 Gy x 5 (25 Gy 
total) via SBRT with simultaneous integrated boost after mandatory placement of fiducials (biliary 
metal stent acceptable as alternative). Table 4 compares Equivalent Dose in 2 Gy fractions 
(EQD2), Biological Equivalent Dose (BED), and treatment delivery and radiobiological 
considerations for selected dose/fractionation schemes that can be used for treating advanced 
pancreatic cancers. 


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Table 4: Biologically equivalent doses of different SBRT regimens for the treatment of LAPC
A biliary metal stent, or other radio-graphically identifiable marker, in or adjacent to the pancreatic 
mass could potentially serve the same function of the fiducials, and it is expected that 20-30% of 
our locally advanced pancreas patients have stents in place. Huhuet at al evaluated the correlation 
of tumor motion with implanted fiducial markers or with biliary stent, and confirmed that both 
fiducial markers and biliary stent motion correlated well with tumor motion, and that tracking of 
both would be clinically appropriate.[66] 
Figure 10 shows an example of a LAPC patient treated with SBRT and SIB, where the primary 
tumor was treated with 5 fractions of 5 Gy (total 25 Gy) under National Cancer Institute (NCI) 
study 15-C-0027 (‘Immune Checkpoint Inhibition (Tremelimumab and/or MEDI4736) in 
Combination With Radiation Therapy in Patients With Unresectable Pancreatic Cancer’) by Dr. J. 
Jones at the Clinical Center. The adjacent diagram delineates an example of dose SIB dose levels 
that can be used to deliver different doses to different areas of tumor involvement or risk. 


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Figure 10: Isodose fields with drop-offs by SBRT with SIB
The safety of the above treatment scheme has also been reported by other institutions. A 
retrospective review from the Moffitt Cancer Center analyzed 73 patients with LAPC or borderline 
resectable pancreatic cancer who underwent chemotherapy followed by SBRT to a dose of 35 Gy 
to the area of vessel involvement and 25 Gy to the remaining tumor over 5 fractions.[67] Thirty 
one of 32 patients with borderline resectable cancer achieved an R0 resection. Median overall 
survival at 1 year for borderline resectable versus LAPC patients was 16.4 versus 15 months. Those 
patients with borderline resectable lesions who attained R0 resection had improved median overall 
survival as compared with nonsurgical patients, although 1-year local control in nonsurgical 
patients was 81%. There was no grade 3 or greater acute toxicities. Four patients were noted to 
have late grade 3 toxicities (3 with GI bleeding requiring embolization and 1 with anorexia 
resulting in feeding tube placement). It is important to note that toxicities due to RT cannot 
infrequently occur in a delayed fashion; for example, in of the largest retrospective reviews on 
SBRT in LAPC median time to grade 2 to 4 toxicities was 6.3 months. At 6 months, the actuarial 
rate of toxicity was 11%, and at 12 months, this rose to 29%.[68]
The optimum sequence of immune-oncology agents and RT has not been established. We have 
elected to start M7824 and M9241 2 weeks prior to SBRT because of maximal MHC expression 
and tumor antigen presentation that is changed by radiation happens within 48-72 hours after 
radiation. While cross-presented antigen, upregulated by cGAS/STING/dsDNA-related 


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mechanisms, and dsDNA released by the irradiated and dying but not-yet-disappeared cells can in 
many tumors persist for very long periods of time as they march towards eventual mitotic 
catastrophe, giving the immunomodulating agents upfront priming the microenvironment towards 
antigen recognition and CD8 T cell response appears to have the highest likelihood of exploiting 
all RT-induced changes which might not be synchronous for immunogenic synergy. Administering 
the M7824 and M9241 beginning 2 weeks prior to SBRT allows for the delivery of radiation 
shortly after M7824 and M9241 have been introduced, with M7824 and M9241 continuing during 
and after the radiation, so that the predicted peak period of antigenicity following radiation 
coincides with activity of the immunomodulatory agents.
1.2.8
Health-related quality of life
It is conceivable that clinical benefit of the tested combined M7824 and M9241 with RT approach 
is limited to improvement in QoL measures of treated patients. For example, some of the studies 
of SBRT listed in Table 3 showed ‘only’ self-reported improvement in pain scores and QoL 
parameters but no change in traditional efficacy readouts response or survival when compared to 
historical controls. To evaluate the impact of M7824 and M9241 in combination with RT on 
patients’ pain scores and treatment-related reported symptoms, scores of symptom subsets of the 
FACT-Hep (Appendix C) will be longitudinally completed before and during the treatment. 
The ‘Functional Assessment of Cancer Therapy’ (FACT-G; version 4) with the hepatobiliary and 
pancreatic specific module (FACT-Hep)’ is a 45-item self-report instrument developed 
specifically to measure HRQoL in patients with hepatobiliary cancer (i.e. liver, bile duct and 
pancreatic cancers; please see (Appendix C).[69] It consists of the FACT-G, which assesses 
symptoms and other HRQoL concerns across four dimensions (physical well-being [PWB; seven 
items], social/family well-being [SWB; seven items], emotional well-being [EWB; six items] and 
functional well-being [FWB; seven items]) together with an 18-item disease-specific hepatobiliary 
cancer subscale (HCS; on page 3 of the instrument) including back and stomach pain, 
gastrointestinal symptoms, anorexia, weight loss and jaundice in patients with hepatobiliary 
cancers. It was developed by a process of item generation based on input from patients with 
hepatobiliary cancers, item reduction based on clinician input, scale construction and 
reliability/validity testing. Respondents of FACT-based questionnaires rate each item using a five-
point Likert-type scale ranging from 0 (not at all) to 4 (very much). The FACT-Hep questionnaire 
has been shown to be a reliable instrument that correlates with clinical indicators of disease 
progression and response to treatment and can aid interpretation of HRQL data. Multiple studies 
in advanced pancreas cancer have reported QoL data in the 2nd and 3rd line setting using the 
instrument, and measures obtained during this study will be compared to these historical controls.
1.2.9
Rationale for this clinical trial
The administration of M7824 and M9241 in combination with SBRT to subjects with locally 
advanced pancreatic cancer is justified by the following:

The synergistic action of PD-L1 inhibition mediated by the dual PD-L1 TGFβ blocker 
M7824 and RT, including the emerging clinical data of improved outcome upon checkpoint 
blockade and RT.

The synergistic action of M9241 and RT.

The synergistic action of M7824 and M9241.


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
Administered dose and schedule of the standard RT is not changed due to the addition of 
M7824 and/or M9241.

M7824 and M9241 and RT have largely non-overlapping toxicity profiles which are 
manageable.
1.2.9.1
Rationale for M7824 and M9241 Dose Levels with special consideration of overlapping 
toxicities with SBRT
The safety run-in of M7824 and M9241 will be carried out in patients with stages III and IV or 
locally advanced pancreas cancer. 
The toxicity profile of M7824 is predominantly benign, see section 1.2.5. 
M7824 and SBRT carry hematological toxicities (anemia for M7824), M9241 and SBRT harbor 
overlaps in hematological and non-hematological GI toxicities in the form of lymphopenia as well 
as LFT elevations (although they were for M9241 reported as clinically not significant). While 
these AEs for monotherapy with M7824 and M9241 appear to be manageable and not life-
threatening (predominantly grade 1 and 2 for M9241) it is not known what the side effect profile 
is in combination with SBRT. Thus, there is a dedicated safety run-in cohort to determine safety 
and tolerability of M7824 and M9241 when combined with SBRT (Phase IB part of the study).
The first 6 patients will receive M7824 at a fixed dose of 1,200 mg on day -14 followed by M7824 
+M9241 combination on cycle 1 day 1.
The rationale for the starting dose of 16.8µg/kg of M9241 via subcutaneous injection every 4 
weeks, which was found to be the MTD of this agent, is based on the clinical safety data of this 
dose in the phase I study of 59 patients conducted at the Center for Cancer Research NIH.[48] 
Due to the transient clinically mild nature of these AEs (see section 1.2.6.1) M9241 is initially 
combined at its MTD of 16.8µg/kg every 4 weeks dose with M7824. 
The safe dose of M7824 and M9241 will then be combined with SBRT. M7824 and M9241 will 
be started 2 weeks prior to start of a 5-day course of SBRT with a second dose of M7824 close to 
start of SBRT. Possible overlapping hematological (leukopenia) or non-hematological toxicity 
with SBRT (transient LFT elevations, GI symptoms) should be manageable with e.g. G-CSF 
support (neupogen; filgrastim) or modifications / adjustments in the RT schedule. Since M7824 
available PK/PD profile suggests no risk of accumulation of the drug upon repeat dosing, the 
second dose of M7824 toxicity before start of SBRT should be predictable and not be cumulative. 
In the event of ≥grade 3 DLTs in the first 6 patients, dose de-escalation of M9241 will occur for 
following patients.
2
ELIGBILITY ASSESSMENT AND ENROLLMENT
2.1
ELIGIBILITY CRITERIA
2.1.1
Inclusion Criteria 

Histologically or cytologically proven pancreatic adenocarcinoma (subjects with endocrine 
or acinar pancreatic carcinoma are not eligible). 

Patients must have stage III or IV pancreatic cancer (Cohort 1) or locally advanced 
pancreas cancer (LAPC), either borderline resectable pancreas cancer (Appendix A) or 
locally advanced, unresectable pancreas cancer (Cohorts 2 and 3).


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
Patient must be eligible to undergo stereotactic body radiation therapy (SBRT) and have 
fiducial markers placed (any metal biliary stents are an acceptable alternative) (Cohorts 2-
3).

Age ≥18 years. Because no dosing or adverse event data are currently available on the use 
of M7824 and M9241 in patients <18 years of age, children are excluded from this study, 
but will be eligible for future pediatric trials.

ECOG performance status of 0 to 1 (Appendix D)

Must have measurable disease, per RECIST 1.1. See Section 6.3 for the evaluation of 
measurable disease. 

Adequate hematological function defined by:
white blood cell (WBC) count ≥ 3 × 109/L 
with absolute neutrophil count (ANC) ≥ 1.0 ×109/L, 
lymphocyte count ≥ 0.5 × 109/L, 
platelet count ≥100 × 109/L, and 
Hgb ≥9 g/ dL (in absence of blood transfusion)

Adequate renal function defined by:
Creatinine OR
Measured or calculated 
creatinine clearance (CrCl) 
(eGFR may also be used in 
place of CrCl) A

< 1.75x institution upper limit of normal OR

> 45 mL/min/1.73 m2 for participant with creatinine 
levels > 1.75 X institutional ULN
A Creatinine clearance (CrCl) or eGFR should be calculated per institutional standard.

Adequate hepatic function defined by:
a total bilirubin level ≤ 3 × ULN, 
an AST level≤5×ULN, 
ALT level ≤5 ×ULN

Patients with treated brain metastases are eligible if follow-up brain imaging after central 
nervous system (CNS)-directed therapy shows no evidence of progression

Patients with new or progressive brain metastases (active brain metastases) or 
leptomeningeal disease are eligible if the treating physician determines that immediate 
CNS specific treatment is not required and is unlikely to be required during the first cycle 
of therapy.

The effects of the study treatment on the developing human fetus are unknown; thus, 
women of childbearing potential and men must agree to use adequate contraception 
(hormonal or barrier method of birth control; abstinence) at the study entry, for the duration 
of study treatment and up to 120 days after the last dose of the drug for males and up to 60 


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days for females. 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.

Patient must be able to understand and willing to sign a written informed consent 
document.
2.1.2
Exclusion Criteria

Treatment with any investigational agent within 28 days before treatment initiation. 

Prior therapy with any antibody / drug targeting T cell coregulatory proteins (immune 
checkpoints) such as anti-PD-1, anti-PD-L1, or anti-CTLA-4 antibody.

Anticancer treatment within designated period before treatment initiation including:
major surgical procedure (such as laparotomy) within 28 days
minor surgical procedure (such as biliary stenting) within 7 days
chemotherapy with published half-life known to be 72 hours within 7 days
chemotherapy with unpublished or half-life greater than 72 hours within 28 days

Previous radiotherapy to the primary tumor (including palliative radiotherapy)

Concurrent treatment with non-permitted drugs, including but not limited to 
immunotherapy or immunosuppressive drugs (see Section 4.2). 

History of any other cancer (except non-melanoma skin cancer or carcinoma in-situ of the 
cervix), unless patient is in complete remission and for a minimum of 3 years. 

Rapidly progressive disease which, in the opinion of the Investigator, may predispose to 
inability to tolerate treatment or trial procedures.

Receipt of any organ transplantation, including allogeneic stem-cell transplantation, except 
of transplants that do not require immunosuppression (e.g., corneal transplant, hair 
transplant) 

Significant acute or chronic infections including tuberculosis (history of exposure or 
history of positive tuberculosis test; plus, presence of clinical symptoms, physical or 
radiographic findings)

Active autoimmune disease that might deteriorate when receiving an immunostimulatory 
agent with the exceptions:
diabetes type I, vitiligo, alopecia, psoriasis, hypo- or hyperthyroid disease not requiring 
immunosuppressive treatment are eligible;
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.


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
Known severe hypersensitivity reactions to monoclonal antibodies (Grade ≥3 NCI-CTCAE 
v5.0), any history of anaphylaxis or history of uncontrolled asthma.

Known alcohol or drug abuse.

Clinically significant cardiovascular / cerebrovascular disease as follows: cerebral vascular 
accident / stroke (< 6 months prior to treatment initiation), myocardial infarction (< 6 
months prior to treatment initiation), unstable angina, congestive heart failure (New York 
Heart Association Classification Class ≥ II), or serious cardiac arrhythmia.

Administration of live vaccines within 30 days prior to treatment initiation. 

HIV, HCV, HBV patients on antiviral drugs are excluded due to the absence of previous 
experience on combination of antiviral and this trial drugs and possible interaction.

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.

Subjects unwilling to accept blood products as medically indicated.

Female patients who are pregnant or breastfeeding. Because there is an unknown but 
potential risk for adverse events in nursing infants secondary to treatment of the mother 
with M7824 or M9241, breastfeeding should be discontinued.
2.1.3
Recruitment Strategies
This protocol may be abstracted into a plain language announcement posted on NIH websites, 
including clinicaltrials.gov and the CCR website, and on NIH social media platforms. Outside 
providers and colleagues may directly refer patients for screening into this study. The study will 
be also presented to PanCan.
2.2
SCREENING EVALUATION
2.2.1
Screening activities performed prior to obtaining informed consent
Minimal risk activities that may be performed before the subject has signed a consent include the 
following: 

Email, written, in person or telephone communications with prospective subjects 

Review of existing medical records to include H&P, laboratory studies, etc. 

Review of existing MRI, x-ray, or CT images

Review of existing photographs or videos

Review of existing pathology specimens/reports from a specimen obtained for diagnostic 
purposes
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 consent for study 
#01-C-0129 on which screening activities will be performed. Assessments performed at outside 


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facilities or on another NIH protocol within the timeframes below may also be used to determine 
eligibility once a patient has signed the consent.
Within 28 days prior to treatment initiation unless otherwise noted below:

Complete medical history and physical examination, including height, weight, vital signs, and 
ECOG performance status.

EKG

Laboratory Evaluation
o
Hematological profile: CBC with differential and platelet count; 
o
Biochemical profile: Acute care panel (that includes sodium, potassium, BUN, 
creatinine), Hepatic panel (that includes AST, ALT, total bilirubin), Mineral panel (that 
includes calcium, phosphorus, albumin, and magnesium), and uric acid; 
o
Serum or urine pregnancy test for female participants of childbearing age (in the 
absence of prior hysterectomy) (7 days prior to treatment initiation);

CT of chest, abdomen and pelvis (or MRI of chest, abdomen and pelvis if clinically indicated);

A brain CT / MRI scan if clinically indicated;

Histologic or cytologic confirmation (at any time point prior to treatment initiation). If there is 
no available documentation, biopsy will be performed to confirm the diagnosis.
2.3
PARTICIPANT REGISTRATION AND STATUS UPDATE PROCEDURES
Registration and status updates (e.g. when a participant is taken off protocol therapy and when a 
participant is taken off-study) will take place per CCR SOP ADCR-2, CCR Participant 
Registration & Status Updates found here.
2.3.1
Treatment assignment procedures (For registration purposes only):
Cohorts
Number
Name
Description
1
Phase IA
Subjects with stage IV or III pancreas cancer, enrolled to M9241 de-
escalation dose levels in combination with M7824.
2
Phase IB
Subjects with locally advanced pancreas cancer (LAPC), enrolled to 
M9241 de-escalation dose levels in combination with M7824 and 
SBRT.
3
Phase II
Subjects with locally advanced pancreas cancer (LAPC), enrolled at 
the recommended for phase 2 combined dose (RP2D) of M7824 and 
M9241 after the RP2D is established in combination with SBRT.
Arms


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Number
Name
Description
1
Arm 1A
De-escalating doses of M9241 in combination with M7824.
2
Arm 1B
De-escalating doses of M9241 in combination with M7824 and SBRT
3
Arm 2
RP2D of M7824 and M9241 in combination with SBRT 
Arm assignment
Subjects in Cohort 1 will be directly assigned to Arm 1A.
Subjects in Cohort 2 will be directly assigned to Arm 1B.
Subjects in Cohort 3 will be directly assigned to Arm 2.
2.4
BASELINE EVALUATION
Tests done at screening do not need to be repeated on baseline if performed in designated time 
frame prior to start of protocol treatment.
Within 28 days prior to first dose:

Complete medical history and physical examination, including weight, vital signs, ECOG 
performance status, and skin assessment

CT of chest, abdomen and pelvis (or MRI of chest, abdomen and pelvis if clinically 
indicated)

EKG

CEA, CA19-9, CA-125

T4, TSH

Amylase/ lipase

Research Quality of Life assessment (subject-reported outcomes / symptom severity 
assessments the 4th version of the ‘Functional Assessment of Cancer Therapy with the 
hepatobiliary and pancreatic specific module (Appendix C). (For English speaking 
subjects only).

Collection of archival tumor sample if available for research (collected within 6 months 
prior to treatment)

Research blood for ADA sampling, cytokines, TNF and cfDNA

Research perfusion MRI (Cohort 1A only)
Within 72 hours prior to start of protocol treatment:

Concomitant Medications and baseline symptom collection;

Hematological profile: CBC with differential and platelet count; 


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
Biochemical profile: Acute care panel (that includes sodium, potassium, BUN, creatinine),  
Hepatic panel (that includes AST, ALT, total bilirubin), Mineral panel (that includes 
calcium, phosphorus, albumin, and magnesium), and uric acid

PT, INR, aPTT, fibrinogen

Urinalysis

Serum or urine pregnancy test for female participants of childbearing age (in the absence 
of prior hysterectomy) 
3
STUDY IMPLEMENTATION
3.1
STUDY DESIGN 
This is an open label Phase I/II trial which consists of safety run-in phases IA and IB and an 
expansion phase II.
During the safety run-in phase IA, the safety and recommended Phase IB dose of M7824 in 
combination with M9241 will be determined in Cohort 1 (Schema 1). 
During safety run-in phase IB the safety and recommended Phase II dose (RP2D) of M7824 in 
combination with M9241 and SBRT will be determined in Cohort 2 (Schema 2). 
During Phase II, when RP2D of M7824 and M9241 in combination with SBRT is estimated, we 
will proceed with enrollment to Cohort 3 to evaluate efficacy of the M7824 and M9241 in 
combination with standard SBRT. 
Patients will receive treatment in cycles consisting of 28 (+/- 3) days (Note: in Phase IA there is 
additional one-time infusion of M7824 at Day -14). 
Administration of M7824 will be every 2 weeks by IV infusion on Days 1 and 15 of every cycle, 
starting on Cycle 1. (Note: in Phase IA there will be additional infusion of M7824 at Day -14). 
Administration of M9241 will be every 4 weeks by subcutaneous injection on Day 1 of every 
cycle, starting on Cycle 1. 
SBRT on this trial will be delivered per standard of care (Phase IB and Phase II), starting on Day 
17 (+5 days) of Cycle 1 and continue for 5 consecutive business days (except federal holidays).
Note: This protocol will proceed to phase IB only after Radiation Safety approval of SBRT 
procedure, currently pending because of new SBRT guidance for pancreatic cancer.
After SBRT completion, treatment with M7824 in combination with M9241 will continue until 
patient meets off treatment criteria (Section 3.11.1). 
For patients who are benefiting from combination therapy, since we don’t know which agent is 
driving the response (i.e. either of the drugs alone or the combination), in the event that one drug 
is causing toxicities and have to be discontinued, it is reasonable to continue the other drug to see 
if the patient might benefit from it. Since it might not be known which of the tow immuno-
oncology agents (M7824 or M9241) contributes to a possible positive signal, omission of one may 
allow a better designation for the beneficial anti-tumor effect. Based on preclinical rationale 
outlined in Section 1.2.3, there is a reasonable expectation that SBRT combined with either M9241 
or M7824 may still be beneficial.


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At Cycle 3 Day 15 (+/- 7 days) patient will undergo imaging and every 2 Cycles (+/-5 days) 
thereafter. 
If during the treatment patient’s tumors become resectable per standard of care, M7824 and/or 
M9241 will be stopped at least 5 days prior to the scheduled date of surgery. Surgery is not part of 
this protocol and will be done as standard of care procedure with enrollment of patient to another 
surgical protocol in NIH or at home institution. 
If surgical exploration does not result in a successful removal of the tumor, patient will be able to 
return to treatment following recovery from surgery (See section 3.5.3). If tumor removed 
successfully, patient will be taken off protocol treatment. 
Schema 1: Phase IA.


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Schema 2: Phase IB
3.1.1
Dose Limiting Toxicity 
The DLT period for the phase IA is 6 weeks (Day -14 to Day 28 of Cycle 1), the DLT period for 
the phase IB is 4 weeks (from Day 1 Cycle 1 to Day 28 Cycle 1).
Any Grade ≥ 3 adverse event (AE), occurring during the DLT evaluation period, except for those 
listed below: 

Adverse event unrelated, or unlikely related to study agents AND probably or definitely related 
to other causes

Grade 3 or 4 clinically asymptomatic neutropenia if not lasting > 1 cycle (14 days) (observed 
on laboratory value only)

Clinically asymptomatic grade 3 thrombocytopenia if not lasting > 1 cycle (14 days) (observed 
on laboratory value only with no clinically discernable bleeding events)

Grade 3 diarrhea or skin toxicity that resolves to Grade ≤ 1 in less than 7 days after medical 
management (e.g., immunosuppressant treatment) has been initiated 

Tumor flare phenomenon defined as local pain, irritation, or rash localized at sites of known 
or suspected tumor.

Transient (≤ 6 hours) Grade 3 flu-like symptoms or fever, which is controlled with medical 
management.

Transient (≤ 24 hours) Grade 3 fatigue, local reactions, headache, nausea, emesis that resolves 
to ≤ Grade 1 or Baseline grade. 


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
Any isolated and single Grade 3 liver function test abnormality in the form of transaminase, 
alkaline phosphatase, or bilirubin elevation with NO other associated laboratory (or other) 
abnormality that is not associated with symptoms or clinical manifestations of hepatitis or any 
immune-related event and which has resolved to Grade ≤ 1 within the subsequent cycle (14 
days)

Any isolated and single Grade 3 amylase or lipase abnormality with no other associated 
laboratory (or other) abnormality that is not associated with symptoms or clinical 
manifestations of pancreatitis and which has resolved to Grade ≤ 1 within the subsequent cycle 
(14 days)

Any isolated and single Grade 3 Hgb decrease (< 8.0 g/dL) that is clinically manageable with 
blood transfusions or erythroid growth factor and has resolved to Grade 2 not requiring blood 
transfusions or erythroid growth factor therapy with the subsequent cycle (14 days).
Failure to resume SBRT after a hold of ≥1 week will be analyzed as a DLT within respective dose 
level group (Phase IB only)
3.1.2
Phase IA/IB: 
Every subject of each dose level group of the phase 1 study will be observed for at least 7 days 
after first dose of M7824 or M7824 and M9241 before the subsequent subject can be treated.
Subjects who do not complete the DLT observation period for reasons other than a DLT will be 
replaced and not included in the evaluation.
The recommended phase 2 dose (RP2D) is the dose levels of M7824 and M9241 in combination 
with SBRT at which ≤1 of 6 individuals experienced a DLT during the first cycle (28 days) of 
combinational treatment with M7824, M9241 and SBRT.
In case of DLT, DLT will be documented and patient, per PI discretion, may continue study 
treatment if toxicity could be managed by interruption of the dose of study treatment or dose 
reductions (See Section 3.4). Patient, once having DLT, will not be used for DLT evaluation on 
another dose level if treated on another dose level.
SBRT
Dose modifications dosage adjustment is based upon the degree of hematologic and non-
hematologic toxicity experienced by the patient at the discretion of the treating radiation 
oncologist. Patients will be monitored with a complete blood count (CBC), including differential 
and platelet count. If marrow suppression is detected, SBRT should be modified or suspended 
according to the standard guidelines on management of RT-associated toxicities and discretion of 
the treating radiation oncologist (See section 3.4.3). These subjects will be part of the DLT 
evaluation of the respective M7824 and M9241 dose level they were accrued to. 
Failure to resume SBRT after a hold of ≥1 week will be analyzed as a DLT within respective dose 
level group. In case of DLT, attributed to SBRT, patients will be taken off SBRT treatment and 
per PI discretion may continue M7824 and M9241 only.
3.1.2.1
Cohort 1, Phase IA, Arm 1A
6 to 12 patients will be enrolled into Arm 1A.
Dose de-escalation will proceed in dose levels of 6 patients. 


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6 subjects will be enrolled in Dose Level 0 (Table 5). Patients will be treated with M7824 starting 
on Day -14 plus M9241 starting on Day 1 of Cycle 1.
If < 2 patients experience a DLT during DLT period, DL 0 will be used as recommended Phase IB 
dose for Arm 1B.
If ≥ 2 patients experience a DLT during DLT period at DL 0, the DL 0 enrollment will be stopped.
The next 6 subjects will be enrolled into Dose Level -1. If < 2 patients experience DLT during 
DLT period, this dose DL -1 will be used as recommended Phase IB dose for Arm 1B. 
If ≥ 2 patients experience a DLT at DL -1, the enrollment will be stopped and no further attempts 
at completing the safety run-in of M7824 in combination with M9241 will be conducted and Arm 
1B and phase II expansion cohort of M7824 and M9241 in combination with SBRT will not be 
carried out. 
Table 5: Dose Levels of M7824 and M9241 in Arm 1A
Dose level
M7824, mg, IV every 2 weeks 
M9241, µg/kg, SQ, every 4 weeks
DL 0
1,200
16.8
DL -1
1,200
12.0
3.1.2.2
Cohort 2, Phase IB, Arm 1B
6 to 12 patients will be enrolled in Arm 1B. Enrollment will start after completion of Arm 1A.
Dose de-escalation will proceed in dose levels of 6 patients.
6 subjects will be enrolled in Dose Level 0 (Table 6) and treated with combination of M7824, 
M9241 and SBRT.
If < 2 patients experience DLT during DLT period, the Dose level 0 will be the RP2D and next 
patients will be enrolled into Cohort 3 the phase II portion of the study. 
If ≥ 2 experience a DLT at DL 0, the Dose Level 0 enrollment will be stopped, and DL -1 will be 
tested in 6 patients. If <2 patients experience a DLT, dose level -1 will be used as RP2D for M7824 
and M9241 in combination with SBRT in the Phase II.
If ≥ 2 patients experience a DLT at DL -1, the dose Level -1 enrollment will be stopped and no 
further attempts at completing the Arm 1B of M7824 and M9241 in combination with SBRT will 
be conducted and Arm 2B and phase II expansion cohort of M7824 and M9241 in combination 
with SBRT will not be carried out.


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Table 6: Dose Levels of M7824 and M9241 in combination with SBRT in Arm 1B.
Dose 
level
M7824, mg, IV 
every 2 weeks 
M9241, µg/kg, SQ, every 4 weeks
SBRT
DL 0
1,200 
MTD of M9241 estimated during Phase IA (16.8 or 12)
5 x 5 Gy 
If MTD estimated during Phase IA is 16.8 then 12.0
DL -1
1,200 
If MTD estimated during Phase IA is 12.0, then 8.0
5 x 5 Gy 
3.1.3
Phase II, Cohort 3, Arm 2
The efficacy part of the study will be conducted with the M7824 and M9241 dose level found to 
be safe in combination with SBRT during phase IB. Once a recommended phase 2 dose of M7824 
and M9241 has been determined, up to 25 subjects will be evaluated at that dose level, inclusive 
of those patients treated at the RP2D during the safety run-in.
Enrollment will start when RP2D is estimated and 28 days of observation after first treatment of 
6th subject at RP2D in Arm 1B have passed.
During first stage of Phase II 16 patients will be enrolled. If 0 to 1 of 16 patients respond (PR or 
CR as defined in Section 6.3), then no further patients will be enrolled. If 2 or more of the first 16 
evaluable patients enrolled have a response (PR or CR), then during second stage accrual will 
continue until a total of 25 evaluable patients have been enrolled. 
3.2
STUDY STOPPING RULES 
For safety reasons, the enrollment will be temporarily halted until an expedited safety report has 
been evaluated by the investigators, IND sponsor, and submitted to the FDA for either of the 
following events attributable to treatment regimen occurring within 28 days of receiving 
investigational agent (s): 
• One occurrence of grade 5 toxicity, attributable to treatment regimen. 
• Two occurrences of grade 4 toxicity, attributable to treatment regimen.
3.3
DRUG ADMINISTRATION
3.3.1
M7824
M7824 will be administered as a 1-hour (-10 minutes / +20 minutes) IV infusion on Days 1 and 
15 of every cycle, starting Cycle 1. In Phase IA there is additional infusion 14 days before Day 1 
of Cycle 1. 
On the days of combined M7824 and M9241 treatment M7824 will be infused at least 30 minutes 
after M9241 injection. 
M7824 will be administered as an intravenous (IV) infusion via a peripheral OR central vascular 
access device (VAD) if patient has VAD already installed. Confirm patient has a titanium port 
before accessing the Central VAD. A 0.2-micron polyethersulfone (PES) in-line filter is mandatory 
for administration.


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Current experience revealed that infusion related reactions (IRRs) to M7824 seldom occur and are 
generally mild to moderate in severity. Therefore, administration of a premedication is generally 
not required.
If an Investigator deems it necessary to administer a premedication to a particular participant, an 
antihistamine (for example, 25-50 mg diphenhydramine) and acetaminophen 500-650 mg 
intravenously or equivalent oral dose is recommended  approximately 30 to 60 minutes prior to 
each dose of M7824. If Grade ≥ 2 infusion reactions are seen during the first two infusions, 
premedication should not be stopped. Steroids as premedication are not permitted.
Hypersensitivity reactions may require immediate intensive care. M7824 should be administered 
in a setting that allows for immediate access to an intensive care unit or equivalent environment 
and administration of therapy for anaphylaxis, such as the ability to implement immediate 
resuscitation measures. Steroids (dexamethasone 10 mg), epinephrine (1: 1,000 dilution), allergy 
medications (IV antihistamines), bronchodilators, or equivalents, and oxygen should be available 
for immediate access. 
A complete guideline for the emergency treatment of anaphylactic reactions according to the 
Working Group of the Resuscitation Council United Kingdom and can be found at 
https://www.resus.org.uk/pages/reaction.pdf
For prophylaxis of flu like symptoms, a nonsteroidal anti-inflammatory drug (NSAID), e.g., 
ibuprofen 400 mg or comparable NSAID dose, may be administered 2 hours before and 8 hours 
after the start of each IV infusion.
Patients must be observed for 2 hours after the first M7824 dose. If no reactions are observed, the 
patients need to be monitored for only 30 minutes after subsequent doses. 
If an allergic reaction occurs, the subject must be treated according to the best available medical 
practice. Please see the guidelines for handling of infusion-related reaction in Table 8. 
Investigators should also monitor subjects closely for potential irAEs, which may become manifest 
after several weeks of treatment. Such events may consist of persistent rash, diarrhea and colitis, 
autoimmune hepatitis, arthritis, glomerulonephritis, cardiomyopathy, or uveitis and other 
inflammatory eye conditions. 
Vital signs must be measured within 30 minutes before and 30 minutes following M7824 infusions. 
3.3.2
M9241
M9241 will be administered as a subcutaneous injection on Day 1 of every cycle.
M9241 will be injected at least 30 minutes before M7824 infusion.
3.3.3
SBRT 
Radiation therapy will be starting on Day 17 (+5 days) of Cycle 1 and continue for 5 consecutive 
business days (except federal holidays). 
A summary of the SBRT schedule in combination with M7824 and M9241 is shown in Schema 
2.


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3.4
DOSE MODIFICATIONS: 
In case of toxicity as defined below, definitely attributed to one of the study drugs and/or SBRT, 
patient may be taken off this drug and/or SBRT and per PI discretion may continue treatment with 
another drug only or drug combined with SBRT. 
When, at the beginning of a treatment cycle, treatment delay related to M7824 is indicated, per PI 
discretion treatment with M9241 and or SBRT might not be delayed. 
If, in the opinion of the investigator, a toxicity is considered to be due solely to one drug, the dose 
of another drug does not require modification.
3.4.1
M7824 
Treatment modifications for reactions caused by M7824 are addressed in Table 7, Table 8, Table 
9, Table 10, Table 11, and Table 12.
Table 7: Treatment Modification Guidance for Symptoms of Infusion-Related Reactions including 
Immediate Hypersensitivity.
NCI-CTCAE Grade
Treatment Modification for M7824
Grade 1 – mild
Mild transient reaction; in general, 
infusion interruption not indicated; 
intervention not indicated.

Increase monitoring of vital signs as medically 
indicated as participants are deemed medically 
stable by the attending Investigator.

Hold infusion if deemed necessary by the 
investigator.
Grade 2 – moderate
Therapy or infusion interruption 
indicated but responds promptly to 
symptomatic treatment (for example, 
antihistamines, 
nonsteroidal 
anti 
inflammatory drugs, narcotics, IV 
fluids); 
prophylactic 
medications 
indicated for  24 h.

Stop the infusion of the study intervention. 

Increase monitoring of vital signs as medically 
indicated as participants are deemed medically 
stable by the attending Investigator.

If symptoms resolve quickly, resume infusion at 
50% of original rate with close monitoring of any 
worsening signs and symptoms, otherwise dosing 
held until resolution of symptoms with mandated 
premedication for the next scheduled visit.

If not improving, consider administration of 
glucocorticoids and stop the infusion for that day.

If the participant has a second IRR Grade ≥ 2 on 
the slower infusion rate despite premedication, the 
infusion should be stopped, and the investigator 
may consider withdrawal of this participant from 
the study.


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NCI-CTCAE Grade
Treatment Modification for M7824
Grade 3 or Grade 4 – severe or life-
threatening
Grade 3: Prolonged (for example, not 
rapidly responsive to symptomatic 
medication and/or brief interruption 
of infusion); recurrence of symptoms 
following 
initial 
improvement; 
hospitalization indicated for clinical 
sequelae.
Grade 
4: 
Life-threatening 
consequences; urgent intervention 
indicated.

Stop the infusion of study intervention immediately 
and disconnect infusion tubing from the participant 
with additional appropriate medical measures and 
closely monitor until deemed medically stable by 
the attending Investigator. Hospitalization and/or 
close monitoring is recommended

Administration of glucocorticoids may be required

For Grade 3 or 4 IRRs, permanent discontinuation 
of study intervention is mandated
Once the infusion is interrupted or rate reduced to 50% of previous infusion rate, it must remain 
decreased for all subsequent infusions. 
For all types and grades of infusion reactions, details about drug physical constitution, method 
of preparation, and infusion must be recorded.
Participants should be instructed to report any delayed reaction immediately.
Once the infusion is interrupted or rate reduced to 50% of previous infusion rate, it must remain 
decreased for all subsequent infusions. 
For all types and grades of infusion reactions, details about drug physical constitution, method 
of preparation, and infusion must be recorded.
Participants should be instructed to report any delayed reaction immediately.
Table 8: Management of immune-mediated adverse events
Immune-related AEs are specific to immunotherapies and vary by organ system. The following 
immune-related AEs are important identified risks for M7824:
 •
Immune-related pneumonitis
•
Immune-related hepatitis
•
Immune-related colitis
•
Immune-related nephritis and renal dysfunction
•
Immune-related endocrinopathies 
•
(thyroid disorders, adrenal insufficiency, type 1 diabetes mellitus, pituitary disorders)
•
Immune related rash
•
Other immune-related events (myositis, myocarditis, encephalitis)
The following immune-related AEs are important potential risks for M7824:


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•
Guillain-Barré syndrome
•
Uveitis
•
Pancreatitis
•
Myasthenia gravis/myasthenic syndrome
Recommended guidance and management for specific irAEs are provided in the current 
National Comprehensive Cancer Network (NCCN) guideline available at http://www.nccn.org.
Requirements in addition to NCCN guidelines:

Permanent treatment discontinuation is required in case of immune-related Grade 4 
rash/inflammatory dermatitis, nephritis, autoimmune hemolytic anemia, hemolytic uremic 
syndrome, 
aplastic 
anemia, 
immune 
thrombocytopenia, 
acquired 
thrombotic 
thrombocytopenic purpura inflammatory arthritis, myositis and polymyalgia-like syndrome.

For Grade 4 immune-related lymphopenia, permanent treatment discontinuation will be 
required, if lymphopenia is considered immune-related in nature, no clear alternative 
explanation exists for the event, and it does not resolve within 14 days. Permanent treatment 
discontinuation is not required when the AE is manifested by a single laboratory value out 
of normal range without any clinical correlates. In this case, treatment should be held until 
the etiology is determined. If the event is not considered immune-related and resolves to 
Grade ≤ 1, restarting treatment may be considered.

For Grade 1 immune-related pneumonitis: continue treatment. If clinically indicated, 
monitor participants weekly or more frequently as needed with history, physical examination 
and pulse oximetry. If symptoms appear and/or changes in the physical exam are noted, treat 
as Grade 2.

For myositis: in case of management with rituximab, treatment should be discontinued.

For Grade 3 or 4 endocrinopathies: withhold until clinically stable or permanently 
discontinue depending on severity.

For hepatitis with no tumor involvement of the liver: withhold if total bilirubin increases to 
more than 1.5 and up to 3 times ULN, permanently discontinue if more than 3 times ULN

Hepatitis with tumor involvement of the liver: permanently discontinue if total bilirubin 
increases to more than 3 times ULN.
Table 9: Management of M7824 mediated Skin Reactions

Hyperkeratosis

Keratoacanthoma

Cutaneous squamous cell carcinoma (cSCC)

Basal cell carcinoma

Actinic keratosis


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Management

Discontinuation or termination not required in most cases. Continuation of treatment should 
be evaluated by the Investigator.

Emollients may be used

Develop diagnostic and treatment plan in collaboration with Investigator and dermatologist

Treatment follow-up will depend on number and localization of lesions.
o
Single lesion: full excision may be recommended
o
Multiple lesion or location not suitable for full excision: Mohrs surgery, cryotherapy 
or other standard treatment options depending on pathology. Retinoids may be used 
per Investigator decision.

Close clinical follow-up for re-evaluation, resolution and potential recurrence should be 
implemented

In general, treatment of M7824 mediated skin lesions should be based on local 
guidelines/standard of care.
Additional consideration: Keratoacanthoma lesions may resolve spontaneously without surgical 
intervention within weeks after discontinuing bintrafusp alfa.
Consult with Medical Monitor as needed for management of M7824 mediated skin lesions.
Table 10: Management of Treatment-Related Anemia
•
All relevant hematological testing for treatment-related anemias should be done prior 
to a blood transfusion, if clinically feasible
Basic Anemia Evaluation

CBC with emphasis on red cell indices

If indicated and at clinical discretion, the following should be considered:
o
Iron studies
o
Serum Folate and Vit B12 values
o
Coagulation factors
o
Fecal occult blood
o
Urinalysis
o
Hormone panel: TSH, Erythropoietin
o
Peripheral blood smear
Further recommendation based on suspected etiology (in addition to basic anemia testing)


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
Suspected Hemolysis
o
bilirubin, LDH, Coombs test, haptoglobin

Suspected bleeding: 
o
Consider imaging/interventional radiology consultation as indicated
o
Consider imaging and/or endoscopy as clinically indicated

Suspected aplastic anemia:
o
Hematology consultation
o
Consider bone marrow aspiration/morphologic evaluation
Additional consideration:  In general, blood transfusions and erythroid growth factors are 
permitted as clinically indicated.
Table 11: Management of Bleeding Adverse Events
Bleeding Adverse Events

Bleeding adverse events are considered an important identified risk for M7824.

In general, mild and moderate mucosal bleedings resolve without discontinuation of 
treatment.

These events may include, but are not limited to the following:
o
Epistaxis
o
Hemoptysis 
o
Gingival bleeding
o
Hematuria
Non-tumor Bleeding
Grading
Management
Grade 2

If resolves to Grade ≤ 1 by the day before the next infusion, study 
intervention may be continued.

If not resolved to Grade ≤ 1 by the day before the next infusion, but is 
manageable and /or not clinically relevant, consult Medical Monitor to assess 
if clinically reasonable to administer the following infusion.
Grade 3

Permanently discontinue treatment unless an alternative explanation can be 
identified (such as concomitant use of antithrombotic agents, traumatic 
events, etc.) 

In case of alternative explanations, hold study treatment until the event 
recovers to Grade ≤ 1


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Grade 4

Treatment must be permanently discontinued if no alternative explanation is 
identified.
Tumor Bleeding
Grade ≥ 2

Study treatment must be held till the event recovers to Grade ≤ 1

Permanently discontinue treatment if the Investigator considers the 
participant to be at risk for additional severe bleeding.
Table 12: Impaired Wound Healing 

Impaired wound healing is considered important potential risk for M7824

Management should be discussed with Medical Monitor for participants requiring 
surgery on study.

It is recommended to hold study intervention for approximately 4 weeks post major 
surgery for observation.

Post-operative wound healing should be closely monitored
3.4.2
M9241
Modifications of M9241 are explained in Table 14
After Dose level -1, no more dose reduction is allowed, and patient will be taken off M9241 
treatment. 
Table 13: M9241 Dose Reduction Levels:
Dose Level (DL)
Agent Dose
0
16.8µg/kg (or 12.0µg/kg) every 4 weeks
-1
12.0µg/kg (or 8.0µg/kg) every 4 weeks
Table 14: M9241 Dose Modification Instructions
(CTCAEv5) Grade
Action
Non-hematological, 
Grade 1 or 2
Continue M9241 therapy at full dose prescribed. Apply 
maximum supportive care recommendations. If prolonged 
duration of Grade 2 adverse event (≥7 days) is affecting quality 
of life, decrease dose to DL -1, if symptoms persist and continue 


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(CTCAEv5) Grade
Action
to affect quality of life for ≥7 more days, permanently 
discontinue M9241.
Non-hematological, 
Grade 3 or 4
(excluding 
cardiac, 
hepatobiliary 
events, 
interstitial pneumonitis or 
Grade 4 inflammatory 
response syndrome)
Apply maximum supportive care recommendations. Hold 
M9241 therapy until recovery to Grade  1 (up to 14 days). 
If non-hematological, symptomatic Grade 3 or 4 adverse events 
NOT resolved to Grade ≤1 within 14 days, discontinue M9241.
If recurrence of adverse event after drug hold/ interruptions is 
observed, and maximum supportive care measures applied, hold 
drug once again until recovery to Grade  1 (up to 14 days) and 
restart drug at DL-1. If adverse event recurs, M9241 must be 
permanently discontinued.
Grade 3 or 4 interstitial 
pneumonitis or Grade 4 
inflammatory 
response 
syndrome
M9241 must be permanently discontinued
Cardiac Adverse Events
Cardiac 
(Severity 
corresponding to NYHA 
criteria)
M9241 therapy to be discontinued permanently in case of 
symptomatic NYHA class III and IV CHF. M9241 therapy to be 
held, continued, or resumed accordingly for patients with NYHA 
class I or II CHF.
Hepatobiliary Adverse Events
Grade 2 AST/ALT 
Hold M9241 for 2 weeks and restart drug at next scheduled dose 
at DL 0 (full dose) if events resolved to ≤ Grade 1.
If adverse events NOT resolved to Grade ≤1 within 2 weeks, re-
start M9241 at DL-1.
Grade 3 and 4 AST/ALT* 
and 
Grade 
>2 
total 
bilirubin elevation
Hold M9241 for 2 weeks; restart drug at next scheduled dose at 
DL-1 if events resolved to ≤Grade 1. 
If adverse events NOT resolved to Grade ≤1 within 2 weeks, 
discontinue M9241
If Grade 3 AST/ALT or Grade 2 total bilirubin events recur after 
dose reduction to DL-1, then discontinue M9241.
Hematological, Grade 1 
or 2
No modification required
Grade 
3 
or 
4 
thrombocytopenia 
associated with bleeding 
M9241 must be permanently discontinued


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(CTCAEv5) Grade
Action
event which does not 
result in hemodynamic 
instability but requires an 
elective 
platelet 
transfusion, or a life-
threatening 
bleeding 
event which results in 
urgent intervention and 
admission to an Intensive 
Care Unit
Grade 
4 
hematologic 
toxicity lasting ≥ 7 days 
despite 
of 
medical 
intervention (Note: Grade 
4 neutropenia lasting >5 
days)
M9241 must be permanently discontinued
Cytokine 
release 
syndrome
M9241 must be permanently discontinued
* retest within 3 days from the first occurrence and then weekly to determine if ALT elevation 
persists
3.4.3
SBRT
Modifications of RT doses during SBRT due to local or systemic toxicities will be made at the 
discretion of the treating radiation oncologist. Early side effects happening during or shortly on or 
after treatment like fatigue, nausea, vomiting, abdominal cramps, diarrhea and skin changes tend 
to be short-term and treatable and will be managed with standard supportive care measures. In the 
rare event of pre-treatment leukopenia or thrombocytopenia, the following guide for dose 
adjustments of SBRT should be followed first:
Table 15: Recommended Dose Reductions for Myelosuppression 
Absolute 
granulocyte count, 
x106/L
Platelet count, 
x106/L
% of selected 
starting dose
≥1,000
And
≥85,000
OK to treat
<1,000
Or
<85,000
Do not start RT


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Hold SBRT for hematological toxicity until resolved to grade ≤ 1. If not resolved within 2 weeks, 
discontinue SBRT.
Dose Modifications for Non-Hematologic Adverse Reactions requiring permanent discontinuation 
of SBRT for any of the following:

Severe grade 3 or higher hepatic toxicity

≥grade 3 GI bleeding or GI perforation
Hold SBRT (Grade 3 or 4) for other non-hematological toxicity until resolved to grade < 1. If not 
resolved within 2 weeks, discontinue SBRT.
No dose modifications are recommended for alopecia, nausea, or vomiting.
3.4.3.1
Management of radiation-treatment related pain (radiation-induced pain flare)
The prophylactic use of dexamethasone or any other steroids is not allowed. Patient should be 
proactively managed with signs of radiation-induced pain flare which includes early hospital 
admission with adequate use of oral and intravenous combination analgesics as required. A pain 
scale should be established early and frequently repeated, patients should be assessed after baseline 
persistent pain has been stabilized with around-the-clock (ATC) analgesics on regular intervals. 
Short-acting opioid analgesics are the primary treatment, dose and/or dosing frequency of the ATC 
analgesic should be adjusted for patients with end-of-dose radiation-induced pain flare. Short-
acting oral opioids can be considered when given preemptively in patients with predictable 
radiation-induced pain flare.
Hospital admission exceeding 1 week for management of radiation-induced pain flare should be 
considered grade 3 AE, hospital admissions to accommodate pain management for radiation-
induced pain flare ≤7 days grade 2 AE.
3.5
ASSESSMENTS ON TREATMENT 
3.5.1
Study assessments
Study assessments are presented in Study Calendar 3.8.
3.5.2
End-of-Treatment Visit and Follow UP
See Study Calendar, Section 3.8.
3.5.3
Treatment pauses for surgery
Surgery is not part of this protocol and will be done as standard of care procedure with enrollment 
of patient to another surgical protocol at the NIH Clinical Center or at home institution. 
If during the treatment patient’s tumors become resectable per standard of care, M7824 and/or 
M9241 will be stopped at least 5 days prior to the scheduled date of surgery. 
If surgery performed outside NIH, we will ask patients to provide the outside surgical pathology 
report for determination of resection status (R0, R1, R2) and tumor sample from this surgery for 
research. 
If surgical exploration does not result in a successful removal of the tumor as defined below:
R0: closest tumor ≥1mm from surgical resection margin
R1: tumor within <1mm of surgical resection margin


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R2: involvement of surgical resection margin with tumor (incomplete tumor clearance)
“open and close”
treatment with M7824 and M9241 will resume 6-8 weeks after surgery when patient recovers. 
SBRT will not be repeated.
If surgical exploration results in a successful removal of the tumor, patient will be taken off study 
treatment.
Before post-surgery re-treatment with M7824 and M9241, Day 1 the following tests and 
examinations must be performed to evaluate safety of re-treatment and estimate baseline for tumor 
evaluations:
Within 28 days:

CT/MRI of chest, abdomen and pelvis;

Research Quality of Life assessment (subject-reported outcomes / symptom severity 
assessments the 4th version of the ‘Functional Assessment of Cancer Therapy with the 
hepatobiliary and pancreatic specific module (Appendix C). (For English speaking 
subjects only) 
Within 3 days:

Physical examination, including weight, vital signs, EKG, and ECOG performance status;

Adverse event and concomitant medications;

Laboratory evaluation:
Hematological profile: CBC with differential and platelet count; 
Biochemical profile: Acute care panel (that includes sodium, potassium, BUN, 
creatinine), Hepatic panel (that includes AST, ALT, total bilirubin), Mineral panel (that 
includes calcium, phosphorus, albumin, and magnesium), and uric acid; 
CEA, CA19-9, CA-125
T4, TSH
Amylase/ lipase
Serum or urine pregnancy test for female participants of childbearing age (in the absence 
of prior hysterectomy)
Urinalysis.
Research blood will not be collected during post-surgery treatment
3.6
QUESTIONNAIRES
The rationale for questionnaires is discussed in Section 1.2.8 and timing is specified in Study 
Calendar 3.8. The average time to complete these instruments is 20 minutes. For English speaking 
subjects only. 


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3.7
RESEARCH IMAGING
Ktrans and Kep perfusion measure of tumoral lesions measured on DCE-MRI with contrast will be 
measured at baseline, before treatment on day 1 of cycles 1 (+/-5 days) and 3 (+/-5 days). The 
scheme ensures perfusion measurements
-
At baseline in the absence of M7824 and M9241
-
After M7824 administration only (examining the effect of M7824 as a stromal modulator 
only; the anti-TGFβ component of the dual checkpoint inhibitor M7824 has been shown to act as 
a stromal modulator increasing perfusion in preclinical models as well as in few patients enrolled 
on 18-C-0061; M7824 in combination with gemcitabine in advanced pancreas cancer)
-
After combined M7824 and M9241 (two doses) administration; this timepoint examines if 
the addition of M9241 alters the stroma and perfusion.
Patients in Cohort 1A only.


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3.8
STUDY CALENDAR
Cycles 
(28+/- 3 days)1
Procedure
Screening
Baseline1
Day -141
Day 1
Day 15
EOT 
visit13, 16
28 Days 
FU14, 16
Long 
Term 
FU15, 16
M7824 2
X
X
X
M9241 3
X
SBRT 4
X (C1 
only)
Medical History
X
Confirmation of 
Pathology
X
Height 
X
Physical 
exam, 
weight, 
vital 
signs, ECOG 5, 17
X
X
X
X
X
X
Skin assessment
X
X18
X
EKG 17
X
X
X6
X6
X
CBC 
with 
differential 
and 
platelets 17
X
X
X
X
X
X
X
Biochemical 
profile 7, 17
X
X
X
X
X
X
X


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Cycles 
(28+/- 3 days)1
Procedure
Screening
Baseline1
Day -141
Day 1
Day 15
EOT 
visit13, 16
28 Days 
FU14, 16
Long 
Term 
FU15, 16
Pregnancy 
testing (urine or 
serum) 17
X
X
X
A brain CT / 
MRI 
scan 
if 
clinically 
indicated
X
Tumor 
evaluation 8, 17
X
X
X (odd 
cycles, 
except 
C3)
X (C3 
only)
X
CEA, 
CA19-9, 
CA-12517 
X
X
X
X
T4 and TSH17
X
X
X
X
Amylase / lipase 
17
X
X
X
X
Urinalysis17 
X
X
X
X
PT, INR, aPTT, 
fibrinogen
X
X
X
Concomitant 
Medications17
X
X
X
X
Baseline 
symptom 
collection
X


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Cycles 
(28+/- 3 days)1
Procedure
Screening
Baseline1
Day -141
Day 1
Day 15
EOT 
visit13, 16
28 Days 
FU14, 16
Long 
Term 
FU15, 16
Collection 
of 
archival 
tumor 
sample 
if 
available 
for 
research
X
FACT-Hep 9, 17
X
X
Adverse events 17
X
X
X
X
X
X
Research MRI 10
X
X
Research blood 
for PK 11
X
X
X
Research blood 
for 
ADA 
sampling 
X
X12
Research blood 
for 
Cytokines 
and TNF 
X
X
Research blood 
for 
circulating 
free tumor DNA 
(cfDNA) assay 
X
X
X
Phone call or e-
mail 
X


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1 Baseline and Day -14 (Arm 1A) or C1D1 (Arm 2A and Arm 3) evaluations do not need to be repeated if performed at screening or 
baseline in designated time frame. All evaluations will be done within 72 hours before treatment initiation on treatment days. If treatment 
does not start within 28 days after enrollment, screening evaluations will be repeated.
2 M7824 will be administered as an IV on Days 1 and 15 of every cycle. Note: Additional infusion on Day -14 in Arm 1A.
3 M9241 will be administered as a subcutaneous injection on Day 1 of every cycle.
4 SBRT Radiation therapy on Day 17 (+5 days) of Cycle 1 and continue for 5 consecutive business days (except federal holidays). It 
will be administered as short course (SBRT) of 5 fractions according to schedule assigned by radiation oncologist.
5 Eye signs and symptoms and assessment of skin should be included into physical exam. If clinically indicated, ophthalmology and 
dermatology consults should be ordered.
6 Cycle 1 only, before study treatment.
7 Biochemical profile: Acute care panel (that includes sodium, potassium, BUN, creatinine), Hepatic panel (that includes AST, ALT, 
total bilirubin), Mineral panel (that includes calcium, phosphorus, albumin, magnesium), uric acid
8 CT of chest, abdomen and pelvis (or MRI of chest, abdomen and pelvis if clinically indicated). Cycle 3 day 15 (+/- 5 days) and every 
2 Cycles (+/-5 days) thereafter. If patient is taken off treatment for reason other than disease progression, imaging evaluations will 
continue during follow up period every 12 weeks (± 2 weeks) until progression. In addition, if PD, a confirmatory scan should be 
obtained 4 weeks (+ 1 week) following initial documentation of PD.
9 Research Quality of Life assessment (subject-reported outcomes / symptom severity assessments the 4th version of the ‘Functional 
Assessment of Cancer Therapy with the hepatobiliary and pancreatic specific module (Appendix C). (For English speaking subjects 
only. At baseline, cycles 2, 4 and every 12 weeks after that. 
10 At baseline, before treatment on day 1 of cycles 1 and 3 (+/-5 days). Cohort 1A only.
11 See Section 5.1.3
12 Before dosing on Cycle 2 day 1 
13 All subjects should undergo an End-of-Treatment visit after discontinuation of M7824 and M9241 for any reason. This visit should 
be performed on the day of or within 7 days after the decision to discontinue trial treatment but before any new antineoplastic therapy 
is started (if possible), whichever occurs earlier. Research samples may be collected as logistically feasible. If it is known to the 
Investigator at the time of the End of-Treatment visit that the subject will start new treatment within 28 days of last treatment or they 
will be unable to return within 28 days of last treatment, assessments associated with the 28-Day Safety Follow-up visit may be 
conducted at the End-of-Treatment visit.


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14 A Safety Follow-up visit is scheduled 4 weeks (28 ± 5 days) after the last administration of M7824 or M9241 but before any new 
therapy is started, if possible, whichever occurs earlier. All SAEs ongoing at the 28-Day Safety Follow-up visit must be monitored and 
followed up by the Investigator until stabilization or until the outcome is known, unless the subject is documented as “lost to follow-
up.” In addition, all trial drug-related SAEs occurring after 28 Day Safety Follow up visit and ongoing at the Safety Follow-up visit 
have to be followed up in the same manner
15 Subjects with PD will be followed every 12 weeks (± 2 weeks) by phone or e-mail for survival and further tumor therapy for 1 year 
after the last dose of study drug. After 1-year subjects will be followed for survival every 6 month. Subjects without progressive disease 
at 28-Day Safety Follow-up visit will be invited to Clinical Center to perform CT scans (or MRI scans if clinically indicated) every 12 
weeks (± 2 weeks) until PD. Outside scans are acceptable. 
16 If subjects are not willing to come to NIH after treatment discontinuation for FU visits, they will be followed by phone call or e-mail.
17 Must be done before re-treatment after surgery.
18 Every 6 weeks


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3.9
COST AND COMPENSATION
3.9.1
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 performed 
outside the NIH Clinical Center, participants may have to pay for these costs if they are not covered 
by insurance company. Medicines that are not part of the study treatment will not be provided or 
paid for by the NIH Clinical Center.
3.9.2
Compensation
None.
3.10 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.
3.11 CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF STUDY CRITERIA
Prior to removal from study, efforts must be made to have all subjects complete a safety visit 
approximately 28 days following the last dose of study therapy.
3.11.1 Criteria for Removal from Protocol Therapy

Patient request to be withdrawn from therapy

Progressive disease as defined in section 6.3. Subjects should continue treatment beyond 
the initial determination of PD, through their next tumor assessment, which in this case 
should be in 4 weeks if: 
There are no new Grade 2 or greater symptoms or significant worsening of existing 
symptoms.
There is no increase in ECOG.
There are no new metastatic lesions 
In the opinion of the Investigator, the subject does not require new anticancer 
therapy.

Excessive toxicity (see section 3.4)

Necessity to administer a non-permitted concomitant drug (see section 4.2)

Surgical exploration results in a successful removal of the tumor 

PI discretion

Positive pregnancy test

The drug manufacturer can no longer provide the study agents
3.11.2 Off -Study Criteria

Death


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
Patient request to be withdrawn from study

Lost to follow up

PI discretion

PI decision to end the study
3.11.3 Lost to Follow-up
A participant will be considered lost to follow-up if he or she fails to return for 3 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 visits 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, a certified letter to the participant’s last known mailing address or local 
equivalent methods). These contact attempts should be documented in the participant’s 
medical record or study file. 

Should the participant continue to be unreachable, he or she will be considered to have 
withdrawn from the study with a primary reason of lost to follow-up.
4
CONCOMITANT MEDICATIONS / MEASURES
4.1
PERMITTED MEDICINES
Any medications (other than those excluded by the clinical trial protocol) that are considered 
necessary to protect subject welfare and will not interfere with the trial medication may be given 
at the Investigator’s discretion. 
4.2
PROHIBITED MEDICINES
The following treatments must not be administered during the trial:
Immunotherapy including interferon, immunosuppressive drugs (for example, systemic 
corticosteroids except for short term treatment of allergic reactions, endocrine replacement 
therapy at low dose prednisone [≤ 10 mg daily] or equivalent, or for the treatment of irAEs or 
other appropriate short-term steroid use), or other experimental pharmaceutical products. Short 
term administration of systemic steroid or other immunosuppressant such as infliximab or 
mycophenolate (that is, for allergic reactions or the management of irAEs) is allowed. Steroids 
with no or minimal systemic effect (topical, inhalation) are allowed. 
Prophylactic use of corticosteroids for infusion related reactions is prohibited.
Herbal remedies with immunostimulating properties (for example, mistletoe extract) or known 
to potentially interfere with major organ function (for example, hypericin).
Any live vaccine therapies for the prevention of infectious disease. Administration of 
inactivated vaccines is allowed (for example, inactivated influenza vaccines).


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If the administration of a non-permitted concomitant drug becomes necessary during the trial, the 
subject will be withdrawn from trial treatment.
5
BIOSPECIMEN COLLECTION
5.1.
CORRELATIVE STUDIES FOR RESEARCH/PHARMACOKINETIC STUDIES
Studies will address the effect on TGFβ concentrations and other soluble factors in serum and/or 
plasma upon response to the study drugs, the impact of the somatic genotype on response to M7824 
and M9241, and changes in the immune phenotype to predict efficacy of the administered 
combination immunotherapy. We also will evaluate intratumoral alterations of the immune milieu 
/ stroma of pre- versus post-treatment archival tissues (pre-treatment biopsy and surgical 
specimen) as well as follow copies of circulating free tumor DNA levels during treatment.
5.1.1
Blood Collection
Blood samples will be originally sent to Blood Processing Core (BPC) for barcoding, initial 
processing and storage. From this facility coded linked samples will be sent to the designated 
places for analysis in batch shipments or upon request. Patients will undergo blood and tissue 
sampling for research purposes on the time points outlined in the Study Calendar 3.8
5.1.2
Tumor and Tissue Collection
Archival tumor samples (collected within 6 months prior to treatment) might be collected at 
baseline and from the surgical specimen when patients undergo resection. 
Test/assay
Volume 
(approx.)
Type 
of 
tube*
Collection point 
Location 
of 
specimen 
analysis 
(and 
original 
processing)
PK M7824 
Blood, 
4 
mL
SST
See section 5.1.3
EMD 
Serono 
(BPC)
ADA by ELISA
Blood, 
4 
mL
SST
See Study calendar 
3.8
EMD 
Serono 
(BPC)
Cytokines by ELISA 
Blood, 
8 
mL
SST
See Study calendar 
3.8
EMD 
Serono 
(BPC)
TNF by ELISA
Blood, 2x3 
mL
Light 
blue 
citrate
See Study calendar 
3.8
EMD 
Serono 
(BPC)
Immune marker panel 
evaluation by IHC
Archival 
tumor 
sample and 
Baseline 
and 
at 
surgery
Laboratory 
of 
Pathology, NCI


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Test/assay
Volume 
(approx.)
Type 
of 
tube*
Collection point 
Location 
of 
specimen 
analysis 
(and 
original 
processing)
surgery 
sample
161 DNA-target panel 
(Oncomine 
v3 
Comprehensive Assay 
v3)
Archival 
tumor 
sample or 
surgery 
sample
Baseline 
or 
at 
surgery
Dr. M. Raffeld, 
Laboratory 
of 
Pathology NCI
Circulating free tumor 
DNA (ctDNA)
Blood, 
6 
mL
EDTA 
(purple top) 
tubes
See Study calendar 
3.8
Dr. M. Raffeld, 
Laboratory 
of 
Pathology 
NCI 
(BPC)
* Tubes/media may be adjusted at the time of collection based upon materials available and/or to ensure 
the best viable samples are collected for planned routine and/or research analysis at the time of procedure.
5.1.3
Pharmacokinetic analysis
Only during Phase IA.
PK samples should be taken:
Day -14
M7824 PK: predose, 1h post infusion of M7824 (+/- 15 minutes),
Cycle 1:
M7824 PK: predose, 1h post infusion of M7824 (+/- 15 minutes),
M7824 day 15 predose. 
The investigation will be done by EMD Serono under CRADA with this company.
5.1.4
ADA
Anti-Drug Antibody development is an accepted mechanism of loss of efficacy administered 
human monoclonal antibodies. Measuring titers will ensure that any lack of efficacy of M7824 
and/or M9241 is not due to ADA development.
Blood will be collected to analyze ADA according to Study Calendar 3.8. Samples positive for 
ADAs will be re-analyzed to determine the titer. The investigation will be done by EMD Serono 
using ELISA under CRADA with this company. 


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5.1.5
Serum cytokines and serum TNF levels
One of the least elaborate ways to confirm that the administered M7824 is active and is engaging 
its target, is to measure suppression of TGFβ levels (via ‘trapping’) and induced changes in the 
cytokine profile systemically. Following TGFβ and cytokine levels longitudinally across treatment 
course will allow detection of lack of M7824 activity and can trigger additional investigations 
(ADA development) into lack of efficacy. Initial circulating TGF-β and cytokine levels (including 
γ-interferon and TNF) will also be tested for correlation with response to M7824 and M9241 or 
M7824 and M9241 in combination with SBRT therapy overall.
Blood will be collected to analyze soluble factors including cytokines and TNF concentrations 
according to Study Calendar 3.8. The investigation will be done by EMD Serono using ELISA 
under CRADA with this company.
5.1.6
Changes in systemic and intratumoral immunogenicity of M7824 and /or M9241 in 
combination with SBRT (Immune marker panel evaluation by IHC)
Preclinical studies show that TGFβ and PD-L1 inhibition and local delivery of rIL-12 cooperate 
immunologically with RT to induce anti-tumor responses reducing immune evasive cues and 
enhancing T cell-mediated anti-tumor responses. Immune profiling of pre- and on-treatment 
specimens including surgical specimens aim to (1) investigate via staining of multiple markers 
using immunohistochemistry immunogenic cooperativity of M7824 and/or M9241 in combination 
with RT, and (2) identify an immunologic footprint, either at baseline measure or treatment-
induced change, associated with response to the combination approach. This information will also 
inform on the design of future combination immunotherapy studies. This will be done in the 
Laboratory of Pathology, NCI.
5.2
SAMPLES FOR GENETIC/GENOMIC ANALYSIS
5.2.1
Description of the scope of genetic/genomic analysis
5.2.1.1
Somatic genomic profile of pancreatic cancers derived from specimens
There is clinical evidence that mutation load drives outcome of immunotherapy in pancreas cancer, 
and emerging evidence that certain neo-epitopes derived from somatic mutations are more 
immunogenic than others. For example, it has been postulated that mutations in chromatin-
remodeling genes, present in up to 17% of pancreas cancer specimens, or variants affecting the 
TGFβ receptor - SMAD axis, are positively associated with outcome to immunotherapy in cancer. 
Thus, early correlations between genotype and clinical outcome of patients aim to (1) improve 
future selection of patients for the dual TGFβ ‘trap’ PD-L1 blockade and M9241 immunocytokine 
therapy in combination with RT approach as well as (2) improve understanding of the mechanism 
of action of these agents in pancreas cancer which would aid design of future combination 
therapies.
We will use baseline archival samples as available for somatic tumor variant sequencing which 
will be performed by the CLIA-approved 50-cancer gene panel of the Molecular Pathology section 
(Dr. M. Raffeld lab). 
5.2.2
Circulating free tumor DNA measures:
Measures of copies of genomic tumor DNA released into the circulation has been shown to be an 
accurate measure of tumor burden in patients with solid organ cancers and to have value to follow 
response to anti-cancer treatment both for the early identification of responders as well as patients 


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to recur after remission. Including longitudinal measurements from baseline and on-treatment of 
circulating free tumor DNA into explorative objectives examines the value of identifying 
responders early and the development of this test as a predictive biomarker for the tested M7824 
M9241 combination treatments with SBRT.
We plan to characterize cfDNA from blood before and during treatment. All samples will be 
subjected to targeted sequencing. This will allow us to characterize somatic point mutations, and 
copy-number changes and will be performed in Dr. M. Raffeld’ s laboratory.
5.2.3
Management of Results
Subjects will be contacted if a clinically actionable gene variant is discovered. Clinically actionable 
findings for the purpose of this study are defined as disorders appearing in the American College 
of Medical Genetics and Genomics recommendations for the return of incidental findings that is 
current at the time of primary analysis. (A list of current guidelines is maintained on the CCR 
intranet: 
https://ccrod.cancer.gov/confluence/display/CCRCRO/Incidental+Findings+Lists). 
Subjects will be contacted at this time with a request to provide a blood sample to be sent to a 
CLIA certified laboratory. 
5.2.4
Genetic counseling
If the research findings are verified in the CLIA certified lab, the subject will be offered the 
opportunity to come to NIH (at our expense) to have genetic education and counseling with the 
NCI Genetics Branch to explain this result. If the subject does not want to come to NIH, a referral 
to a local genetic healthcare provider will be provided (at their expense). This is the only time 
during the course of the study that incidental findings will be returned. No interrogations regarding 
clinically actionable findings will be made after the primary analysis.
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 
will not be sent outside the National Institutes for Health (NIH) without appropriate approvals 
and/or agreements, if required.
All samples will be barcoded, with data entered and stored in the secure databases. These databases 
create a unique barcode ID for every sample and sample box, which cannot be traced back to 
patients without database access. The data recorded for each sample includes the patient ID, name, 
trial name/protocol number, time drawn, cycle time point, dose, material type, as well as box and 
freezer location. Patient demographics associated with the clinical center patient number are 
provided in the system. For each sample, there are notes associated with the processing method 
(delay in sample processing, storage conditions on the ward, etc.).
Barcoded samples are stored in barcoded boxes in a locked freezer at either -20 or -800C according 
to stability requirements. 
Access to stored clinical samples is restricted. Samples will be stored until requested by a 
researcher named on the protocol. All requests are monitored and tracked in database. All 
researchers are required to sign a form stating that the samples are only to be used for research 
purposes associated with this trial (as per the IRB approved protocol) and that any unused samples 
must be returned. It is the responsibility of the NCI Principal Investigator to ensure that the samples 
requested are being used in a manner consistent with IRB approval.


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5.3.1 Samples Managed by Dr. Figg’s Blood Processing Core (BPC) 
BPC contact information 
Please e-mail at NCIBloodcore@mail.nih.gov at least 24 hours before transporting samples (the 
Friday before is preferred).
For sample pickup, page 102-11964.
For immediate help, call 240-760-6180 (main blood processing core number) or, if no answer, 
240-760-6190 (main clinical pharmacology lab number).
For questions regarding sample processing, contact NCIBloodcore@mail.nih.gov.
5.3.1
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 in sections 
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. The PI will record 
any loss or unanticipated destruction of samples as a deviation. Reports will be made per the 
requirements of section 7.2.
If the patient 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.
6
DATA COLLECTION AND EVALUATION 
6.1
DATA COLLECTION
The PI will be responsible for overseeing entry of data into an in-house password protected 
electronic system (C3D) and Labmatrix ensuring data accuracy, consistency and timeliness. The 
principal investigator, associate investigators/research nurses and/or data manager will assist with 
the data management efforts. Primary and final analyzed data will have identifiers so that research 
data can be attributed to an individual human subject participant. 
All adverse events, including clinically significant abnormal findings on laboratory evaluations, 
regardless of severity, will be followed until return to baseline or stabilization of event.
Document AEs from the administration of the first study intervention through 28 days after the 
last study agent (s) is administered. Beyond 28 days after the last intervention, 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


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
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 patient’s 
outcome.
6.1.1
PK Data
The exact time of each blood draw for PK analysis will be recorded.
6.1.2
Tumor data
The tumor disease information that will be documented and verified at the Screening visit for each 
subject includes:
Detailed history of the tumor, including histopathological diagnosis, grading and staging in 
accordance with the Union Internationale Contre le Cancer Tumor Node Metastasis 
Classification at diagnosis (UICC TNM).
o The T and M category (T1-3 vs T4 and M0 or M1) of the tumor at the time of study entry, 
based on screening assessments
All therapy used for prior treatment of the tumor (including surgery, radiotherapy and 
chemotherapy, immunotherapy).
Any other conditions that were treated with chemotherapy, radiation therapy, or 
immunotherapy.
6.1.3
Concomitant Medications and Therapies
All concomitant medications taken by the subject during the trial, from the date of signature of 
informed consent are to be recorded in the appropriate section of the eCRF, noting the name, dose, 
duration and indication of each drug. Nondrug interventions should also be recorded in the eCRF.
The following outcome criteria will be captured if surgery performed while patient is on study: 
-
Number of patients explored
-
Number of patients to undergo resection
-
Number of R0, R1, and R2 resection
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 breech in our plan to protect 
subject confidentiality and trial data has occurred, his will be reported expeditiously per 
requirements in section 7.2.1. 
6.2
DATA SHARING PLANS
6.2.1
Human Data Sharing Plan
The PI will share coded linked human data generated in this research for future research: 

in an NIH-funded or approved public repository clinicaltrials.gov and dbGaP

in BTRIS 

in publication and/or public presentations


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
with approved outside collaborators under appropriate agreements

at the time of publication or shortly thereafter.
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
For the purposes of this study, patients should be re-evaluated for response at Cycle 3 day 15 (+/- 
5 days) and every 2 Cycles (+/-5 days) thereafter. In addition, if PD, a confirmatory scan should 
be obtained 4 weeks (+ 1 week) following initial documentation of PD. 
Response and progression will be evaluated in this study using the new international criteria 
proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline 
(version 1.1) [[70, 71]] and Modified Immune-related response criteria (6.4). Changes in the 
largest diameter (unidimensional measurement) of the tumor lesions and the shortest diameter in 
the case of malignant lymph nodes are used in the RECIST criteria. 
6.3.1
Disease Parameters
For the purpose of this study, the primary pancreatic tumor should be the target lesions with no 
other disease present. However, for the purpose of defining criteria for progression of disease, all 
RECIST criteria are reviewed here:
Measurable disease: Measurable lesions are defined as those that can be accurately measured in at 
least one dimension (longest diameter to be recorded) as: 

By chest x-ray: >20 mm; 

By CT scan: 
o
Scan slice thickness 5 mm or under as >10 mm 
o
Scan slice thickness >5 mm: double the slice thickness 

With calipers on clinical exam: >10 mm. 
All tumor measurements must be recorded in millimeters (or decimal fractions of centimeters).
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.


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‘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 patient, 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. 
6.3.2
Methods for Evaluation of Measurable Disease
All measurements should be taken and recorded in metric notation using a ruler or calipers. All 
baseline evaluations should be performed as closely as possible to the beginning of treatment and 
never more than 4 weeks before the beginning of the treatment.
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. Imaging-based evaluation is 
preferred to evaluation by clinical examination unless the lesion(s) being followed cannot be 
imaged but are assessable by clinical exam.
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.


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6.3.3
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 only 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 the measure of primary tumor status to follow for determining response: 
CT or MRI images of primary tumor mass. 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 3.8.
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 3.11.1). Before stopping the treatment, progressive disease should be 
confirmed by imaging 4 weeks after progression has been diagnosed according to RECIST 
1.1. If progression is based on the occurrence of a new lesion in an area not scanned at Baseline, a 
further on-study scan 4 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 symptoms or worsening of existing symptoms.
There is no new lesion outside the pancreas
There is no decrease in ECOG PS.
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 and M9241 
in combination with CRT anymore 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 (Error! Reference source not 
found.). In the case of a PR or CR, a confirmatory CT or MRI scan should be done no sooner 
than 4 weeks. 


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The Investigator may perform scans in addition to a scheduled trial scan for medical reasons or if 
the Investigator suspects PD. 
Table 16. Response Criteria for Patients 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
PR
Non-
CR/Non-
PD/not 
evaluated
No
PR
>4 wks. Confirmation**
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:
Patients 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.


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Subjects who have experienced SD, PR, or CR should continue treatment through the end of 
24 months, although additional treatment is possible. If the Investigator believes that a subject may 
benefit from treatment beyond 24 months, it may be permissible. 
6.3.4
Responses
6.3.4.1
Best overall response (BOR) 
The duration of best overall response is measured from the time measurement criteria are met for 
CR, PR or SD (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.
6.3.4.2
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. Stable Disease (SD) when sum of all target lesions does not qualify for 
CR/PR/PD for Target Lesion Response and Persistence of non-target lesions on Non-Target 
Lesion Response.
6.4
IMMUNE-RELATED RESPONSE CRITERIA (IRRECIST)
Modified immune-related response criteria (irRECIST) will also be employed in this study. This 
new classification is based on the recent learning from clinical studies with cancer 
immunotherapies that even if some new lesions appear at the beginning of a treatment or if the 
total tumor burden does not increase substantially, tumor regressions or stabilizations might still 
occur later. For this trial, the concepts of the irRECIST are combined with RECIST 1.1. Please 
refer to Appendix E for further details.
6.5
TOXICITY CRITERIA
The following adverse event management guidelines are intended to ensure the safety of each 
patient 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#ctc_50). 
We are also using additional grading criteria for radiation related adverse events (section 3.4.3.1) 
7
NIH REPORTING REQUIREMENTS / DATA AND SAFETY MONITORING PLAN
7.1
DEFINITIONS
Please refer to definitions provided in Policy 801: Reporting Research Events found here.


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7.2
OHSRP OFFICE OF COMPLIANCE AND TRAINING / IRB REPORTING
7.2.1
Expedited Reporting 
Please refer to the reporting requirements in Policy 801: Reporting Research Events and Policy 
802 Non-Compliance Human Subjects Research found here. Note: Only IND Safety Reports that 
meet the definition of an unanticipated problem will need to be reported per these policies.
7.2.2
IRB Requirements for PI Reporting at Continuing Review
Please refer to the reporting requirements in Policy 801: Reporting Research Events found here
7.3
NCI CLINICAL DIRECTOR REPORTING 
Problems expeditiously reported to the OHSRP in iRIS will also be reported to the NCI Clinical 
Director. A separate submission is not necessary as reports in iRIS will be available to the Clinical 
Director.
In addition to those reports, all deaths that occur within 30 days after receiving a research 
intervention should be reported via email to the Clinical Director unless they are due to progressive 
disease. 
To report these deaths, please send an email describing the circumstances of the death to Dr. Dahut 
at NCICCRQA@mail.nih.gov within one business day of learning of the death.
7.4
NIH REQUIRED DATA AND SAFETY MONITORING PLAN
7.4.1
Principal Investigator/Research Team 
The clinical research team will meet on a weekly basis when patients are being actively treated on 
the trial to discuss each patient. Decisions about dose level enrollment and dose de-escalation will 
be made based on the toxicity data from prior patients. 
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 patient 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.
8
SPONSOR PROTOCOL/SAFETY REPORTING
8.1
DEFINITIONS
8.1.1
Adverse Event 
Any untoward medical occurrence in a patient 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))


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8.1.2
Serious Adverse Event (SAE)
An adverse event or suspected adverse reaction is considered serious if in the view of the 
investigator or the sponsor, it results in any of the following:

Death,

A life-threatening adverse event (see section 8.1.3)

Inpatient hospitalization or prolongation of existing hospitalization:
o
A hospitalization/admission that is pre-planned (i.e., elective or scheduled surgery 
arranged prior to the start of the study), a planned hospitalization for pre-existing 
condition, or a procedure required by the protocol, without a serious deterioration in 
health, is not considered a serious adverse event.
o
A hospitalization/admission that is solely driven by non-medical reasons (e.g., 
hospitalization for patient or subject convenience) is not considered a serious adverse 
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 patient or subject and may require 
medical or surgical intervention to prevent one of the outcomes listed in this definition.
8.1.3
Life-threatening 
An adverse event or suspected adverse reaction is considered "life-threatening" if, in the view of 
either the investigator or sponsor, its occurrence places the patient or subject at immediate risk of 
death. It does not include an adverse event or suspected adverse reaction that, had it occurred in a 
more severe form, might have caused death. (21CFR312.32)
8.1.4
Severity
The severity of each Adverse Event will be assessed utilizing the CTCAE version 5.0.
8.1.5
Relationship to Study Product
All AEs will have their relationship to study product assessed using the terms: related or not 
related. 

Related – There is a reasonable possibility that the study product caused the adverse event. 
Reasonable possibility means that there is evidence to suggest a causal relationship 
between the study product and the adverse event.

Not Related – There is not a reasonable possibility that the administration of the study 
product caused the event.


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8.1.6
Adverse Events of Special Interest (AESI)
Adverse events of special interest (AESIs) are serious or nonserious AEs that are of clinical interest 
and should be closely followed.
AESIs include following:
•
Infusion-related reactions including immediate hypersensitivity.
•
Immune-related adverse events.
•
M7824 mediated skin reactions.
•
Anemia.
•
Bleeding AEs
8.2
ASSESSMENT OF SAFETY EVENTS
AE information collected will include event description, date of onset, assessment of severity and 
relationship to study product and alternate etiology (if not related to study product), date of 
resolution of the event, seriousness and outcome. The assessment of severity and relationship to 
the study product will be done only by those with the training and authority to make a diagnosis 
and listed on the Form FDA 1572 as the site principal investigator or sub-investigator. AEs 
occurring during the collection and reporting period will be documented appropriately regardless 
of relationship. AEs will be followed through resolution.
SAEs will be:

Assessed for severity and relationship to study product and alternate etiology (if not related 
to study product) by a licensed study physician listed on the Form FDA 1572 as the site 
principal investigator or sub-investigator.

Recorded on the appropriate SAE report form, the medical record and captured in the 
clinical database.

Followed through resolution by a licensed study physician listed on the Form FDA 1572 
as the site principal investigator or sub-investigator.
For timeframe of recording adverse events, please refer to section 6.1. All serious adverse events 
recorded from the time of first investigational product administration must be reported to the 
Sponsor with the exception of any listed in section 8.4.
8.3
REPORTING OF SERIOUS ADVERSE EVENTS
Any AE that meets a 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


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Following the assessment of the SAE by OSRO, other supporting documentation of the event may 
be requested by the OSRO Safety and should be provided as soon as possible.
8.4
WAIVER OF EXPEDITED REPORTING TO CCR 
As death due to disease progression is part of the study objectives (PFS and OS), and captured as 
an endpoints in this study, death 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.
Hospitalization that is deemed to be due to disease progression, and not attributable to the 
intervention will not be reported as an SAE. The event, and the assessment that it was caused by 
disease progression will be documented in the medical records. The causality assessment of 
hospitalization will be re‐evaluated any time when new information is received. If the causality 
assessment changes from disease progression to related to the study intervention, SAE report will 
be sent to the Sponsor in an expedited manner according to section 8.3. If there is any uncertainty 
whether the intervention is a contributing factor to the event, the event should be reported as AE 
or SAE as appropriate.
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 patient 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 after 
the Investigator becomes aware of it. 
Pregnancy itself is not regarded as an SAE. However, congenital abnormalities or birth defects and 
spontaneous miscarriages that meet serious criteria (section 8.1.2) should be reported as SAEs. 
The outcome of all pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, 
normal birth, or congenital abnormality) should be followed up and documented.
8.6.2
Paternal exposure
Male patients should refrain from fathering a child or donating sperm during the study and for 120 
days after the last dose of study drug.
Pregnancy of the patient’s partner is not considered to be an AE. However, the outcome of all 
pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, normal birth, or 
congenital abnormality) occurring from the date of the first dose until 120 days 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. CCR will report an AE as a suspected adverse 


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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 with 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 NON-ADHERENCE REPORTING
Protocol non-adherence is defined as any noncompliance with the clinical trial protocol, 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 non-adherence identified by the 
Staff or the site Monitor on the OSRO Site Protocol Non-Adherence Log.  The protocol-specific, 
cumulative non-adherence log should be maintained in the site essential documents file and 
submitted to OSRO via OSROMonitoring@mail.NIH.gov on the first business day of each 
month over the duration of the study. In addition, any non-adherence to the protocol should be 
documented in the participant’s source records and reported to the local IRB per their guidelines. 
OSRO required protocol non-adherence reporting is consistent with E6(R2) GCP: Integrated 
Addendum to ICH E6(R1): 4.5 Compliance with Protocol; 5.18.3 (a), and 5.20 Noncompliance; 
and ICH E3 16.2.2 Protocol deviations.
9
CLINICAL MONITORING 
Clinical site monitoring is conducted to ensure that the rights of the participants are protected, that 
the study is implemented per the approved protocol, Good Clinical Practice and standard operating 
procedures, and that the quality and integrity of study data and data collection methods are 
maintained.  Monitoring for this study will be performed by NCI CCR Office of Sponsor and 
Regulatory Oversight (OSRO) Monitoring 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. The intensity and frequency of monitoring will 
be based on several factors, including study type, phase, risk, complexity, expected enrollment 
rate, and any unique attributes of the study and the site. OSRO Monitoring visits and related 
activities will be conducted throughout the life cycle of each protocol, with the first activity being 
before study start 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 take place at the study 
site(s).  Monitoring visit reports will describe visit activities, observations, findings of protocol 
non-adherence and associated action items or follow-up required for resolution of findings.  
Monitoring reports will be distributed to the study PI, NCI CCR QA, coordinating center (if 
applicable) and the OSRO regulatory file.
If protocol non-adherence is identified by the Monitor (i.e., any noncompliance with the clinical 
trial protocol, GCP, or protocol-specific procedural requirements on the part of the participant, the 


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Investigator, or the site Staff) the Monitor will note the observation, review with site Staff and if 
unresolved, request that the Staff document the non-adherence on the protocol-specific OSRO Site 
Protocol Non-Adherence Log (see Section 8.8).
10 STATISTICAL CONSIDERATIONS
10.1 STATISTICAL HYPOTHESIS
10.1.1 Primary endpoints:

To determine the safety and tolerability and the recommended phase 2 dose (RP2D) of 
M7824 and M9241 in combination with SBRT as neoadjuvant / perioperative treatment in 
subjects with pancreas cancer:
number, severity, and duration of treatment-related AEs for the combination 
treatment of M7824 and M9241 administered in combination with a 5-day course 
of SBRT according to CTCAE v5.0 
rate of completion of neoadjuvant SBRT courses when given with M7824 and 
M9241. 

To determine a preliminary estimate of efficacy as best overall response (BOR) according 
to RECIST 1.1 of M7824 and M9241 in combination with SBRT as neoadjuvant / 
perioperative treatment in subjects with locally advanced pancreas cancer will be measured 
by 
Best Overall Response (BOR) according to RECIST 1.1 
10.1.2 Secondary endpoints

Overall survival in patients after completion of SBRT in combination with M9241 and 
M7824.

Progression-free survival of all patients and PFS of patients who did not undergo surgical 
resection (expressed as median PFS). 

Fraction of patients with LAPC who can undergo surgical resection after M7824 and 
M9241 in combination with SBRT treatment.

Time-to-recurrence in patients who underwent surgical resection will be measured as time 
from surgical resection to disease recurrence (expressed in months).

Rate of complete pathologic response will be measured as fraction of patients who had a 
complete pathologic response of all patients who underwent surgery.
10.2
 SAMPLE SIZE DETERMINATION
Phase I: 
The investigational agents M7824 and M9241 will be first tested in combination for safety and 
tolerability prior to assessing both in combination with SBRT. The safety phase IA run-in of 
M7824 and M9241 will accrue either pancreatic cancer patients with locally advanced surgically 
unresectable disease or patients with stage IV disease.
Dose Level 0 of 1,200 mg for M7824 every 2 weeks will be tested in combination with 16.8µg/kg 
of M9241 every four weeks will be first given to 6 patients as a safety run-in. If there are 0-1 


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DLTs, the study will proceed to the phase IB of M7824 and M9241 in combination with SBRT 
starting with DL0.
If there are ≥2 DLTs at DL0, 6 patients will be enrolled at DL -1 (1,200 mg M7824 q2 weeks and 
12µg/kg every 4 weeks ). If 6 patients at the DL-1 have 0-1 DLTs, DL-1 will be combined with 
SBRT and the study will move to phase IB. If 2 or more DLTs are seen at the DL-1, there will be 
no further attempts of combining M7824 with M9241 and neither the M7824 and M9241 in 
combination with SBRT phase IB or the phase II part will be carried out. The first safety run-in of 
M7824 in combination with M9241 might have a minimum of 6 and a maximum of 12 patients.
The safe dose of M7824 and M9241 will then be given in combination with a 5-day course of 
SBRT. Estimated during phase IA DL of M7824 and M9241 will be given to 6 patients. If there 
are 0-1 DLTs in the first 6 subjects, the dose of M7824 and M9241 will be used as the 
recommended phase 2 dose and the study will proceed to the phase II part. If there are ≥2 DLTs 
in the initial combination with SBRT, there will be a dose reduction of M9241 (if recommended 
dose was 16.8 µg/kg, M9241 will be reduced to 12 µg/kg, if the safe dose of M9241 when 
combined with M7824 in the phase IA part was 12.0 µg/kg, the dose will be reduced to 8.0µg/kg). 
If there are 0-1 DLTs in the first 6 subjects, this dose of M7824 and M9241 will be used as the 
recommended phase 2 dose and the study will proceed to the phase II part. If there are ≥2 DLTs 
in 6 patients treated with the reduced M7824 levels in combination with SBRT, no further attempts 
will be made to combine M7824 and M9241 with SBRT and the study will not proceed to the 
phase II part. The second safety run-in of M7824 and M9241 in combination with SBRT might 
have a minimum of 6 and a maximum of 12 patients.
Following determination of safe doses of M7824 and M9241 when combined with SBRT the study 
may proceed to the phase II part. Thus, a minimum of 12 and a maximum of 24 evaluable patients 
will be enrolled in the phase I cohorts.
Phase II:
The study will be conducted using a Simon two-stage phase 2 minimax design. The objective of 
the trial will be to determine whether this novel combination of M7824 and M9241 in combination 
with SBRT can be associated with a response rate (PR + CR; RECIST) that can rule out 10% 
(p0=0.10) in favor of an improved response rate of 30% (p1=0.30). Using alpha=0.10 (probability 
of accepting a poor agent) and beta=0.10 (probability of rejecting a good agent), initially 16 
evaluable patients will be enrolled into the phase II study, including up to 6 patients from the 
completed safety cohort Phase IB of M7824 and M9241 in combination with SBRT if they are 
completely eligible for the phase II portion of the trial. If 0 to 1 of 16 patients respond, then no 
further patients will be enrolled. If 2 or more of the first 16 evaluable patients enrolled have a 
response (PR or CR), then accrual will continue until a total of 25 evaluable patients have been 
enrolled. If 2 to 4 of the 25 has a clinical response, then this will be considered inadequate for 
further investigation of this regimen. If 5 or more of 25 (20%) respond, then this will warrant 
further investigation in a subsequent trial. Under the null hypothesis (10% response rate), the 
probability of early termination is 51.5%. 
Thus, with up to 24 participants in the phase I cohort and up to 25 evaluable participants in phase 
II, the trial may require up to 49 participants to be treated. This number may be reduced by up to 
6 patients if there are <2 DLTs in the second safety run-in of M7824 and M9241 in combination 
with SBRT and those patients are included in phase II. To allow for a small number of inevaluable 


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patients, the accrual ceiling will be set at 52 participants. With an anticipated accrual rate of 10 
patients per year, it is expected that the trial may complete accrual within 5 years.
10.3 POPULATIONS FOR ANALYSIS
Evaluable for overall response: all patients who receive at least one dose of M7824 and M9241 in 
combination with SBRT at the dose level determined to be safe in the safety run-in Phase IB of 
M7824 and M9241 in combination with SBRT will be included in the statistical analyses 
performed.
Evaluable for toxicity: All patients will be evaluable for toxicity from the time of their first 
treatment with M7824 and M9241 in combination with SBRT.
Evaluable for MTD: Subjects enrolled to the safety run-in portion of the study are evaluable. 
However, subjects who do not complete the DLT observation period for reasons other than a DLT 
will be replaced and not included in the evaluation.
10.4 STATISTICAL ANALYSES
10.4.1 General Approach
Patients who are in the safety evaluation will have the number of patients with a DLT determined. 
Patients who are in the efficacy evaluation and patients from the safety run-in administered the 
M7824 and M9241 in combination with SBRT dose used in the phase II part of the study will have 
the fraction of clinical responses determined.
10.4.2 Analysis of the primary endpoints
For the patients in the dose de-escalation portion, the safety and tolerability and the recommended 
phase 2 dose (RP2D) of M7824 and M9241 in combination with SBRT as neoadjuvant / 
perioperative treatment in subjects with pancreas cancer will be evaluated by reporting the number, 
severity, and duration of treatment-related AEs for the combination treatment of M7824 and 
M9241 administered in combination with a 5-day course of SBRT according to CTCAE v5.0 . The 
rate of completion of neoadjuvant SBRT courses when given with M7824 and M9241 will be 
reported as well using descriptive statistics.
Patients who are in the efficacy evaluation will have the fraction objective responses measured by 
RECIST1.1 determined by dividing the number of patients with an objective response by the 
number of evaluable patients who are treated at the MTD and reported along with two sided 80% 
and 95% confidence intervals.
10.4.3 Analysis of the secondary endpoints
The secondary endpoints will be analyzed as follows:

Overall survival in patients after completion of SBRT in combination with M9241 and 
M7824 and Progression-Free Survival (PFS) of all patients and PFS of patients who did 
not undergo surgical resection (expressed as median PFS). Overall survival and PFS will 
be determined in all patients treated at the MTD of M7824 and M9241 in combination with 
SBRT, as well as patients who did not undergo surgery, using Kaplan-Meier curves.

Fraction of patients with LAPC who are able to undergo surgical resection after M7824 
and M9241 in combination with SBRT treatment. This will be reported along with a 95% 
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
Time-to-recurrence in patients who underwent surgical resection will be measured as time 
from surgical resection to disease recurrence (expressed in months). Time-to-recurrence in 
patients will be calculated via Kaplan-Meier curves. Any comparisons with published 
results will be interpreted as being exploratory. 

Rate of complete pathologic response will be measured as fraction of patients who had a 
complete pathologic response of all patients who underwent surgery. This will be reported 
along with a 95% confidence interval.
10.4.4 Safety analyses
Patients in the phase I portion of the trial will be assessed for toxicity by reporting the grades of 
toxicity and the type of toxicity observed for all patients. Patients will be enrolled and evaluated 
in the phase I cohorts of the trial as described in the phase I sample size determination section. 
Patients will continue to be enrolled onto the phase II cohort if the cumulative fraction of patients 
with greater or equal grade 3 DLT is less than 1/3.
10.4.5 Baseline descriptive statistics
Limited demographic and clinical characteristics of all patients will be reported, for both the phase 
I and the phase II cohorts.
10.4.6 Planned interim analyses:
Toxicity will be assessed within each group of 6 patients accrued in the phase I cohorts M7824 in 
combination with M9241, and M7824 and M9241 in combination with SBRT. The fraction of 
patients who respond in the phase IB part who received M7824 and M9241 in combination with 
SBRT will be included into the efficacy assessment of the phase II cohort, as indicated in the phase 
II sample size determination section. 
10.4.7 Exploratory analyses
The following are the exploratory objectives, along with the method of analysis of each:

To determine M7824 PKs. This will be done using descriptive measures only.

To determine ADA profile of M7824 in combination with M9241. This will be done using 
descriptive measures only.

To evaluate serum cytokines and tumor necrosis factor (TNF) levels pre-treatment and on-
treatment. These measures will be evaluated using descriptive statistics. Comparisons 
between pre-treatment and on-treatment levels may be done using a paired test such as a 
Wilcoxon signed rank test.

To correlate the tumoral immune infiltrate via IHC with clinical outcome, the levels will 
be compared between responders and non-responders using an exact Wilcoxon rank sum 
test. 

To evaluate impact of genomic profile of advanced pancreatic cancers on clinical response 
to M7824 and M9241 in combination with SBRT. The prevalence of common somatic 
mutations identified within the 50-cancer gene panel (Molecular Pathology; Dr. M. 
Raffeld; for example, KRAS, TP53, SMAD/TGBR2, CDKN2A) obtained from each 
patient will be compared between responders and non-responders. This will be done using 


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either a Fisher’s exact test, Cochran-Armitage trend test, or exact Wilcoxon rank sum test 
depending on the distributions of values. 

To correlate circulating free tumor DNA (ctDNA) levels with clinical course of pancreatic 
cancer patients treated with M7824 and M9241 in combination with SBRT. The levels will 
be compared between responders and non-responders using an exact Wilcoxon rank sum 
test. 

To measure subjective Health-related Quality of Life (HRQoL) affecting disease-specific 
symptoms and treatment-related concerns pre-treatment and on-study and compare 
HRQoL scores with historical controls of other QoL interventions in advanced pancreas 
cancer patients. Health-related Quality of Life (HRQoL) scores measuring patient-reported 
disease-specific symptoms and treatment-related concerns will be compared between 
responders and non-responders using an exact Wilcoxon rank sum test. The results will 
also be compared informally with historical controls of other QoL interventions in 
advanced pancreas cancer patients, using descriptive methods.

To evaluate the impact of M7824 in combination with M9241 on tumoral perfusion 
measured by perfusion-weight Dynamic Contrast-enhanced (DCE) Magnetic Resonance 
Imaging (DCE-MRI). This will be done using descriptive statistics.
11 COLLABORATIVE AGREEMENT
11.1 COOPERATIVE RESEARCH AND DEVELOPMENT AGREEMENT (CRADA)
A CRADA (02666) is in place with EMD Serono for the supply of M7824 and M9241.
12 HUMAN SUBJECTS PROTECTIONS 
12.1 RATIONALE FOR SUBJECT SELECTION
No individual who meets the criteria for eligibility will be excluded from participation based on 
their race, ethnicity, gender, or socioeconomic status. Particular attention will be made to acquire a 
broad and diversified population.
12.2 PARTICIPATION OF CHILDREN
Individuals under the age of 18 will not be eligible to participate in this study because they are 
unlikely to have pancreatic cancer, and because of unknown toxicities in pediatric patients.
12.3 PARTICIPATION OF SUBJECTS UNABLE TO GIVE CONSENT
Adults unable to give consent are excluded from enrolling in the protocol. However, re-consent may 
be necessary and there is a possibility, though unlikely, that subjects could become decisionally 
impaired. For this reason and because there is a prospect of direct benefit from research participation 
(Section 12.4.2), all subjects will be offered the opportunity to direct their wishes for research and 
care to a surrogate, 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 a LAR, as needed.
Please see section 12.5.1 for consent procedure.


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12.4 RISK/BENEFIT ASSESSMENT FOR ALL PARTICIPANTS
12.4.1 Known Potential Risks 
The primary risk to patients participating in this research study is from the toxicity of M7824 and 
M9241, or from both drugs in combination with SBRT. M7824 and M9241 are investigational 
agents designed to enhance antitumor efficacy of standard treatment, standard CRT in this protocol. 
The protocol provides for detailed and careful monitoring of all patients to assess for toxicity.
12.4.1.1 Risk of Rapid Progression
Three large studies of bintrafusp alfa were recently stopped when the drug manufacturer reviewed 
data that suggested that the studies would not be likely to prove the study treatment better than 
standard treatments. This data also suggested that there may be a portion of patients that have either 
no benefit from bintrafusp alfa, or that bintrafusp alfa will make the tumor grow faster. This has 
been described with other immunotherapy approaches also with studies suggesting this happens in 
about 15% of cases.
12.4.1.2 Risks of Blood Collection 
Risks of blood draws include pain and bruising in the area where the needle is placed, 
lightheadedness, and rarely, fainting and infection. When large amounts of blood are collected, low 
red blood cell count (anemia) can develop.
12.4.1.3 Risks of EKG
Risks include some minor skin irritation from the electrodes
12.4.1.4 Risks of exposure to ionizing radiation 
Subjects in Cohort 1 in this study may be exposed to radiation from up to 7 CT scans per year for 
disease assessment (approximately 7.7 rem per year). This amount is more than would be expected 
from everyday background radiation. Being exposed to excess radiation can increase the risk of 
cancer. The risk of getting cancer from the radiation exposure in this study is 0.8 out of 100 (0.8%) 
and of getting a fatal cancer is 0.4 out of 100 (0.4%).
During a year in this research study subjects in Cohort 2 and 3 will be exposed to 25 Gy (5 Gy X 5 
days) of radiation from stereotactic body radiation therapy or SBRT. These subjects will also receive 
a much smaller amount of radiation from up to 7 CT scans for disease assessment.  The amount of 
radiation from these scans adds minimal additional risk to the higher radiation doses received in the 
course of treatment.  This radiation is currently under review by the NIH Radiation Safety 
Committee.
12.4.1.5 Risks of CT Scans
In addition to the radiation risks discussed above, CT scans may include the risks of an allergic 
reaction to the contrast. Participants might experience hives, itching, headache, difficulty breathing, 
increased heartrate and swelling
12.4.1.6 Questionnaires risk
Questionnaires may contain questions that are sensitive in nature. The patients are asked to only 
answer questions they are comfortable with.
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There are no risks of urine collection.
12.4.1.8 Risks of MRIs (DCE-MRI)
This study involves MRIs performed for research purposes. The main risk is allergic reaction to IV 
administered contrast agent. This risk is in the range of 1 to 1.5 %. There is also risk of 
claustrophobia during MRI and feeling uncomfortable because of loudness of the scanner.
12.4.1.9 Risk of losing data 
This includes the risk that data obtained during this study can be released to members of the public, 
insurers, employers, or law enforcement agencies. Although there are no plans to release results to 
the patients, family members or health care providers, this risk will be included in the informed 
consent document
12.4.1.10
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.
12.4.1.11
Non-Physical Risks of Genetic Research
Risk of receiving unwanted information
Anxiety and stress may arise as a result of the anticipation that unwanted information regarding 
disease related DNA sequencing or disease tendencies, or misattributed paternity. Patients will be 
clearly informed that the data related to DNA sequencing and genetic analysis is coded, 
investigational and will not be shared with patients, family members or health care providers.
Risk related to possibility that information may be released
This includes the risk that data related to genotype, DNA sequencing or risk for disease tendency or 
trait can be released to members of the public, insurers, employers, or law enforcement agencies. 
Although there are no plans to release results to the patients, family members or health care 
providers, this risk will be included in the informed consent document.
12.4.2 Known Potential Benefits
The potential benefit to a patient 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
For patients with locally advanced pancreas cancer, median overall survival is in the range of 9 
months. It is possible that treatment on this protocol may reduce tumor burden, improve resection 
rates, increase survival, or lessen symptoms caused by the cancer. 
Potential adverse reactions attributable to the administration of the study drugs utilized in this trial 
are discussed in sections 1.2.5.1, 1.2.6.1, 1.2.7. All care will be taken to minimize side effects, but 
they can be unpredictable in nature and severity
A number of clinically appropriate strategies to minimize risks to patients have been built into the 
protocol through the means of inclusion/exclusion criteria, monitoring strategies, and management 
guidelines. Overall, the potential benefit of the study therapy in subjects with pancreas cancer 
outweigh the risks associated with study treatment.


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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) (e.g., legally authorized representative [LAR] for reconsent 
purposes if participant is an adult unable to consent) 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.
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. 
Manual (non-electronic) signature on electronic document:
When a manual signature on an electronic document is used for the documentation of consent 
at the NIH Clinical Center, this study will use the following to obtain the required signatures:

Adobe platform (which is not 21 CFR Part 11 compliant); or,  

iMedConsent platform (which is 21 CFR Part 11 compliant). 
During the consent process, participants and investigators will view individual copies of the 
approved consent document on screens at their respective locations if remote consent); the 
same screen may be used when in the same location but is not required.
Both the investigator and the 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 here.
12.5.1 Consent Process for Adults Who Lack Capacity to Consent to Research Participation
For participants addressed in section 12.3, an LAR will be identified consistent with Policy 403 and 
informed consent obtained from the LAR, as described in Section 12.5.
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 


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provided by the suspending or terminating party to study participants, associate investigators, 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
Study may resume once concerns about safety, protocol compliance, and data quality are addressed, 
and satisfy the sponsor, IRB and as applicable, Food and Drug Administration (FDA).
13.2 QUALITY ASSURANCE AND QUALITY CONTROL
The clinical site will perform internal quality management of study conduct, data and biological 
specimen collection, documentation and completion. An individualized quality management plan 
will be developed to describe a site’s quality management.
Quality control (QC) procedures will be implemented beginning with the data entry system and data 
QC checks that will be run on the database will be generated. Any missing data or data anomalies 
will be communicated to the site(s) for clarification/resolution.
Following written Standard Operating Procedures (SOPs), the monitors will verify that the clinical 
trial is conducted and data are generated and biological specimens are collected, documented 
(recorded), and reported in compliance with the protocol, International Conference 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 
regulatory authorities.
13.3 CONFLICT OF INTEREST POLICY
The independence of this study from any actual or perceived influence, such as by the 
pharmaceutical industry, is critical. Therefore, any actual conflict of interest of persons who have a 
role in the design, conduct, analysis, publication, or any aspect of this trial will be disclosed and 
managed. Furthermore, persons who have a perceived conflict of interest will be required to have 
such conflicts managed in a way that is appropriate to their participation in the design and conduct 
of this trial. The study leadership in conjunction with the NCI has established policies and 
procedures for all study group members to disclose all conflicts of interest and will establish a 
mechanism for the management of all reported dualities of interest.


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13.4 CONFIDENTIALITY AND PRIVACY
Participant confidentiality and privacy is strictly held in trust by the participating investigators, their 
staff, and the sponsor. 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 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 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 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 privacy to participants.
14 PHARMACEUTICAL AND INVESTIGATIONAL DEVICE INFORMATION
14.1 M7824 (146972) 
14.1.1 Acquisition and Accountability
Investigational M7824 is manufactured and supplied for the trial by EMD Serono Research and 
Development Institute. Drug will be delivered directly to the NIH Pharmacy. Individual IV bags 
will be prepared for each study participant according to assigned dose by NIH Pharmacy personnel. 
IV bags will be delivered from NIH Pharmacy to patient unit where drug will be infused to the 
patient.
14.1.2 Administration.
Please, see section 3.3.1


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14.1.3 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. 
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
14.1.4 Storage and Stability:
Store intact vials, both lyophilized and liquid formulations, in the refrigerator (2°C – 8°C). Do NOT 
freeze the vials. The vials must be stored in the original packaging and protected from light until 
use.
Store reconstituted lyophilized vials and diluted infusion solutions at room temperature.
Reconstituted lyophilized vials, if not used immediately, are stable at room temperature for up to 24 
hours.
When diluted with 0.9% Sodium Chloride Injection, USP to a concentration of 0.16 mg/mL to 9.6 
mg/mL, chemical and physical in-use stability has been demonstrated for 72 hours when stored at 
room temperature.
14.1.1 Toxicity
Please refer to section 1.2.5 for details.
14.2
 M9241 (146972)
14.2.1 Acquisition and Accountability
Investigational M9241 is manufactured and supplied for the trial by EMD Serono Research and 
Development Institute. Drug will be delivered directly to the NIH Pharmacy. Individual syringes 
will be prepared for each study participant according to assigned dose by NIH Pharmacy personnel. 
Syringes will be delivered from NIH Pharmacy to patient unit where drug will be infused to the 
patient.
14.2.1 Administration.
Please, see section 3.3.2
14.2.2 Formulation and Preparation
M9241 is supplied as 1.5 mg/mL in 2 mL clear type 1 glass vials. Each vial contains 1 mL of the 
sterile M9241 solution.
14.2.3 Storage and Stability:
Store the intact vials in the refrigerator (2ºC – 8ºC), in the original packaging.
Stored the syringes prepared for SC injection at controlled room temperature (15ºC – 25ºC).


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M9241 may be administered undiluted or doses may be diluted with 0.9% Sodium Chloride 
Injection, USP to a concentration =/> 0.05 mg/mL (50 mcg/mL).
Although chemical stability has been demonstrated for 24 hours at 25°C for syringes prepared as 
above, the manufacturer recommends immediate use and pharmacy will assign a 4-hour expiration 
to prepared syringes.
14.2.1 Toxicity
Please refer to section 1.2.6.1 for details. 
14.3 STEREOTACTIC BODY RADIATION THERAPY  
The radiation device is an FDA cleared commercial device located in the NIH Clinical Center. The 
device will be used/investigated in accordance with labeling and therefore will be IDE exempt under 
812.2 (c) – category 1.
14.3.1 Toxicity
Please refer to Section 3.4.3 for details.


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15 REFERENCES 
1.
Siegel, R.L., K.D. Miller, and A. Jemal, Cancer statistics, 2016. CA Cancer J Clin, 2016. 
66(1): p. 7-30.
2.
Rahib, L., et al., Projecting cancer incidence and deaths to 2030: the unexpected burden 
of thyroid, liver, and pancreas cancers in the United States. Cancer Res, 2014. 74(11): p. 
2913-21.
3.
Ma, J. and A. Jemal, The rise and fall of cancer mortality in the USA: why does 
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16 APENDICES
16.1 APPENDIX A: DIAGNOSTIC CRITERIA OF BORDERLINE RESECTABLE PANCREAS CANCER
Criteria
Year
SMV/PV
MDACC
2006
•
Short-segment occlusiona
AHPBA/SSO/SSAT
2009
•
Tumor abutment
•
Encasement, but without encasement of the nearby arteries
•
Short segment venous occlusion resulting from either tumor thrombus 
or encasementa
Intergroup
(Alliance)
2013
•
Interface between tumor and vessel ≥180°
•
Occlusiona
ISGPS
2014
•
Distortion or narrowing
•
Occlusiona
NCCN 2017
2017
•
Contact >180°
•
Contact ≤180° with contour irregularity of the vein or thrombosis of 
the veina
SMV – superior mesenteric, PV- portal vein.
a With suitable vessel proximal and distal.
Artery criteria.


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Criteria
Year
GDA
HA
CA
SMA
MDACC
2006
•
Short-segment 
encasement/abutment of CHA
•
Abutment ≤180°
AHPBA/SSO/SSAT 2009
•
Encasement 
up to the 
HA
•
Short segment encasement or 
direct abutment
•
No extension
•
Abutment ≤180°
Intergroup 
(Alliance)
2013
•
Reconstructable, short-segment 
interface between tumor and 
vessel of any degree
•
Interface between tumor 
and vessel < 180°
•
Interface 
between tumor 
and 
vessel < 180°
ISGPS 
2014
•
Encasement 
up to the 
HA
•
Short segment encasement or 
direct abutment
•
No extension
•
Abutment ≤180°
NCCN 
2017
Head/uncinate process;
•
Contact with CHA without 
extension to HA bifurcation
•
Contact with variant arterial 
anatomy (ex: accessory/replaced 
RHA, replaced CHA, the origin of 
replaced or accessory artery)
Head/uncinate process;
•
No extension
Body/tail:
•
Contact with the CA of 
≤180°
•
Contact with the CA of 
>180° without 
involvement of the aorta 
and with intact and 
uninvolved GDA
•
Contact ≤180°
GDA, gastroduodenal artery; HA, hepatic artery; CA, celiac axis; SMA, superior mesenteric artery; CHA, common hepatic artery; RHA, right 
hepatic artery


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16.2 APPENDIX B: M9241 MULTIPLE DOSE PK PROFILE IN HUMANS AND M9241-INDUCED ALTERATIONS IN PLASMA CYTOKINE 
PROFILES AND PERIPHERAL BLOOD IMMUNE CELL PHENOTYPE.
M9241 and plasma cytokine levels are shown from human subjects who received ≥2 doses of 16.8µg/kg M9241 by subcutaneous 
injection. Values for immune cell subsets are the frequency of the subset out of all PBMC shown as median (IQR). Graphs 
depicting three of these subsets. Changes of the immune chekcpoints TIM3 and PD-1 on NK between two administrations are 
shown.


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PK
Timepoint (Days)
PK (ng/mL)
0
50
100
150
37-DL8
38-DL8
39-DL8
40-DL8
41-DL8
42-DL8
8
15
C2
8
C3
22
15
22
C1
IL-10
Timepoint (Days)
IL-10 (pg/mL)
0
5
10
15
20
25
37-DL8
38-DL8
39-DL8
40-DL8
41-DL8
42-DL8
8
15
C2
8
C3
22
15
22
C1
IFN
Timepoint (Days)
IFN (pg/mL)
0
1000
2000
3000
4000
37-DL8
38-DL8
39-DL8
40-DL8
41-DL8
42-DL8
8
15
C2
8
C3
22
15
22
C1
IL-8
Timepoint (Days)
IL-8 (pg/mL)
0
100
200
300
37-DL8
38-DL8
39-DL8
40-DL8
41-DL8
42-DL8
8
15
C2
8
C3
22
15
22
C1
IL-12p70
Timepoint (Days)
IL-12p70 (pg/mL)
0
200
400
600
800
1000
37-DL8
38-DL8
39-DL8
40-DL8
41-DL8
42-DL8
8
15
C2
8
C3
22
15
22
C1
TNF
Timepoint (Days)
TNF (pg/mL)
0
10
20
30
37-DL8
38-DL8
39-DL8
40-DL8
41-DL8
42-DL8
8
15
C2
8
C3
22
15
22
C1
DL8: 16.8 mcg/kg


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Immune cell subset
Day 1
(Pre treatment)
Day 8
(Post 1 cycle)
Direction of
the change
P-value
Adjusted
P-value
CD4-EMRA-PD-L1+
0.06 (0.04-0.09) 0.03 (0.01-0.05)
Down
0.002
0.038
NK-Tim3+
0.07 (0.02-0.24) 0.49 (0.08-1.42)
Up
0.0059
0.047
NK-Mature Tim3+
0.07 (0.03-0.21) 0.93 (0.25-1.53)
Up
0.002
0.018
NKT-PD1+
0.08 (0.03-0.13) 0.22 (0.08-0.35)
Up
0.002
0.008
pDC
0.2 (0.1-0.4)
0.1 (0.1-0.2)
Down
0.0039
0.02
D1
D8
0.0
0.5
1.0
1.5
2.0
2.5
NK-Tim3+
% of PBMCs
D1
D8
0.0
0.2
0.4
0.6
0.8
NKT-PD1+
% of PBMCs
D1
D8
0.0
0.2
0.4
0.6
0.8
1.0
pDC
% of PBMCs


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16.3 APPENDIX C: FACT-HEP VERSION 4


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16.4 APPENDIX D:PERFORMANCE STATUS CRITERIA
ECOG Performance Status Scale
Grade
Descriptions
0
Normal activity. Fully active, able to carry on all pre-disease 
performance without restriction.
1
Symptoms, but ambulatory. Restricted in physically strenuous activity, 
but ambulatory and able to carry out work of a light or sedentary nature 
(e.g., light housework, office work).
2
In bed <50% of the time. Ambulatory and capable of all self-care, but 
unable to carry out any work activities. Up and about more than 50% 
of waking hours.
3
In bed >50% of the time. Capable of only limited self-care, confined to 
bed or chair more than 50% of waking hours.
4
100% bedridden. Completely disabled. Cannot carry on any self-care. 
Totally confined to bed or chair.
5
Dead.


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16.5 APPENDIX E:MODIFIED IMMUNE-RELATED RESPONSE CRITERIA (IRRECIST)
This new classification is based on the recent learning from clinical studies with cancer 
immunotherapies that even if some new lesions appear at the beginning of a treatment or if the 
total tumor burden does not increase substantially, tumor regressions or stabilizations might still 
occur later. The irRC were created using bi-dimensional measurements (as previously widely used 
in the World Health Organization criteria). For this trial, the concepts of the irRC are combined 
with RECIST 1.1 to come up with the modified irRC. 
For modified irRC, only target and measurable lesions are taken into account. In contrast to the 
RECIST 1.1 criteria, the modified irRC criteria (a) require confirmation of both progression and 
response by imaging at 6 weeks after initial imaging and (b) do not necessarily score the 
appearance of new lesions as progressive disease if the sum of lesion diameters of target lesions 
(minimum of 10 mm per lesion, maximum of 5 target lesions, maximum of 2 per organ) and 
measurable new lesions does not increase by ≥ 20%. 
The same method of assessment and the same technique should be used to characterize each 
identified and reported target lesion(s) at baseline, during the trial, and at the end of trial visit. All 
measurements should be recorded in metric notation. The modified irRC based on RECIST 1.1 are 
displayed below. 


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Overall Responses Derived from Changes in Index, Non-Index, and New Lesions

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: 11/24/2021
Page 1 of 22
                                                                   CC ICF template v. 09.27.19
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
PRINCIPAL INVESTIGATOR:
Udo Rudloff, MD, PhD.
STUDY TITLE:
A Phase I/II Study of The Immune Checkpoint Inhibitor 
M7824 and the Immunocytokine M9241 in Combination 
with Stereotactic Body Radiation Therapy (SBRT) in 
Adults with Advanced Pancreas Cancer.
STUDY SITE:
NIH Clinical Center
Cohort: 
Phase 1A - Affected patient  
Consent Version:
11/24/2021 
WHO DO YOU CONTACT ABOUT THIS STUDY? 
Udo Rudloff, MD, PhD, by phone at 240-760-6238 or email rudloffu@mail.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 make 
a decision 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 pancreatic cancer and your 
doctor has found that you are not a candidate for curative surgery.
The purpose of this study is to find a safe combination dose of M7824, M9241 and radiation 
(SBRT) and to see if this dose will cause your tumors to shrink.
The study is divided into 3 parts.  In phase 1A, we will try to find a safe dose combination for 
M7824 and M9241.  In phase 1B, we will try to find a safe dose combination for M7824, M9241 
and radiation (SBRT). In phase 2, we will determine if the dose found in phase 1B will cause 
your tumors to shrink. You will participate in phase 1A of the study and will not receive 
radiation. 
The use of M7824 and M9241 in this study is considered investigational which means these 
drugs have not been approved by the U.S. Food and Drug Administration (FDA) to treat cancer. 
However, the FDA has given us permission to use these drugs in this study. 
M7824 is a drug that blocks pathways that cancer cells use to prevent your immune system from 
fighting your cancer.
M9241 is designed to trigger your immune system to fight your cancer.
IRB NUMBER: 20C0074
IRB APPROVAL DATE: 02/08/2022


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 11/24/2021
Page 2 of 22
                                                                   CC ICF template v. 09.27.19
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
Although M7824 and M9241 have both been studied independently in clinical trials, there is no 
clinical data for the combination M7824 and M9241.
Radiation therapy is sometimes used with drugs to treat symptoms caused by the tumor. We also 
believe it helps prevent tumors from evading your immune system.
There are other drugs that may be used to treat your disease, and these can be given by your 
regular cancer doctor, if you are not in this study. For example: chemotherapy that is known as 
platinum-based (such as cisplatin) or taxane based (such as paclitaxel, abraxane or docetaxel are 
some possible treatments that you could receive. The treatment being given in this study and the 
side effects are different than if you were to receive standard care. For example: standard 
platinum-/taxane-based chemotherapies are known to cause changes in blood counts, nausea, 
vomiting, fatigue, and neuropathy (tingling and/or numbness most often in the fingers and toes). 
These new drugs (M7824 and M9241), belong to a group of drugs called immune checkpoint 
inhibitors and although they may cause similar side effects, they have also been found to cause 
skin problems (such as rash), problems with the immune system, and bleeding.
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.
If you decide to join this study, here are some of the most important things that you should know 
that will happen:

First, we will perform tests to find out if you fit the study requirements. We will do 
standard blood tests and scans to test your health and see the status of your disease.

You will have study treatment with just the combination of M7824 and M9241 (group 
1A)).

M7824 is given as an IV (intravenous) infusion. A small plastic tube is put into a vein in 
your arm and the medication is given once every two weeks. It could also be given 
through a central catheter if you already have one installed.

M9241 is an injection given under the skin. This is similar to receiving a vaccine shot 
and is given every four weeks.

You will not generally need to stay in the hospital for this study.

We will need to see you at the Clinical Center every 2 weeks while you are receiving 
study treatment. Study treatment will last for as long as you are tolerating and benefiting 
from the study drugs. Each visit should last no more than 8 hours. At your visits you will 
have clinical, laboratory and imaging tests to see how you are doing.  We will ask you 
to complete questionnaires (if you read English) and collect required blood samples, 
tissue (if you have surgery while on study) and scans from you for both clinical and 
research purposes.

We hope that during the study treatment your tumors shrink, and you become a candidate 
for curative surgery. In this case we will stop study treatment and you will have surgery 
at your home institution or with enrollment to another clinical trial here at the Clinical 
IRB NUMBER: 20C0074
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PATIENT IDENTIFICATION
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Center. If your cancer is removed completely, you will not get any further study therapy. 
If your cancer is removed only partially, you can continue study therapy after you 
recover from the surgery.

As described above and later in more detail in this consent form, you may have side 
effects if you take part in this study. Some can be mild or very serious, temporary, long-
lasting, or permanent, and may include death. You will be seen regularly during the 
study. You will have clinical, laboratory, and imaging tests to see how you are doing and 
see how your disease is responding. 

It is possible that the low red blood cell counts and/or bleeding may be so severe that 
you require a blood transfusion.

After the study treatment has ended, we would like to see you in the Clinical Center 
approximately one week and one month later to check on your health. After that we are 
planning to contact you by phone or e-mail to learn about your health status, and to see 
how you are doing, for the rest of your life or until the study is stopped. If you stop study 
treatment for reasons other than worsening of your disease, we will continue to invite 
you for imaging studies approximately every 12 weeks until your disease gets worse. 
You can have these studies done locally and send us the results.

Some drugs and vaccines are not allowed during this study. Please, let you doctor know 
about all medicines you are taking or planning to take.
This study may benefit you by shrinking of your tumor or lessening of your symptoms, such as 
pain, that are caused by the cancer. Even if you do not benefit from this study, the results from 
our research will help others in the future.
You are free to stop taking part 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 more about the research study. This information 
should be considered before you make your choice. Members of the study team will talk with you 
about the information described in this document. Some people have personal, religious, or ethical 
beliefs that may limit the kinds of medical or research treatments they would want to receive (such 
as blood transfusions). Take the time needed 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 to be 
in this study, you are being asked to give permission for this person as their decision-maker. The 
term “you” refers to you as the decision-maker and/or the individual being asked to participate in 
this research, throughout the remainder of this document. 
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 
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IRB APPROVAL DATE: 02/08/2022


PATIENT IDENTIFICATION
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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?
This is a research study. The purpose of this study is to find a safe combination dose of M7824, 
M9241 and radiation (SBRT) and see if this dose will cause your tumors to shrink. 
The study is divided into 3 parts. In phase 1A, we will try to find a safe dose combination for 
M7824 and M9241.  In phase 1B, we will try to find a safe dose combination for M7824, M9241 
and radiation (SBRT). In phase 2, we will determine if the dose found in phase 1B will cause your 
tumors to shrink. 
You will participate in phase 1A of the study and will not receive radiation. 
We are asking you to join this research study because you have pancreatic cancer and your doctor 
has found that you are not a candidate for curative surgery.
The use of M7824 and M9241 in this study is considered investigational which means these drugs 
have not been approved by the U.S. Food and Drug Administration (FDA) to treat cancer. 
However, the FDA has given us permission to use these drugs in this study. 
M7824 is a drug that blocks pathways that cancer cells use to prevent your immune system from 
fighting your cancer.
M9241 is designed to trigger your immune system to fight your cancer.
Radiation therapy is sometimes used with drugs to treat symptoms caused by the tumor and may 
also help prevent tumors from evading your immune system.
WHAT WILL HAPPEN DURING THE STUDY?
You will get study treatment in cycles (1 Cycle = 28 days).
You will get a treatment combination of M7824 + M9241.
M7824 will be given to you through an IV (intravenous catheter, a small plastic tube that is put 
into a vein, usually in your arm) once every 2 weeks (on days 1 and 15 of every cycle). You will 
have additional infusion on Day -14, that is, two weeks before the start of cycle 1.
M9241 is an injection given under the skin. This is similar to receiving a vaccine shot and will be 
done once every 4 weeks (on day 1 of every cycle).
If your doctor is convinced that you have unacceptable side effects caused by one of study 
treatment drugs, this drug will be stopped, and you may continue study treatment with the other 
drug if your study doctor finds that it is in your interest.  
If you have serious side effects caused by the study treatment, treatment can be paused and 
restarted if you feel better and your doctor thinks it is in your best interest. The dose of M9241 
may be reduced at that time.
Study treatment will continue until you have unacceptable side effects (both drugs), or you are no 
longer benefiting from the study therapy.
IRB NUMBER: 20C0074
IRB APPROVAL DATE: 02/08/2022


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
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If during the study treatment your tumors shrink, and you become a candidate for curative surgery, 
we will stop study treatment, so you can have surgery. This surgery will be done at your home 
institution or with enrollment to another clinical trial here at the Clinical Center. If your cancer is 
removed completely, you will not get this study treatment anymore. If your cancer is removed only 
partially, you can continue this study treatment after you recover from the surgery. Before you 
continue study treatment, we will do standard clinical exams and tests to make sure you are still 
eligible for this study. 
Study treatment and all study related procedures will be done during outpatient visits without 
planned hospitalization.
Some drugs and vaccines are not allowed during this study.
Please, let your study doctor know about all medicines you are taking or planning to take. 
Do not start any new drugs, herbal remedies, or dietary supplements before talking to your 
study doctor. 
Before you begin the study
Before you begin this study, you will need to have standard clinical exams and tests to make sure 
you are eligible for this study. The exams and tests are part of regular cancer care. These tests will 
be done under a separate protocol. 
You will also be asked to provide documentation to confirm your diagnosis. If documentation is 
not available, we will perform a biopsy (collect a sample of your tumor) to confirm your diagnosis.
If study treatment does not start within 28 days after enrollment to this study, some tests may need 
to be repeated.
During the study
Ongoing procedures before study treatment and on the first day of each cycle: 

Physical examination, including weight, vital signs.

Review of your medications and your ability to perform your normal activities.

Discussion of any symptoms you might be having

Routine blood tests to find out if you are anemic, have low blood counts, and if your liver, 
kidneys, thyroid, clotting system and other organs are working well

Pregnancy test if you are a woman who can have children

Blood test for tumor markers

Routine urine test
Additional Procedures:

Physical examination, including weight, vital signs, discussion of your symptoms and 
assessment of your ability to perform your normal activities on day 15 of each cycle

Electrocardiogram (EKG – a record of your heartbeat) to evaluate your heart before study 
treatment, on days 1 and 15 of cycle 1.
IRB NUMBER: 20C0074
IRB APPROVAL DATE: 02/08/2022


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
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
Routine blood tests to find out if you are anemic, have low blood counts, and if your liver, 
kidneys, and other organs are working well on Day 15 of each cycle .
Imaging assessments - a CT scans (a series of x-ray images taken of parts of your body) of 
chest, abdomen and pelvis before study treatment, approximately 10 weeks after beginning 
of the study treatment and every 8 weeks after that.
When you are finished taking the drugs (study treatment)
Approximately 7 and 28 days after you have finished taking the study drug, you will be asked to 
return to the Clinical Center for safety follow up visits. At these visits, you will be asked questions 
about your health, get a physical exam and undergo blood tests for clinical and research purposes. 
An EKG will also be performed.
If you have been taken off study treatment for reasons other than worsening of your disease, you 
will continue to have imaging studies approximately every 12 weeks until worsening of your 
disease. You can have these studies at home institution and send us results.
If you are unable to return for these visits, we will obtain the information from you by telephone 
or e-mail.
Once you stop coming to Clinical Center for safety visits and your scans, we will call or e-mail 
you every 3 months for first year and every 6 months after that to ask you about your general well-
being.
Blood draws 
You will have blood drawn during the study. These samples will be drawn to monitor your health 
during the study participation at every visit to the Clinical Center (about 3 tablespoons at each 
visit) and for research purposes, as described in the next sections (about 2 tablespoons at visits to 
occur once a month). If you participate in Group 1A, you will have additional blood drawn (less 
than 1 tablespoon) before treatment, on days -14 and day 15 of cycle 1 as explained in the next 
section.
Additional research testing
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 and perform tests 
for purposes of research only. 
The samples will be used to check drugs levels and stability in the blood and to look at the effects 
of the therapy on the immune system and the tumor:

Blood samples to study:
(Drug levels in your blood on days -14 and day 1 of cycle 1 collected before study 
treatment and approximately 1 hour after study treatment, and on day 15 of cycle 1 
before study treatment. 
Stability of drugs and how immune system is affected by the study treatment before 
treatment and on day 1 of every cycle.
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PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
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
We will ask you to provide samples of your tumors from previous surgeries or biopsies if 
available and from surgery while on study if you have the surgery. Samples will be used to 
study your tumor genes and effects of therapy on the tumor. 
Tumor and blood samples collected for research purposes on this study may be used to 
look for specific changes in the DNA in tumors that could be used to develop new ways of 
diagnosing and treating cancer. 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. Normal tissue contains the DNA (instructions) that you were born with, 
DNA in tumor cells has changed – or mutated – and we think that change in the DNA is 
what causes tumors to form and to grow. 
To look at your DNA, we may use do what is called “DNA sequencing.” This is where we 
will do special tests in the lab to look at the sequence, or order, of how your DNA or RNA 
are put together. This is what makes you unique. 
To determine which parts of the DNA have mutated, we will compare the DNA in your 
tumor cells to DNA from normal cells. We will then analyze the results from similar tumors 
to see if there are any changes in the DNA that are common to a particular type of tumor.
However, you should know that the analyses that we perform in our laboratory are for 
research purposes only; they are not nearly as sensitive as the tests that are performed in a 
laboratory that is certified to perform genetic testing or testing for routine clinical care. For 
these reasons, we will not give you the results of the research tests done on your research 
samples in most cases. There may be exceptions to what we share with you and this is 
described later in this consent form in the section for Return of research results.

Magnetic Resonance Imaging (MRI) to evaluate how well the drugs circulate in your tumor 
before start of study treatment, on day 1 of cycles 1 and 3. 
You will be asked to complete questionnaires to determine you general well-being and function - 
before start of study treatment on cycles 2, 4, every 12 weeks after that. It will take you about 20 
minutes and will only be done if you can complete the surveys in English.
HOW LONG WILL THE STUDY TAKE?
You will come to the NIH Clinical Center to get study treatment and check status of your health 
every two weeks until your disease gets worse or you have unacceptable side effects at which time 
we will stop study treatment.
Visits will range from 4-8 hours in length.
After stopping study treatment, we would like to see you in the NIH Clinical Center one week and 
one month later and follow you after that for the rest of your life by telephone or e-mail. 
If you stop study treatment for reasons other than worsening of your disease, we would like to 
invite you for imaging studies approximately every 12 weeks until worsening of your disease.
HOW MANY PEOPLE WILL PARTICIPATE IN THIS STUDY?
We plan to have up to 15 people take part in the first phase of this study.
IRB NUMBER: 20C0074
IRB APPROVAL DATE: 02/08/2022


PATIENT IDENTIFICATION
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WHAT ARE THE RISKS AND DISCOMFORTS OF BEING IN THE STUDY?
The drug used in this study may affect how different parts of your body work such as your liver, 
kidneys, heart, and blood. The study doctor will be testing your blood and will let you know if 
changes occur that may affect your health.
Here are important points about side effects:

The study doctors do not know who will or will not have side effects.

Some side effects may go away soon, some may last longer.

Some side effects may be serious and may even result in death.
Here are important points about how you and the study doctor can make side effects less of a 
problem:

Tell the study doctor if you notice or feel anything different so they can see if you are 
having a side effect.

The study doctor may be able to treat some side effects.

The study doctor may adjust the study drugs to try to reduce side effects.
M7824
Common side effects (occurring in more than 5 % of patients)

Fatigue (tiredness and lack of energy) 

Nausea 

Diarrhea

Constipation

Vomiting

Swelling of your lower legs or hands

Fever

Decreased appetite

Loss of body fluids (dehydration)

Skin growths called keratoacanthomas 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, breast, blood 
in the urine, stool, or bleeding in the internal organs or skull, coughing up or vomiting 
blood. Bleeding may also occur at sites of disease (tumor sites).  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 
IRB NUMBER: 20C0074
IRB APPROVAL DATE: 02/08/2022


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
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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

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
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 study 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-related side effects are possible. These side effects are caused by over activity 
of your body’s immune system. The immune system normally works to protect you from things 
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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 in 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)

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 eyes) 

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)

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 
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PATIENT IDENTIFICATION
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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.
M9241
M9241 is in the early stages of development and, as such, the potential side effects are not 
completely known. A recent study of 58 patients treated at the NCI with M9241 alone showed that 
the majority of patients experience some side effects (81.4%) but very few patients experience 
serious study treatment-related side effects (3.4%).
The following drug-related side effects have been observed in more than 10% of the 58 
participants treated with M9241:

decreased white blood cells (including lymphocytes and neutrophils) which increases the 
risk of infection

fever

decreased liver function, as seen by increased liver enzymes in the blood

increased blood sugar

anemia caused by decreased number of red blood cells

flu-like symptoms

increased alkaline phosphatase (an enzyme found in the blood)

decreased platelets, which increases the risk of bleeding 

tiredness

decreased albumin levels in the blood

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
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Risks from Blood Collection 
Side effects of blood draws include pain and bruising in the area where the needle was placed, 
lightheadedness, and rarely, fainting. When large amounts of blood are collected, low red blood 
cell count (anemia) can develop.
Risks from CT scans
If contrast dye is used, there is a risk for allergic reaction to the dye. If you are allergic to or 
sensitive to medications, contrast dye, iodine, or shellfish, please notify your study doctor. If you 
have had kidney failure or other kidney problems in the past, please notify your study doctor.
Risk from Electrocardiogram
You may experience some minor skin irritation from the electrodes.
Risks of urine collection
There are no risks of urine collection. 
Risks from Questionnaires 
Questionnaires may contain questions that are sensitive in nature. You may only answer questions 
that you are comfortable with.
Risks from 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.
It is not known if MRI 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. The scan will not be done if the pregnancy test is positive. 
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.
During part of the MRI you will receive gadolinium, a contrast agent, through an intravenous (iv) 
catheter. It will be done for both research and medical purposes. 
IRB NUMBER: 20C0074
IRB APPROVAL DATE: 02/08/2022


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
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MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
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” which has resulted in a very small number of deaths.  A blood test 
of your kidney function may be done within the month before an MRI scan with gadolinium 
contrast. You will not receive gadolinium for a research MRI scan if your kidney function is not 
normal or if you received gadolinium within the previous month. 
Most of the gadolinium contrast leaves the body in the urine.  However, the FDA recently 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 than others.  In this study, we 
will use the gadolinium contrast drugs that are less likely to remain. 
Please tell your research team if you have had any MRI scans in the past 12 months. 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.
What are the risks of radiation from being in the study? 
You will be exposed to radiation from up to 7 CT scans used to plan your treatment and measure 
your progress. The amount of radiation exposure you will receive from these procedures is equal 
to approximately 7.7 rem. A rem is a unit of absorbed radiation. 
IRB NUMBER: 20C0074
IRB APPROVAL DATE: 02/08/2022


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 11/24/2021
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MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
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 that you get in this study will expose you to the roughly the same amount of radiation 
as 26 years 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 0.8 out of 100 (0.8%) and of getting a fatal cancer is 0.4 out of 100 (0.4%).
You may not participate in this study if you are pregnant. If you are able to become 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.
Privacy Risks Associated with Genetic Testing
It may be possible that genetic information from you could be used by law enforcement agencies 
or other entities to identify you or your blood relatives.
Psychological or Social Risks Associated with Return of Incidental or Secondary Findings
As part of the research study, it is possible that you could learn that you have genetic risks for 
another disease or disability. This may be upsetting and, depending on what you learn, might create 
a need to make challenging decisions about how to respond. 
Although your genomic information is unique to you, you share some genomic similarities with 
your children, parents, brothers, sisters, and other blood relatives. Therefore, learning your 
research results could mean something about your family members and might cause you or your 
family distress. Before joining the study, it may be beneficial to talk with your family members 
about whether and how they want you to share your results with them. 
Protections against misuse of genetic information 
This study involves genetic testing on samples.  Some genetic information can help predict future 
health problems of you and your family and this information might be of interest to your employers 
or insurers. However, the Genetic Information Nondiscrimination Act (GINA) is a federal law that 
makes it illegal for health insurance companies, group health plans, and most employers to 
discriminate against you based on your genetic information. However, GINA does not prevent 
discrimination from companies that sell life insurance, disability insurance, or long-term care 
insurance. GINA also does not protect you against discrimination based on an already-diagnosed 
genetic condition or disease.
WHAT ARE THE BENEFITS OF BEING IN THE STUDY?
You might not benefit from being in this study. 
IRB NUMBER: 20C0074
IRB APPROVAL DATE: 02/08/2022


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
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CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
However, the potential benefit to you might include shrinking of your tumor or lessening of your 
symptoms, such as pain, that are caused by the cancer.
Are there any potential benefits to others that might result from the study?
In the future, other people might benefit from this study because what we learn in this study may 
eventually be used to treat others with your disease. 
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 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.
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.
Return of research results
When we are examining your DNA, it is possible that we could identify possible changes in other 
parts of your DNA that are not related to this research. These are known as “incidental medical 
findings”. 
These include: 

Changes in genes that are related to diseases other than cancer. 

Changes in genes that are not known to cause any disease. These are known as normal 
variations. 

Changes in genes that are new and of uncertain clinical importance. This means that we do not 
know if they could cause or contribute to a disease or if they are normal variations. 
Since the analyses that we perform in our laboratory are not nearly as sensitive as the tests that are 
performed in a laboratory that is certified to perform genetic testing, the genetic changes that we 
find may or may not be valid. Therefore, we do not plan to inform you of all of the genetic results 
of testing on your tissue and blood that is performed in our research lab. However, in the unlikely 
event that we discover a finding believed to be clinically important based on medical standards at 
the time we first analyze your results, we will contact you. This could be many years in the future.
IRB NUMBER: 20C0074
IRB APPROVAL DATE: 02/08/2022


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 11/24/2021
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MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
EARLY WITHDRAWAL FROM THE STUDY 
Your doctor may decide to stop your therapy for the following reasons:

if your disease worsens or comes back during study treatment

if you become pregnant

if you have side effects from the study treatment that your doctor thinks are too severe

if you need treatment that is not allowed on this study

if study drugs become unavailable

if new information shows that another treatment would be better for you

if the study is stopped for any reason
In this case, you will be informed of the reason therapy is being stopped.
After the therapy is stopped, we would like to see you for a safety visit approximately one week 
and one month after stopping therapy.
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.
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 pancreatic cancer, or other 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
IRB NUMBER: 20C0074
IRB APPROVAL DATE: 02/08/2022


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
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CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
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 similar to this research 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. These researchers will not have 
access to any of your identifiers, such as your name, date of birth, address, or medical 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.
IRB NUMBER: 20C0074
IRB APPROVAL DATE: 02/08/2022


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 11/24/2021
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MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
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 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 specimens 
and data.
COMPENSATION, REIMBURSEMENT, AND PAYMENT
Will you receive compensation for participation in the study?
Some NIH Clinical Center studies offer compensation for participation in research. The amount 
of compensation, if any, is guided by NIH policies and guidelines.
You will not receive compensation for participation in this study. 
Will you receive reimbursement or direct payment by NIH as part of your participation?
Some NIH Clinical Center studies offer reimbursement or payment for travel, lodging or meals 
while participating in the research. The amount, if any, is guided by NIH policies and guidelines.
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.
IRB NUMBER: 20C0074
IRB APPROVAL DATE: 02/08/2022


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
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MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY

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 M7824 and M9241 developed by EMD 
Serono through a joint study with your study team and the company. The company also provides 
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 
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 NIH and other government agencies, like the Food and Drug Administration (FDA), 
which are involved in keeping research safe for people.

National Institutes of Health Intramural Institutional Review Board

The study Sponsor Center for Cancer Research of National Cancer Institute.

Qualified representatives from EMD Serono, the pharmaceutical company who provides 
M7824 and M9241.
When results of an NIH research study are reported in medical journals or at scientific meetings, 
the people who take part are not named and identified. In most cases, the NIH will not release any 
information about your research involvement without your written permission. However, if you 
sign a release of information form, for example, for an insurance company, the NIH will give the 
IRB NUMBER: 20C0074
IRB APPROVAL DATE: 02/08/2022


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
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MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
insurance company information from your medical record. This information might affect (either 
favorably or unfavorably) the willingness of the insurance company to sell you insurance.
If we share your specimens or data with other researchers, in most circumstances we will remove 
your identifiers before sharing your specimens or data. You should be aware that there is a slight 
possibility that someone could figure out the information is about you. 
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 a 
court. 
The Certificate does not protect your information when it: 
1. is disclosed to people connected with the research, for example, information may be used 
for auditing or program evaluation internally by the NIH; or 
2. is required to be disclosed by Federal, State, or local laws, for example, when information 
must be disclosed to meet the legal requirements of the federal Food and Drug 
Administration (FDA); 
3. is for other research;
4. is disclosed with your consent. 
The Certificate does not prevent you from voluntarily releasing information about yourself or your 
involvement in this research. 
The Certificate will not be used to prevent disclosure to state or local authorities of harm to self or 
others including, for example, child abuse and neglect, and by signing below you consent to those 
disclosures. Other permissions for release may be made by signing NIH forms, such as the Notice 
and Acknowledgement of Information Practices consent.
Privacy Act
The Federal Privacy Act generally protects the confidentiality of your NIH medical information 
that 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 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.
IRB NUMBER: 20C0074
IRB APPROVAL DATE: 02/08/2022


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
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MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
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, Udo Rudloff, 
MD, PhD, rudloffu@mail.nih.gov, 240-760-6238. 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: 20C0074
IRB APPROVAL DATE: 02/08/2022


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
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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: 20C0074
IRB APPROVAL DATE: 02/08/2022