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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
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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 1
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precis 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 nonresectable 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 (PDL1) 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 antitumor 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 antitumor activity of M7824 in locally advanced pancreas cancer.
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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.
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eligibility

Histologically or cytologically proven pancreatic adenocarcinoma.  
Patient must be eligible to undergo stereotactic body radiation therapy (SBRT) (Cohorts 2-3).  
2 Patients must have measurable disease.  
Age ≥18 years 3
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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.
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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 |  
| Version date: 11/10/2021 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 |  
| Version date: 11/10/2021 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 |  
6  
| Version date: 11/10/2021 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 |  
7  
| Version date: 11/10/2021 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 |  
| 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  |  
9
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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
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1 introduction 1.1 study 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.
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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)
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1.1.3 exploratory objectives

To determine ADA profile of M7824 in combination with M9241.  
To determine the PK of M7824 in combination with M9241.  
To evaluate serum cytokines and tumor necrosis factor (TNF) levels pre-treatment and ontreatment.  
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).
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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).
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1.2.1 neoadjuvant therapy for locally

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**).  
  
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]  
  
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 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 prodrug; 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.  
  
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.
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1.2.2 radiation and immunotherapy a

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.[1416] 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 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]
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1.2.3 radiation therapy counters immune

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 welldescribed "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]
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1.2.4 current progress in immunotherapy

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: 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 immuneediting 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, 0.420.65; 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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1.2.4 current progress in immunotherapy

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**).  
  
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 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. 
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.  
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**. 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 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.  
 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).  
  
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

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 infusionrelated 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.  
| Grade 1/2                    | Grade 3    | Grade 4   |          |
|------------------------------|------------|-----------|----------|
| n (%)                        | n (%)      | 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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table 1 adverse events of

| Grade 1/2                   | Grade 3    | Grade 4   |            |          |    |
|-----------------------------|------------|-----------|------------|----------|----|
| n (%)                       | n (%)      | 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  | 12 (20.3%) | 1 (1.7%) | 0  |
| phosphatase 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.
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table 2. overview of known

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 IL12 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.
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1.2.7 neoadjuvant rt for pancreas

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 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 ]
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table 3 series of studies

| # of             | Radiation                       |                            |                                 |                     |                     |               |
|------------------|---------------------------------|----------------------------|---------------------------------|---------------------|---------------------|---------------|
| Study type       | patients                        | dose                       | Chemotherapy                    | Median followup     | Overall survival    | Local control |
| Retrospective    | 7777777                         | 25 Gy/1                    | Gemcitabine based   6 months    | 1 year: 21%         | 84%                 |               |
| (96%)            |                                 |                            |                                 |                     |                     |               |
| 25-33 Gy/5       | Gemcitabine based   14.5 months | 1 year: 73%                | 61%                             |                     |                     |               |
| Retrospective    | 88                              | (72%)                      | (LAPC)                          | Median: 18.4        |                     |               |
| FOLFIRINOX (15%) | 10.5 months                     | months                     |                                 |                     |                     |               |
| (BRPC)           |                                 |                            |                                 |                     |                     |               |
| Prospective      | 23                              | 30 Gy/3                    | Gemcitabine                     | 9 months            | Median: 10.6 months | NR            |
| Phase II         | 20                              | 25 Gy/1                    | Gemcitabine based   NR          | 1 year: 50%         | 8-94%               |               |
| (100%)           |                                 |                            |                                 |                     |                     |               |
| 24–36 Gy/3       |                                 |                            |                                 |                     |                     |               |
| Retrospective    | 47                              | Gemcitabine based   21 mos | Median: 20 months               | 85%                 |                     |               |
| (100%)           | (survivors)                     |                            |                                 |                     |                     |               |
| Prospective      | 20                              | 20–25 Gy/1                 | NR (68%)                        | 14.5 months         | Median 14.4 months  | 65%           |
| 24–30 Gy/3       |                                 |                            |                                 |                     |                     |               |
| Pilot            | 10                              | 25 Gy/S                    | NR                              | Median 12.2 months  | NR                  |               |
| Concurrent       |                                 |                            |                                 |                     |                     |               |
| gemcitabine      |                                 |                            |                                 |                     |                     |               |
| (100%)           |                                 |                            |                                 |                     |                     |               |
| Phase II         | 3 Gy/5                          | Median: 13.9 months        |                                 |                     |                     |               |
| 49               | Gemcitabine based   13.9 months | 78%                        |                                 |                     |                     |               |
| (100%)           |                                 |                            |                                 |                     |                     |               |
| 36 Gy/3          |                                 |                            |                                 |                     |                     |               |
| Retrospective    | 12                              | Gemcitabine based   NR     | 1 year: 92%                     | NR. CR seen in 25%. |                     |               |
| Median: 47.2     |                                 |                            |                                 |                     |                     |               |
| 24 Gy/1          | (92%)                           | months                     |                                 |                     |                     |               |
| Prospective      | 157                             | 30 Gy/S                    | Gemcitabine based   14.0 months | Median: 18.1 months | 7% in non-surgical  |               |
| (82%)            | patient                         |                            |                                 |                     |                     |               |
| FOLFIRINOX (14%) |                                 |                            |                                 |                     |                     |               |
| Retrospective    | 24                              | 20-24 Gy/1                 | Gemcitabine based   12.5 months | 1 year 80.4%        | 66%                 |               |
| (79%)            | Median 26.7                     |                            |                                 |                     |                     |               |
| months           |                                 |                            |                                 |                     |                     |               |  
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 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.  
Table 4: Biologically equivalent doses of different SBRT regimens for the treatment of LAPC  
| EQD2                                                                                 |                     |                  |                 |                    |                 |
|--------------------------------------------------------------------------------------|---------------------|------------------|-----------------|--------------------|-----------------|
| alpha/beta                                                                           | 8 Gy x 1            | 5 Gy x 5         | 3 Gy,x 12       | 6.6 Gy  x 5        | 25 Gy.x 1       |
| 3                                                                                    | 17                  | 40               | 43.2            | 63                 | 140             |
| 7                                                                                    | 13                  | 3                | 40              | 50                 | 88              |
| 12                                                                                   | 39                  | 46               | 72              |                    |                 |
| 10 (tumor)                                                                           | 31                  |                  |                 |                    |                 |
| BED                                                                                  |                     |                  |                 |                    |                 |
| alpha/beta                                                                           | 8 Gy x 1            | 5 Gy x 5         | 3 Gy.x 12       | 6.6 Gy, x 5        | 25 Gyx 1        |
| 3                                                                                    | 29                  | 67               | 72              | 106                | 233             |
| 7                                                                                    | 17                  | 42               | 51              | 64                 | 114             |
| 10 (tumor)                                                                           | 14                  | 37               | 47              | 55                 | 87              |
| Current Uses of Hypofractionated Dose, Fractionation in Stage III-IV Pancreas Cancer |                     |                  |                 |                    |                 |
| 25 GYx 1                                                                             |                     |                  |                 |                    |                 |
| Dose, fx                                                                             | 8 Gy x 1            | 5 Gy x 5         | 3 Gy.x 12       | 6.6 Gy x 5         |                 |
| Preoperative LAPC                                                                    | .ocally advanced,   |                  |                 |                    |                 |
| Metastatic,                                                                          | Metastatic,         | Standard of Care |                 |                    |                 |
| Common Use                                                                           | improve rate of     | nt surgical      |                 |                    |                 |
| palliative                                                                           | palliative          | for LAPO         |                 |                    |                 |
| ngative margins                                                                      | cndidate            |                  |                 |                    |                 |
| Fiducials                                                                            | no                  | no               | yes             | yes                |                 |
| required?                                                                            |                     |                  |                 |                    |                 |
| R diobiology                                                                         | Predicted immune    | Possible immune  | Not predicted   | Predicted/possible | Not predicted   |
| (mmune)                                                                              | adjuvant            | adjuvant         | immune adjuvant | immune adjuvant    | immune adjuvant |
| R adiobiology                                                                        | Excellent, but more |                  |                 |                    |                 |
| Intermediate                                                                         | Intermediate        | Good for pre-op  | Good            |                    |                 |
| (tumor control)                                                                      | dodenal ulcer risk  |                  |                 |                    |                 |  
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.  
 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 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.
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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 fivepoint 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.
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1.2.9 rationale for this clinical

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.  
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 lifethreatening (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.
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2 eligbility assessment and enrollment

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).  
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 23).  
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                                                                                    |    | < 1.75x institution upper limit of normal OR                                            |
|--------------------------------------------------------------------------------------------------|-----|-----------------------------------------------------------------------------------------|
| Measured or calculated  creatinine clearance (CrCl)  (eGFR may also be used in  place of CrCl) A |    | > 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
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.
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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.  
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.
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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.
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2.2 screening evaluation 2.2.1 screening

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 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.
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2.3 participant registration and status

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.
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2.3.1 treatment assignment procedures (for

| Number   | Name     | Description                                                                                                                                                                                      |
|----------|----------|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| 1        | Phase IA | Subjects with stage IV or III pancreas cancer, enrolled to M9241 deescalation 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. |
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arms

| 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.
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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; 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)
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3 study implementation 3.1 study

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 immunooncology 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.  
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.
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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.  
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)
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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.
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sbrt

Dose modifications dosage adjustment is based upon the degree of hematologic and nonhematologic 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.
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3.1.2.1 cohort 1 phase ia

6 to 12 patients will be enrolled into Arm 1A. Dose de-escalation will proceed in dose levels of 6 patients. 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.  
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   |
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3.1.2.2 cohort 2 phase ib

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.  
| Dose   | M7824, mg, IV                                      | M9241, µg/kg, SQ, every 4 weeks                     | SBRT   |
|--------|----------------------------------------------------|-----------------------------------------------------|--------|
| level  | every 2 weeks  1,200                               | MTD of M9241 estimated during Phase IA (16.8 or 12) |        |
| DL 0   | 5 x 5 Gy                                           |                                                     |        |
| 1,200  | If MTD estimated during Phase IA is 16.8 then 12.0 |                                                     |        |
| DL -1  | If MTD estimated during Phase IA is 12.0, then 8.0 | 5 x 5 Gy                                            |        |  
Table 6: Dose Levels of M7824 and M9241 in combination with SBRT in Arm 1B.
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3.1.3 phase ii cohort 3

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 6 th 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.
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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.
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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. 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.
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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.
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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.  
| Immediate Hypersensitivity.                                                                                                                                                                             |                                                                                                                                                                                                                                                  |                                                                                                                                        |              |    |        |           |    |     |
|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------------------------------------|--------------|----|--------|-----------|----|-----|
| NCI-CTCAE Grade                                                                                                                                                                                         | Treatment Modification for M7824                                                                                                                                                                                                                 |                                                                                                                                        |              |    |        |           |    |     |
| Grade 1 - mild                                                                                                                                                                                          |                                                                                                                                                                                                                                                 | Increase monitoring of vital signs as medically  indicated as participants are deemed medically  stable by the attending Investigator. |              |    |        |           |    |     |
| Mild transient reaction; in general,  infusion interruption not indicated;  intervention not indicated.                                                                                                 |                                                                                                                                                                                                                                                 | Hold                                                                                                                                   | infusion     | if | deemed | necessary | by | the |
| investigator.                                                                                                                                                                                           |                                                                                                                                                                                                                                                  |                                                                                                                                        |              |    |        |           |    |     |
| Grade 2 - moderate                                                                                                                                                                                      |                                                                                                                                                                                                                                                 | Stop the infusion of the study intervention.                                                                                           |              |    |        |           |    |     |
| 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. |                                                                                                                                                                                                                                                 | 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.                            |                                                                                                                                        |              |    |        |           |    |     |  
| Version date: 11/10/2021 NCI-CTCAE Grade                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         | Treatment Modification for M7824                                                    |                                                                                                                                                                                                                                                                                                   |
|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Grade 3 or Grade 4 - severe or lifethreatening                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  |                                                                                    | 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 |
| 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.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           |                                                                                    | Administration of glucocorticoids may be required                                                                                                                                                                                                                                                 |
|                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 | For Grade 3 or 4 IRRs, permanent discontinuation  of study intervention is mandated |                                                                                                                                                                                                                                                                                                   |
| Grade                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            | 4:                                                                                  | Life-threatening                                                                                                                                                                                                                                                                                  |
| consequences;                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    | urgent                                                                              | intervention                                                                                                                                                                                                                                                                                      |
| indicated. 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. |                                                                                     |                                                                                                                                                                                                                                                                                                   |
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table 8 management of immune-mediated

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 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:   |
|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|  
- 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.
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table 9 management of m7824

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.
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table 10 management of treatment-related

- 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)
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.
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table 11 management of bleeding

|    | 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                                                                                                                        |                                                                                                                                                                    |  
| 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. |             |                                                                                                           |           |    |     |              |           |     |
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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
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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  |
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table 14 m9241 dose modification

| (CTCAEv5) Grade    | Action                                                                                                                                                                                     |
|--------------------|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Non-hematological, | Continue M9241 therapy at full dose prescribed. Apply                                                                                                                                      |
| Grade 1 or 2       | 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 |  
| (CTCAEv5) Grade                                                                    | Action to affect quality of life for ≥7 more days, permanently  discontinue M9241.                                                                                                                                                                                                                                                                                                                                  |         |            |      |                  |      |
|------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------|------------|------|------------------|------|
| Non-hematological,  Grade 3 or 4                                                   | Apply                                                                                                                                                                                                                                                                                                                                                                                                               | maximum | supportive | care | recommendations. | Hold |
| M9241 therapy until recovery to Grade  1 (up to 14 days).                         |                                                                                                                                                                                                                                                                                                                                                                                                                     |         |            |      |                  |      |
| (excluding                                                                         | cardiac,                                                                                                                                                                                                                                                                                                                                                                                                            |         |            |      |                  |      |
| hepatobiliary                                                                      | events,                                                                                                                                                                                                                                                                                                                                                                                                             |         |            |      |                  |      |
| interstitial pneumonitis or  Grade 4 inflammatory  response syndrome)              | 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, restart 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  No modification required or 2 Grade 3 or 4  thrombocytopenia  associated with bleeding  M9241 must be permanently discontinued                                                                                    |                                                                                                                                                                                                                                                                                                                                                                                                                     |         |            |      |                  |      |  
| (CTCAEv5) Grade   | Action                                 |                                        |     |
|-------------------|----------------------------------------|----------------------------------------|-----|
| event             | which                                  | does                                   | not |
| result            | in                                     | hemodynamic                            |     |
| instability but requires an  elective platelet  transfusion, or a lifethreatening 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                                | M9241 must be permanently discontinued |     |
| syndrome          |                                        |                                        |     |  
* retest within 3 days from the first occurrence and then weekly to determine if ALT elevation persists
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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,   | % of selected   |                 |
|-----------------------------------------|-------------------|-----------------|-----------------|
| x106 /L                                 | starting dose     |                 |                 |
| ≥1,000                                  | And               | ≥85,000         | OK to treat     |
| <1,000                                  | Or                | <85,000         | Do not start RT |  
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. Shortacting 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 radiationinduced pain flare ≤7 days grade 2 AE.
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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 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
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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

| Procedure                                                                                | Screening         | Baseline1            | Day -141   | (28+/- 3 days)1 Cycles   | EOT   |    |    |
|------------------------------------------------------------------------------------------|-------------------|----------------------|------------|--------------------------|-------|----|----|
| visit13, 16                                                                              | 28 Days  FU14, 16 | Long  Term  FU15, 16 |            |                          |       |    |    |
| Day 1                                                                                    | Day 15            |                      |            |                          |       |    |    |
| 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  |  
| Procedure                                                                    | Screening         | Baseline1                    | Day -141     | (28+/- 3 days)1 Cycles   | EOT   |
|------------------------------------------------------------------------------|-------------------|------------------------------|--------------|--------------------------|-------|
| visit13, 16                                                                  | 28 Days  FU14, 16 | Long  Term  FU15, 16         |              |                          |       |
| Day 1                                                                        | Day 15            |                              |              |                          |       |
| 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                                                             | X                 | X                            | X            | X                        |       |
| 17 Urinalysis17                                                              | X                 | X                            | X            | X                        |       |
| PT, INR, aPTT,  fibrinogen                                                   | X                 | X                            | X            |                          |       |
| Concomitant  Medications17                                                   | X                 | X                            | X            | X                        |       |
| Baseline  symptom  collection                                                | X                 |                              |              |                          |       |  
| Procedure                     | Screening         | Baseline1            | Day -141   | (28+/- 3 days)1 Cycles   | EOT   |    |
|-------------------------------|-------------------|----------------------|------------|--------------------------|-------|----|
| visit13, 16                   | 28 Days  FU14, 16 | Long  Term  FU15, 16 |            |                          |       |    |
| Day 1                         | Day 15            |                      |            |                          |       |    |
| 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 email                               | X                 |                      |            |                          |       |    |  
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.  
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 followup." 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

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.
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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.
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3.11 criteria for removal from

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.
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3.11.1 criteria for removal from

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
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3.11.2 off -study criteria

Death Patient request to be withdrawn from study Lost to follow up PI discretion PI decision to end the study
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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.
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4 concomitant medications / measures

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.
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4.2 prohibited medicines the following

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).
If the administration of a non-permitted concomitant drug becomes necessary during the trial, the subject will be withdrawn from trial treatment.
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5 biospecimen collection 5.1. correlative

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.
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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
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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            | Type               | of    | Collection point   | Location   | of     |
|-----------------------|-------------------|--------------------|-------|--------------------|------------|--------|
| (approx.)             | tube*             | specimen  analysis | (and  |                    |            |        |
| original  processing) |                   |                    |       |                    |            |        |
| PK M7824              | Blood,            | 4                  | SST   | See section 5.1.3  | EMD        | Serono |
| mL                    | (BPC)             |                    |       |                    |            |        |
| ADA by ELISA          | Blood,            | 4                  | SST   | See Study calendar | EMD        | Serono |
| mL                    | 3.8               | (BPC)              |       |                    |            |        |
| Cytokines by ELISA    | Blood,            | 8                  | SST   | See Study calendar | EMD        | Serono |
| mL                    | 3.8               | (BPC)              |       |                    |            |        |
| TNF by ELISA          | Blood, 2x3        | Light              | blue  | See Study calendar | EMD        | Serono |
| mL                    | citrate           | 3.8                | (BPC) |                    |            |        |
| Immune marker panel   | Archival          |                    |       |                    |            |        |
| evaluation by IHC     | tumor  sample and | Baseline           | and   | at                 | Laboratory | of     |
| surgery               | Pathology, NCI    |                    |       |                    |            |        |  
| Test/assay                                                   | Volume                                      | Type               | of   | Collection point   | Location   | of   |          |
|--------------------------------------------------------------|---------------------------------------------|--------------------|------|--------------------|------------|------|----------|
| (approx.)                                                    | tube*                                       | 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                 | Dr.        | M.   | Raffeld, |
| surgery                                                      | Laboratory                                  | of                 |      |                    |            |      |          |
| Pathology NCI                                                |                                             |                    |      |                    |            |      |          |
| Circulating free tumor                                       | Blood,                                      | 6                  | EDTA |                    |            |      |          |
| DNA (ctDNA)                                                  | mL                                          | (purple            | top) |                    |            |      |          |
| tubes                                                        | See Study calendar                          | Dr.                | M.   | Raffeld,           |            |      |          |
| 3.8                                                          | 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.
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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.
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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

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.
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5.1.6 changes in systemic and

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 treatmentinduced 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.
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5.2 samples for genetic/genomic analysis

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 chromatinremodeling 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).
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5.2.2 circulating free tumor dna

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 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.
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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.
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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.
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5.3 sample storage tracking and

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. 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.
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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.
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6 data collection and evaluation

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 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.
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6.1.1 pk data

The exact time of each blood draw for PK analysis will be recorded.
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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.
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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**.