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Abbreviated Title: M7824/Gemcitabine for AAPC CC Protocol \#: 18C0061 C Version Date: 03/20/2019 NCT Number: NCT03451773 Title: A Phase IB/II Single-arm Study of M7824 (MSB0011359C) in Combination with Gemcitabine in Adults with Previously Treated Advanced Adenocarcinoma of the Pancreas.  
NCI Principal Investigator Udo Rudloff, MD, PhD
Pediatric Oncology Branch Center for Cancer Research National Cancer Institute Building 10, Room 2B38D Bethesda, MD 20892 Phone: 240-760-6238 E-Mail: rudloffu@mail.nih.gov
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investigational agent 1

| Drug Name:    | M7824                                                 |
|---------------|-------------------------------------------------------|
| IND Number:   | 136852                                                |
| Sponsor:      | Center for Cancer Research, National Cancer Institute |
| Manufacturer: | EMD Serono                                            |  
Commercial Agent: Gemcitabine
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precis background

x M7824 is an investigational agent in phase IB/II clinical development with dual activity against 7*)ȕVLJQDOLQJ 7*)ȕOLJDQG µWUDS¶H[WUDFHOOXODUGRPDLQRI KXPDQ7*)ȕ UHFHSWRU ,,DQG
immune checkpoint ligand inhibition (PD-/LQKLELWLRQDYHOXPDE IXOO\KXPDQ ,J*P$E
directed against human PD-/ZLWKDQDFFHSWDEOHWR[LFLW\SURILOHDQGHDUO\VLJQDOVRIDQWLcancer activity including in pancreas cancer.  
x *HPFLWDELQH ƍƍ-'LIOXRUGHVR[\F\WLGLQH LV D VWDQGDUG-of-care nucleoside analogue in pancreas cancer with immunomodulatory mechanisms of actions in pancreas cancer patients.  
x Preclinical studies in autochthonous and syngeneic murine models have shown thaW 7*)ȕ inhibition and PD-L1 inhibition cooperate with gemcitabine to achieve reduction of tumor JURZWK DQG H[WHQVLRQ RI VXUYLYDO induce anti-tumor immunity, and reprogram the immune landscape.
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objectives

x To determine the safety and tolerability of M7824 in combination with gemcitabine in subjects with metastatic or locally advanced pancreas cancer.  
x To determine best overall response (BOR) rate according to Response Evaluation Criteria
(RECIST 1.1) in advanced pancreas cancer subjects.
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eligibility

x Histologically confirmed diagnosis of adenocarcinoma of the pancreas.  
x Patients must have progressed on prior chemotherapeutic regimen.  
x Concurrent treatment with non-permitted drugs and other interventions, prior therapy with any antibody / drug targeting T cell co-regulatory proteins (immune checkpoints) such as anti-PD 1, anti PD-L1, or anti-F\WRWR[LF7O\PSKRF\WHDQWLJHQ-4 (CTLA 4 antibody) is not allowed.
Design:  
x The proposed study is a phase IB/II study of M7824 in combination with gemcitabine in a safety run-in of 6-18 patients and, if safe and tolerated, will proceed WRDQH[SDQVLRQShase II cohort with a standard Simon µ0LQLPD[GHVLJQ¶.
2
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table of contents

PRÉCIS 2  
| TABLE OF CONTENTS   | 3                                                                                                            |    |
|---------------------|--------------------------------------------------------------------------------------------------------------|----|
| 1                   | Introduction                                                                                                 | 9  |
| 1.1                 | Study Objectives:                                                                                            | 9  |
| 1.1.1               | Primary Objectives:                                                                                          | 9  |
| 1.1.2               | Secondary Objectives:                                                                                        | 9  |
| 1.1.3               | ([SORUatory Objectives:                                                                                      | 9  |
| 1.2                 | Background and Rationale                                                                                     | 9  |
| 1.2.1               | Pancreas cancer                                                                                              | 9  |
| 1.2.2               | 0DELIXQFWLRQDOIXVLRQSURWHLQWDUJHWLQJ7*)ȕVLJQDOLQJDQGWKH3URJUDPPHG death-ligand 1 (PD-L1) 10                                                                                                              |    |
| 1.2.3               | 3UHFOLQLFDOUDWLRQDOIRUWKHFRPELQDWLRQLPPXQRWKHUDS\DSSURDFKRIGXDO7*)ȕDQG PD-L1 inhibition and gemcitabine in pancreas cancer 11                                                                                                              |    |
| 1.2.4               | Preclinical rationale for the combination of gemcitabine and PD-L1 inhibition in  pancreas cancer            | 13 |
| 1.2.5               | 3UHFOLQLFDOUDWLRQDOHIRUWKHFRPELQDWLRQRIJHPFLWDELQHDQG7*)ȕLQKLELWLRQ                                                                                                              | 14 |
| 1.2.6               | Preclinical rationale using M7824 in combination with gemcitabine                                            | 18 |
| 1.2.7               | 6DIHW\RIFRPELQHG7*)ȕDQG3'-/LQKLELWLRQE\WKHGXDO7*)ȕ-PD-L1 inhibitor  M7824 25                                                                                                              |    |
| 1.2.8               | Pharmacokinetic / Pharmacodynamic profile of M7824 including human phase I  findings                         | 27 |
| 1.2.9               | Summary of Clinical Findings of M7824 including Adverse Events (AEs) in Pancreas  Cancer Patients to date 29 |    |
| 1.2.10              | Rationale for the Clinical Trial                                                                             | 31 |
| 1.2.11              | Rationale for 0'RVH/HYHOVZLWKVSHFLDOFRQVLGHUDWLRQRIRYHUODSSLQJWR[LFLWLHV with gemcitabine 32                                                                                                              |    |
| 1.2.12              | Rationale for Gemcitabine Dose Selection and Safety Measures                                                 | 33 |
| 1.2.13              | Gemcitabine in Pancreas Cancer                                                                               | 36 |
| 1.2.14              | &OLQLFDOVDIHW\GDWDRIJHPFLWDELQHLQFRPELQDWLRQZLWK7*)ȕLQKLELWLRQWRGDWH                                                                                                              | 40 |
| 1.2.15              | Clinical safety data of gemcitabine in combination with PD-L1 inhibition to date.                            | 40 |
| 1.2.16              | Health-related Quality of Life                                                                               | 41 |
| 1.2.17              | Justification of Research Studies                                                                            | 41 |
| 1.2.18              | Amendment B                                                                                                  | 43 |
| 2                   | ELIGBILITY ASSESSMENT AND ENROLLMENT                                                                         | 44 |  
| Version date: 03/20/2019  2.1 Eligibility Criteria   | 44                                                                |    |
|------------------------------------------------------|-------------------------------------------------------------------|----|
| 2.1.1                                                | Inclusion Criteria                                                | 44 |
| 2.1.2                                                | ([FOXVLRQ&ULWHULD                                                                   | 45 |
| 2.1.3                                                | Recruitment Strategies                                            | 46 |
| 2.2                                                  | Screening Evaluation                                              | 46 |
| 2.3                                                  | Registration Procedures                                           | 47 |
| 2.3.1                                                | Treatment Assignment Procedures (For registration purposes only): | 47 |
| 2.4                                                  | Baseline Evaluation                                               | 48 |
| 3                                                    | STUDY IMPLEMENTATION                                              | 48 |
| 3.1                                                  | Study Design                                                      | 48 |
| 3.1.1                                                | 'RVH/LPLWLQJ7R[LFLW\                                                                   | 49 |
| 3.1.2                                                | Phase IB Safety Run-In (Dose de-escalation)                       | 50 |
| 3.1.3                                                | Phase II Cohort                                                   | 52 |
| 3.2                                                  | Study Stopping Rules                                              | 52 |
| 3.3                                                  | Drug Administration                                               | 52 |
| 3.3.1                                                | M7824.                                                            | 52 |
| 3.3.2                                                | Gemcitabine                                                       | 53 |
| 3.4                                                  | Dose modifications:                                               | 54 |
| 3.4.1                                                | M7824                                                             | 54 |
| 3.4.2                                                | Gemcitabine                                                       | 66 |
| 3.5                                                  | Assessments on Treatment                                          | 67 |
| 3.5.1                                                | End-of-Treatment Visit                                            | 68 |
| 3.5.2                                                | Post-Treatment Follow-up                                          | 68 |
| 3.6                                                  | Questionnaires                                                    | 68 |
| 3.7                                                  | Study Calendar                                                    | 69 |
| 3.8                                                  | Criteria for Removal from Protocol Therapy and Off Study Criteria | 74 |
| 3.8.1                                                | Criteria for Removal from Protocol Therapy                        | 74 |
| 3.8.2                                                | Off -Study Criteria                                               | 74 |
| 3.8.3                                                | Off Protocol Therapy and Off-Study Procedure                      | 74 |
| 4                                                    | CONCOMITANT MEDICATIONS / MEASURES                                | 74 |
| 4.1                                                  | Permitted Medicines                                               | 74 |
| 4.2                                                  | Prohibited Medicines                                              | 75 |
| 5                                                    | BIOSPECIMEN COLLECTION                                            | 75 |  
4
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5

| Version date: 03/20/2019  5.1. Correlative Studies for Research/Pharmacokinetic Studies   | 75                                                                        |    |
|-------------------------------------------------------------------------------------------|---------------------------------------------------------------------------|----|
| 5.1.1                                                                                     | Tumor and Tissue Collection                                               | 77 |
| 5.1.2                                                                                     | 0XOWLSOH[HGLPPXQRKLVWRFKHPLFDOHYDOXDWLRQRILPPXQHFHOOSRSXODWLRQ in tumor  samples                                                                           | 77 |
| 5.1.3                                                                                     | Pharmacokinetics of M7824 and gemcitabine                                 | 78 |
| 5.1.4                                                                                     | Soluble Factors Investigation                                             | 78 |
| 5.1.5                                                                                     | ADA Analysis.                                                             | 78 |
| 5.2                                                                                       | Sample Storage, Tracking and Disposition                                  | 79 |
| 5.2.1                                                                                     | 6DPSOHV0DQDJHGE\'U)LJJ¶V%ORRG3URFHVVLQJ&RUH%3&                                                                           | 79 |
| 5.2.2                                                                                     | Sample Data Collection                                                    | 79 |
| 5.2.3                                                                                     | Sample Storage                                                            | 79 |
| 5.2.4                                                                                     | Procedures for Storage of Tissue Specimens in the Laboratory of Pathology | 80 |
| 5.2.5                                                                                     | Protocol Completion/Sample Destruction                                    | 80 |
| 5.3                                                                                       | Samples for Genetic/Genomic Analysis                                      | 80 |
| 5.3.1                                                                                     | Description of the scope of genetic/genomic analysis                      | 80 |
| 5.3.2                                                                                     | Privacy and Confidentiality of medical information/biological specimens   | 81 |
| 5.3.3                                                                                     | Management of Results                                                     | 81 |
| 5.3.4                                                                                     | Genetic counseling                                                        | 81 |
| 6                                                                                         | DATA COLLECTION AND EVALUATION                                            | 82 |
| 6.1                                                                                       | Data Collection                                                           | 82 |
| 6.1.1                                                                                     | Tumor data                                                                | 82 |
| 6.1.2                                                                                     | Concomitant Medications and Therapies                                     | 83 |
| 6.2                                                                                       | Data Sharing Plans                                                        | 83 |
| 6.2.1                                                                                     | Human Data Sharing Plan                                                   | 83 |
| 6.2.2                                                                                     | Genomic Data Sharing Plan                                                 | 83 |
| 6.3                                                                                       | Response Criteria                                                         | 83 |
| 6.3.1                                                                                     | Disease Parameters                                                        | 84 |
| 6.3.2                                                                                     | Methods for Evaluation of Measurable Disease                              | 85 |
| 6.3.3                                                                                     | Response Criteria                                                         | 85 |
| 6.3.4                                                                                     | Responses                                                                 | 88 |
| 6.4                                                                                       | Immune-related Response Criteria (irRECIST)                               | 88 |
| 6.4.1                                                                                     | Immune-related BOR (irBOR)                                                | 88 |
| 6.5                                                                                       | To[LFLW\&ULWHULD                                                                           | 89 |  
| Version date: 03/20/2019  7 SAFETY REPORTING REQUIREMENTS / DATA AND SAFETY MONITORING  PLAN 89 7.1 Definitions 89 7.1.1 Adverse Event 89 7.1.2 Suspected adverse reaction 89 7.1.3 8QH[SHFWHGDGYHUVHUHDFWLRQ 89 7.1.4 Serious 89 7.1.5 Serious Adverse Event 89 7.1.6 Disability 90 7.1.7 Life-threatening DGYHUVHGUXJH[SHULHQFH 90 7.1.8 Protocol Deviation (NIH Definition) 90 7.1.9 Non-Compliance (NIH Definition) 90 7.1.10 Unanticipated Problem 90 7.2 NIH Intramural IRB and Clinical Director Reporting 90 7.2.1 1,+,QWUDPXUDO,5%DQG1&,&'([SHGLWHG5HSRUWLQJRI8QDQWLFLSDWHG3UREOHPVDQG Deaths 90 7.2.2 NIH Intramural IRB Requirements for PI Reporting at Continuing Review 91 7.2.3 NIH Intramural IRB Reporting of IND Safety Reports 91 7.3 IND Sponsor Reporting Criteria 91 7.3.1 Reporting Pregnancy 91 7.4 Reporting Criteria to the Pharmaceutical Collaborators 92 7.4.1 EMD-Serono 92 7.5 Data and Safety Monitoring Plan 93 7.5.1 Principal Investigator/Research Team 93 7.5.2 Sponsor Monitoring Plan 93 8 STATISTICAL CONSIDERATIONS 94 8.1 Statistical Considerations 94 8.1.1 Primary efficacy endpoints 94 8.1.2 Secondary efficacy endpoints 94 8.2 Sample size determination 94 8.2.1 Populations for analysis 95 8.3 Description of Statistical Analyses 96 8.3.1 General Considerations 96   |
|---|  
6  
| Version date: 03/20/2019  8.3.2 Analysis of the primary efficacy endpoints   | 96                                                     |     |
|------------------------------------------------------------------------------|--------------------------------------------------------|-----|
| 8.3.3                                                                        | Analysis of the secondary efficacy endpoints           | 96  |
| 8.3.4                                                                        | Safety analyses                                        | 96  |
| 8.3.5                                                                        | Baseline descriptive statistics                        | 96  |
| 8.3.6                                                                        | Planned interim analyses:                              | 96  |
| 8.3.7                                                                        | ([SORUDWRU\DQDO\VHV                                                        | 96  |
| 9                                                                            | COLLABORATIVE AGREEMENTS                               | 97  |
| 9.1                                                                          | Cooperative Research and Development Agreement (CRADA) | 97  |
| 10                                                                           | HUMAN SUBJECTS PROTECTIONS                             | 97  |
| 10.1                                                                         | Rationale For Subject Selection                        | 97  |
| 10.2                                                                         | Participation of Children                              | 97  |
| 10.3                                                                         | Participation of subjects unable to give consent       | 97  |
| 10.4                                                                         | Evaluation of Benefits and Risks/Discomforts           | 98  |
| 10.4.1                                                                       | Risks                                                  | 98  |
| 10.4.2                                                                       | Benefits                                               | 99  |
| 10.5                                                                         | Risks/Benefits Analysis for All Participants           | 99  |
| 10.6                                                                         | Consent Process and Documentation                      | 99  |
| 10.6.1                                                                       | Re-Consent via Telephone                               | 99  |
| 11                                                                           | PHARMACEUTICAL INFORMATION                             | 100 |
| 11.1                                                                         | M7824                                                  | 100 |
| 11.1.1                                                                       | Status:                                                | 100 |
| 11.1.2                                                                       | Brief Mechanism of Action/Drug Classification:         | 100 |
| 11.1.3                                                                       | How Supplied:                                          | 100 |
| 11.1.4                                                                       | Storage:                                               | 100 |
| 11.1.5                                                                       | Reconstitution:                                        | 100 |
| 11.1.6                                                                       | Stability:                                             | 101 |
| 11.1.7                                                                       | Administration:                                        | 101 |
| 11.1.8                                                                       | Compatibility:                                         | 101 |
| 11.1.9                                                                       | Preparation of Infusion:                               | 101 |
| 11.1.10                                                                      | Hazards and Precautions:                               | 102 |
| 11.1.11                                                                      | Labeled:                                               | 102 |
| 11.2                                                                         | Gemcitabine                                            | 102 |
| 11.2.1                                                                       | 7R[LFLW\                                               | 102 |  
7  
| 11.2.2   | Formulation                    | 104   |
|----------|--------------------------------|-------|
| 11.2.3   | Preparation                    | 104   |
| 11.2.4   | Stability and Storage          | 104   |
| 11.2.5   | Administration Procedures      | 105   |
| 11.2.6   | Incompatibilities and Overdose | 105   |
| 12       | References                     | 106   |
| 13       | Appendices                     | 109   |
| 13.1     | $SSHQGL[$3HUIRUPDQFH6WDWXV&ULWHULD                                | 109   |
| 13.2     | $SSHQGL[%)DFW-Hep                                | 110   |
| 13.3     | Appendi[&0RGLILHG,PPXQH-related Response Criteria (irRECIST)                                | 113   |  
8
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1 introduction 1.1 study objectives

1.1.1 Primary Objectives:  
Phase IB
x To determine the safety and tolerability of M7824 in combination with gemcitabine in subjects with metastatic or locally advanced pancreas cancer.  
9 Phase II
x To determine the best overall response (BOR) rate according to Response Evaluation Criteria (RECIST 1.1) in advanced pancreas cancer subjects.  
1.1.2 Secondary Objectives:
x To assess progression-free survival (PFS) according to RECIST 1.1 x To characterize overall survival (OS) x To assess the immune-related BOR (irBOR) using the immune-related RECIST
(irRECIST)
1.1.3 ([SORUDWRU\2EMHFWLYHV:
x Determine the impact of M7824 on tumor perfusion by Dynamic Contrast Enhanced MRI (DCE-MRI)
x To evaluate impact of genomic profile of advanced pancreatic cancers on clinical response to M7824 x To correlate circulating free tumor DNA (cftDNA) levels with clinical course of pancreatic cancer patients treated with M7824 in combination with gemcitabine x To evaluate the intratumoral immunogenicity of M7824 in combination with gemcitabine x 7R FKDUDFWHUL]H SODVPD &PD[ DQG &PLQ RI 0 and gemcitabine when given in combination x To measure subjective Health-related Quality of Life (HRQoL) affecting diseasespecific symptoms and treatment-related concerns.
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1.2 background and rationale 1.2.1

Pancreas cancer is a life-threatening disease. AACR estimates deaths due to pancreas cancer to rank 2nd among all cancer-related deaths in the U.S. by 2030 [1]3DQFUHDVFDQFHULVLQRI cases diagnosed in the later stages of its progression (stage III and IV), resulting in poor prognosis with a median survival of 6 to 9 months from symptom onset and less than 6 months from diagnosis (**Figure 1**).[2]  There is no standardized second-line therapy in pancreas cancer. FDA has approved 5-FU-based (FOLFIRINOX) and gemcitabine-based (gemcitabine + DEUD[DQH [nab-SDFOLWD[HO@) regimens for 1st line therapy, but there is no evidence of clinical efficacy of the currently empirically chosen 2nd line regimens in randomized studies.[3, 4] )2/),5,12; D WR[LF WULSOHW FRPELQDWLRQ RI R[DOLSODWLQLULQRWHFDQDQGIOXRURXUDFLOH[WHQGVPHGLDQRYHUDOOVXUYLYDOLQSDWLHQWVZLWKORFDOO\ advanced or metastatic pancreatic cancer to merely 11.1 compared to 6.8 months with gemcitabine alone.[3] A similar marginal improvement in median overall survival from 6.7 months in the gemcitabine group to 8.5 months in the nab-SDFOLWD[HOLQFRPELQDWLRQZLWKJHPFLWDELQHJURXSOHG to FDA approval of this combination in 2013.[4] New therapies are urgently needed.[5]
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1.2.2 0delixqfwlrqdoixvlrqsurwhlqwdujhwlqj7)uvljqdolqjdqgwkh3urjudpphg death-ligand 1 (pd-l1)

M7824 is a novel bifunctional fusion protein. It includes an antibody component (fully human IgG1 mAb) directed against human PD-L1 which is identical to avelumab, a PD-L1 immune checkpoint inhibitor recently approved for metastatic Merkel cell carcinoma and in clinical testing, either as monotherapy or in combination with standard of care or radiation therapy, for several VROLG RUJDQ PDOLJQDQFLHV 7KH VHFRQG FRPSRQHQW RI 0 LV D 7*)ȕ-neutralizing trap FRPSRQHQWFRQVLVWLQJRIWKHH[WUDFHOOXODUGRPDLQRIKXPDQ7*)ȕUHFHSWRU ,,ZKLFKHIILFLHQWO\ ELQGV7*)ȕOLJDQGV7*)ȕȕDQGȕZKLFKLVIXVHGWR&+-&WHUPLQXVRIWKH,J*YLDDIOH[LEOH glycine-serine linker (Figure 2).  Dual targeting of the PD-/DQG7*)ȕSDWKZD\VUHSUHVHQWVDUDWLRQDOWKHUDSHXWLFVWUDWHJ\EHFDXVH these 2 key immune evasion pathways have independent and complementary immunosuppressive functions, thereby raising the possibility of synergistic antitumor activity. 1.2.3 3UHFOLQLFDOUDWLRQDOIRUWKHFRPELQDWLRQLPPXQRWKHUDS\DSSURDFKRIGXDO7*)ȕDQG3'-
L1 inhibition and gemcitabine in pancreas cancer Combination immunotherapy approaches are a promising new therapeutic strategy in pancreas and are currently under active investigation. In pancreatic cancer, one of the most clinically advanced combination immunotherapy strategies is combination vaccines in combination with metronomic cisplatin, given as an immunomodulator (as gemcitabine in combination with M7824 in this study) (Le DT). In a prespecified per-protocol analysis of patients who received at least three doses (two doses of Cy/GVAX plus one of CRS-RUWKUHHRI&\*9$;RYHUDOOVXUYLYDOZDVH[WHQGHGWR
YHUVXV  PRQWKV DUP $ Y % +5  3   DQ HIIHFWVLPLODU WR WKDW RI ILUVW OLQH
FOLFIRINOX combination therapy versus gemcitabine. Enhanced mesothelin-specific CD8 Tcell responses were associated with longer OS, regardless of treatment arm. Preclinically, a large number of promising combination immunotherapies have been identified which are awaiting clinical testing [6]. 7DUJHWLQJ7*)ȕVLJQDOLQJDVSDUWRIFRPELQDWLRQLPPXQRWKHUDS\LVKHUHE\SDUWLFXODUO\DWWUDFWLYH DV 7*)ȕ OLJDQGV 7*)ȕ  DQG  DUH  RQH RI WKH PRVW DEXQGDQW F\WRNLQHV LQ WKH WXPRU microenvironment and H[HUWLPPXQHVXSSUHVVLYHIXQFWLRQRQDYDULHW\RILPPXQHHIIHFWRUV 7KXV7*)ȕLQKLELWLRQSRVVLEO\DIIRUGVUHSURJUDPPLQJWRZDUGVDQDQWL-tumor environment on a number of different cellular levels not requiring the combination of several agents directed against individual immune cell populations (Figure 3).  
  
0DQ\ W\SHV RI FHOOV LQ WKH WXPRU PLFURHQYLURQPHQW SURGXFH 7*)ȕ LQFOXGLQJ WKH WXPRU FHOOV
WKHPVHOYHV LPPDWXUH P\HORLG FHOOV UHJXODWRU\ 7 FHOOV DQG VWURPDO ILEUREODVWV WKHVH FHOOV collectively genHUDWH D ODUJH UHVHUYRLU RI 7*)ȕ LQ WKH H[WUDFHOOXODU PDWUL[ 7*)ȕ VLJQDOLQJ contributes to tumor progression by promoting metastasis, stimulating angiogenesis, and suppressing innate and adaptive antitumor immunity [8] As a broadly immunosuppressive factor, 7*)ȕGLUHFWO\GRZQUHJXODWHVWKHHIIHFWRUIXQFWLRQRIDFWLYDWHGF\WRWR[LF7FHOOVDQGQDWXUDONLOOHU (NK) cells and potently induces the differentiation of naïve CD4+ T cells to the immunosuppressive regulatory T cells (Treg) phenotype.[9] ,Q DGGLWLRQ 7*)ȕ SRODUL]HV macrophages and neutrophils to a wound-healing phenotype (alternative activation of PDFURSKDJHV0SKHQRW\SHWKDWLVDVVRFLDWHGZLWKSURGXFWLRQRILPPXQRVXSSUHVVLYHF\WRNLQHV [10] As a therapeutic VWUDWHJ\QHXWUDOL]DWLRQRI7*)ȕDFWLYLW\KDVWKHSRWHQWLDOWRFRQWUROWXPRU growth by restoring effective antitumor immunity, blocking metastasis, and inhibiting angiogenesis. 2QWKHRWKHUKDQG7*)ȕKDVJURZWKLQKLELWRU\HIIHFWVRQQRUPDOHSLWKHOLDOFHlls, functioning as a regulator of epithelial cell homeostasis, and it acts as a tumor suppressor during early FDUFLQRJHQHVLV$VWXPRUVSURJUHVVWRZDUGPDOLJQDQF\WKHJURZWKLQKLELWRU\HIIHFWVRI7*)ȕRQ the tumor are lost via mutation in one or more of WKH7*)ȕ SDWKZD\ VLJQDOLQJFRPSRQHQWV RU through oncogenic reprogramming [6@ 8SRQ ORVV RI VHQVLWLYLW\ WR 7*)ȕ LQKLELWLRQ WKH WXPRU FRQWLQXHVWR SURGXFH KLJKOHYHOV RI7*)ȕZKLFKWKHQ VHUYHWRSURPRWHtumor growth [6] The 7*)ȕ F\WRNLQH LV RYHUH[SUHVVHG LQ YDULRXV FDQFHU W\SHV LQFOXGLQJ SDQFUHDV FDQFHU ZLWK correlation to tumor stage.[6, 7@+LJKOHYHOV RI7*)ȕ KDYHDOVR EHHQ IRXQGLQDXWRFKWKRQRXV models of pancreas cancer.[7] A high level of TGF-ȕ ZDV IRXQG LQ VHUXP RI SDWLHQWV ZLWK pancreatic adenocarcinoma suggesting that TGF-ȕFRXOGSRVVLEO\EHFRPHDPDUNHUIRUPRQLWRULQJ disease activity.[11] The programmed death 1 (PD-1) / PD-/ D[LV LV DQ LPSRUWDQW PHFKDQLVP IRU WXPRU LPPXQH evasion.[12] (IIHFWRU 7 FHOOV FKURQLFDOO\ VHQVLQJ DQWLJHQ WDNH RQ DQ H[KDXVWHG SKHQRW\SH DUH marked by PD-H[SUHVVLRQDQGHQJDJHZLWKWXPRUFHOOV RYHUH[SUHVVLQJ3'-L1. Blocking the D[LVUHVWRUHVWKHHIIHFWRUIXQFWLRQLQWKHse T cells. Additionally, in the tumor microenvironment, myeloid cells, macrophages, parenchymal cells, and T cells upregulate PD-L1. To date, single agent immune checkpoint inhibition in patients with advanced pancreatic cancers did not show objective response rates, indicating that a dual inhibition approach with PD-L1 inhibition in combination with gemcitabine, or PD-/LQKLELWLRQZLWK7*)ȕQHXWUDOL]DWLRQRU– as suggested in this protocol with both might be necessary to overcome immune evasive cues of the pancreas cancer stroma and an attractive option to be investigated. [13] 1.2.4 Preclinical rationale for the combination of gemcitabine and PD-L1 inhibition in pancreas cancer Immunologic studies in human pancreas cancer subjects have shown that gemcitabine has, in  
  
DGGLWLRQ WR LWV F\WRWR[LF PHFKDQLVP RI DFWLRQ ZHDN LPPXQRPRGXODWRU\ IXQFWLRQ E\ UHGXFLQJ
peripheral MDSCs, T-UHJV DQG 7*)ȕ OHYHOV LQ SDQFUHDV FDQFHU SDWLHQWV ZLWKRXW DIIHFWLQJ
proliferative capDFLW\RIF\WRWR[LF&'7FHOOV (**Figure 4**). When tested in the autochthonous Rasdriven 3G[-1-&UH LSL-KrasG12D/+ Ink4a(p16)/Arf(p19)IOR[IOR[ (KP16) model, gemcitabine given at sub-equivalent human doses increased intratumoral CD8+ T cells as well anti-tumor activity of CD8+ T when co-cultured with KP16 cancer cells (**Figure 4**). When combined with human equivalent doses of anti-PD-L1, gemcitabine in combination with PD-L1 blockade, as suggested in the proposed study (anti-PD-/FRPSRQHQWDYHOXPDERI0H[WHQGHGVXUYLYDOFRPSDUHG to PD-L1 inhibition or gemcitabine alone.  
vehicle and gemcitabine-treated (40mg/kg twice weekly, animals harvested after 1 week). C Kaplan-0HLHUDQDO\VLVRI.3PLFHZLWKFRQILUPHGPPSDQFUHDWLFWXPRUVUDQGRPL]HGWRYHKLFOHDQWL**PD-L1, 40mg/kg gemcitabine twice weekly, or anti-PD-L1 in combination with gemcitabine.**
1.2.5 PrecliniFDOUDWLRQDOHIRUWKHFRPELQDWLRQRIJHPFLWDELQHDQG7*)ȕLQKLELWLRQ  
1.2.5.1 3UHFOLQLFDOUDWLRQDOHXVLQJWKH7*)ȕUHFHSWRU,VPDOOPROHFXOHLQKLELWRU/<LQ
combination with gemcitabine
Due to the inherent immunogenicity of M7824 as a humanized antibody and H[WUDFHOOXODUhuman 7*)ȕ UHFHSWRU ,,FRPSRQHQWZKHQDGPLQLVWHUHGWRWKH IXOO\LPPXQHFRPSHWHQWDXWRFKWKRQRXV KP16 mice, initial VWXGLHVZLWKWKH7*)ȕLQKLELWRU/<KDYHEHHQFDUULHGRXWWRVXSSRUWWKH XVH RI WKH GXDO 7*)ȕ DQG 3'-L1 inhibitor M7824 in combination with gemcitabine. Administration of M7824 to fully immune competent mice sensitizes the animals after 3 or 4 doses causing significant cytokine release and immune changes which carry the risk of false negative and positive readouts of studies in rodents with M7824. /< OLNH 0 DFWV DV D 7*)ȕ VLJQDOLQJ LQKLELWLQJ DJHQW /< VXSSUHVVHV GRZQVWUHDP 7*)ȕ UHFHSWRU VLJQDOLQJ WKURXJK ELQGLQJ WR WKH 7*)ȕ UHFHSWRU , suppress SKRVSKRU\ODWLRQDQGGLPHUL]DWLRQZLWK7*)ȕUHFHSWRU,,60$'DFWLYDWLRQDQGXOWLPDWHO\7*)ȕmediated gene transcription. M7824 shows similar end effector function like suppression of 60$'DFWLYDWLRQDQG7*)ȕ-mediated gene transcription, however its upstream mechanism is via WUDSSLQJRIIUHHXQERXQG7*)ȕOLJDQGV7*)ȕ/7*)ȕ/DQG7*)ȕ/:HOLNHWRVWLSXODWHWKDW ZLWKUHJDUGWRHIIHFWLYHQHVVRI7*)ȕ-mediated signal transduction, M7824 is likely to be the more efficacious agent due to
(1) 0RUH SHUVLVWHQW DQG PDLQWDLQHG HOLPLQDWLRQ RI WUDSSHG 7*)ȕ OLJDQGV DV VXJJHVWHG E\
human PK/PD studies)  
(2) 6XSSUHVVLRQ RI 7*)ȕ HVFDSH VLJQDOLQJ SDWKZD\V LQFOXGLQJ %03 DQG $/. UHFHSWRU
VLJQDOLQJ 7*)ȕ OLJDQGV KDYH EHHQ VKRZQ WR VWLPXODWH UHFHSWRU ,¶V RI $/. DQG %03 UHFHSWRUVZKLFKDUH SDUWRIWKH7*)ȕ VXSHUIDPLO\7KHVHSUR-survival receptors are not LQKLELWHGE\WKH7*)ȕUHFHSWRU,VPDOOPROHFXOHLQKLELWRU/<FRPSDUHGWR0 LPSO\LQJPRUHHIILFDFLRXVVXSSUHVVLRQRISURPLVFXRXV7*)ȕHIIHFWV
Using the autochthonous Ras-driven 3G[-1-&UH LSL-KrasG12D/+ Ink4a(p16)/Arf(p19)IOR[IOR[
(KP16) PRGHO7*)ȕLQKLELWLRQLQFRPELQDWLRQZLWKJHPFLWDELQHFRRSHUDWLYHO\
(1) 6XSSUHVVHVWXPRUJURZWKDQGH[WHQGVVXUYLYDOFigure 5)
Version date: 03/20/2019  
  
(2) Reduces immune evasive cues in the tumor microenvironment (Figure 6)  
  
JHPFLWDELQHUHGIRUGD\VSULRUWRKDUYHVWDQGWXPRUGLJHVW7ȕ5**-I blockade in combination with**
gemcitabine reduces CD4+FoxP3+ T regulatory cells (23.2% vs 11.0%; p=0.0010), increased LQWUDWXPRUDO&'H&'D7 FHOOV  YV  S  UHGXFHG&'E*U**-1+ MDSCs**
YVS LQPXULQHSDQFUHDWLFFDQFHUV **with no impact on CD206+F4/80+Gr1-** WXPRUDVVRFLDWHGPDFURSKDJHVYVS FRPSDUHGWRYHKLFOH-treated tumors in the examined cancers (t test; 2-tailed; * p<0.05; ** p<0.01). Right, immunohistochemically co-stain of anti-CD4 (brown) and FoxP3 (red), arrows indicate lymphocytes with positive anit-CD4 and nuclear FoxP3 stain.  
(3) Increases in vitro anti-tumor immunity (**Figure 7**)  
  
Figure 7 7*)ȕEORFNDGHLQFRPELQDWLRQZLWKJHPFLWDELQHLQFUHDVHVDQWL**-tumor cellular immunity in**
murine pancreatic cancers. Left top, Induction of IFN-**ȖVHFUHWLRQE\LVRODWHGLQWUDWXPRUDO&'D7**
cells from KP16 tumors treated with vehicle (EODFN/<EOXHJHPFLWDELQHRUDQJHRUWKH
FRPELQDWLRQRI/<DQGJHPFLWDELQHLQUHGIROORZLQJKRXUVFR**-culture by KP16 pancreatic**
FHOOVDQGPHDVXUHGE\(/,6SRWDVVD\1VWLPXODWLRQRIVSOHQLF&'D7FHOOVVKRZQRQWKHULJKW
Increased expression of T cell activation markers 4-**%%&'YVS DQG2;** (CD134) (4.2% vs 6.7%; p=0.014), and decreased PD-**H[SUHVVLRQOHYHOVRQ&'DYV** S LQ/<LQFRPELQDWLRQZLWKJHPFLWDELQH-treated tumors (t test; 2-tailed; * p<0.05; ** p<0.01).  
M7824 with dual anti-PD-L1 and anti-7*)ȕDFWLRQPLJKWRYHUFRPHFRRSHUDWLYHO\LQGXFHG3'- /XSUHJXODWLRQE\7*)ȕEORFNDGHDQGJHPFLWDELQH In vitro and in vivo studies of LY364947 and gemcitabine show that both agents cooperatively  
 upregulate PD-L1 on cancer cells, a possible mechanism limiting the combined anti-7*)ȕ LQ combination with gemcitabine approach (Figure 8, **)LJXUH**). On human Panc1 cells treated for 24 hours with LY634947 and gemcitabine not affecting growth and not showing any additivity on in vitro drug response testing flow cytometry measured the fraction of PD-/SRVLWLYHFHOOVDV in vehicle-WUHDWHGLQ/<LQJHPFLWDELQH-WUHDWHGDQGLQFHOOVWUHDWHG with both (**Figure 8**).  
Figure 8 Cooperative upregulation of PD-L1 expression on human Panc1 pancreas cancer cells. Flow  
 cytometry of PD-**/H[SUHVVLRQRI3DQFFHOOV WUHDWHGZLWKYHKLFOH EODFN0/<0** (Panc1) and 100nM (KP16) gemcitabine (orange), or the combination (in red). Previous drug UHVSRQVH WHVWLQJ RI JHPFLWDELQH LQ FRPELQDWLRQ ZLWK   DQG 0 /< VKRZHG QR FRRSHUDWLYH LPSDFW RI /< /< DQG JHPFLWDELQH RQ JURZWK *HPFLWDELQH DQG /< concentrations not affecting growth were selected for PD-L1 expression experiments.  
That upregulation of PD-/ LV D UHVLVWDQFH PHFKDQLVP RI FRPELQHG 7*)ȕ EORFNDGH DQG gemcitabine and targeting PD-L1, as suggested with the dual anti-PD-/7*)ȕIXQFWLRQRI0 LQWKLV FOLQLFDO SURWRFROPLJKWLPSURYH FOLQLFDO RXWFRPHLV VKRZQLQ D VXUYLYDO H[SHULPHQW RI transgenic KP16 animals treated with LY634947 plus gemcitabine versus LY634947 plus gemcitabine plus PD-L1 inhibition (**Figure 10**). Kaplan Meier analysis VKRZV H[WHQVLRQ RI survival with the triplet combination (purple curve) YHUVXV7*)ȕLQKLELWLRQSOXVJHPFLWDELQH(red curve) suggesting that M7824 with dual PD-/DQG7*)ȕLQKLELWLRQPLJKWEHVXSHULRUWR7*)ȕ inhibition alone.  
  
TGF E inhibitor/G em citabine/D **-PD-L1 Survival Curve**
untitled h1
1.2.6 preclinical rationale using m7824

The inability to confidently administer M7824 for prolonged periods of time (beyond 10 - 14 days)
due to the development of allogeneic immune responses against human sequences of M7824 has been a limiting factor in small animal studies with M7824. However, the following 3 preclinical H[SHULPHQWDOVHULHVDUHSUHVHQWHGWRVXSSRUWWKHFRPELQDWLRQRI0ZLWKJHPFLWDELQH
untitled h1
reduction of primary tumor weight

The C57B/L Panc02 model is a syngeneic orthotopic injection model of pancreas cancer inducing pancreatic tumors through the injection of KRAS-mutant murine Panc02 into the pancreas of immunocompetent C57B/L6 wild type mice. These tumors are populated by immune cell populations from the host as they grow. While main immune population like tumor-associated macrophages, MDSCs, and T-regs have been identified in the later stages of Panc02 tumors, there are differences to the immune landscape of autochthonous murine models of pancreas cancer or human pancreatic cytoarchitecture. M7824, given on day 3, 5, and 7, in combination with gemcitabine reduced primary pancreatic tumor weight in this model with, in this model, no further cooperative effect on reduction of tumor growth compared to M7824 alone (**Figure 11**).  
  
Figure 11 M7824 in addition to gemcitabine reduces weights of Panc02 tumors (left). Animals were administered 3 doses of M7824 and 1 dose of gemcitabine (as indicated in table) and were harvested 28 days after start of treatment.  
&RQWUDU\ WR DERYH H[SHULPHQWV LQ WKH DXWRFKWKRQRXV .3 PXULQHPRGHO RI SDQFUHDV FDQFHU Panc02 mice were only given one single dose of gemcitabine, M7824 was due to its immunogenic WR[LFLW\OLPLWHGWRLQMHFWLRQVDQGWXPRUVZHUHDOORZHGWRJURZEDFNIRU an additional 14 days upon end of treatment with M7824 and gemcitabine. In addition, the known predominantly sarcomatoid histology of Panc02 tumors is considerably different from KP16 or KPC tumors, or human pancreas cancer specimens.  
To assess cooperativity between M7824 and gemcitabine in a cancer model with an approved standard of care gemcitabine and with a greater epithelial tumor component than in the Panc02 model, M7824 and gemcitabine were also tested in the C57B/L6 MB49 preclinical bladder cancer model (**Figure 12**). Improvement of clinical outcome in MB49 C57B/L6 mice treated with M7824 and gemcitabine compared to M7824 or gemcitabine monotherapy:
,PPXQHFRPSHWHQW&%/-PLFHZHUHVXEFXWDQHRXVO\LQRFXODWHGZLWK0%FHOOV[ज़6 per mouse) and when tumors reached 100mmज़WUHDWHGZLWKHLWKHU0ȝJi.e., day 2, 5, 8), gemcitabine (120 mg/kg, day 0), or a combination of the tZR,VRW\SHFRQWUROȝJi.e., day 2, 5, 8) and/or PBS (0.2 mL, imp., day 0) were administered as controls. Tumor volume, overall survival, and body weight were assessed. Neither M7824 nor gemcitabine treatment alone significantly inhibited MB49 tumor growth relative to control treatment (day 16), whereas the combination of M7824 with gemcitabine significantly inhibited tumor growth compared with Abbreviated Title: M7824/Gemcitabine for AAPC Version date: 03/20/2019 M7824 (p<0.001, day 16) or gemcitabine (p<0.001) monotherapies (Figure 12). Furthermore, M7824 and gemcitabine combination therapy modestly extended the median survival of MB49 tumor-bearing mice relative to M7824 and gemcitabine monotherapy (p<0.05). Assessment of body weight indicated that all treatments were well tolerated, as no major decreases in body weight were observed throughout the observation period (data not shown).  
  
Figure 12 M7824 in cooperation with gemcitabine improves clinical outcome in the MB49 syngeneic bladder cancer model. A Reduction of tumor volume in animals treated with both M7824 and gemcitabine (in orange) compared to animals receiving monotherapy of M7824 (red) or gemcitabine (blue). Treatment schedules listed in table on the right. B Individual tumor volume measurements per animal per group. C Kaplan Meier analysis of treatment cohorts shows extension of survival in animals receiving combination treatment compared to M7824 and gemcitabine monotherapy .
untitled h1
m7824 induces additional anti-tumor perturbations

Figure 4 has shown that gemcitabine cooperates with PD-L1 inhibition to extend survival of autochthonous KP16 pancreatic cancer. Comparing changes in the immune landscape of murine cancers upon treatment with avelumab, the PD-L1 component of M7824, with changes induced by M7824, PD-L1 inhibition through the avelumab fusion plus TGFβ inhibition, shows enhanced changes reprogramming the tumor microenvironment towards an anti-tumor immune milieu (Table 1). Most notably, treatment with the dual TGFβ-PD-L1 inhibitor M7824 had positive effects on the innate immune system (NK cells, MDSCs, DCs and M1 macrophages) that are not associated with PD-L1 blockade attesting to a second, cooperative anti-TGFβ function.  
| PD Response            | Anti-PD-L1       | M7824   |    |
|------------------------|------------------|---------|----|
| Proliferation          |                  |         |    |
| Activation             | t                | t       |    |
| Degranulation          |                  |         |    |
| Adaptive Immunity      | PD-1 expression  | f       | 4  |
| (CD8+ T cell response) | CXCR3 expression | t       | ↑  |
| Eomes expression       | t                | ↑       |    |
| Tumor CD8+ T cells     | t                |         |    |
| Tumor Tregs            | *                | ↑       |    |
| NC                     |                  |         |    |
| Splenic MDSCs          | 20% .            |         |    |
| Tumor MDSCs            | 10% ↓            | 50% ↓   |    |
| Splenic NK cells       | NC               |         |    |
| Innate Immunity        | Tumor NK cells   | NC      | A  |
| NC                     |                  |         |    |
| DC maturation          | t                |         |    |
| NC                     |                  |         |    |
| Tumor M1/M2 ratio**    |                  |         |    |  
M7824 has also been combined with other chemotherapeutics in solid organ cancer models with the combination of M7824 with standard-of-care therapeutic agent(s) showing superior efficacy compared to individual M7824 or chemo monotherapy. These include:
The therapeutic potential of M7824 was explored in combination with various standard of-care therapies. In combination with the core components of the FOLFOX chemotherapy regimen (oxaliplatin, fluorouracil and oxaliplatin), an additive enhancement in efficacy was demonstrated against MC38 colorectal carcinoma. This finding is in line with results shown in Figure 5 where blockade of TGF b signaling inhibition, via the use of the TBRI small molecule inhibitor LY2109761, cooperates as shown with gemcitabine to suppress tumor growth and extend survival in genetically engineered animal models of pancreas cancer. In combination with fractionated, localized radiotherapy, a highly synergistic antitumor effect was achieved with only a single low dose of M7824 in the MC38 tumor model. An augmented antitumor effect was also observed when M7824 was combined with pazopanib in a mouse renal cell carcinoma model, and with anti- CTLA-4 in a B16 melanoma model. Immunological readouts from these combination studies consistently showed additive immunomodulatory effects that correlated with antitumor response as shown in Figure 6 where TGF blockade and gemcitabine synergistically reprogram the immune landscape of KP16 pancreatic tumors towards an anti-tumor phenotype by, among others, cooperatively reducing T regulatory cells, MDSCs, or increasing intratumoral CD8+ T cells. Of note, TGF b signaling inhibition in combination with gemcitabine not only decreases T regulatory cells, it also decreases their anti-tumor immune evasive function. Figure 13 shows that intratumoral CD4+CD25+ T regulatory cells isolated from murine KP16 pancreatic tumors treated with TGFβ inhibition and gemcitabine impair upon co-culture anti-tumor activity of CD8+ T cells significantly less than T regulatory cells isolated from vehicle-treated tumors. Overall, above  
 FRPELQDWLRQ WUHDWPHQW GDWD VXJJHVW WKDW 0 FDQ EH H[SORUHG DV D FRPELQDWLRQ SDUWQHU LQ different clinical settings for the treatment of cancer patients as proposed in this study.  
Figure 13 CD4+CD25+ intratumoral T regulatory cells isolated from murine pancreatic tumors WUHDWHGIRUGD\VZLWK/<LQFRPELQDWLRQZLWKJHPFLWDELQHKDYHUHGXFHGDQWL**-tumor efficacy**
compared to T regulatory cells isolated from vehicle-treated tumors. ELISpot assay of CD8+ T cells and KP16 cancer cells after addition of no T regulatory cells (black), 10,000 CD4+CD25+ cells from YHKLFOH WUHDWHG WXPRUV EOXH DQG  IURP/<**-combination with gemcitabine-treated**
tumors (red) (representative ELISpots of three groups on the left; summary of N=3 mice per group, right).  
7RVKRZWKDW7UHJXODWRU\FHOODQGP\HORLGLPPXQHSRSXODWLRQVFRRSHUDWLYHO\DIIHFWHGE\7*)ȕ LQKLELWLRQDQGJHPFLWDELQHLQDERYHVWXGLHVDQGE\WKHGXDO7*)ȕ-PD-L1 inhibitor are connected WR7*)ȕVLJQDOLQJDQG7*)ȕOHYHOVLQKXPDQVDPSOHVZHFRUUHODWHGLQFOLQLFDOVSHFLPHQVIURP The Cancer Genome Atlas (TCGA) and the International Cancer Genome Consortium (ICGC) GDWDVHWVH[SUHVVLRQOHYHOVRIDSUHYLRXVO\YDOLGDWHG7*)ȕUHVSRQVHVLJQDWXUe (TGRS) as well as 7*)ȕJHQHH[SUHVVLRQOHYHOVZLWKH[SUHVVLRQOHYHOVRI
x 7UHJXODWRU\FHOOPDUNHUFRPELQDWLRQ)R[3DQG&'7UHJXODWRU\FHOOV
x Monocyte/macrophage-lineage cell marker combination CD11b and CD33 (Figure 14).  
There was a strong association (p<1016) between TGFbeta-dependency measured by high H[SUHVVLRQOHYHOVRIWKH7*)ȕ5HVSRQVH6LJQDWXUH7%56DQGWRDOHVVHUGHJUHH7*)ȕOLJDQG
OHYHOVDQGH[SUHVVLRQOHYHOVRIWKHLPPXQHFHOOSRSXODWLRQ-selective markers CD25high )R[3high
(T regulatory cells) CD11bhigh CD33high (human MDSC markers) both in all cancers and in SDQFUHDWLFFDQFHUJHQHH[SUHVVLRQVHWV7KHVHILQGLQJVVXJJHVWWKDWLQWUDWXPRUDO7*)ȕVLJQDOLQJ is connected to T regulatory cell and myeloid immune cell population levels and that these immune cell populatiRQVDUHLQGHHGUHJXODWHGE\7*)ȕZKLFKVXSSRUWVDERYHILQGLQJVRIDOWHUHG7UHJDQG 0'6&FHOOIUDFWLRQVXSRQ7*)ȕLQKLELWLRQ
23 Abbreviated Title: M7824/Gemcitabine for AAPC
Version date: 03/20/2019  
  
  
CD25high FoxP3high and CD11bhigh CD33high was defined by the median of all observations for each marker across all included cancer samples
,Q VXPPDU\ 7*)ȕ VLJQDOLQJ LQKLELWLRQ LQ FRPELQDWLRQ ZLWK JHPFLWDELQH LQGXFHV LPPXQHmediated cooperative mechanisms resulting in improved anti-tumor activity, suppression of tumor growth, and improved survival. These results attest to the immunomodulatory function of gemcitabine in pancreas cancer, an observation also made in human pancreas cancer patients (pancreas cancer patients treated with gemcitabine have been shown to have decreased MDSC, decreased T regulatory cell levels, increased T effector / T-UHJUDWLRVDQGUHGXFHG7*)ȕOLJDQG levels [13]), and justify the pursuit of a cRPELQDWLRQLPPXQHWKHUDS\DSSURDFKRI7*)ȕVLJQDOLQJ inhibition and gemcitabine. 1.2.7 6DIHW\RIFRPELQHG7*)ȕDQG3'-/LQKLELWLRQE\WKHGXDO7*)ȕ-PD-L1 inhibitor M7824 Targeting both, PD-1 / PD-/DQG7*)ȕVLJQDOLQJD[LVLVDWWUDFWLYHDVDQDQWLWXPRUDSSURDch. A UHFHQWUHSRUWIRXQGWKDWEORFNDGHRI7*)ȕVLJQDOLQJLQ7FHOOVRUGHOHWLRQRI7*)ȕIURP7FHOOV in a mouse model led to diminished PD- H[SUHVVLRQ LQ WXPRU-infiltrating CD8+ T cells.[14] Concomitant PD- DQG 7*)ȕ EORFNDGH FDQ UHVWRUH SUR-inflammatory cytokines.[15] These findings are consistent with our data generated in the transgenic pancreatic cancer KP16 mouse model showing decreased PD-H[SUHVVLRQRQ&'7FHOOVDQGWKDWDGGLWLRQDO3'-L1 blockade is ablH WR H[WHQG VXUYLYDO ZKHQ DGGHG WR 7*)EHWD LQKLELWLRQ DQG JHPFLWDELQH 6LPLODUO\ Ln a PXULQHPRGHORIKHSDWRFHOOXODUFDUFLQRPD7*)ȕDSSHDUHGWRLQFUHDVHWKHH[SUHVVLRQRI3'-L1 in dendritic cells, which in turn promoted T-cell apoptosis and increased percentage of CD25+, )R[S 7 UHJXODWRU\ FHOOV[16] Additionally, higher levels of circulating myeloid-derived VXSSUHVVRUFHOOV0'6&VDVLJQLILFDQWVRXUFHRI7*)ȕDUHDVVRFLDWHGZLWKIDLOXUHWRUHVSRQGWR anti-PD-1 therapy. Finally, the addition of PD-/LQKLELWLRQWR7*)ȕ EORFNDGHLQFRPbination with gemcitabine as shown in **Figure 10**H[WHQGVVXUYLYDOLQWKHDXWRFKWKRQRXV.3SDQFUHDV cancer model. 6LPLODUO\WKHGXDO7*)ȕ-PD-L1 inhibitor M7824 has been shown in syngeneic preclinical breast cancer models to enhances antitumor activity and prolongs survival above the effect of either the anti-PD-/DQWLERG\DYHOXPDERU7*)ȕ5,,FRQWURODORQH7XPRU UH-FKDOOHQJHH[SHULPHQWVLQ
cured mice show durable protective immunity. In vivo studies showed that the antitumor effects ZHUHPHGLDWHGE\&'7FHOOVDVLQDERYHGHVFULEHG.3DQLPDOH[SHULPHQWVDQG1.FHOOV CD8+ T-cell tumor infiltrates were observed and, overall, the CD8+ response was associated with long term protective immunity. Importantly, in the syngeneic MC38 model, M7824 showed VLJQLILFDQWO\EHWWHUHIILFDF\WKDQWKHFRPELQDWLRQRIDYHOXPDESOXV7*)ȕ7UDSFRQWUROVXSSRUWLQJ the rationale of combining the 2 active moieties in 1 molecule. Thus, given the emerging picture for PD-1 / PD-L1 class, in which responses are apparent but with room for increase in effect size, it is assumed that co-targeting a complementary immune modulation step will improve tumor response and it is H[SHFWHGWKDWWKHDQWL-PD-L1 function of M7824 suppresses the immune evasive signal of increased PD-/H[SUHVVLRQRQFDQFHUFHOOVDQG KHQFHHQKDQFHHIILFDF\RIWKH7*)ȕLQKLELWLRQSOXVJHPFLWDELQHFRPELQDWLRQDSSURDFK $ EULHI VXPPDU\ RI VDIHW\ H[SHULHQFH with the PD-1 inhibitors nivolumab (Opdivo®) and pembrolizumab (Keytruda®) is given here, based on prescribing information (refer to current label information for updated information). For pembrolizumab the section on Warnings and Precautions includes adverse reactions of immune-PHGLDWHG SQHXPRQLWLV immune-PHGLDWHG FROLWLV  LPPXQH-PHGLDWHG KHSDWLWLV  LPPXQH-mediated K\SRSK\VLWLV  UHQDO IDLOXUH  DQG LPPXQH-PHGLDWHG QHSKULWLV immune-PHGLDWHG K\SHUWK\URLGLVP  DQG K\SRWK\URLGLVP  DQG D YDULHW\ RI RWKHU immune-PHGLDWHGDGYHUVHUHDFWLRQVRFFXUULQJLQOHVVWKDQRISDWLHQWV,QDGGLWLRQDZDUQLQJ IRU HPEU\RIHWDO WR[LFLW\ LV SURYLGHG )RU QLYROXPDE WKH VHFWLRQ RQ :DUQLQJ DQG 3UHFDXWLRQV includes adverse reactions of immune-PHGLDWHGSQHXPRQLWLVZLWKIDWDOLPPXQH-mediated SQHXPRQLWLV LQ   LPPXQH-PHGLFDWHG FROLWLV  LPPXQH-mediated hepatitis LPPXQH-PHGLDWHG QHSKULWLV DQG UHQDO G\VIXQFWLRQ  LPPXQH-mediated K\SHUWK\URLGLVPDQGK\SRWK\URLGLVPDQGDYDULHW\RIRWKHULPPXQH-mediated adverse UHDFWLRQVRFFXUULQJLQOHVVWKDQRISDWLHQWV,QDGGLWLRQDZDUQLQJIRUHPEU\RIHWDOWR[LFLW\LV provided.  
6DIHW\ H[SHULHQFH ZLWK YDULRXV 7*)E targeting agents described in the literature suggests no overlapping immune-related profile with compounds of the anti-PD-1 / anti-PD-L1 class. In Phase ,WULDOVWKHH[SHULHQFHZLWKDPROHFXOHZLWKDKLJKO\VLPLODUPHFKDQLVPWRWKHM7824 7*)ȕ trap moiety, the anti-TGFE-and 3 antibody IUHVROLPXPDEVKRZHGQRGRVHOLPLWLQJWR[LFLW\XS
to 15 mg/kg and no immune related events.[17] There were no DLTs and the only major AEs were skin lesions, mainly keratoacanthomas, some with atypical features, one event of squamous cell carcinoma, plus hyperkeratosis of the skin. Immune events were not reported. A syndrome known as Ferguson-Smith disease is caused by mutations in TGFE is associated with the formation of keratoacanthomas, similar to the findings described for fresolimumab.[18] Therefore, it is plausible that skin tumors observed during fresolimumab treatment may be related to TGFE
inhibition. A neutralizing antibody against TGFE-7ȕ0ZDVZHOOWROHUDWHGZKHQVWXGLHGDV
high as 240 mg with diarrhea as the only DLT event. Notably, one event of low Hgb was observed in the high dose group. This is notable since the only preclinical finding associated with M7824 was decreased Hgb. Trabedersen, an antisense oligonucleotide WKDWLQKLELWV7*)ȕH[SUHVVLRQ was associated with thrombocytopenia that was moderate.[19] ,QOLQHZLWKDERYHHDUO\FOLQLFDOH[SHULHQFHRIVLPLODUDQWL-7*)ȕDJHQWVWKHWR[LFLW\ profile of M7824 is predominantly benign and highly comparable to that of avelumaE LQ WKH UHFHQWO\ UHOHDVHGUHVXOWVRIWKHSKDVH,VWXG\1&7µ3KDVH7ULDORI0D%LIXQFWLRQDO)XVLRQ Protein Targeting PD-/DQG7*)ȕLQ$GYDQFHG6ROLG7XPRUV¶ZLWKGRVHHVFDODWLRQFRKRUWVRI DQGPJNJ H[FHHGLQJWKHPJIOat starting dose in this study) M7824 given 2weekly, the MTD was not reached: Data suggested overall good tolerance. One out of 16 patients GHYHORSHGDNHUDWRDFDQWKRPDZKLFKFRXOGEHUHODWHGWRWKH7*)ȕLQKLELWLRQPHFKDQLVPRI0 There was no grade 4-5 TEAEs. The only DLT observed was colitis. Overall, the MTD was not H[FHHGHG DW GRVHV XS WR  PJNJ IRU IXUWKHU GHWDLOV SOHDVH DOVR VHH Section **1.2.8**. Pharmacokinetic / Pharmacodynamic including human phase I findings of M7824). 2QWKHRWKHUKDQGWR[LFRORJLFDOILQGLQJVZLWK0LQF\QRPROJXVPRQNH\LQGLFDWHGDGHFUHDVH LQUHGEORRGFHOOVFRPSDUHGZLWKWKHFRQWUROJURXSYDOXHV and related parameters (Hgb and KHPDWRFULW 7KHVH GHFUHDVHV ZHUH UHYHUVLEOH GXULQJ WKH UHFRYHU\ SHULRG thus, anemia is FRQVLGHUHGDSRWHQWLDOULVNRIWKHFRPSRXQG'XHWRWKHLQYROYHPHQWRI7*)ȕLQUHSDLURIVNLQDQG other tissue injuries, alterations in wound healing or repair of tissue damage is considered a potential risk. Overall, evidence suggests non-RYHUODSSLQJWR[LFLW\ SURILOHV IRU DQWL-PD-L1 and anti-7*)ȕDJHQWFODVVHV7KHUHLVDWKHRUHWLFDOSRWHQWLDORILU$(VWKDWZRXOGEHWKHFRQVHTXHQFH of a GRXEOHEORFNDGHRIQHJDWLYHUHJXODWRU\ORRSVRIWKHLPPXQHV\VWHPKRZHYHUWKDWZDVQRW seen in the several hundred of patients treated with 1,200mg M7824 to date. For full SUHFOLQLFDOWR[LFRORJ\DQGLQYLYRSKDUPDFRORJ\ILQGLQJVRI0LQFOXGLQJLQPice and non-human primates, please refer to the latest version of the Investigator Brochure of M7824. 1.2.8 Pharmacokinetic / Pharmacodynamic profile of M7824 including human phase I findings Preclinical PK data and PK / PharmDyn analysis for M7824 is available from mice and cynomolgus monkeys. The single-dose data in monkey shows non-linearity between the low doses of 0.8 and 4 mg/kg versus the high dose of 20 mg/kg, which had reduced clearance, suggesting a VDWXUDEOHFRPSRQHQW7KH7*)ȕ ELQGLQJZDVDVVHVVHGDnd showed suppression for prolonged SHULRGV EH\RQG GUXJ H[SRVXUH DW DOO GRVHOHYHOV KRZHYHU baseline data contained data below lower limit of quantification and therefore these data were not considered relevant for PK/PharmDyn projections. The fusion protein appeared stable since there was no evidence of intralinker cleavage. Mouse PK / PharmDyn models for tumor and peripheral blood (CD3+ splenic) PD-L1 occupancy were also generated. A brief summary of PK and PK / PharmDyn is as follows:
x The predicted human terminal half-life (t1/2) for M7824 LVDSSUR[LPDWHO\GD\V  
x 6LPXODWLRQV SUHGLFWWKDWD PJNJ GRVHZLOO SURYLGHDQDYHUDJHH[SRVXUH RIDSSUR[LPDWHO\
7 ȝJP/LQKXPDQV
x Based on PK / PharmDyn modeling and human projections:
o $W D KXPDQ GRVH RI  PJNJ  3'-L1 total occupancy at PD[LPXP VHUXP
concentration observed post-dose (CPD[) LV H[SHFWHGLQ 3%0&V SURYLGLQJ DSSUR[LPDWHO\
WRWDORFFXSDQF\LQWXPRU
o $WDKXPDQGRVHRIPJNJPRUHWKDQRI3'-L1 total occupancy at CPD[ LVH[SHFWHG
in PBMCs and tumor o $W D KXPDQ GRVH RI  PJNJ  HIIHFW LV SURMHFWHG LQ WXPRU UHJUHVVLRQ LQ WKH
PK / 3KDUP'\QPRGHOFRPSDUHGZLWKDWPJNJ
x Human projections indicate a dose of 7.5 mg/kg and higher (range 4 to 20 mg/kg), on a biweekly schedule is needed to achieve full efficacy based on a mouse tumor model in which complete tumor regressions were observed x Anti-GUXJ DQWLERGLHV ZHUH REVHUYHG LQ VRPH DQLPDOV KRZHYHU WKH LPSDFW RQ 3. RU
PK / PharmDyn is not known. Preclinical antidrug antibody formation is not predictive of human antibodies.
M7824 effectively engaged PD-L1 and reduced levels of all thrHH7*)ȕOLJDQGVE\VHYHUDORUGHUV of magnitude to undetectable levels. PD-/HQJDJHPHQWDQGVXSSUHVVLRQRI7*)ȕOLJDQGOHYHOV was maintained throughout the 14-day dosing interval (**Figure 15**). In the recently released initial phase I dose escalation cohort of M7824, 12 subjects had enrolled in the dose-escalation part of the study with 3 subjects treated at each dose level of M7824: 1, 3, 10, and 20 mg/kg, once every 2 weeks. Median age was 56 years (range: 34 to 78). All had ECOG PS 0 or 1, with a median of 4 prior therapies (range: 2 to 7). 1RVXEMHFWH[SHULHQFHGD'/7DQGQRVXEMHFWZDVGLVFRQWLQXHGIURPWUHDWPHQWIRUGUXJ-related treatment-emergent adverse events (TEAEs). No subject was reported with a TEAE with a Preferred Term of infusion-UHODWHG UHDFWLRQ  VXEMHFWV ZHUH reported with TEAEs that were classified as "infusion-UHODWHG UHDFWLRQV´ZLWKWKH3UHIHUUHG7HUPVRIDEGRPLQDOSDLQS\UH[LD and back pain. 2YHUDOORIVXEMHFWVKDGGUXJ-related TEAEs. All drug related TEAEs were Grade 1 or 2: mouth hemorrhaJH  VXEMHFWV  GU\ PRXWK HSLVWD[LV LQIOXHQ]D-like illness, PDFXORSDSXODUUDVKSUXULWLVVXEMHFWHDFK To date, 1 subject with pancreatic cancer (3 mg/kg cohort) has been reported with a confirmed PR according to RECIST (ongoing at 6 moQWKV,QDGGLWLRQ6'KDVEHHQUHSRUWHGVXEMHFWV including 1 subject in the 1 mg/kg cohort, and 2 subjects in each of the 3 and 10 mg/kg cohorts. )LYHVXEMHFWVZHUHUHSRUWHGZLWKD%25RI3'$WWKHWLPHRIWKHGDWDFXWRIIVXEMHFWV
(UHPDLQHGRQWUHDWPHQW
All subjects from the first 3 dose levels were evaluable for PK analysis showing at 3 and 10 mg/kg dose-OLQHDUSKDUPDFRNLQHWLFVDQGDQDSSUR[LPDWHW1/2 of 150 hours (6.25 days). Subjects from the 1, 3, 10, and 20 mg/kg dose levels were evaluable for PD-L1 target occupancy. At 3 mg/kg and above, PD-L1 target occupancy was high throughout the entire dosing interval  
 IURP&PD[WKURXJK&PLQ$OOVXEMHFWVIURPWKHILUVWGRVHOHYHOVZHUHHYDOXDEOHIRU7*)ȕ SODVPDFRQFHQWUDWLRQV$IWHU0LQIXVLRQ7*)ȕDQGFRQFHQWUDWLRQVZHUHXQGHWHFWDEOH
LQ DOO VXEMHFWV DW DOO GRVHV DQG UHPDLQHG VXSSUHVVHG WKURXJKRXW WKH GRVLQJ LQWHUYDO 7*)ȕ suppression was also evident in all subjects but its degree was dependent on dose and drug concentrations. These data indicate that full pharmacological activity of both modes of action of M7824 is generally achieved in peripheral blood at the dose of 3 mg/kg.  
Figure 15 PD-**/WDUJHWRFFXSDQF\DQGUHGXFWLRQRI7*)ȕOLJDQGVLQKXPDQVXEMHFWVWUHDWHGRQWK**e
'Phase 1 Trial of M7824, a Bifunctional Fusion Protein Targeting PD-**/DQG7*)ȕ¶1&7** Patients from the 3, 10, and 20 mg/kg dose levels were evaluable for PD-L1 target occupancy by PBMC assay, which reached saturating levels rapidly peripherally throughout the entire dosing LQWHUYDO ULJKW 3ODVPD FRQFHQWUDWLRQV RI 7*)ȕ ȕ DQG ȕ ZHUH VXEVWDQWLDOO\ UHGXFHG LI QRW
undetectable, after M7824 infusion for the entire dosing period (right). 1.2.9 Summary of Clinical Findings of M7824 including Adverse Events (AEs) in Pancreas Cancer Patients to date As of March 21st, DWOHDVW1 SDWLHQWVZLWKDGLDJQRVLVKDYHUHFHLYHGDWOHDVWRQHRUPRre, doses of 1,200mg of M7824. **Table 2** lists both drug-related and not-related AEs for items in which !RISDWLHQWVH[SHULHQFHWKHHYHQWRULIWKH event was Grade 3 or higher. Overall, the drug was well tolerated at the 1,200mg dose level with a typical AE profile for an advanced cancer patient FRKRUW2IQRWHDQHPLDZDVRXWZDVWKHPRVWJUDGHRUJUHDWHUWR[LFLW\7KHRQO\ other graGHWR[LFLWLHVRFFXUULQJLQPRUHWKDQSHUFHQWRIVWXG\VXEMHFWVZHUHIDWLJXHRXWRI DQGDEGRPLQDO GLVFRPIRUW  RXW 7KHUHZHUH  VXEMHFWVZLWKJUDGH events listed as related to M7824. These include G4: lipase increased (1 event), and G3: anemia (2), colitis (1), diarrhea (1), ALT increase (1).  
Table 2 Adverse Events (AEs) in pancreatic cancer cohort patients on EMR200647-001 dosed with 1,200mg M7824 (SMC 380 Expansion cut-off 21 Mar2017, First dose before 21 Feb 2017; N=36). Both drug-related and not drug-related AEs for items in which > 5% of patients experience the event, or if the event was Grade 3 or higher, are listed.  
| Primary System Organ Class   | Any Grade   | Grade  >=3   |         |       |
|------------------------------|-------------|--------------|---------|-------|
| Preferred Term               | n (%)       | n (%)        | n (%)   | n (%) |
| Anemia                       | 8 (22.2)    | 6 (16.7)     | 1 (2.8) | 0     |
| Leukocytosis                 | 3 (8.3)     | 3 (8.3)      | 0       | 0     |
| Palpitations                 | 2 (5.6)     | 0            | 0       | 0     |
| Abdominal Distention         | 4 (11.1)    | 0            | 0       | 0     |
| Abdominal Pain               | 9 (25.0)    | 4 (11.1)     | 0       | 0     |
| Abdominal Pain (upper)       | 2 (5.6)     | 0            | 0       | 0     |
| Ascites                      | 4 (11.1)    | 0            | 0       | 0     |
| Constipation                 | 9 (25.0)    | 2 (5.6)      | 0       | 0     |
| Diarrhea                     | 6 (16.7)    | 1 (2.8)      | 0       | 0     |
| Dysphagia                    | 2 (5.6)     | 0            | 0       | 0     |
| GI Hemorrhage                | 2 (5.6)     | 2 (5.6)      | 0       | 0     |
| Gingival Bleeding            | 2 (5.6)     | 0            | 0       | 0     |
| Melena                       | 2 (5.6)     | 0            | 0       | 0     |
| Nausea                       | 9 (25.0)    | 0            | 0       | 0     |
| Upper GI hemorrhage          | 1 (2.8)     | 1 (2.8)      | 0       | 0     |
| Vomiting                     | 7 (19.4)    | 0            | 0       | 0     |
| Chills                       | 3 (8.3)     | 0            | 0       | 0     |
| Fatigue                      | 13 (36.1)   | 4 (11.1)     | 0       | 0     |
| Malaise                      | 2 (5.6)     | 0            | 0       | 0     |
| Peripheral Edema             | 5 (13.9)    | 0            | 0       | 0     |
| Pyrexia                      | 9 (25.0)    | 0            | 0       | 0     |  
| Version date: 03/20/2019  Bile duct obstruction   | 1 (2.8)   | 1 (2.8)   | 0       | 0       |
|---------------------------------------------------|-----------|-----------|---------|---------|
| Cholangitis                                       | 2 (5.6)   | 1 (2.8)   | 0       | 0       |
| Biliary Tract Infection                           | 1 (2.8)   | 1 (2.8)   | 0       | 0       |
| Pneumonia                                         | 2 (5.6)   | 1 (2.8)   | 0       | 0       |
| Sepsis                                            | 1 (2.8)   | 1 (2.8)   | 1 (2.8) | 0       |
| UTI                                               | 3 (8.3)   | 3 (8.3)   | 0       | 0       |
| ALT increased                                     | 3 (8.3)   | 0         | 0       | 0       |
| AST increased                                     | 5 (13.9)  | 0         | 0       | 0       |
| Blood Alk Phos Increased                          | 1 (2.8)   | 1 (2.8)   | 0       | 0       |
| Blood Bilirubin Increased                         | 3 (8.3)   | 2 (5.6)   | 1 (2.8) | 0       |
| GGT Increased                                     | 1 (2.8)   | 1 (2.8)   | 0       | 0       |
| Lipase increased                                  | 1 (2.8)   | 1 (2.8)   | 1 (2.8) | 0       |
| Weight decreased                                  | 3 (8.3)   | 0         | 0       | 0       |
| Decreased Appetite                                | 9 (25.0)  | 2 (5.6)   | 0       | 0       |
| Hypercalcemia                                     | 1 (2.8)   | 1 (2.8)   | 0       | 0       |
| Hypokalemia                                       | 2 (5.6)   | 1 (2.8)   | 0       | 0       |
| Hyponatremia                                      | 2 (5.6)   | 2 (5.6)   | 1 (2.8) | 0       |
| Hypophosphatemia                                  | 1 (2.8)   | 1 (2.8)   | 0       | 0       |
| Arthralgia                                        | 2 (5.6)   | 0         | 0       | 0       |
| Musculoskeletal Pain                              | 2 (5.6)   | 0         | 0       | 0       |
| Cancer Pain                                       | 1 (2.8)   | 1 (2.8)   | 0       | 0       |
| Keratoacanthoma                                   | 2 (5.6)   | 0         | 0       | 0       |
| Malignant Neoplasm                                | 1 (2.8)   | 1 (2.8)   | 0       | 0       |
| Progression  Malignant Pleural Effusion           | 3 (8.3)   | 1 (2.8)   | 0       | 0       |
| Pancreatic Carcinoma                              | 1 (2.8)   | 1 (2.8)   | 1 (2.8) | 1 (2.8) |
| Dizziness                                         | 4 (13.9)  | 3 (8.3)   | 1 (2.8) | 1 (2.8) |
| Embolic Stroke                                    | 1 (2.8)   | 1 (2.8)   | 1 (2.8) | 1 (2.8) |
| Headache                                          | 3 (8.3)   | 0         | 0       | 0       |
| Peripheral Motor Neuropathy                       | 1 (2.8)   | 1 (2.8)   | 0       | 0       |
| Somnolence                                        | 1 (2.8)   | 1 (2.8)   | 0       | 0       |
| Anxiety                                           | 1 (2.8)   | 1 (2.8)   | 0       | 0       |
| Cough                                             | 2 (5.6)   | 0         | 0       | 0       |
| Dyspnea                                           | 4 (11.1)  | 0         | 0       | 0       |
| Hiccups                                           | 2 (5.6)   | 1 (2.8)   | 0       | 0       |
| Nasal Congestion                                  | 2 (5.6)   | 0         | 0       | 0       |
| Pleural Effusion                                  | 2 (5.6)   | 0         | 0       | 0       |
| Pulmonary Embolism                                | 2 (5.6)   | 2 (5.6)   | 0       | 0       |
| Respiratory Failure                               | 1 (2.8)   | 1 (2.8)   | 1 (2.8) | 0       |
| Pruritis                                          | 3 (8.3)   | 0         | 0       | 0       |
| Rash                                              | 4 (11.1)  | 0         | 0       | 0       |
| Hypertension                                      | 2 (5.6)   | 1 (2.8)   | 0       | 0       |  
3UHOLPLQDU\ FOLQLFDOHIILFDF\ VLJQDO RIWKH1  SDQFUHDWLFFDQFHU0PRQRWKHUDS\FRKRUW (provided by EMD Serono): Preliminarily, additional clinical activity has been seen with objective responses and prolonged disease stabilization. However, the cohort is being actively reviewed and remains dynamic. In addition, after discussion among NCI investigators on multiple protocols using M7824, multiple EOHHGLQJ HYHQWV UDQJLQJ IURP ORZ JUDGH JLQJLYDO EOHHGLQJ DQG HSLVWD[LV WR PRUH VHULRXV hemoptysis, GI bleeding and hematuria have been observed. Some of these events can be attributed to bleeding events related to cancer directly and others bleeding events can be attributed to colitis RU F\VWLWLV ZKLFK LV D NQRZQ WR[LFLW\ RI DQWL-PD-L1 agents including M7824. However, there remains the possibility that M7824 may increase the overall risk of bleeding in ways that may not be directly related to direct tumor bleeding or inflammatory bleeding events described with checkpoint inhibitors like M7824. It is hypothesized that this possible increased bleeding risk may EHGXHWR7*)EHWDLQKLELWLRQZKLFKKDVDQHIIHFWRQDQJLRJHQHVLVEOHHGLQJKDVDOVREHHQREVHUYHG in patients receiving M7824 and may be drug-related (e.g., gum bleeding, nose bleeds, coughing up blood, blood in their urine, or blood in the stool). Accordingly, patients will be notified of the same possible risk in the informed consent document for this study. 1.2.10 Rationale for the Clinical Trial The administration of M7824 in combination with gemcitabine to subjects with advanced pancreatic tumors who have progressed on 1st-line systemic chemotherapy is justified by the following:  
x PD-L1 inhibition, one of the dual components of M7824, in combination with gemcitabine FRRSHUDWLYHO\ H[WHQGVsurvival compared to PD-L1 inhibition or gemcitabine monotherapy alone in autochthonous murine pancreatic cancer models x 7*)ȕ EORFNDGH WKH VHFRQG FRPSRQHQW RI 0 LQ FRPELQDWLRQ ZLWK JHPFLWDELQH
FRRSHUDWLYHO\ LQKLELWV WXPRU JURZWK DQG H[WHQGV VXUYLYDO FRPSDUHG WR 7*)ȕ LQKLELWRU RU gemcitabine monotherapy alone in autochthonous murine pancreatic cancer models x Upregulation of PD-/XSRQ7*)ȕLQKLELWLRQis a mechanism of resistance to optimal efficacy RI7*)ȕEORFNDGHLQFRPELQDWLRQZLWKJHPFLWDELQHDQGWKe addition of PD-L1 inhibition to 7*)ȕEORFNDGHDQGJHPFLWDELQHIXUWKHUH[WHQGVVXUYLYDOµWULSOHLPPXQRWKHUDS\FRPELQDWLRQ¶
x Pancreatic tumor weights are further reduced by the addition of gemcitabine compared to M7824 therapy alone in the syngeneic Panc02 pancreatic cancer mouse model x M7824 either in combination with gemcitabine, or in combination with other systemic chemotherapy agents, additively reduces tumor growth compared to respective monotherapies in other syngeneic mouse models (MB49 bladder cancer, MC38 colon cancer)
x 6DIHW\ H[SHULHQFH ZLWK 7*)ȕ-targeting agents described in the literature suggests no overlapping immune-related adverse profile with the PD-1/PD-L1 class or with gemcitabine.  
x :LWKWKHH[FHSWLRQRIDQHPLD0DQGJHPFLWDELQHKDYHQon-RYHUODSSLQJWR[LFLW\SURILOHV x &OLQLFDOH[SHULHQFHZLWK0WR-date at the proposed 1,200mg flat dose level in pancreas cancer patients demonstrates an acceptable safety profile and as monotherapy clinical antitumor activity in multiple solid tumor types including pancreas cancer.  
1.2.11 5DWLRQDOHIRU0'RVH/HYHOVZLWKVSHFLDOFRQVLGHUDWLRQRIRYHUODSSLQJWR[LFLWLHV
with gemcitabine
The rationale for the starting dose of M7824 of 1,200mg is based on the clinical safety of this dose LQ PXOWLSOH SKDVH , H[Sansion cohorts of M7824 including in pancreas cancer, the preclinical margin considerations to the NOAEL of the pivotal safety assessments, the PK/PD findings of the SKDVH,VWXG\VKRZLQJKLJKO\HIIHFWLYH7*)ȕVXSSUHVVLRQDQGQHDUFRPSOHWH3'-L1 occupancy, DV ZHOO DV VDIHW\ H[SHULHQFH RI DYHOXPDE LQFOXGLQJ VDIHW\ HYDOXDWLRQ RI DYHOXPDE OHDGLQJ WR regulatory approval of avelumab for metastatic Merkel cell and urothelial cancer in 2017 (https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/761049s000lbl.pdf). The pivotal preclinical safety assessment of M7824 in non-human primate showed no adverse, HIIHFWVH[FHSWDWUHQGRIUHYHUVLEOHUHGEORRGFHOOUHGXFWLRQZLWKDssociated parameters (Hgb and hematocrit) and with no dose dependency. The NOAEL was set at the highest dose, 140 mg/kg administered weekly. Based on allometric scaling, the human equivalent of 140 mg/kg in monkey is 45 mg/kg/week or 90 mg/kg every 2 weeks (3,150mg/week or 6,300mg flat dose levels for 70kg individual every two weeks), as calculated by standard guidance (Food and Drug Administration [FDA] 2005), and is more than 5-fold higher than the chosen 1,200mg flat dose. In this regard, it should be noted that cross-VSHFLHV ELRORJ\ RI 7*)ȕ LV H[SHFWHG WR EH KLJKO\ VLPLODU EHWZHHQ KXPDQPRXVHDQGF\QRPROJXVSULPDWHVLQFH7*)ȕLVDQH[WUHPHO\KLJKO\FRQVHUYHGJHQHZLWK WKHPRXVHVHTXHQFH IRU7*)ȕGLIIHULQJE\RQO\RQHDPLQRDFLGDQGWKHcynomolgus monkey SUHGLFWHGWREHLGHQWLFDOWRKXPDQ)RU7*)ȕWKHDPLQRDFLGVHTXHQFHLVSUHGLFWHGWREH LGHQWLFDODFURVVPRXVHKXPDQDQGcynomolgus primate. With regard to the PD-L1 component of M7824, it can be noted for the selected 1,200mg flat starting dose that PD-L1 inhibition by avelumab (the PD-L1 component of M7824) has resulted LQH[SHFWHGLPPXQHIHDWXUHVZLWKDFXUUHQWO\DFFHSWDEOHVDIHW\SURILOHWKDWFRQWLQXHVWREHDVVHVVHG (refer to the current avelumab IB and https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/761049s000lbl.pdf). In dose escalation, avelumab did not achieve an MTD up to 20 mg/kg (1,400mg in 70kg individual), with only 1 DLT observed at the highest dose (refer to the current avelumab IB). To date, safety H[SHULHQFHKDVEHHQFROOHFWHGLQPRUHWKDQVXEMHFWVZLWKVROLGWXPRUVH[SRVHGWRWKHPJNJ GRVHDVGHVFULEHGIXUWKHULQWKLVVHFWLRQ7KHH[SRVXUHRI0ZLOOOLNHOy be similar at the same dose strength since the molarity for PD-/ELQGLQJLVDSSUR[LPDWHO\OHVVRI0EXWWKH half-OLIHLVSUHGLFWHGWREHDSSUR[LPDWHO\WRPRUH 2QHRIWKHSRWHQWLDOFRQFHUQVRI7*)ȕOLJDQG-binding agents has been the unknown therapeutic window between tumor-selective effects in the microenvironment of cancer and systemic WR[LFLWLHV%LQGLQJRI0WR IUHH7*)E in the periphery is projected to be substantial since 7*)ȕOHYHOVDUHYHU\ORZDSSUR[LPDWHO\QJP/[20] Human PK simulations suggest that a 1 PJNJGRVHZRXOGSURYLGHDQDYHUDJHH[SRVXUHRIDSSUR[LPDWHO\ȝJP/DSSUR[LPDWHO\WR
400 fold higher than the EC50 or IC50 for TGFE binding (17.9 ng/mL) and interference (38.3 ng/mL) assays. However, IRUWKLVPROHFXOHZKLFKELQGV7*)ȕDWPRODUUDQJHV(&50 and IC50 FDQQRW EH UHJDUGHG DV D IL[HG DIILQLW\ FRQVWDQW DQGLVWKHUHIRUH GLIILFXOWWR HVWLPDWHLQ KXPDQ
dosing. At a dose of 0.1 mg/kg on a biweekly dose schedule, the Ctrough is projected to be 150 ng/mL. However, from a safety standpoint, binding of TGFE in the periphery is of little consequence since circulating, free TGFE is unrelated to its functional tissue activity. TGFE
cytokines function not as circulating endocrines, but predominantly as autocrine and paracrine in the local environment including tumor environment.[8] This lack of interference with essential WLVVXHKRPHRVWDVLVUHJXODWHGE\7*)ȕLVFRUURERUDWHGE\WKHODFNRIGUXJ-related SAEs in the 36 pancreas cancer patients treated who received at least 1 dose of 1,200mg M7824 to date. While GHWDLOHG LQWUDWXPRUDO 7*)ȕ OHYHOV DQG 3.  3'G\Q PHDVXUHs of treated subjects are awaited, optimal effects of M7824 -PHGLDWHG7*)ȕLQKLELWLRQDWPJNJUDQJHWRPJNJEDVHGRQ YDULDELOLW\ EHWZHHQ VXEMHFWV LV SUHGLFWHG WR UHDFK HIIHFWLYH WXPRU JURZWK LQKLELWLRQ RI DSSUR[LPDWHO\7DNHQWRJHWKHUthe clinical safety data and preclinical NOAEL determinations in monkey (up to predicted 6,300mg in a highly-conserved target), 1,200mg is a reasonable starting dose from a safety perspective which offers anti-tumor efficacy. Thus, together with the benign nature of preclinical and clinical safety assessments for M7824 other than Hgb changes overall suggesting a low likelihood for systemic immune synergies or RYHUODSSLQJWR[LFLWLHVEHWZHHQWKH3'-/DQG7*)ȕ pathways, and gemcitabine, based on the to date  
x preclinical and clinical safety of M7824 administered at the 1,200mg dose level, and x non-RYHUODSSLQJWR[LFLW\SURILOHZLWKJHPFLWDELQH
dose-adjustments or discontinuation of drug(s) for each drug - M7824 and gemcitabine - will be made / carried out separDWHO\EDVHGRQWKHREVHUYHGWR[LFLW\SURILOH 1.2.12 Rationale for Gemcitabine Dose Selection and Safety Measures 7RDFFRXQWIRUSRVVLEOHJHPFLWDELQHWR[LFLW\H[DFHUEDWHGWKURXJKWKHFRPELQDWLRQZLWK0 the following two safety measures have been taken. The standard dose level of gemcitabine is 1,000 mg/m2 over 30 minutes once weekly for the first 7 weeks, then one week rest, then once weekly for 3 weeks of each 28-day cycle. Over the past decade there has been increased efforts to bring advances in pharmacogenomics to the bedside. **Figure 16** shows steps involved in catalyzing gemcitabine transport, intracellular activation, and metabolism. Previous retrospective studies have shown an association of nucleotide polymorphisms (SNP) of drug metabolic genes ZLWKWR[LFLW\RI-GLIOXRUR- GHR[\F\WLGLQHJHPFLWDELne)-based chemoradiotherapy and possibly clinical outcome including KHPDWRORJLFWR[LFLW\DQGRYHUDOl survival.  
Gemcitabine enters the cell via facilitated transport of nucleoside transporters and becomes activated through ATP-UHTXLULQJSKRVSKRU\ODWLRQE\GHR[\F\WLGLQHNLQDVHG&.WRWKHDFWLYHWULphosphatide metabolite dFdCTP in a rate-limiting step. The primary elimination route of gemcitabine is deamination by cytidine deaminase (CDA) to its main metabolite ¶¶- GLIOXRURGHR[\XULGLQH (dFdU) as the critical enzyme controlling gemcitabine levels. Due to this critical role of CDA in gemcitabine metabolism, pharmacogenomic VWXGLHVH[SORULQJ associations of small nucleotide polymorphisms (SNPs) in gemcitabine-metabolizing genes with clinical outcome have both in pancreas cancer and NSCLC focused on CDA and here on the CDA
Lys27Gln genotype (rs2072671, CDA 79A>C polymorphism.4)RURWKHUSRO\PRUSKLVPV
either in CDA or other gemcitabine-metabolizing genes, available clinical correlative studies are much rarer and evidence less robust. There are also large ethnic differences in SNP frequencies between Caucasian and Asian populations described. In the predominantly Caucasian pancreas cancer patient population and based on analysis of samples from the large phase III randomized RTOG 9704 study, rates of CDA Lys27Gln polymorphism genotyping showed the KRPR]\JRXV ZLOG W\SH /\V/\V ZDV IRXQG LQ ZKHUHDVWKHKHWHUR]\JRXV/\V*OQDQGKRPR]\JRXVYDULDQW*OQ*OQZDVIRXQGLQDQG [21] There was a statistically significant increased riVNIRUVHYHUHKHPDWRORJLFDOWR[LFLW\
JUDGHLQSDUWLFXODUIRUWKHKRPR]\JRXVCDA Lys27Gln*OQYDULDQWRGGVUDWLR25
S  EXW QRW IRU QRQ-KHPDWRORJLFDO WR[LFLWLHV RU VXUYLYDO ,PSRUWDQWO\ WKLV DVVRFLDWLRQ ZDV specific for the gemcitabine-treated patients and not seen in the cohort which received 5-FU. There have been other studies with similar, albeit less strong and in part conflicting, findings reported. In a retrospective analysis of 154 patients with potentially resectable pancreas cancer investigators IURPWKH0'$QGHUVRQ&DQFHU&HQWHUH[DPLQHG613VLQJHPFLWDELQH-metabolizing genes and LPSDFWRQVXUYLYDODQGWR[LFLW\&'$&7DQGQRW&'$&!$.4ZDVDVVRFLDWHGZLWK QHXWURSHQLF WR[LFLW\ [22] in a small study of 31 patients with NSCLC, patients carrying the nonsynonymous CDA SNP 79A >C (CDA K27Q KDG D ORZHU JHPFLWDELQH FOHDUDQFH DV compared to wild-type patients, but the risk for chemotherapy-DVVRFLDWHG QHXWURSHQLD  YV
3   DQG VHYHUH QHXWURSHQLD  YV  3  26) failed to reach statistical significance what might have been due to the small sample size. [23] The mean lower CDA activity of CDA 79A>C carriers was later confirmed in healthy subjects. [24] Of note, in Japanese cancer SDWLHQWVRIWKHWZRH[DPLQHG&'$KDSORW\SHVKDUERULQJWKHQRQ-synonymous SNPs CDA 79A>C
(Lys27Gln) and 208G>A (Ala70Thr) variants, 208G>A (Ala70Thr) was associated with higher drug-UHODWHGWR[LFLWLHVEXW&'$79A>C (Lys27Gln) was not. [25] The recently released European FFCD-
&OLQLFDO7ULDOµ,mpact of Cytidine Deaminase Activity on Clinical Outcome in GemcitabineMonotherapy Treated Patients¶ IURP WKH Fédération Francophone de Cancérologie Digestive DLPHGWR SURVSHFWLYHO\ H[DPLQHLPSDFW RI&'$DFWLYLW\ DIIHFWHGE\ 613LQ  SDWLHQWVZLWK resected pancreatic cancer.[26] Surprisingly, only 5 out of 120 (4.65) of patients were found to have a CDA polymorphism and the study ultimately lacked statistical power to detect on impact oQ JHPFLWDELQH WR[LFLW\ )LQDOO\ ERWK µPHWD-DQDO\VHV¶ FRQGXFWHG RQ WKH VXEMHFW RI &'$ polymorphisms and outcome of gemcitabine to date, did demonstrate a moderate impact of CDA 79A >C (CDA K27Q) SRO\PRUSKLVP RQ KHPDWRORJLFDOWR[LFLW\LQ JHPFLWDELQH-treated patients quoting:
- The homozygote mutant CDA Lys27Gln/Gln genotype was associated with an OR of 3.25 S [27], and
- patients with the variant CDA 79C>A allele H[SHULHQFHG PRUH JUDGH  Oeukopenia 25 &, 1.357-6.605) and more severe neutropenia 25 &,- 10.981) [28]  
  
Thus, to increase safety of patients treated with gemcitabine in combination of M7824, and in particular to account for any enhanced gemcitabine-GULYHQWR[LFLWLHVGXHWRWKHFRPELQDWLRQZLWK gemcitabine, patients will be genotyped prior to study treatment with the Drug Metabolizing
(Q]\PHVDQG7UDQVSRUWHU '0(73OXVJHQRW\SLQJSODWIRUP $II\PHWUL[ SDWients will be cosigned onto NCI 16-C-0076 "Prospective Screening for Patient Specific Genotypes and Phenotypes that Influence Drug Dosing and Trial Selection in Cancer Patients", PI: Dr. William D. Figg). Depending on the genotyping results (turnaround time 1 - 2 weeks), patients will be VWUDWLILHG LQWR ORZ DQG KLJK JHPFLWDELQH WR[LFLW\ ULVN JURXSV DGPLQLVWHUHG VWDUWLQJ GRVH RI JHPFLWDELQH'D\ZLOOEHDGMXVWHGDFFRUGLQJWRF\WLGLQHGHDPLQDVH&'$WKHPDMRUHQ]\PH responsible for gemcitabine clearance) rs2072671, CDA 79A>C polymorphism status:  
x Wild type including synonymous variants of both alleles and heterozygous, monoallelic UV &'$ $!& SRO\PRUSKLVP .4 ZLOO UHFHLYH  RI VWDQGDUG
gemcitabine dose (1,000mg/m2 weekly)
x Homozygous, biallelic rs2072671, CDA 79A>C polymorphisms (K27Q) will receive RIVWDQGDUGJHPFLWDELQHGRVHPJP2 weekly)
Upon Day 43, start of cycle \#5, after the initial 4 doses of gemcitabine, patients who have received OHVVWKDQRIWKHVWDQGDUGJHPFLWDELQHGose (initially tested positive for either heterozygous or homozygous CDA variants) and who have not shown any gemcitabine-UHODWHGWR[LFLW\ ZLOO
continue with standard (1,000mg/m2) gemcitabine dose.  
DMET samples will be drawn under NCI 16-C-0076 and sent to the Clinical Pharmacology Program for processing and analysis at Baseline. This analysis will be performed by the CLIA Molecular Diagnostics Laboratory, Frederick, MD (CLIA certificate 21D0947274) through Dr. :LOOLDP')LJJ¶V/DERUDWRU\&&5NCI. 1.2.13 Gemcitabine in Pancreas Cancer *HPFLWDELQH+&OLVDQXFOHRVLGHDQDORJXHWKDWH[KLELWVDQWLWXPRUDFWLYLW\*HPFLWDELQH+&OLV-  
 GHR[\--GLIOXRURF\WLGLQHPRQRK\GURFKORULGHȕ-isomer). The structural formula is as follows:
The empirical formula for gemcitabine HCl is C9H11F2N3O4 - HCl. It has a molecular weight of 299.66. Gemcitabine HCl is a white to off-white solid. It is soluble in water, slightly soluble in methanol, and practically insoluble in ethanol and polar organic solvents. The clinical formulation is supplied in a sterile form for intravenous use only. Vials of Gemzar contain either 200 mg or 1 J RI JHPFLWDELQH +&O H[SUHVVHG DV IUHH EDVH IRUPXODWHG ZLWK PDQQLWRO  PJ RU  J respectively) and sodium acetate (12.5 mg or 62.5 mg, respectively) as a sterile lyophilized SRZGHU+\GURFKORULFDFLGDQGRUVRGLXPK\GUR[LGHPD\KDYHEHHQDGGHGIRUS+DGMXVWPHQW
untitled h1
clinical pharmacokinetics

*HPFLWDELQHH[KLELWVFHOOSKDVHVSHFLILFLW\SULPDULO\NLOOLQJFHOOVXQGHUJRLQJ'1$V\QWKHVLV6phase) and also blocking the progression of cells through the G1/S-phase boundary. Gemcitabine is metabolized intracellularly by nucleoside kinases to the active diphosphate (dFdCDP) and WULSKRVSKDWH G)G&73 QXFOHRVLGHV 7KH F\WRWR[LF HIIHFW RI JHPFLWDELQH LV DWtributed to a combination of two actions of the diphosphate and the triphosphate nucleosides, which leads to inhibition of DNA synthesis. First, gemcitabine diphosphate inhibits ribonucleotide reductase, which is responsible for catalyzing the reactions that generate the GHR[\QXFOHRVLGH triphosphates for DNA synthesis. Inhibition of this enzyme by the diphosphate nucleoside causes a reduction in WKH FRQFHQWUDWLRQV RI GHR[\QXFOHRWLGHV LQFOXGLQJ G&73 6HFRQG JHPFLWDELQH WULSKRVSKDWH competes with dCTP for incorporation into DNA. The reduction in the intracellular concentration of dCTP (by the action of the diphosphate) enhances the incorporation of gemcitabine triphosphate into DNA (self-potentiation). After the gemcitabine nucleotide is incorporated into DNA, only one additional nucleotide is added to the growing DNA strands. After this addition, there is inhibition of further DNA synthesis. DNA polymerase epsilon is unable to remove the gemcitabine nucleotide and repair the growing DNA strands (masked chain termination). (from https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/020509s077lbl.pdf).
untitled h1
human pharmacokinetics

Gemcitabine disposition was studied in 5 patients who received a single 1,000 mg/m2 /30 minute infusion of radiolabeled drug (https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/020509s077lbl.pdf). Within one (1) ZHHNWRRIWKHGRVHZDVUHFRYHUHGDOPRVWHQWLUHO\LQWKHXULQH*HPFLWDELQH DQGWKHLQDFWLYHXUDFLOPHWDEROLWH-GHR[\--GLIOXRURXULGLQHG)G8DFFRXQWHGIRURI WKH H[FUHWHG GRVH 7KH PHWDEROLWH G)G8 LV DOVR IRXQG in plasma. Gemcitabine plasma protein ELQGLQJLVQHJOLJLEOH7KHSKDUPDFRNLQHWLFVRIJHPFLWDELQHZHUHH[DPLQHGLQSDWLHQWVDERXW 2/3 men, with various solid tumors. Pharmacokinetic parameters were derived using data from patients treated for varying durations of therapy given weekly with periodic rest weeks and using both short infusions (<70 minutes) and long infusions (70 to 285 minutes). The total Gemzar dose
untitled h1
table 3 pk parameters of

varied from 500 to 3,600 mg/m2. Gemcitabine pharmacokinetics are linear and are described by a 2-compartment model. Population pharmacokinetic analyses of combined single and multiple dose studies showed that the volume of distribution of gemcitabine was significantly influenced by duration of infusion and gender. Clearance was affected by age and gender. Differences in either clearance or volume of distribution based on patient characteristics or the duration of infusion result in changes in half-life and plasma concentrations. **Table 3** shows plasma clearance and half-life of gemcitabine following short infusions for typical patients by age and gender. Gemcitabine half-life for short infusions ranged from 32 to 94 minutes, and the value for long infusions varied from 245 to 638 minutes, depending on age and gender, reflecting a greatly increased volume of distribution with longer infusions. The lower clearance in women and the elderly results in higher concentrations of gemcitabine for any given dose. The volume of distribution was increased with infusion length. Volume of distribution of gemcitabine was 50 L/m2 following infusions lasting <70 minutes, indicating that gemcitabine, after short infusions, LVQRWH[WHQVLYHO\GLVWULEXWHGLQWRWLVVXHV)RUORQJLQIXVLRQVWKHYROXPHRIGLVWULEXWLRQURVHWR 370 L/m2, reflecting slow equilibration of gemcitabine within the tissue compartment. The PD[LPXPSODVPDFRncentrations of dFdU (inactive metabolite) were achieved up to 30 minutes DIWHUGLVFRQWLQXDWLRQRIWKHLQIXVLRQVDQGWKHPHWDEROLWHLVH[FUHWHGLQXULQHZLWKRXWXQGHUJRLQJ further biotransformation. The metabolite did not accumulate with weekly dosing, but its HOLPLQDWLRQLVGHSHQGHQWRQUHQDOH[FUHWLRQDQGFRXOGDFFXPXODWHZLWKGHFUHDVHGUHQDOIXQFWLRQ The effects of significant renal or hepatic insufficiency on the disposition of gemcitabine have not been assessed. The active metabolite, gemcitabine triSKRVSKDWHFDQEHH[WUDFWHGIURPSHULSKHUDO blood mononuclear cells. The half-life of the terminal phase for gemcitabine triphosphate from mononuclear cells ranges from 1.7 to 19.4 hours. Data from 2 clinical trials evaluated the use of Gemzar in patients with locally advanced or metastatic pancreatic cancer.[13, 29] The first trial compared Gemzar to 5-Fluorouracil (5-FU) in patients who had received no prior chemotherapy. A second trial studied the use of Gemzar in pancreatic cancer patients previously treated with 5-FU or a 5-FU-containing regimen. In both studies, the first cycle of Gemzar was administered intravenously at a dose of 1,000 mg/m2 over PLQXWHVRQFHZHHNO\IRUXSWRZHHNVRUXQWLOWR[LFLW\QHFHVVLWDWHGKROGLQJDGRVHIROORZHG by a week of rest from treatment with Gemzar. Subsequent cycles consisted of injections once weekly for 3 consecutive weeks out of every 4 weeks. The primary efficacy parameter in these studies was "clinical benefit response," which is a measure of clinical improvement based on analgesic consumption, pain intensity, performance status, and weight change. Definitions for improvement in these variables were formulated prospectively during the design of the 2 trials. A patient was considered a clinical benefit responder if either:
I. WKH SDWLHQW VKRZHG D  UHGXFWLRQLQ SDLQLQWHQVLW\ 0HPRULDO 3DLQ $VVHVVPHQW
Card) or analgesic consumption, or a 20-point or greater improvement in performance status (Karnofsky Performance Scale) for a period of at least 4 consecutive weeks, without showing any sustained worsening in any of the other parameters. Sustained worsening was defined as 4 consecutive weeks with either any increase in pain intensity or analgesic consumption or a 20-point decrease in performance status occurring during the first 12 weeks of therapy. OR:  
II. the patient was stable on all of the aforementioned parameters, and showed a marked, VXVWDLQHG ZHLJKW JDLQ  LQFUHDVH PDLQWDLQHG IRU  ZHHNV QRW GXH WR IOXLG accumulation. The first study was a multi-center (17 sites in US and Canada),
III. prospective, single-blinded, two-arm, randomized, comparison of Gemzar and 5-FU in patients with locally advanced or metastatic pancreatic cancer who had received no prior treatment with chemotherapy. 5-FU was administered intravenously at a weekly dose of 600 mg/m2 for 30 minutes. The results from this randomized trial are shown in Table 4. Patients treated with Gemzar had statistically significant increases in clinical benefit response, survival, and time to disease progression compared to 5-FU.[13] The Kaplan-Meier curve for survival is shown in **Figure 17**. No confirmed objective tumor responses were observed with either treatment.  
Abbreviated Title: M7824/Gemcitabine for AAPC Version date: 03/20/2019  
| Table 4 Randomized trial of gemcitabine versus 5-fluorouracil in pancreas cancer (Burris HA, 1997)   |                        |                     |         |
|------------------------------------------------------------------------------------------------------|------------------------|---------------------|---------|
| Gemzar Versus 5-FU in Pancreatic Cancer                                                              |                        |                     |         |
| Gemzar                                                                                               | 5-FU                   |                     |         |
| Number of patients                                                                                   | 63                     | 63                  |         |
| Male                                                                                                 | 34                     | 34                  |         |
| Female                                                                                               | 29                     | 29                  |         |
| Median age                                                                                           | 62 years               | 61 years            |         |
| 37 to 79                                                                                             |                        |                     |         |
| Range                                                                                                | 36 to 77               |                     |         |
| Stage IV disease                                                                                     | 71.4%                  | 76.2%               |         |
| Baseline KPSª ≤ 70                                                                                   | 69.8%                  | 68.3%               |         |
| Clinical benefit response                                                                            | 2.2%                   | 4.8%                | p=0.004 |
| (N =14)                                                                                              | (N=3)                  |                     |         |
| Survival                                                                                             | p=0.009                |                     |         |
| Median                                                                                               | 5.7 months             | 4.2 months          |         |
| 6-month probability b                                                                                | (N=30) 46%             | (N=19) 29%          |         |
| 9-month probability b                                                                                | (N=14) 24%             | (N=4) 5%            |         |
| l-year probability'                                                                                  | (N=9) 18%              | (N=2) 2%            |         |
| Range                                                                                                | 0.2 to 18.6 months     | 0.4 to 15.1+ months |         |
| 95% C.I. of the median                                                                               | 4.7 to 6.9 months      | 3.1 to 5.1 months   |         |
| Time to Disease Progression                                                                          | p=0.0013               |                     |         |
| 2.1 months                                                                                           | 0.9 months             |                     |         |
| Median                                                                                               |                        |                     |         |
| Range                                                                                                | 0.1+ to 9.4 months     | 0.1 to 12.0+ months |         |
| 95% C.I. of the median                                                                               | 1.9 to 3.4 months      | 0.9 to 1.1 months   |         |
| Karnofsky Performance Status.                                                                        |                        |                     |         |
| b                                                                                                    | Kaplan-Meier estimates |                     |         |
| ° N=number of patients.                                                                              |                        |                     |         |  
° N=number of patients.  
+ No progression at last visit; remains alive.  
The p-value for clinical benefit response was calculated using the two-sided test for difference in binomial proportions. All other p-values were calculated using the Logrank test for difference in overall time to an event.  
  
Clinical benefit response was achieved by 14 patients treated with Gemzar and 3 patients treated with 5-FU. One patient on the Gemzar arm showed improvement in all 3 primary parameters (pain intensity, analgesic consumption, and performance status). Eleven patients on the Gemzar arm and 2 patients on the 5-FU arm showed improvement in analgesic consumption and/or pain intensity with stable performance status. Two patients on the Gemzar arm showed improvement in analgesic consumption or pain intensity with improvement in performance status. One patient on the 5-FU arm was stable with regard to pain intensity and analgesic consumption with improvement in performance status. No patient on either arm achieved a clinical benefit response based on weight gain. 1.2.14 Clinical safety data RIJHPFLWDELQHLQFRPELQDWLRQZLWK7*)ȕLQKLELWLRQ to date. To date OLPLWHG GDWD RQ 7*)ȕ VLJQDOLQJLQKLELWLRQ FRPELQHGwith F\WRWR[LF FKHPRWKHUDS\ DUH DYDLODEOH 7KH ODUJHVW FOLQLFDO H[SHULHQFH RI 7*)ȕ LQKLELWLRQ LQ FRPELQDWLRQ ZLWK V\VWHmic FKHPRWKHUDS\LQFOXGHVJHPFLWDELQHDQGFRPHVIURPWKH7*)ȕUHFHSWRU,VPDOOPROHFXOHLQKLELWRU
galunisertib (LY2157299 monohydrate), a small molecule inhibitor of transforming growth factorbeta signaling pathway in clinical development for various solid organ malignancies including pancreatic cancer. In a phase IB study, when combined with gemcitabine, the combination (Phase
,KDGWKHH[SHFWHGPDQDJHDEOHWR[LFLW\RIJHPFLWDELQH in the form of myelosuppression with no increased immune-related adverse events.[30] The following large randomized phase II study (gemcitabine + galunisertib (GG) v gemcitabine + placebo (GP)) confirmed the safety of the phase I dose of galunisertib (LY2157299 monohydrate) in combination with standard dose gemcitabine (1,000mg/m2, as proposed in this study) with the majority of grade 3 and 4 AEs related to study GUXJDQGQRDGGLWLRQDOWR[LFLWLHVV\QHUJLVWLFDOO\LQGXFHGWhrough the combination. The most frequent CTC grade 3/4 adverse events possibly related to study treatment (GG vs GP) ZHUHDQHPLD  YV  QHXWURSHQLD  YV DQGWKURPERF\WRSHQLD  YV and are consistent with a gemcitabine-GULYHQWR[LFLW\SURILOHRIWKHcombination with no DGGLWLYHRUQHZWR[LFLW\ZLWKWKHDGGLWLRQRI7*)ȕLQKLELWLRQ. The efficacy evaluation of the study showed no statistically significant difference between the two groups, combination with the immune checkpoint inhibitor durvalumab is currently tested in clinical trials (NCT02734160 A Study of Galunisertib (LY2157299) and Durvalumab (MEDI4736) in Participants with Metastatic Pancreatic Cancer).
untitled h1
1.2.15 clinical safety data of

With the recognition of immunomodulatory activity of certain chemotherapeutic agents (as an H[WHQVLRQ RI WKH FRQFHSW RI Petronomic chemotherapy WKDW PRUH F\WRWR[LFLW\ LV QRW DOZD\V warranted), there is a current large interest combining immune checkpoint inhibitors with systemic chemotherapy. By causing apoptotic cell death of cancer cells, chemotherapy can be immunogenic by stimulating anticancer immune effectors directly or mitigating immunosuppressive mechanisms.[31] Systemic chemotherapy may stimulate Immunosurveillance by antigenicity, immunogenicity or susceptibility.[32] $QWLJHQLFLW\LVWKHUHVXOWRILQFUHDVLQJWKHH[SUHVVLRQDQGRU presentation of tumor-associated antigens on the cell surface of cancer cells. There are currently not less than 6 trials registered on clinicaltrials.gov combining gemcitabine with various immune checkpoint inhibitors. Several phase IB studies have shown safety of the combined immune FKHFNSRLQWLQKLELWRUDQGFKHPRWKHUDS\DSSURDFK$VH[DPSOHVDUHOLVWHG Pembrolizumab, in combination with gemcitabLQHJHPFLWDELQHDQGGRFHWD[HOJHPFLWDELQHDQG nab-SDFOLWD[HORUJHPFLWDELQHDQGYLQRUHOELQHor irinotecan (I) (Pembro Plus study) which showed the safety of combination with transaminitis, F\WRSHQLD¶V, rash, diarrhea, fatigue, nausea and vomiting being WKH PRVW FRPPRQ PLOG WR[LFLWLHV DQG HIILFDF\ VLJQDOV LQ VHYHUDO WXPRU W\SHV
including pancreas cancer.[33] More importantly, the recently released results of the KEYNOTE021 study in NSCLC show that RYHUDOO WR[LFLWLHV LQ patients in the pembrolizumab plus chemotherapy group ZDVVLPLODUEHWZHHQJURXSV>@RISDWLHQWVLQWKHSHPEUROL]XPDE plus chemRWKHUDS\JURXSDQG>@RILQWKHFKHPRWKHUDS\DORQHJURXS[34] The most common grade 3 or worse treatment-related adverse events in the pembrolizumab plus chemotherapy group were anemia VHYHQ >@ RI  DQG GHFUHDVHG QHXWURSKLO FRXQW WKUHH >@ DQ DGGLWLRQDO VL[ HYHQWV HDFK RFFXUUHG LQ WZR  IRU DFXWH NLGQH\ LQMXU\ GHFUHDVHG lymphocyte count, fatigue, neutropenia, and sepsis, and thrombocytopenia which were also not different between the groups.[34] Avelumab, the PD-L1 parent component of M7824, is currently in combination with standard chemotherapy in third line gastric cancer (JAVELIN Gastric 300), standard of care chemoradiotherapy (SoC CRT) in advanced head and neck carcinomas (JAVELIN Head and Neck 100), as well as other solid organ malignancies without the emerge of synergistic tR[LFLWLHV
EHWZHHQDYHOXPDEDQGWKHF\WRWR[LFFKHPRWKHUDS\>(0'6HURQR@
untitled h1
1.2.16 health-related quality of life

It is conceivable that clinical benefit of the tested combined M7824 gemcitabine approach is limited to LPSURYHPHQWLQ4R/PHDVXUHVRIWUHDWHGSDWLHQWV)RUH[DPSOHRQHRIWKHLQLWLDOVWXGLHV RIJHPFLWDELQHVKRZHGµRQO\¶LPSURYHPHQWLQSDLQVFRUHVDQG4R/SDUDPHWHUVEXWQRFKDQJHLQ
traditional efficacy readouts response or survival. To evaluate the impact of M7824 in combination ZLWK JHPFLWDELQH RQ SDWLHQWV¶ SDLQ VFRUHV DQG WUHDWPHQW-related reported symptoms scores of symptom subsets of the FACT-Hep (**Appendix B**) will be longitudinally completed before and during the treatment. TKH µ)XQFWLRQDO$VVHVVPHQW RI&DQFHU7KHUDS\¶ZLWKWKH KHSDWRELOLDU\DQG SDQFUHDWLF VSHFLILF module (FACT-Hep)¶ LV D 45-item self-report instrument developed specifically to measure HRQoL in patients with hepatobiliary cancer (i.e. liver, bile duct and pancreatic cancers).[35] It assesses symptoms and other HRQoL concerns across four dimensions (physical well-being, social/family well-being, emotional well-being and functional well-being together with an 18-item disease-specific hepatobiliary cancer subscale including back and stomach pain, gastrointestinal V\PSWRPV DQRUH[LD ZHLJKW ORVV DQG MDXQGLFH LQ SDWLHQWV ZLWK KHSDWRELOLDU\ cancers. It was developed by a process of item generation based on input from patients with hepatobiliary cancers, item reduction based on clinician input, scale construction and reliability/validity testing. Respondents of FACT-based questionnaires rate each item using a five-point Likert-type scale ranging from 0 (not at all) to 4 (very much).
untitled h1
1.2.17 justification of research studies

As a possible stromal modulator µEUHDNLQJWKHEDUULHURIWKHGHQVHPLFURHQYLURQPHQWRISancreatic WXPRUVDQGHQDEOLQJLQFUHDVHGGUXJGHOLYHU\LQWRWKHVHWXPRUV¶, the impact of M7824 onto tumoral perfusion measured by Dynamic Contrast Enhanced MRI (DCE-MRI) will be compared pre-start of M7824 and after first dose M7824. Previous preclinical work (data not shown) has measured increased perfusion by DCE-MRI of murine autochthonous pancreatic tumor after pre-treatment ZLWK WZR GRVHV RI WKH 7*)ȕ UHFHSWRU , VPDOO PROHFXOH LQKLELWRU /< 7R HYDOXDWH RI radiologic assessments via DCE-MRI can function as a reliable biomarker for response to M7824, either after monotherapy, or after M7824 in combination with gemcitabine, baseline perfusion measures of a target lesion will be compared by serial DCE-MRI at time points designated in Study Calendar (Section 3.7) 1.2.17.2 Somatic genomic profile of pancreatic cancers derived from specimens: There is strong preclinical evidence, including from autochthonous models of pancreas cancer, WKDWWKHXQGHUO\LQJJHQRW\SHRISDQFUHDWLFFDQFHUVPLJKWJRYHUQERWUHVSRQVHWR7*)ȕDVZHOODV LPPXQHFKHFNSRLQWEORFNDGH,QSDUWLFXODUYDULDQWVDIIHFWLQJWKH7*)ȕUHFHSWRU- 60$'D[LV have been cited as potentially protective against an initial pro-WXPRUHIIHFWRI7*)ȕLQKLELWLRQGXH WR WKH WXPRU VXSSUHVVLYH IXQFWLRQ RI 7*)ȕ LQ WKH HSLWKHOLDO FDQFHU FRPSDUWPHQW 7KXV HDUO\ correlations between genotype and clinical outcome of patients aim to (1) improve future selection RISDWLHQWVIRUWKHGXDO7*)ȕµWUDS¶3'-L1 blockade in combination with gemcitabine approach as well as (2) improve understanding of the mechanism of action of M7824 in pancreas cancer.
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1.2.17.3 6huxpfwrnlqhvdqgvhuxp7)uohyhov

One of the least elaborate ways to confirm that the administered M7824 is active and is engaging LWVWDUJHWLVWRPHDVXUHVXSSUHVVLRQRI7*)ȕOHYHOVYLDµWUDSSLQJ¶DQGLQGXFHGFKDQJHVLQWKH F\WRNLQHSURILOHV\VWHPLFDOO\)ROORZLQJ7*)ȕDQGF\WRNLQHOHYHOVORQJLWXGLQDOO\DFURVVWUHDWment course will allow detection of lack of M7824 activity and can trigger additional investigations (ADA development) into lack of efficacy.
untitled h1
1.2.17.4 ada

Anti-Drug Antibody development is an accepted mechanism of loss of efficacy administered human monoclonal antibodies. Measuring titers will ensure that lack of efficacy of M7824 is not due to ADA development. 1.2.17.5 Evaluate the intratumoral immunogenicity of M7824 in combination with gemcitabine on pre- and on-treatment biopsies:
3UHFOLQLFDO VWXGLHV VKRZ WKDW 7*)ȕ inhibition and gemcitabine cooperate immunologically to induce anti-tumor responses reducing immune evasive cues of the intratumoral immune milieu and enhancing T cell-mediated anti-tumor responses. The flow cytometry studies on pre- and ontreatment tumor biopsies aim to (1) investigate immunogenic cooperativity of M7824 in combination with gemcitabine in human tumors, (2) identify an immunologic landscape likely to response to the pursued combination approach, and (3) aid to develop longitudinal predictive biomarkers for later improved patient selection (correlation with immune cell changes pre- and on-treatment and clinical outcome).
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1.2.17.6 rationale for circulating free

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 FLUFXODWLQJ IUHH WXPRU '1$ LQWR H[SORUDWLYH REMHFWLYHV H[DPLQHV WKH YDOXH RI LGHQWLI\LQJ responders early and the development of this test as a predictive biomarker for the tested M7824 gemcitabine combination treatment. 1.2.17.7 Rationale for abbreviated PK studies M7824 and gemcitabine: AbbreviatHG 3. PHDVXUHPHQWV RI ERWK 0 DQG JHPFLWDELQH ZLOO EH WDNHQ WR H[FOXGH WKDW 0DQGJHPFLWDELQHSKDUPDFRORJ\DUHLQWHUGHSHQGHQW0SODVPD&PD[DQG&Pin levels will be compared to PK PHDVXUHVWDNHQGXULQJ0PJIODWGRVHPRQRWKHUDS\H[SDQVLRQ FRKRUWVJHPFLWDELQHSODVPD&PD[DQG&PLQOHYHOVZLOOEHcorrelated to initial DMET genotyping and compared between the two JHPFLWDELQHWR[LFLW\ULVNJURXSs). Gemcitabine PKs will be used to adjust gemcitabine schedule during the study, patients in the high-risk group who have not VKRZQDQ\WR[LFLW\DQGZKRVH3.VGRQ¶WVKRZDQ\HOHYDWHG&PD[DQG&PLQOHYHOVFDQKDYHWKHLU
doses increased to the standard 1,000 mg/m2 level.
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1.2.18 amendment b

With this amendment we want to update DLT definition. Originally, we inadvertently left out DLT definitions DQGGLGQRWH[FOXGHDGYHUVHHYHQWVZLWKFOHDUHYLGHQFHRIDQDOWHUQDWLYHFDXVDOLW\RU H[SHFWHGDQGVKRUWO\UHVROYHG As a result, there were DLTs, that in the opinion of the PI, are not related to study treatment or H[SHFWHGDQGFDQEHH[FOXGHGEXWZHUHQRWPHQWLRQHGDVH[FOXVLRQV 6RDGKHULQJWRWKHFXUUHQW'/7GHILQLWLRQLQWKHSURWRFROFDSWXULQJµ$Q\'/76HFWLRQ**3.1.1**), we have 2 DLTs and per protocol need to go to lower dose of study drug M7824. However, we are reluctant to do this, as (1) the combination treatment is generally well tolerated in the 6 patients on study so far, and (2) there are some early signs of clinical efficacy (no patient came off study yet due to progression of disease, there are 2 biochemical responses) with original dose level 0
(1,200mg flat dose M7824) and we do not want to risk the potential benefit with lowering of M7824 dose unnecessarily, in particular in a disease like pancreatic cancer where drug delivery and drug penetration is a major issue. In several hundreds of patients treated with the standard 1,200mg flat dose, many of these patients treated at the Clinical Center, M7824 was found to have a very favorable side-effect profile nearly identical to approved immune checkpoint inhibitors like pembrolizumab or nivolamab. While we ZDQWWRFDSWXUHDQ\SRVVLEOHDGGLWLYHWR[LFLW\VLJQDOZKHQFRPELQLQJ0DQGJHPFLWDELQHZH also do not want to unnecessarily lower M7824 dose levels in a disease where the lack of sufficient LQWUDWXPRUDOH[SRVXUHOHYHOVGXHWRWKHXQLTXHQHVVRISDncreas cancer (high interstitial pressures, SRRUYDVFXODUL]DWLRQLVDPDMRULPSHGLPHQWWRWKHHIILFDF\RIDSSURYHGF\WRWR[LFWKHUDSLHV While we have not seen any formal PRs yet (for two patients also too early), none of the pancreas cancer patients treated so far have shown despite widely metastatic disease radiologic progression of disease (all stable disease). 7KHUH KDYH EHHQWZRODUJH GURSV !LQWXPRUPDUNHUOHYHOV RFFXUULQJDIWHU!PRQWKVRI therapy (which we consider consistent with the mechanism of immunotherapy). Dose level -1 (500 mg of M7824) potentially will deprive patients of efficacious doses in a disease where drug penetration and low intratumoral drug levels are a significant impediment of therapeutic efficacy and should only occur if the new drug combination is found not safe at the respective dose level. With this amendment we want to omit current patients from the DLT analysis and repeat the entire safety run-in with 6 new study subjects under the new DLT criteria.
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2 eligbility assessment and enrollment

2.1.1 Inclusion Criteria
x Patient must be able to understand and willing to sign a written informed consent document  
x $JH\HDUV%HFDXVHQRGRVLQJRUDGYHUVHHYHQWGDWDDUHFXUUHQWO\DYDLODEOHRQWKHXVH
of M7824 in combination with gemcitabine in patients <18 years of age, children are H[FOXGHGIURPWKLVVWXG\EXWZLOOEHHOLJLEOHIRUIXWXUHSHGLDWULFWULDOV
x Histologically or cytologically proven pancreatic adenocarcinoma (subjects with endocrine or acinar pancreatic carcinoma are not eligible).  
x Patients must have disease that is not amenable to potentially curative resection.  
x Subjects must have progressed on or after standard first-line systemic chemotherapy. x ECOG performance status of 0 to 1 (**Appendix A)**
x Must have evaluable or measurable disease per RECIST 1.1. See Section 6.3 for the evaluation of measurable disease.  
x Adequate hematological function defined by:
¾ ZKLWHEORRGFHOO:%&FRXQWî9/L ¾ ZLWKDEVROXWHQHXWURSKLOFRXQW$1&î9/L,
¾ O\PSKRF\WHFRXQWî9/L, ¾ SODWHOHWFRXQWî9/L, and
¾ Hgb J dL (more than 48 hours post-completion of blood transfusion))
x Adequate hepatic function defined by:
¾ DWRWDOELOLUXELQOHYHOîULN, ¾ an AST levelî8/1
¾ ALT OHYHOî8/1.  
x Adequate renal function defined by:
¾ Creatinine up to 1.5-times upper institutional limits OR creatinine clearance (CrCl)
>50 mL/min/1.73 m2 OR within normal as predicted by the Cockcroft-Gault formula:
&U&O íDJH (y)[ZHLJKWLQNJ[LIIHPDOH [P2
[Serum Creatinine (mg/dL) [SW¶V%6$P2)
x The effects of the study WUHDWPHQW RQ WKH GHYHORSLQJ KXPDQ IHWXV DUH XQNQRZQ WKXV
women of childbearing potential and men must agree to use adequate contraception KRUPRQDO RU EDUULHUPHWKRG RI ELUWKFRQWURODEVtinence) within 28 days prior to study entry, for the duration of study participation and up to 120 days after the last dose of the drug. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately.
2.1.2 ([FOXVLRQ&ULWHULD
x Patients who are receiving any other investigational agents  
x 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.  
x Anticancer treatment within designated period before enrollment including:
¾ minor surgical procedure (such as biliary stenting) within 14 days
¾ major surgical procedure or radiation treatment within 28 days
¾ FKHPRWKHUDS\RUH[SHULmental drug treatment with published half-life known to be 72 hours within 14 days
¾ H[SHULPHQWDOGUXJWUHDWPHQWZLWKXQSXEOLVKHGRUKDOI-life greater than 72 hours within 28 days
¾ radiotherapy for measurable lesions delivered in a normal organ-sparing technique within 21 days H[FHSWIRUpalliative radiotherapy)
x Concurrent treatment with non-permitted drugs including herbal remedies with LPPXQRVWLPXODWLQJ SURSHUWLHV IRU H[DPSOH PLVWOHWRH H[WUDFW RU NQRZQ WR SRWHQWLDOO\ interfere with major organ function (IRUH[DPSOHK\SHULFLQ (see Section 4.2).  
x Previous malignant disease (other than the target malignancy to be investigated in this trial)
within the last 3 years. Subjects with a history of cervical carcinoma in situ, superficial or non-invasive bladder cancer, or basal cell or squamous cell carcinoma in situ previously WUHDWHGZLWKFXUDWLYHLQWHQWDUH127H[FOXGHG.  
x Rapidly progressive disease which, in the opinion of the Investigator, may predispose to inability to tolerate treatment or trial procedures.  
x Subjects with active central nervous system (CNS) metastases causing clinical symptoms RUPHWDVWDVHVWKDWUHTXLUHWKHUDSHXWLFLQWHUYHQWLRQDUHH[cluded. Subjects with a history of treated CNS metastases (by surgery or radiation therapy) are not eligible unless they have fully recovered from treatment, demonstrated either no clinical or radiographic progression for at least 2 months, and do not require continued steroid therapy. Subjects with CNS
metastases incidentally detected during Screening which do not cause clinical symptoms and for which standard of care suggests no therapeutic intervention is needed are eligible.  
x Receipt of any organ transplantation, including allogeneic stem-cell transplantation, e[FHSW
transplants that do not require immunosuppression (e.g., corneal transplant, hair transplant)
x Significant acute or chronic infections including tuberculosis KLVWRU\ RI H[SRVXUH RU
KLVWRU\ RI SRVLWLYH WXEHUFXORVLV WHVW plus, presence of clinical symptoms, physical or radiographic findings)
x Active autoimmune disease that might deteriorate when receiving an immunostimulatory agent ZLWKWKHH[FHSWLRQV:
¾ diabetes type I, vitiligo, alopecia, psoriasis, hypo- or hyperthyroid disease not requiring immunosuppressive treatment are eligible  
¾ subjects requiring hormone replacement with corticosteroids are eligible if the steroids are administered only for the purSRVHRIKRUPRQDOUHSODFHPHQWDQGDWGRVHVPJ of prednisone or glucocorticoid equivalent per day
¾ administration of steroids for other conditions through a route known to result in a PLQLPDO V\VWHPLF H[SRVXUH WRSLFDO LQWUDQDVDO intra-ocular, or inhalation) is acceptable.  
x Known severe hypersensitivity reactions to monoclonal antibodies (Grade 3 NCI-CTCAE
v5.0DQ\KLVWRU\RIDQDSK\OD[LV or history of uncontrolled asthma.  
x Known severe hypersensitivity to gemcitabine. x 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 in combination with gemcitabine, breastfeeding should be discontinued.  
x Known alcohol or drug abuse.  
x Clinically significant cardiovascular / cerebrovascular disease as follows: cerebral vascular accident / stroke (< 6 months prior to enrollment), myocardial infarction (< 6 months prior to enrollment), unstable angina, congestive heart failure (New York Heart Association Classification Class  II), or serious cardiac arrhythmia.  
x Clinically relevant diseases IRU H[DPSOH LQIODPPDWRU\ ERZHO GLVHDVH and / or uncontrolled medical conditions, which, in the opinion of the Investigator, might impair WKHVXEMHFW¶VWolerance or ability to participate in the trial.  
x Vaccine administration of live attenuated vaccines within 28 days of enrollment.  
x Patients with known contrast allergies requiring pre-medication with steroids. x HIV, HCV, HBV positive patients on antiviral drugs DUHH[FOXGHGGXHWRthe absence of SUHYLRXVH[SHULHQFHwith concurrent use of antiviral medications and the investigational drug product to be evaluated in the current study and possible for adverse pharmacokinetic and/or pharmacodynamic interactions.  
x Known inherited bleeding disorder and/or history of bleeding diathesis such as vWF
deficiency.  
2.1.3 Recruitment Strategies o Hematological profile: CBC with differential and platelet count
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2.2 screening evaluation

The study will be posted on the CCR website and on clinicaltrials.gov. Within 28 days prior to enrollment unless otherwise noted below:
x Complete PHGLFDO KLVWRU\ DQG SK\VLFDO H[DPLQDWLRQ, including height, weight, vital signs, EKG, and ECOG performance status.  
x Laboratory Evaluation  
o Biochemical profile: electrolytes, BUN, creatinine, AST, ALT, total bilirubin, calcium, phosphorus, albumin, magnesium, uric acid o TB testing (if clinically indicated)
o Serum or urine pregnancy test for female participants of childbearing age (in the absence of prior hysterectomy) (7 days prior to enrollment)
x CT of chest, abdomen and pelvis (or MRI abdomen)
x Tumor evaluation / tumor measurements x $EUDLQ&705,VFDQLIFOLQLFDOO\LQGLFDWHG x Histologic or cytologic confirmation (at any time point prior to enrollment). If there is no available documentation, biopsy will be performed to confirm the diagnosis.
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2.3 registration procedures

Authorized staff must register an eligible candidate with NCI Central Registration Office (CRO) within 24 hours of signing consent. A registration Eligibility Checklist from the web site (http://home.ccr.cancer.gov/intra/eligibility/welcome.htm) must be completed and sent via encrypted email to: NCI Central Registration Office ncicentralregistration-l@mail.nih.gov. After confirmation of eligibility at Central Registration Office, CRO staff will call pharmacy to advise them of the acceptance of the patient on the protocol prior to the release of any investigational agents. Verification of Registration will be forwarded electronically via e-mail to the research team. A recorder is available during non-working hours. 2.3.1 Treatment Assignment Procedures (**For registration purposes only**):  
Number Name Description  
| Subjects with pancreas cancer enrolled to M7824 de-escalation dose  levels.   |          |                                                                                            |
|-------------------------------------------------------------------------------|----------|--------------------------------------------------------------------------------------------|
| 2                                                                             | Phase II | Subjects with pancreas cancer enrolled at the RP2D of M7824 after the  RP2D is established |
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arm assignment

Subjects in Cohort 1 will be directly assigned to Arm 1.  
| 1   | Arm 1   | Gemcitabine (dose based on genetic testing results) + de-escalating  dose of M7824   |
|-----|---------|--------------------------------------------------------------------------------------|
| 2   | Arm 2   | Gemcitabine (dose based on genetic testing results) + RP2D of  M7824                 |  
Subjects in Cohort 2 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 M7824 infusion. Within 28 days prior to first dose:
x CT of chest, abdomen and pelvis (or MRI abdomen)  
x Tumor evaluation / measurements x Optional tumor research biopsy (only in patients enrolled onto the phase II)
x Research blood for DMET genotyping (see section 5.3) x Research Perfusion evaluation - DCE-MRI
x Research Quality of Life assessment (subject-reported outcomes / symptom severity DVVHVVPHQWVWKH WK YHUVLRQ RIWKH µ)XQFWLRQDO Assessment of Cancer Therapy with the hepatobiliary and pancreatic specific module (FACT-Hep **Appendix B**). (For English speaking subjects only).
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3 study implementation 3.1 study

This is an open label Phase IB/II trial, accruing initially one cohort to determine the safety and recommended Phase II dose (RP2D) of M7824 in combination with gemcitabine (Phase IBDQG WRH[DPLQHWKHVDIHW\DQGefficacy of the M7824 in combination with gemcitabine in the following cohort (Phase II). Up to 2 dose levels of M7824 will be tested in the safety run-in cohort IB with up to 12 subjects enrolled. Once a recommended phase 2 dose has been determined, up to 20 subjects will be evaluated at that dose level in the Phase II cohort, inclusive of those patients treated at the RP2D during the safety run-in. Patients will receive treatment in cycles consisting of 14 (+/- 3) days. Administration of M7824 will be every 2 weeks by IV infusion starting on day 1 of cycle 1. The starting M7824 dose is 1,200 mg. Gemcitabine will be administered IV once a week starting on day 1 of cycle 2 for 4 weeks (cycles 2-3). Then, once weekly for 3 weeks with one week without gemcitabine starting on day 1 of cycle 4 (cycles 4-13). Gemcitabine will be discontinued after 6 months of total gemcitabine therapy. After gemcitabine discontinuation, treatment with M7824 will continue until patient meets off treatment criteria (Section **3.8.1)**.  
In all patients, gemcitabine dosage will be adjusted according to DMET genotyping and risk SURILOLQJUHVXOWVSDWLHQWVZLWKORZULVNwild type including synonymous variants of both alleles and heterozygous, monoallelic rs2072671, CDA 79A>C polymorphism (K27Q)) or high risk (homozygous, biallelic rs2072671, CDA 79A>C polymorphisms (K27Q)).  
Patients with low risk will be assigned to standard dosage of 1,000 mg/m2 per dose.  
Patients with high risk will be started on 600 mg/m2 per dose for first 4 doses of gemcitabine. After  
 4 doses of gemcitabine, patients in this category will continue on 600 mg/m2 per dose or standard 1,000 mg/m2 per dose (see Section **3.3.2**).  
Figure 18 Design of phase IB/II study of M7824 in combination with gemcitabine in patients with advanced pancreas cancer.  
3.1.1 'RVH/LPLWLQJ7R[LFLW\ The DLT period is two cycles, 28 days. DLT is defined as follows:
¾ Febrile neutropenia of any grade  
¾ $Q\*UDGHDGYHUVHHYHQW (AE), occurring during the DLT evaluation period, **except**
for those listed below:
x Adverse event for which there is a clear evidence of an alternative causality (i.e., other than M7824 or the study combination)
x Grade 3 or 4 neutropenia if lasts < 1 cycle (14 days)
x Grade 3 thrombocytopenia if lasts < 1 cycle (14 days)  
x Any Grade 3 autoimmune thyroid-UHODWHGWR[LFLW\WKDWFOLQLFDOO\UHVROYHWR*UDGH
within 7 days of initiating therapy x *UDGHGLDUUKHDRUVNLQWR[LFLW\WKDWUHVROYHVWR*UDGHLQOHVVWKDQGD\VDIWHU
medical management (e.g., immunosuppressant treatment) has been initiated x Tumor flare phenomenon defined as local pain, irritation, or rash localized at sites of known or suspected tumor.  
x 7UDQVLHQW24 hours) Grade 3 flu-like symptoms or fever, which is controlled with medical management.  
x Transient 48 hours) Grade 3 fatigue, local reactions, headache, nausea, emesis that UHVROYHVWR*UDGHRU%DVHOLQHJUDGH
x 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 PDQLIHVWDWLRQV RI SDQFUHDWLWLV DQG ZKLFK KDV UHVROYHG WR *UDGH   ZLWKLQ WKH
subsequent cycle (14 days)
x 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).  
x Grade 3 infusion-related reactions resolving within 6 hours from the end of infusion and controlled with medical management.  
x 6NLQOHVLRQUHODWHGWR7*)ȕLQKLELWLRQLHNHUDWRDFDQWKRPDVTXDPRXVFHOOFDUFLQRPD
that is local and can be resected with negative resection margins, x *UDGH  VNLQ WR[LFLW\ WKDW UHVROYHV WR  *UDGH  LQ OHVV WKDQ  GD\V DIWHU PHGLFDO
management (eg. immunosuppressant treatment, adequate and optimal anti diarrhea therapy) has been initiated.  
x Single laboratory values out of normal range that are assessed as unrelated to study treatment according to the investigator, do not have any clinical correlate, and resolve WR*UDGHZLWKLQGD\VZLWKDGHTXDWHPHGLFDOPDQDJHPHQW
3.1.2 Phase IB Safety Run-In (Dose de-escalation)
Following Amendment B, participants will be enrolled to 2 dose levels as follows: The first 3 participants will be enrolled on DL0 and if 0/3 or 1/3 have a DLT during DLT period, WKHQH[WJURXSRISDUWLFLSDQWVZLOOEHHQUROOHG ,IQRPRUHWKDQ 1/6 H[SHULHQFHD'/7 during '/7SHULRGDFFUXDOPD\SURFHHGLQWKHSKDVH,,H[SDQVLRQFRKRUWDQG'/ will be the RP2D of M7824. If 2 or more in 3-6 subjects at DL0 have a DLT during DLT period, then subsequent subjects will enroll at DL-1. If 0/3 or 1/3 have a DLT at DL-1 GXULQJ'/7SHULRGWKHQWKHQH[WJURXSRI participants will be enrolled at DL-1. If no more than 1/6 H[SHULHQFHD DLT, then accrual may proceed to the phase II H[SDQVLRQFRKRUWDQG'/-1 will be the RP2D of M7824. If 2 or more in 3-6 subjects at DL-1 have a DLT during DLT period, then , no further attempts at completing the safety run-in will be conducted and the protocol will be closed to further accrual.  
x 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 *UDGHZLWKLQWKHVXEVHTXHQWF\FOH14 days)
The dose de-escalation scheme in the safety run-in will use the following dose levels (**Table 5**):  
| Dose   | M7824, mg, IV every 2   | Gemcitabine, mg/m2 , IV every week*             |
|--------|-------------------------|-------------------------------------------------|
| level  | weeks                   | Dose assigned according to polymorphism testing |
| DL 0   | 1,200                   | Assigned dose                                   |
| DL -1  | 500                     | Assigned dose                                   |  
*Starting in cycle 2 (day 15) gemcitabine will be administered weekly for 4 weeks, then 3 weeks on 1 week off for no more than 6 months total of gemcitabine therapy Every subject in each dose level group of the safety run-in will be observed for at least 7 days after first dose of M7824 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. Once a total of 6 subjects have been treated ZLWKSDWient having DLT and 28 days of observation have passed (completion of DLT period) after the first treatment of the 6th subject, patients can be DFFUXHGWRWKHSKDVH,,H[SDQVLRQFRKRUW The recommended phase 2 dose (RP2D) is the dose level of M7824 at which  LQGLYLGXDO H[SHULHQFHGDDLT during the first 2 cycles of treatment (28 days). In case of DLT patients will be taken off study treatment (M7824 and gemcitabine)
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3.1.2.1 m7824

Intra-patient M7824 dose de-escalation is not permitted for subjects enrolled in the safety run-in cohort. Subject enrolled onto safety run-in cohorts who have either had a DLT or completed the DLT evaluation period will be part of the DLT evaluation of the respective phase I dose level.  
3.1.2.2 Gemcitabine During Phase I portion of this trial, gemcitabine starting dose levels will be adjusted according to results of polymorphism testing of the CDA gene using the DMET platform of the Clinical Pharmacology Program (as per NCI 16-C-0076) (See Section **3.3.2**). If patients develop side effects related to gemcitabine, dose modifications according to label are recommended: 'RVH PRGLILFDWLRQV GRVDJH DGMXVWPHQW LV EDVHG XSRQ WKH GHJUHH RI KHPDWRORJLF WR[LFLW\ H[SHULHQFHGE\WKHSDWLHQW&OHDUDQFHLQZRPHQDQGWKHHOGHUO\LVUHGXFHGDQGZRPHQare less able to progress to subsequent cycles. Patients will be monitored prior to each dose with a complete blood count (CBC), including differential and platelet count. If marrow suppression is detected, gemcitabine therapy should be modified or suspended according to the guidelines in Section **3.4.2.** These subjects will be part of the DLT evaluation of the respective M7824 dose level they were accrued to. )DLOXUHWRUHVXPHJHPFLWDELQHDIWHUDKROGRIZHHNZLOOEHDQDO\]HGDVD'LT within respective dose level group.  
For patients receiving 600 mg/m2 gemcitabine per dose gemcitabine dosage will not be reduced and gemcitabine will be withheld.
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3.1.3 phase ii cohort

The efficacy part of the study will be conducted with the M7824 dose level found to be safe in combination with gemcitabine during phase IB. Once a recommended phase 2 dose of M7824 has been determined, up to 20 subjects will be evaluated at that dose level, inclusive of those patients treated at the RP2D during the safety run-in.  
Enrollment into phase II part of the study can commence after DLT period of 6th subject of respective DLT cohort is complete.  
Gemcitabine dosage will be assigned per Section **3.3.2**
During first stage of Phase II 13 patients will be enrolled. If 0 of 13 patients respond, then no further patients will be enrolled. If 1 or more of the first 13 evaluable patients enrolled have a response (PR or CR), then during second stage accrual will continue until a total of 20 evaluable patients have been enrolled. Since it may take several weeks for a response to be identified, a pause in the accrual of 6 weeks will be made before accruing to the second stage.
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3.2 study stopping rules

For safety reasons, the protocol will be temporarily halted XQWLODQH[SHGLWHGVDIHW\UHSRUWis sent to and reviewed by the FDA and the SAE has been evaluated by the investigators for either of the following events attributable to treatment regimen occurring within 30 days of receiving investigational agents:
2QHRFFXUUHQFHRIJUDGHWR[LFLW\ 7ZRRFFXUUHQFHVRIJUDGHWR[LFLW\
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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 Day 1 of each cycle (14 days) before gemcitabine.  
M7824 is administered as an intravenous (IV) infusion via a peripheral OR central vascular access device (VAD). Confirm patient has a titanium port before accessing the Central VAD. A 0.2micron polyethersulfone (PES) in-line filter is mandatory for administration. In order to mitigate potential infusion-related reactions, premedication with an antihistamine and with aFHWDPLQRSKHQ IRU H[DPSOH 25-50 mg diphenhydramine po and 500-1,000 mg acetaminophen po or IV equivalent) DSSUR[LPDWHO\60 to 120 minutes prior to each dose of M7824 is mandatory for the first 2 infusions and is optional and at the discretion of the Investigator after the second infusion. ,I *UDGH   LQIXVLRQ UHDFWLRQV DUH VHHQ GXULQJ WKH ILUVW WZR LQIXVLRQV, premedication should not be stopped. Steroids as premedication are not permitted. As with all monoclonal antibody therapies, there is a risk of allergic reaction including anaphylactic shock. M7824 should be administered in a setting that allows for immediate access WRDQLQWHQVLYHFDUHXQLWRUHTXLYDOHQWHQYLURQPHQWDQGDGPLQLVWUDWLRQRIWKHUDS\IRUDQDSK\OD[LV such as the ability to implement immediate resuscitation measureV6WHURLGVGH[DPHWKDVRQH mg), epinephrine (1:1,000 dilution), allergy medications (IV antihistamines), bronchodilators, or equivalents, DQGR[\JHQVKRXOGEHDYDLODEOHIRULPPHGLDWHDFFHVV 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 6**. 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. For vital signs measurements see Study Calendar (Section **3.7)**. 3.3.2 Gemcitabine Gemcitabine starting dose levels will be adjusted according to results of polymorphism testing of the CDA gene using the DMET platform of the Clinical Pharmacology Program (as per NCI 16- C-0076):  
| DMT testing - CDA polymorphism                                                   | Gemcitabine,  mg/m2 , IV,  first 4 doses   | Gemcitabine, mg/m2 , IV following 4  doses   |            |
|----------------------------------------------------------------------------------|--------------------------------------------|----------------------------------------------|------------|
| Wild                                                                             | type                                       | including                                    | synonymous |
| mutation or heterozygous, monoallelic  rs2072671, CDA 79A>C polymorphism  (K27Q) | 1,000                                      | 1,000                                        |            |
| Homozygous                                                                       | 600                                        | 1,000 if QR - JUDGH WR[LFLW\ DQG JHPFLWDELQH &PD[ PHDVXUHV <30μg/mL  LIQR•JUDGHWR[LFLW\ or •JUDGH WR[LFLW\ resolved within 2 weeks and  JHPFLWDELQH &PD[ PHDVXUHV >30μg/mL  Discontinue gemcitabine if - JUDGH WR[LFLW\ is not resolved within 2 weeks                                              |            |  
On day 1 of cycles 2, 3, 4 and 5 gemcitabine infusion will immediately commence upon completion of M7824 infusions as gemcitabine PK must be collected. On all other days when both drugs are given on the same day, gemcitabine may be administered anytime on this day after M7824 infusion. ,QFDVHRIORFDOLQIXVLRQUHDFWLRQVFRQWUDODWHUDOH[WUHPLWLHVRURWKHUDFFHVVURXWHVVKRXOG be used for gemcitabine infusions. Gemcitabine will be given starting on Cycle 2 at the assigned dosage over 30 (+/- 10) minutes once weekly for the first consecutive 4 weeks (**Figure** ). Starting on Cycle 4 once weekly for 3 weeks with one week without gemcitabine. Gemcitabine will be discontinued after cycle 13 (6 months total of gemcitabine treatment).
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3.4 dose modifications

3.4.1 M7824 During Phase IB dose modification of M7824 are not allowed. During Phase II modification of M7824 will proceed as described in this section. 3.4.1.1 Adverse Drug Reactions (ADRs) Requiring Treatment Discontinuation Certain ADRs, defined as an AE assessed as related to M7824 by the Investigator, may require dose interruption, or permanent treatment discontinuation of M7824. For certain ADRs assessed to be immune-related, **Table 7**, Management of Immune-Related Adverse Events criteria may supersede this section. These criteria may allow the subject to continue study if medically indicated. Any Grade 4 ADRs require permanent treatment discontinuation H[FHSWIRU single laboratory values out of normal range that do not have any clinical correlate and resolve to Grade 1 or Baseline grade within 7 days with adequate medical management.
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any grade 3 adrs require

x 7UDQVLHQW   KRXUV*UDGH  IOX-like symptoms or fever, which is controlled with medical management.  
x 7UDQVLHQWKRXUV*UDGHIDWLJXHORFDOUHDFWLRQVKHDGDFKHQDXVHDHPHVLVWKDWUHVROYHV
WR*Uade 1 or Baseline grade.  
x Tumor flare phenomenon defined as local pain, irritation, or rash localized at sites of known or suspected tumor.  
x Any single *UDGH3 drug-related transaminase, alkaline phosphatase, or bilirubin abnormality with no other associated laboratory (or other) abnormality that is not associated with symptoms or clinical manifestations of hepatitis. If the liver function abnormality not associated with symptoms or clinical manifestations of hepatitis has not resolved to Grade  1 within the subsequent 2 cycles (28 days), the subject should permanently discontinue treatment with M7824.  
x Any single *UDGH   GUXJ-related amylase or lipase abnormality with no other associated laboratory (or other) abnormality that is not associated with symptoms or clinical manifestations of pancreatitis. If the amylase or lipase abnormality not associated with symptoms or clinical manifestations of pancreatitis has not resolved to Grade  1 within the subsequent 2 cycles (28 days), the subject should permanently discontinue treatment with M7824.  
x Grade 3 Hgb decrease (< 8.0 g/dL) that is clinically manageable with blood transfusions or erythroid growth factor use does not require treatment discontinuation.  
x Increases in Eastern Cooperative Oncology Group performance status (ECOG PS)   that resolves to d 2 by Day 1 of the QH[W cycle (infusions should not be given if the ECOG 36LV 3 on the day of planned M7824 administration DQGVKRXOGEHGHOD\HGXQWLO(&2*36).  
x Keratoacanthoma and squamous cell carcinoma of the skin. Any suspicious skin lesion should be biopsied and be surgically removed and a dermatological consult obtained.  
x Grade 3 or 4 symptomatic endocrinopathies (e.g., thyroiditis or hypophysitis), treatment should be delayed, and treatment started according to (**Table 7**). If condition improves to Grade 1, treatment may be resumed. If   FRQVHFXWLYH GRVHV DUH PLVVHGdiscontinuation of M7824 should be considered.  
x Other immune-related ADRs, see Immune-Related Adverse Events (**Table 7**)
3.4.1.2 Adverse Drug Reactions Requiring Management:
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any grade 2 adr should

x ,ID*UDGH$'5UHVROYHVWR*UDGHE\WKHODVWGD\RIWKHFXUUHQWF\FOHWUHDWPHQWPD\
continue.  
x ,ID*UDGH$'5GRHVQRWUHVROYHWR*UDGHE\WKHODVWGD\RIWKHFXUUHQWF\FOH but it is manageable and / or not clinically relevant, it is possible the infusion will be given on the following cycle. If at the end of the following cycle, the event has not resolved to Grade 1, permanently discontinuing of treatment with M7824 should be considered.  
x Upon the second occurrence of the same Grade 2 ADR in the same subject H[FHSWIRUfatigue and hormone insufficiencies that can be managed by replacement therapy), permanently discontinuing treatment with M7824 should be considered.  
x Infusion-related reactions and hypersensitivity reactions (Grades 1 to 4) should be handled according to the Guidelines provided in **Table 6**.  
3.4.1.3 Infusion-related Reactions
Signs and symptoms usually develop during or shortly after drug infusion and generally resolve completely within 24 hours of completion of infusion.  
Symptoms:
x Fever x Chills x Rigors x Diaphoresis x Headache Management: (please see **Table 6**)
Table 6 Treatment Guidelines for Symptoms of Infusion-related Reactions Caused by M7824  
| NCI-CTCAE Grade                                                        | Infusion of M7824                                                                                    | Treatment                                                                                                                                                                                    | Premedication at  subsequent  dosing   |
|------------------------------------------------------------------------|------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------|
| Grade 1 - mild                                                         | Decrease                                                                                             | the                                                                                                                                                                                          | M7824                                  |
| LQIXVLRQ UDWH E\  and monitor closely for  any worsening.                                                                        | Increase monitoring of  vital signs as  medically indicated  until the subject is  medically stable. | None                                                                                                                                                                                         |                                        |
| Mild transient  UHDFWLRQLQIXVLRQ interruption not  LQGLFDWHG intervention not  indicated.                                                                        | The total infusion time  for M7824 should not  H[FHHGPLQXWHV                                                                                                      |                                                                                                                                                                                              |                                        |
| Grade 2 - moderate                                                     | Stop M7824 infusion.                                                                                 | Monitor symptoms.  Therapy include but is  not limited to:  IV fluids  Antihistamines  NSAIDS  Acetaminophen  Opioids  Increase monitoring of  vital signs as medically  indicated until the | Subject to be premedicated 1.5h (±  30 minutes) prior  to infusion of  M7824 with:                                        |
| Therapy or infusion  interruption indicated  but responds  promptly to  symptomatic  treatment (for  H[DPSOH antihistamines,  NSAIDs, narcotics,  ,9IOXLGV prophylactic                                                                        | If                                                                                                   | symptoms                                                                                                                                                                                     | resolve                                |
| within                                                                 | one                                                                                                  | hour                                                                                                                                                                                         | of                                     |
| stopping drug infusion,  the infusion may be  UHVWDUWHG DW  RI WKH original infusion rate  (e.g., from 100 mL/hr.  to 50 mL/hr.).                                                                        | Diphenhydramine  50 mg po (or  equivalent dose of  antihistamine).                                   |                                                                                                                                                                                              |                                        |
| Otherwise dosing will  be held until symptoms  resolve and the subject | Acetaminophen  500-1,000 mg PO  (or equivalent                                                       |                                                                                                                                                                                              |                                        |  
| Version date: 03/20/2019  NCI-CTCAE Grade                                                                                                                                                                                                                                  | Infusion of M7824                 | Treatment                                                                                 | Premedication at  subsequent  dosing     |           |
|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-----------------------------------|-------------------------------------------------------------------------------------------|------------------------------------------|-----------|
| medications indicated                                                                                                                                                                                                                                                      | should                            | be                                                                                        | pre                                          |           |
| PHGLFDWHG IRU WKH QH[W                                                                                                                                                                                                                                                                            |                                   |                                                                                           |                                          |           |
| for d 24 hours.                                                                                                                                                                                                                                                            | scheduled dose.                   | subject                                                                                   | is                                       | medically |
| stable.  Subjects who develop  Grade 2 toxicity  despite adequate  premedication  should be  permanently  discontinued from  further trial  treatment  administration.                                                                                                     | dose of  antipyretic).            |                                                                                           |                                          |           |
| Grade 3                                                                                                                                                                                                                                                                    | x                                 | Stop the M7824  infusion  immediately and  disconnect infusion  tubing from the  subject. | Therapy includes but is  not limited to: | Subject to be premedicated 1.5h (±  30 minutes) prior  to infusion of  M7824 with:           |
| x Grade 3:  Prolonged (for  H[DPSOHQRW rapidly  responsive to  symptomatic  medication and /  or brief  interruption of  LQIXVLRQ recurrence of  symptoms  following initial  LPSURYHPHQW hospitalization  indicated for  clinical sequelae.                                                                                                                                                                                                                                                                            | IV fluids  Antihistamines  NSAIDS | Diphenhydramine  50 mg po (or  equivalent dose of  antihistamine).                        |                                          |           |
| If resolved within 6  hours, infusion may  be restarted by  discretion of PI                                                                                                                                                                                               | Acetaminophen  Opioids  2[\JHQ    | Acetaminophen  500-1,000 mg PO  (or equivalent  dose of  antipyretic).                    |                                          |           |
| Pressors  Corticosteroids  Epinephrine                                                                                                                                                                                                                                     |                                   |                                                                                           |                                          |           |
| Increase monitoring of  vital signs as medically  indicated until the  subject is medically  stable.  Hospitalization may be  indicated.  Subjects who develop  Grade 3 toxicity  despite adequate  premedication should  be permanently  discontinued from  further trial |                                   |                                                                                           |                                          |           |  
| Version date: 03/20/2019  NCI-CTCAE Grade                                                                                                | Infusion of M7824   | Treatment                                                                                                             | Premedication at  subsequent  dosing     |                       |
|------------------------------------------------------------------------------------------------------------------------------------------|---------------------|-----------------------------------------------------------------------------------------------------------------------|------------------------------------------|-----------------------|
| treatment  administration.                                                                                                               |                     |                                                                                                                       |                                          |                       |
| x Grade 4: Lifethreatening  FRQVHTXHQFHV urgent  intervention  indicated.                                                                                                                                          | x                   | Subjects have to be  withdrawn  immediately from  M7824 treatment  and must not  receive any further  M7824 treatment | Therapy includes but is  not limited to: | No subsequent  dosing |
| IV fluids  Antihistamines  NSAIDS  Acetaminophen  Opioids  2[\JHQ Pressors  Corticosteroids  Epinephrine                                 |                     |                                                                                                                       |                                          |                       |
| Increase monitoring of  vital signs as medically  indicated until the  subject is medically  stable.  Hospitalization may be  indicated. |                     |                                                                                                                       |                                          |                       |
| 16$,'V QRQVWHURLGDODQWL-inflammatory drugs.                                                                                                                                          |                     |                                                                                                                       |                                          |                       |
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additional modifications for subjects with

If, in the event of a Grade 2 infusion-related reaction that does not improve or worsens after implementation of the modifications indicated in **Table 6** (including reducing the infusion rate by WKH ,QYHVWLJDWRUPD\ FRQVLGHUWUHDWPHQW ZLWKFRUWLFRVWHURLGVDQGWKHLQIXVLRQ RI M7824 should be stopped for that day. $WWKHQH[WLQIXVLRQWKH,QYHVWLJDWRUPD\FRQVLGHUWKHDGGLWLRQRI H2-blocker DQWLKLVWDPLQHVIRUH[DPSOHIDPRWLGLQHRUUDQLWLGLQHLQDGGLWLRQWRSUHPHGLFDWLRQ for select subjects. However, prophylactic steroids are NOT permitted. If the subject has a second infusion-UHODWHG UHDFWLRQ*UDGHRQWKHVORZHULQIXVLRQ UDWHZLWKRr without the addition of further medication to premedication, the infusion should be stopped and the subject removed from M7824 treatment. 3.4.1.4 Severe Hypersensitivity Reactions and Flu-like Symptoms If a hypersensitivity reaction occurs, the subject must be treated according to the best available medical practice including ACLS guidelines. Subjects should be instructed to report any delayed reactions to the Investigator immediately.  
A. Symptoms x Impaired airway x 'HFUHDVHGR[\JHQVDWXUDWLRQ x Confusion x Lethargy x Hypotension x Pale / clammy skin x Cyanosis B. Management x (SLQHSKULQHLQMHFWLRQDQG,9GH[DPHWKDVRQH x 3DWLHQW VKRXOG EH SODFHG RQ FDUGLDF EORRG SUHVVXUH KHDUW UDWH DQG R[\JHQ VDWXUDWLRQ
monitor immediately x Alert intensive care unit for possible transfer if required
)RUSURSK\OD[LVRIIOX-OLNHV\PSWRPVD16$,'IRUH[DPSOH ibuprofen 400 mg or comparable NSAID dose, may be administered 2 hours before and 8 hours after the start of each dose of M7824 IV infusion. 3.4.1.5 Immune-Related Adverse Events Since inhibition of PD-/DQG7*)ȕVLJQDOLQJVWLPXODWHVWKHLPPXQHV\VWHPLU$(VPD\RFFXU Treatment of irAEs is mainly dependent upon severity (NCI-CTCAE grade):
x Grade 1 to 2: treat symptomatically or with moderate dose steroids, more frequent monitoring  
x Grade 1 to 2 (persistent): manage similar to high grade AE (Grade 3 to 4) x Grade 3 to 4: treat with high dose corticosteroids
Treatment of irAEs should follow guidelines set forth in **Table 7** below: Table 7 Management of Immune-Related Adverse Events  
| Gastrointestinal irAEs                           |                                                                  |                                                                                            |
|--------------------------------------------------|------------------------------------------------------------------|--------------------------------------------------------------------------------------------|
| Severity of Diarrhea/Colitis  (NCI-CTCAE v5)     | Initial Management                                               | Follow-up Management                                                                       |
| Grade 1  Diarrhea: < 4 stools/day over  Baseline | Continue M7824 therapy  Symptomatic treatment (e.g.  loperamide) | Close monitoring for worsening  symptoms  Educate subject to report worsening  immediately |  
| Version date: 03/20/2019  Colitis: asymptomatic                                                                                         | If worsens:  Treat as Grade 2, 3 or 4.                                                                         |                                                                                                                                                                                                                                                                                                                                                              |
|-----------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Grade 2  Diarrhea: 4 to 6 stools per day over  %DVHOLQH,9IOXLGVLQGLFDWHG KRXUVQRWLQWHUIHULQJZLWK$'/ &ROLWLVDEGRPLQDOSDLQEORRGLQ stool                                                                                                                                         | Withhold M7824 therapy                                                                                         | ,ILPSURYHVWR*UDGH"                                                                                                                                                                                                                                                                                                                                                              |
| Symptomatic treatment                                                                                                                   | Resume M7824 therapy  If persists > 5-7 days or recurs:  Treat as Grade 3 or 4.                                |                                                                                                                                                                                                                                                                                                                                                              |
| Grade 3 to 4  'LDUUKHD*UDGH•VWRROVSHU GD\RYHU%DVHOLQHLQFRQWLQHQFH,9 IOXLGV• KLQWHUIHULQJZLWK$'/ Colitis (Grade 3): severe abdominal  pain, medical intervention indicated,  peritoneal signs  Grade 4: life-threatening,  perforation                                                                                                                                         | Withhold M7824 for  Grade 3.  Permanently discontinue  M7824 for Grade 4 or  recurrent Grade 3.                | If improves:  &RQWLQXHVWHURLGVXQWLO*UDGH"WKHQ WDSHURYHUDWOHDVWPRQWKUHVXPH M7824 therapy following steroids taper  (for initial Grade 3).                                                                                                                                                                                                                                                                                                                                                              |
| 1.0 to 2.0 mg/kg/day  prednisone IV or equivalent  Add prophylactic antibiotics  for opportunistic infections  Consider lower endoscopy | If worsens, persists > 3 to 5 days, or  recurs after improvement:  $GGLQIOL[LPDEPJNJLIQR contrainGLFDWLRQ1RWHLQIOL[LPDEVKRXOG not be used in cases of perforation or  sepsis.                                                                                                                |                                                                                                                                                                                                                                                                                                                                                              |
| Dermatological irAEs                                                                                                                    |                                                                                                                |                                                                                                                                                                                                                                                                                                                                                              |
| Grade of Rash                                                                                                                           |                                                                                                                |                                                                                                                                                                                                                                                                                                                                                              |
| (NCI-CTCAE v5)                                                                                                                          | Initial Management                                                                                             | Follow-up Management                                                                                                                                                                                                                                                                                                                                         |
| Grade 1 to 2                                                                                                                            | Continue M7824 therapy                                                                                         |                                                                                                                                                                                                                                                                                                                                                              |
| &RYHULQJ"ERG\VXUIDFHDUHD                                                                                                                                         | Symptomatic therapy (for  H[DPSOHDQWLKLVWDPLQHV topical steroids)                                                                                                                | If persists > 1 to 2 weeks or recurs:  Withhold M7824 therapy  Consider skin biopsy  Consider 0.5-1.0 mg/kg/day prednisone or  equivalent. Once improving, taper steroids  over at least 1 month, consider  prophylactic antibiotics for opportunistic  infections, and resume M7824 therapy  following steroids taper.  If worsens:  Treat as Grade 3 to 4. |
| Grade 3 to 4  *UDGH&RYHULQJ!ERG\ VXUIDFHDUHD Grade 4: Life threatening  consequences                                                                                                                                         | Withhold M7824 for  Grade 3.  Permanently discontinue for  Grade 4 or recurrent Grade 3.  Consider skin biopsy | ,ILPSURYHVWR*UDGH" 7DSHUVWHURLGVRYHUDWOHDVWPRQWK resume M7824 therapy following steroids  taper (for initial Grade 3).                                                                                                                                                                                                                                                                                                                                                              |  
| Version date: 03/20/2019                      | Dermatology consult  1.0 to 2.0 mg/kg/day  prednisone or equivalent  Add prophylactic antibiotics  for opportunistic infections  Pulmonary irAEs                                                                                                    |                                                                                  |
|-----------------------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------|
| Grade of Pneumonitis  (NCI-CTCAE v5)          | Initial Management                                                                                                                                                                                                                                  | Follow-up Management                                                             |
| Grade 1                                       | Consider withholding M7824                                                                                                                                                                                                                          |                                                                                  |
| Radiographic changes only                     | therapy  Monitor for symptoms every  2 to 3 days  Consider Pulmonary and  Infectious Disease consults                                                                                                                                               | Re-assess at least every 3 weeks  If worsens:  Treat as Grade 2 or Grade 3 to 4. |
| Grade 2                                       | Withhold M7824 therapy                                                                                                                                                                                                                              |                                                                                  |
| Mild to moderate new symptoms                 | Pulmonary and Infectious  Disease consults  0RQLWRUV\PSWRPVGDLO\ consider hospitalization  1.0 to 2.0 mg/kg/day  prednisone or equivalent  Add prophylactic antibiotics  for opportunistic infections  Consider bronchoscopy, lung  biopsy                                                                                                                                                                                                                                                     | Re-assess every 1 to 3 days  If improves:  :KHQV\PSWRPVUHWXUQWR*UDGH" taper steroids over at least 1 month, and  then resume M7824 therapy following  steroids taper  If not improving after 2 weeks or  worsening:  Treat as Grade 3 to 4.                                                                                  |
| Grade 3 to 4  *UDGH6HYHUHQHZV\PSWRPV 1HZZRUVHQLQJK\SR[LD Grade 4: Life-threatening                                               | Permanently discontinue  M7824 therapy.  Hospitalize.  Pulmonary and Infectious  Disease consults.  1.0 to 2.0 mg/kg/day  prednisone or equivalent  Add prophylactic antibiotics  for opportunistic infections  Consider bronchoscopy, lung  biopsy | ,ILPSURYHVWR*UDGH" Taper steroids over at least 1 month  If not improving after 48 hours or  worsening:  Add additional immunosuppression (for  H[DPSOHLQIOL[LPDEF\FORSKRVSKDPLGH IV immunoglobulin, or mycophenolate  mofetil)                                                                                  |
| Hepatic irAEs                                 |                                                                                                                                                                                                                                                     |                                                                                  |
| Grade of Liver Test Elevation  (NCI-CTCAE v5) | Initial Management                                                                                                                                                                                                                                  | Follow-up Management                                                             |
| Grade 1  Grade 1 AST or ALT > ULN to 3.0  [8/1DQGRU7RWDOELOLUXELQ! 8/1WR[8/1                                               | Continue M7824 therapy                                                                                                                                                                                                                              | Continue liver function monitoring  If worsens:   Treat as Grade 2 or 3 to 4.    |  
| Version date: 03/20/2019  Grade 2  $67RU$/7!WR"[8/1 DQGRUWRWDOELOLUXELQ!WR"[ ULN                                               | Withhold M7824 therapy  Increase frequency of  monitoring to every 3 days.                                                                                                                                                                                                                                                                 | ,IUHWXUQVWR*UDGH" 5HVXPHURXWLQHPRQLWRULQJUHVXPH M7824 therapy.  If elevation persists > 5 to 7 days or  worsens:  Treat as Grade 3 to 4.                                          |
|-----------------------------------------------|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------------------|
| Grade 3 to 4  $67RU$/7![8/1DQGRUWRWDO ELOLUXELQ![8/1                                               | Permanently discontinue  M7824 therapy  Increase frequency of  monitoring to every 1 to  2 days  1.0 to 2.0 mg/kg/day  prednisone or equivalent  Add prophylactic antibiotics  for opportunistic infections  Consult gastroenterologist/  hepatologist  Consider obtaining MRI/CT  scan of liver and liver biopsy  if clinically warranted | ,IUHWXUQVWR*UDGH" Taper steroids over at least 1 month  If does not improve in > 3 to 5 days,  worsens or rebounds:  Add mycophenolate mofetil 1 gram (g)  twice daily  If no response within an additional 3 to 5  days, consider other immunosuppressants  per local guidelines.                                          |
| Renal irAEs                                   |                                                                                                                                                                                                                                                                                                                                            |                                          |
| Grade of Creatinine Increased  (NCI-CTCAE v5) | Initial Management                                                                                                                                                                                                                                                                                                                         | Follow-up Management                     |
| Continue renal function monitoring            |                                                                                                                                                                                                                                                                                                                                            |                                          |
| Grade 1  &UHDWLQLQHLQFUHDVHG!8/1WR[                                               | Continue M7824 therapy                                                                                                                                                                                                                                                                                                                     | If worsens:  Treat as Grade 2 to 3 or 4. |
| ULN  Grade 2 to 3  &UHDWLQLQHLQFUHDVHG!DQG"[ ULN                                               | Withhold M7824 therapy  Increase frequency of monitoring to  every 3 days  1.0 to 2.0 mg/kg/day prednisone or  equivalent.  Add prophylactic antibiotics for  opportunistic infections  Consider renal biopsy                                                                                                                              | ,IUHWXUQVWR*UDGH" Taper steroids over at least 1  month, and resume M7824 therapy  following steroids taper.  If worsens:  Treat as Grade 4.  ,IUHWXUQVWR*UDGH" Taper steroids over at least 1  month.                                          |
| Grade 4  &UHDWLQLQHLQFUHDVHG![8/1                                               | Permanently discontinue M7824  therapy  Monitor creatinine daily  1.0 to 2.0 mg/kg/day prednisone or  equivalent.  Add prophylactic antibiotics for  opportunistic infections  Consider renal biopsy  Nephrology consult                                                                                                                   |                                          |  
| Cardiac irAEs                                                                                                                                                                            |                                                                                                                                                                                                                                                                                                                                                                                                        |                      |          |         |     |
|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------------------|----------|---------|-----|
| Myocarditis                                                                                                                                                                              | Initial Management                                                                                                                                                                                                                                                                                                                                                                                     | Follow-up Management |          |         |     |
| New onset of cardiac signs or  symptoms and / or new laboratory  cardiac biomarker elevations (e.g.  troponin, CK-MB, BNP) or cardiac  imaging abnormalities suggestive  of myocarditis. | Withhold M7824 therapy.                                                                                                                                                                                                                                                                                                                                                                                | If                   | symptoms | improve | and |
| immune-mediated etiology is  ruled out, re-start M7824  therapy.                                                                                                                         |                                                                                                                                                                                                                                                                                                                                                                                                        |                      |          |         |     |
| Hospitalize.  In the presence of life threatening cardiac  decompensation, consider transfer to a  IDFLOLW\ H[SHULHQFHG LQ DGYDQFHG KHDUW failure and arrhythmia management.  If symptoms do not  improve/worsen, viral  P\RFDUGLWLVLVH[FOXGHGDQG immune-mediated etiology is  suspected or confirmed  following cardiology consult,  manage as immune-mediated  myocarditis.  Cardiology consult to establish etiology  and rule-out immune-mediated  myocarditis.  Guideline based supportive treatment as  per cardiology consult. *  Consider myocardial biopsy if  recommended per cardiology consult.                                                                                                                                                                                          |                                                                                                                                                                                                                                                                                                                                                                                                        |                      |          |         |     |
| Immune-mediated myocarditis                                                                                                                                                              | Permanently discontinue M7824.  Guideline based supportive treatment as  appropriate as per cardiology consult. *  1.0 to 2.0 mg/kg/day prednisone or  equivalent  Add prophylactic antibiotics for  opportunistic infections.  Once improving, taper steroids  over at least 1 month.  If no improvement or  worsening, consider additional  immunosuppressants (e.g.  azathioprine, cyclosporine A). |                      |          |         |     |
| *Local guidelines, or e.g. ESC or AHA guidelines  ESC guidelines website: https://www.escardio.org/Guidelines/Clinical-Practice-Guidelines  AHA guidelines website:  KWWSSURIHVVLRQDOKHDUWRUJSURIHVVLRQDO*XLGHOLQHV6WDWHPHQWVVHDUFKUHVXOWVMVS"T \ W 001  Endocrine irAEs  Endocrine Disorder Initial Management Follow-up Management  Grade 1 or Grade 2  endocrinopathies  (hypothyroidism,  hyperthyroidism, adrenal  insufficiency, type I diabetes  mellitus)  Continue M7824 therapy  Endocrinology consult if needed  Continue hormone  replacement/suppression and  monitoring of endocrine  function as appropriate. Start thyroid hormone replacement  therapy (for hypothyroidism),  anti-thyroid treatment (for  hyperthyroidism), corticosteroids (for  adrenal insufficiency) or insulin (for  Type I diabetes mellitus) as  appropriate.  Rule-out secondary endocrinopathies  (i.e. hypopituitarism / hypophysitis)                                                                                                                                                                                          |                                                                                                                                                                                                                                                                                                                                                                                                        |                      |          |         |     |  
| Version date: 03/20/2019  Grade 3 or Grade 4  endocrinopathies  (hypothyroidism,  hyperthyroidism, adrenal  insufficiency, type I diabetes  mellitus)                                                                                                                                                                                                                                                                                               | Withhold M7824 therapy  Consider hospitalization  Endocrinology consult                          | Resume M7824 once symptoms  and/or laboratory tests improve  to Grade "ZLWKRUZLWKRXW hormone  replacement/suppression).   |
|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------------------------------------|---|
| Start thyroid hormone replacement  therapy (for hypothyroidism),  anti-thyroid treatment (for  hyperthyroidism), corticosteroids (for  adrenal insufficiency) or insulin (for  type I diabetes mellitus) as  appropriate.                                                                                                                                                                                                                           | Continue hormone  replacement/suppression and  monitoring of endocrine  function as appropriate. |   |
| Rule-out secondary endocrinopathies  (i.e. hypopituitarism / hypophysitis)                                                                                                                                                                                                                                                                                                                                                                          |                                                                                                  |   |
| Hypopituitarism/Hypophysitis                                                                                                                                                                                                                                                                                                                                                                                                                        | If secondary thyroid and/or adrenal                                                              |   |
| (secondary endocrinopathies)                                                                                                                                                                                                                                                                                                                                                                                                                        | insufficiency is confirmed (i.e.  subnormal serum FT4 with  inappropriately low TSH and/or low  serum cortisol with inappropriately  low ACTH):  x Refer to endocrinologist for  dynamic testing as indicated and  measurement of other hormones  (FSH, LH, GH/IGF-1, PRL,  testosterone in men, estrogens in  women)  x Hormone  replacement/suppressive therapy  as appropriate  x Perform pituitary MRI and visual  ILHOGH[DPLQDWLRQDVLQGLFDWHG                                                                                                  | Resume M7824 once symptoms  and hormone tests improve to  Grade "ZLWKRUZLWKRXW hormone replacement).  In addition, for hypophysitis  with abnormal MRI, resume  M7824 only once shrinkage of  the pituitary gland on MRI/CT  scan is documented.  Continue hormone  replacement/suppression therapy  as appropriate.   |
| If hypophysitis confirmed:  x Continue M7824 if mild  symptoms with normal MRI.  Repeat the MRI in 1 month  x Withhold M7824 if moderate,  severe or life-threatening  symptoms of hypophysitis and/or  abnormal MRI. Consider  hospitalization. Initiate  corticosteroids (1 to 2 mg/kg/day  prednisone or equivalent)  followed by corticosteroids taper  during at least 1 month.  x Add prophylactic antibiotics for  opportunistic infections. |                                                                                                  |   |  
| Version date: 03/20/2019                                                                                                                                            | Other irAEs (not described above)                                                                                                                                                                                |                                 |
|---------------------------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------|
| Grade of other irAEs                                                                                                                                                | Initial Management                                                                                                                                                                                               | Follow-up Management            |
| (NCI-CTCAE v5)                                                                                                                                                      |                                                                                                                                                                                                                  |                                 |
| Grade 2 or Grade 3 clinical signs  or symptoms suggestive of a  potential irAE                                                                                      | Withhold M7824 therapy pending                                                                                                                                                                                   | If irAE is ruled out, manage as |
| clinical investigation                                                                                                                                              | appropriate according to the  diagnosis and consider restarting M7824 therapy  If irAE is confirmed, treat as  Grade 2 or 3 irAE.                                                                                                                                                                                                                  |                                 |
| Grade 2 irAE or first occurrence                                                                                                                                    | Withhold M7824 therapy                                                                                                                                                                                           |                                 |
| of Grade 3 irAE                                                                                                                                                     | 1.0 to 2.0 mg/kg/day prednisone or  equivalent  Add prophylactic antibiotics for  opportunistic infections  Specialty consult as appropriate                                                                     | ,ILPSURYHVWR*UDGH" Taper steroids over at least 1  month and resume M7824  therapy following steroids taper.                                 |
| Recurrence of same Grade 3                                                                                                                                          | Permanently discontinue M7824                                                                                                                                                                                    |                                 |
| irAEs                                                                                                                                                               | therapy  1.0 to 2.0 mg/kg/day  prednisone or equivalent  Add prophylactic antibiotics for  opportunistic infections  Specialty consult as appropriate                                                            | ,ILPSURYHVWR*UDGH" Taper steroids over at least 1  month.                                 |
| Grade 4                                                                                                                                                             | Permanently discontinue M7824  therapy  1.0 to 2.0 mg/kg/day  prednisone or equivalent and/or other  immunosuppressant as needed  Add prophylactic antibiotics for  opportunistic infections  Specialty consult. | ,ILPSURYHVWR*UDGH" Taper steroids over at least 1  month                                 |
| Requirement for 10 mg per day  or greater prednisone or  equivalent for more than 12  weeks for reasons other than  hormonal replacement for  adrenal insufficiency | Permanently discontinue M7824  therapy  Specialty consult                                                                                                                                                        |                                 |
| Persistent Grade 2 or 3 irAE  lasting 12 weeks or longer                                                                                                            |                                                                                                                                                                                                                  |                                 |
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3.4.1.6 anemia

x If after the 28-Day-DLT period the subject H[SHULHQFHs a Grade 3 Hgb decrease (< 8.0 g/dL) that is clinically manageable with blood transfusions or erythroid growth factor use, this does not require treatment discontinuation  
x If Hgb < 7 g/dL, the Investigator should consider blood transfusion x In case of any Hgb < 8 g/dL, the Investigator should use discretion to initiate anemia work up, including Coombs, haptoglobin, indirect bilirubin and peripheral smear, and prothrombin time (PT), activated partial thromboplastin time (aPTT), international normalized ratio (INR+JEUHGEORRGFHOOVDQGKHPDWRFULWDUHWREHFORVHO\PRQLWRUHG
x ,IDVXEMHFWH[SHULHQFHVVLJQLILFDQWDnemia of Hgb <9.0 g/dl, then the amount of blood to be drawn may be reduced by not taking blood for soluble factors, 7*)ȕ, circulating free tumor DNA, and PK studies. In particular, on M7824 infusion Days 1, 15, 29, and 43 (cycles \#1 - 4) with pre- and post-infusion PK measurements total blood draw volume may be as high as 24.5 mL on day of infusion. CBC counts will be monitored closely to detect GHYHORSPHQWRIDQHPLDDQGH[SHGLWLRXVO\UHVWULFWEORRGGUDZVThe decision to reduce the time points for these biomarkers will be taken by the Principal Investigator. This will be documented. Blood will continue to be taken as scheduled for safety analyses and ADAs.  
3.4.1.7 Rash with Hyperkeratosis / Keratoacanthoma / Squamous Cell Carcinoma of the Skin
Monitoring will include skin assessments every 4 weeks with biopsy of suspicious lesions. Dermatological consults should be requested as needed. 3.4.1.8 Alterations in Wound Healing or Tissue Damage Repair Management should be discussed on a case-by-case basis. Dermatological consults should be requested as needed. 3.4.1.9 Dose Interruptions for Adverse Events not Related to Study Drug In case of Grade 3 and Grade 4 AEs not study drug related, the study treatment may be interrupted based on the Investigator assessment and the subject will be medically treated for the event. If the AE reduces to a lower tolerable grade the study treatment might be resumed in the subsequent cycle. If the AE remains the same despite the PHGLFDOWUHDWPHQWXQWLOWKHQH[WWUHDWPHQWVHFRQG
cycle after the AE occurred) DFRQVLGHUDWLRQRIDSRVVLEOHH[WHQVLRQRIWKHGRVHLQWHUUXSWLRQIRUXS to 3 additional cycles is allowed. If upon the resumed study treatment, WKHVXEMHFWH[SHULHQFHVWKHVDPH$(, permanent withdrawal from the study treatment should be considered. Grade 3 and 4 laboratory abnormalities that do not have clinical significance and are not related to study drugs do not require dose interruption. 3.4.2 Gemcitabine 7R[LFLWLHVDOLJQHGZLWKJHPFLWDELQHWR[LFLW\SURILOHZLOOOHDGWRGRVHreduction of the nucleoside analogue (of the selected starting dose according to DMET genotypingSOHDVHVHH**Table 8** below). Table 8 Recommended Dose Reductions for Gemcitabine for Myelosuppression in Pancreatic Cancer and Non-Small Cell Lung Cancer  
| Absolute  granulocyte count,  x106/L   |               | Platelet count,   | % of selected   |
|----------------------------------------|---------------|-------------------|-----------------|
| x106/L                                 | starting dose |                   |                 |  
| -             | And   | -               |        |         |
|-------------|-------|---------------|-------|---------|
| 500-999     | Or    | 50,000-99,999 |        |         |
| <500        | Or    | <50,000       | Hold, | restart |
| gemcitabine | after |               |       |         |
| recover to Grade 1 at  RIGRVH             |       |               |       |         |
| ,I*UDGH•KHPDWRORJLFWR[LFLW\SRVVLEO\UHODWHGWRgemcitabine, restart gemcitabine after recover             |       |               |       |         |  
,I*UDGHKHPDWRORJLFWR[LFLW\SRVVLEO\UHODWHGWRgemcitabine, restart gemcitabine after recover to Grade DWRIWKHGRVH  
Dose Modifications for Non-Hematologic Adverse Reactions Permanently discontinue gemcitabine for any of the following:  
x 8QH[SODLQHGG\VSQHDRURWKHUHYLGHQFHRIVHYHUHSXOPRQDU\WR[LFLW\
x 6HYHUHKHSDWLFWR[LFLW\
x Hemolytic-uremic syndrome x Capillary leak syndrome x Posterior reversible encephalopathy syndrome
Withhold gemcitabine or reduce dose to  for other severe (Grade 3 or 4) non-hematological WR[LFLW\XQWLOUHVROYHGFor patients receiving 600mg/m2 gemcitabine dose will not be reduced and gemcitabine will be withheld. No dose modifications are recommended for alopecia, nausea, or vomiting.
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3.5 assessments on treatment

In this trial, the treatment with M7824 will continue until patient meets off treatment criteria (Section **3.8.1**). In the case of PD, subjects will continue treatment and have confirmatory scans 4 weeks after the initial scan documenting PD. In case of confirmation of PD per RECIST patient will come off treatment. For subjects who achieve a PR or CR on M7824 gemcitabine combination therapy and then subsequently develop disease progression after stopping therapy, due to reasons other than PD (AE which later resolve), 1 re-initiation course of treatment at the same dose and schedule of M7824 only is allowed at the discretion of the Investigator. Gemcitabine will not be administered again. The Investigator will need to confirm that the benefit of re-initiating treatment outweighs risks of WR[LFLWLHV involved, such as that which led to initial treatment discontinuation. In order to be eligible for re-WUHDWPHQWWKHVXEMHFWPXVWQRWKDYHH[SHULHQFHGDQ\WR[LFLW\WKDWOHGWRSHUPDQHQW treatment discontinuation of the initial M7824 therapy. Prior to re-initiation of the study treatment, malignant disease needs to be radiologically re-staged to assess all known sites of the disease and to establish a new baseline for subsequent tumor measurements. Relevant safety laboratory samples must be drawn and results available and verified prior to re-initiating treatment. Patients should be reconsented at this point. Subjects who re-initiate treatment will stay on study and will be treated and monitored according to the Study Calendar 3.7. During re-treatment no research procedures will be done. A time window of up to 3 days before or 1 day after a scheduled visit day (-3 / +1 days) will be permitted for all study procedures. In addition, the tumor evaluation has a tumor assessment visiting time window (repeat imaging) of 5 days prior to dosing (-5 days). Furthermore, if any Screening/Baseline procedures are conducted within 3 days prior to Day 1 of Cycle 1 the assessments scheduled on Cycle 1, Day 1 do not need to be repeated.
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3.5.1 end-of-treatment visit

All subjects should undergo an End-of-Treatment visit after discontinuation of M7824 for any reason. This visit should be performed on the day or within 7 days after the decision to discontinue trial treatment but before any new antineoplastic therapy is started (if possible). 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-ofTreatment visit. The discontinuation visit consists of assessments indicated in Study Calendar, Section 3.7. 3.5.2 Post-Treatment Follow-up
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3.5.2.1 28-day safety follow-up visit

A Safety Follow-up visit is scheduled 4 weeks (28 ± 5 days) after the last administration of M7824 but before any new therapy is started, if possible, whichever occurs earlier. The 28-Day Safety Follow-up visit will comprise a full assessment for safety, immunogenicity, and tumor response as appropriate, which will include assessments indicated in Study Calendar, Section **3.7.**
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3.5.2.2 long-term follow-up

All SAEs ongoing at the 28-Day Safety Follow-up visit must be monitored and followed up by the Investigator until stabilization or until the outcome is known, unless the subject is documented as "lost to follow-up." In addition, all trial drug-related SAEs occurring after 28-Day Safety Follow-up visit and ongoing at the Safety Follow-up visit have to be followed up in the same manner. Subjects without PD at the 28-Day Safety Follow-up visit will be followed till disease progression (CT / MRI scans every 12 weeks with the first assessment 12 weeks after the previous tumor assessment until PD). Subjects with PD after the 28-Day Safety Follow-up visit, will be followed quarterly (± 14 days) for survival (including assessment of any further anticancer therapy) by phone call or e-mail for 1 year. Survival follow up will continue every 6 months after that.