Clinical trial NCT03451773
Conditions: Cancer of Pancreas Pancreas Cancer Pancreatic Adenocarcinoma Pancreatic Cancer Pancreatic Neoplasms
Keywords: TGF Ligand Trap Extracellular Domain of Human TGF Receptor II Avelumab Human IgG1 mAb Directed Against Human PD-L1 Health-Related Quality of Life
Sponsor: National Cancer Institute (NCI)
Start date: 2018-05-17; Completion date: 2020-05-05
Enrollment: 7 participants; Allocation: NON_RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
Background:

Pancreas cancer ranks 4th in all cancer-related deaths in the United States (U.S.) Gemcitabine is a standard treatment for it. M7824 (MSB0011359C) blocks a pathway that prevents the immune system from effectively fighting cancer. The two drugs together might help people with pancreas cancer.

Objective:

To test if giving M7824 together with gemcitabine is safe and causes tumors to shrink.

Eligibility:

People ages 18 and older with pancreatic cancer already treated with standard therapies

Design:

Participants will be screened with:

Medical history

Physical exam

Scans in a machine that takes pictures of the body

Blood, urine, and heart tests

Some participants may have a tumor sample removed.

Participants will get M7824 by intravenous (IV) once every 2 weeks. They will continue until their disease gets worse or they have unacceptable side effects.

After the first dose, participants will also get gemcitabine by IV once weekly for 7 weeks. Then they will get it as follows for up to 6 months: Skip 1 week, get the drug once a week for 3 weeks, skip 1 week.

Before treatment on the first day of each cycle, participants will repeat screening tests. They will also have:

Optional tumor biopsies before and after 3 cycles of therapy

Questions about their well-being and function

Genetic testing of tissue and blood samples

Participants will have a follow-up visit 4-5 weeks after they stop therapy. This includes a physical exam, blood and urine tests, and maybe a scan. If their disease does not get worse, they will be invited for scans every 12 weeks.

Detailed description:
Background:

* M7824 (MSB0011359C) is an investigational agent in phase IB/II clinical development with dual activity against transforming growth factor beta (TGF)-beta signaling (TGF-beta ligand trap; extracellular domain of human TGF-beta receptor II) and immune checkpoint ligand inhibition (PD-L1 inhibition; avelumab, fully human immunoglobulin G1 (IgG1) monoclonal antibody (mAb) directed against human PD-L1) with an acceptable toxicity profile and early signals of anti-cancer activity including in pancreas cancer.
* Gemcitabine (2 \<=,2 \<=-Difluorodeoxycytidine) is a standard-of-care nucleoside analogue in pancreas cancer with immunomodulatory mechanisms of actions in pancreas cancer patients.
* Preclinical studies in autochthonous and syngeneic murine models have shown that TGF-beta inhibition and PD-L1 inhibition cooperate with gemcitabine to achieve reduction of tumor growth and extension of survival induce anti-tumor immunity and reprogram the immune landscape.

Objectives:

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

Eligibility:

* Histologically confirmed diagnosis of adenocarcinoma of the pancreas.
* Patients must have progressed on prior chemotherapeutic regimen.
* Concurrent treatment with non-permitted drugs and other interventions, prior therapy with gemcitabine or any antibody / drug targeting T cell co-regulatory proteins (immune checkpoints) such as anti-PD 1, anti PD-L1, or anti-cytotoxic T lymphocyte antigen-4 (CTLA 4 antibody) is not allowed.

Design:

\- 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 to an expansion phase II cohort with a standard Simon Minimax design.

Arms: arm 1: Gemcitabine (dose based on genetic testing results) + de-escalating dose of M7824 arm 2: Gemcitabine (dose based on genetic testing results) + RP2D of M7824
Interventions: intervention 1: M7824 intervention 2: Gemcitabine
Intervention descriptions: intervention 1: 1,200 or 500mg every 2 weeks by intravenous (IV) infusion intervention 2: Standard (1,000 mg/m\^2) or reduced (600 mg/m\^2 for 4 doses) intravenous (IV) once a week for first 4 weeks. Then, once weekly for 3 weeks with one week rest. Gemcitabine will be discontinued after 6 months of therapy

Protocol documents:
Prot_SAP_000.pdf: 
Abbreviated Title: M7824/Gemcitabine for AAPC 
Version date: 03/20/2019 
1 
 
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 
 
Investigational Agent:     
 
Drug Name: 
M7824 
IND Number: 
136852 
Sponsor: 
Center for Cancer Research, National Cancer Institute 
Manufacturer: 
EMD Serono  
 
Commercial Agent: Gemcitabine 
 
 
 


Abbreviated Title: M7824/Gemcitabine for AAPC 
Version date: 03/20/2019 
2 
 
PRÉCIS  
Background: 
x M7824 is an investigational agent in phase IB/II clinical development with dual activity against 
7*)ȕVLJQDOLQJ7*)ȕOLJDQGµWUDS¶H[WUDFHOOXODUGRPDLQRI KXPDQ7*)ȕUHFHSWRU,,DQG
immune checkpoint ligand inhibition (PD-/LQKLELWLRQDYHOXPDEIXOO\KXPDQ,J*P$E
directed against human PD-/ZLWKDQDFFHSWDEOHWR[LFLW\SURILOHDQGHDUO\VLJQDOVRIDQWL-
cancer activity including in pancreas cancer. 
x *HPFLWDELQH ƍƍ-'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.  
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.  
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[LF7O\PSKRF\WHDQWLJHQ-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 WRDQH[SDQVLRQShase II 
cohort with a standard Simon µ0LQLPD[GHVLJQ¶. 
 
 
 


Abbreviated Title: M7824/Gemcitabine for AAPC 
Version date: 03/20/2019 
3 
 
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 
0DELIXQFWLRQDOIXVLRQSURWHLQWDUJHWLQJ7*)ȕVLJQDOLQJDQGWKH3URJUDPPHG
death-ligand 1 (PD-L1) 
10 
1.2.3 
3UHFOLQLFDOUDWLRQDOIRUWKHFRPELQDWLRQLPPXQRWKHUDS\DSSURDFKRIGXDO7*)ȕDQG
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 
3UHFOLQLFDOUDWLRQDOHIRUWKHFRPELQDWLRQRIJHPFLWDELQHDQG7*)ȕLQKLELWLRQ 
14 
1.2.6 
Preclinical rationale using M7824 in combination with gemcitabine 
18 
1.2.7 
6DIHW\RIFRPELQHG7*)ȕDQG3'-/LQKLELWLRQE\WKHGXDO7*)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/HYHOVZLWKVSHFLDOFRQVLGHUDWLRQRIRYHUODSSLQJWR[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 
&OLQLFDOVDIHW\GDWDRIJHPFLWDELQHLQFRPELQDWLRQZLWK7*)ȕLQKLELWLRQWRGDWH 
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 


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4 
 
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/LPLWLQJ7R[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 


Abbreviated Title: M7824/Gemcitabine for AAPC 
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5 
 
5.1. 
Correlative Studies for Research/Pharmacokinetic Studies 
75 
5.1.1 
Tumor and Tissue Collection 
77 
5.1.2 
0XOWLSOH[HGLPPXQRKLVWRFKHPLFDOHYDOXDWLRQRILPPXQHFHOOSRSXODWLRQ 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 
6DPSOHV0DQDJHGE\'U)LJJ¶V%ORRG3URFHVVLQJ&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 


Abbreviated Title: M7824/Gemcitabine for AAPC 
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6 
 
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[SHFWHGDGYHUVHUHDFWLRQ 
89 
7.1.4 
Serious 
89 
7.1.5 
Serious Adverse Event 
89 
7.1.6 
Disability 
90 
7.1.7 
Life-threatening DGYHUVHGUXJH[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%DQG1&,&'([SHGLWHG5HSRUWLQJRI8QDQWLFLSDWHG3UREOHPVDQG
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 


Abbreviated Title: M7824/Gemcitabine for AAPC 
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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 


Abbreviated Title: M7824/Gemcitabine for AAPC 
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8 
 
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 
$SSHQGL[$3HUIRUPDQFH6WDWXV&ULWHULD 
109 
13.2 
$SSHQGL[%)DFW-Hep 
110 
13.3 
Appendi[&0RGLILHG,PPXQH-related Response Criteria (irRECIST) 
113 
 
 
 


Abbreviated Title: M7824/Gemcitabine for AAPC 
Version date: 03/20/2019 
9 
 
 
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. 
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 disease-
specific symptoms and treatment-related concerns. 
1.2 
Background and Rationale 
1.2.1 Pancreas cancer 
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]3DQFUHDVFDQFHULVLQRI
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] 


Abbreviated Title: M7824/Gemcitabine for AAPC 
Version date: 03/20/2019 
10 
 
 
Figure 1 Percent patients at different AJCC stages at time of initial diagnosis of pancreas cancer (per 
7th edition of American Joint Committee on Cancer, AJCC; left) of more than 6,000 pancreas cancer 
patients presenting between 2000 and 2005 to Memorial Sloan-Kettering Cancer Center, NY, and 
their corresponding 5-year survival rates (right) from MSKCC Pancreatic Cancer Registry. 
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[DOLSODWLQLULQRWHFDQDQGIOXRURXUDFLOH[WHQGVPHGLDQRYHUDOOVXUYLYDOLQSDWLHQWVZLWKORFDOO\
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[HOLQFRPELQDWLRQZLWKJHPFLWDELQHJURXSOHG
to FDA approval of this combination in 2013.[4] New therapies are urgently needed.[5]  
1.2.2 0DELIXQFWLRQDOIXVLRQSURWHLQWDUJHWLQJ7*)ȕVLJQDOLQJDQGWKH3URJUDPPHG
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 
FRPSRQHQWFRQVLVWLQJRIWKHH[WUDFHOOXODUGRPDLQRIKXPDQ7*)ȕUHFHSWRU,,ZKLFKHIILFLHQWO\
ELQGV7*)ȕOLJDQGV7*)ȕȕDQGȕZKLFKLVIXVHGWR&+-&WHUPLQXVRIWKH,J*YLDDIOH[LEOH 
glycine-serine linker (Figure 2).  


Abbreviated Title: M7824/Gemcitabine for AAPC 
Version date: 03/20/2019 
11 
 
Figure 2 Anti-PD-/7*)ȕ7UDS02YHUFRPLQJWZRPDMRULPPXQRVXSSUHVVLYHPHFKDQLVPV. 
Dual targeting of the PD-/DQG7*)ȕSDWKZD\VUHSUHVHQWVDUDWLRQDOWKHUDSHXWLFVWUDWHJ\EHFDXVH
these 2 key immune evasion pathways have independent and complementary immunosuppressive 
functions, thereby raising the possibility of synergistic antitumor activity. 
1.2.3
3UHFOLQLFDOUDWLRQDOIRUWKHFRPELQDWLRQLPPXQRWKHUDS\DSSURDFKRIGXDO7*)ȕDQG3'-
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-RUWKUHHRI&\*9$;RYHUDOOVXUYLYDOZDVH[WHQGHGWR
 YHUVXV  PRQWKV DUP $ Y % +5  3    DQ HIIHFW VLPLODU WR WKDW RI ILUVW OLQH
FOLFIRINOX combination therapy versus gemcitabine. Enhanced mesothelin-specific CD8 T-
cell 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]. 
7DUJHWLQJ7*)ȕVLJQDOLQJDVSDUWRIFRPELQDWLRQLPPXQRWKHUDS\LVKHUHE\SDUWLFXODUO\DWWUDFWLYH
DV 7*)ȕ OLJDQGV 7*)ȕ  DQG  DUH  RQH RI WKH PRVW DEXQGDQW F\WRNLQHV LQ WKH WXPRU
microenvironment and H[HUWLPPXQHVXSSUHVVLYHIXQFWLRQRQDYDULHW\RILPPXQHHIIHFWRUV
7KXV7*)ȕLQKLELWLRQSRVVLEO\DIIRUGVUHSURJUDPPLQJWRZDUGVDQDQWL-tumor environment on a 
number of different cellular levels not requiring the combination of several agents directed against 
individual immune cell populations (Figure 3).


Abbreviated Title: M7824/Gemcitabine for AAPC 
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12 
 
Figure 3 3OHLRWURSLFHIIHFWVRI7*)ȕVLJQDOLQJJHQHUDWHVDQLPPXQRWROHUDQWWXPRUenvironment. 
Block of suppression of T cells and NK cells, block of activation of regulatory T cells (Treg) and 
H[KDXVWLRQ RI HIIHFWRU 7 FHOOV WKURXJK 7*)ȕ LQKLELWLRQ KDYH WKHUDSHXWLF SRWHQWLDO LQ QRYHO
immunotherapy strategies. (adapted from [7]). 
 
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*)ȕGLUHFWO\GRZQUHJXODWHVWKHHIIHFWRUIXQFWLRQRIDFWLYDWHGF\WRWR[LF7FHOOVDQGQDWXUDONLOOHU
(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 
PDFURSKDJHV0SKHQRW\SHWKDWLVDVVRFLDWHGZLWKSURGXFWLRQRILPPXQRVXSSUHVVLYHF\WRNLQHV 
[10] As a therapeutic VWUDWHJ\QHXWUDOL]DWLRQRI7*)ȕDFWLYLW\KDVWKHSRWHQWLDOWRFRQWUROWXPRU
growth by restoring effective antitumor immunity, blocking metastasis, and inhibiting 
angiogenesis.  
2QWKHRWKHUKDQG7*)ȕKDVJURZWKLQKLELWRU\HIIHFWVRQQRUPDOHSLWKHOLDOFHlls, functioning as a 
regulator of epithelial cell homeostasis, and it acts as a tumor suppressor during early 
FDUFLQRJHQHVLV$VWXPRUVSURJUHVVWRZDUGPDOLJQDQF\WKHJURZWKLQKLELWRU\HIIHFWVRI7*)ȕRQ
the tumor are lost via mutation in one or more of WKH7*)ȕSDWKZD\VLJQDOLQJFRPSRQHQWVRU
through oncogenic reprogramming [6@ 8SRQ ORVV RI VHQVLWLYLW\ WR 7*)ȕ LQKLELWLRQ WKH WXPRU
FRQWLQXHVWRSURGXFHKLJKOHYHOVRI7*)ȕZKLFKWKHQVHUYHWRSURPRWHtumor growth [6] The 


Abbreviated Title: M7824/Gemcitabine for AAPC 
Version date: 03/20/2019 
13 
 
7*)ȕ F\WRNLQH LV RYHUH[SUHVVHG LQ YDULRXV FDQFHU W\SHV LQFOXGLQJ SDQFUHDV FDQFHU ZLWK
correlation to tumor stage.[6, 7@+LJKOHYHOVRI7*)ȕKDYHDOVREHHQIRXQGLQDXWRFKWKRQRXV
models of pancreas cancer.[7] A high level of TGF-ȕ ZDV IRXQG LQ VHUXP RI SDWLHQWV ZLWK
pancreatic adenocarcinoma suggesting that TGF-ȕFRXOGSRVVLEO\EHFRPHDPDUNHUIRUPRQLWRULQJ
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[SUHVVLRQDQGHQJDJHZLWKWXPRUFHOOVRYHUH[SUHVVLQJ3'-L1. Blocking the 
D[LVUHVWRUHVWKHHIIHFWRUIXQFWLRQLQWKHse 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-/LQKLELWLRQZLWK7*)ȕQHXWUDOL]DWLRQRU– 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\RIF\WRWR[LF&'7FHOOV (Figure 4). When tested in the autochthonous Ras-
driven 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-/FRPSRQHQWDYHOXPDERI0H[WHQGHGVXUYLYDOFRPSDUHG
to PD-L1 inhibition or gemcitabine alone. 
 
Figure 4 A Gemcitabine moderately increases infiltration of CD8+ T cells in murine pancreatic 
tumors and enhances in vitro anti-tumor responses of isolated CD8+ T cells. Flow cytometry profiles 
of KP16 tumors treated with vehicle (black) or 40mg/kg twice weekly gemcitabine (orange; animals 
1IRUGD\V&'&'IUDFWLRQJDWHGRQWRWDODOLYHFHOOV%,QWHUIHURQJDPPDUHOHDVHPHDVXUHG
by ELISpot assay of co-cultured CD8+ T cells isolated from tumors (left) and spleen (right) from 


Abbreviated Title: M7824/Gemcitabine for AAPC 
Version date: 03/20/2019 
14 
 
vehicle and gemcitabine-treated (40mg/kg twice weekly, animals harvested after 1 week). C Kaplan-
0HLHUDQDO\VLVRI.3PLFHZLWKFRQILUPHGPPSDQFUHDWLFWXPRUVUDQGRPL]HGWRYHKLFOHDQWL-
PD-L1, 40mg/kg gemcitabine twice weekly, or anti-PD-L1 in combination with gemcitabine. 
 
1.2.5 PrecliniFDOUDWLRQDOHIRUWKHFRPELQDWLRQRIJHPFLWDELQHDQG7*)ȕLQKLELWLRQ 
1.2.5.1 3UHFOLQLFDOUDWLRQDOHXVLQJWKH7*)ȕUHFHSWRU,VPDOOPROHFXOHLQKLELWRU/<LQ
combination with gemcitabine 
Due to the inherent immunogenicity of M7824 as a humanized antibody and H[WUDFHOOXODUhuman 
7*)ȕUHFHSWRU,,FRPSRQHQWZKHQDGPLQLVWHUHGWRWKHIXOO\LPPXQHFRPSHWHQWDXWRFKWKRQRXV
KP16 mice, initial VWXGLHVZLWKWKH7*)ȕLQKLELWRU/<KDYHEHHQFDUULHGRXWWRVXSSRUWWKH
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\ODWLRQDQGGLPHUL]DWLRQZLWK7*)ȕUHFHSWRU,,60$'DFWLYDWLRQDQGXOWLPDWHO\7*)ȕ-
mediated gene transcription. M7824 shows similar end effector function like suppression of 
60$'DFWLYDWLRQDQG7*)ȕ-mediated gene transcription, however its upstream mechanism is via 
WUDSSLQJRIIUHHXQERXQG7*)ȕOLJDQGV7*)ȕ/7*)ȕ/DQG7*)ȕ/:HOLNHWRVWLSXODWHWKDW
ZLWKUHJDUGWRHIIHFWLYHQHVVRI7*)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
UHFHSWRUVZKLFKDUHSDUWRIWKH7*)ȕVXSHUIDPLO\7KHVHSUR-survival receptors are not 
LQKLELWHGE\WKH7*)ȕUHFHSWRU,VPDOOPROHFXOHLQKLELWRU/<FRPSDUHGWR0
LPSO\LQJPRUHHIILFDFLRXVVXSSUHVVLRQRISURPLVFXRXV7*)ȕHIIHFWV 
Using the autochthonous Ras-driven 3G[-1-&UH LSL-KrasG12D/+ Ink4a(p16)/Arf(p19)IOR[IOR[ 
(KP16) PRGHO7*)ȕLQKLELWLRQLQFRPELQDWLRQZLWKJHPFLWDELQHFRRSHUDWLYHO\ 
(1) 6XSSUHVVHVWXPRUJURZWKDQGH[WHQGVVXUYLYDOFigure 5) 


Abbreviated Title: M7824/Gemcitabine for AAPC 
Version date: 03/20/2019 
15 
 
Figure 5 Left; suppression of tumor growth of pancreatic tumors after 14 days of treatment with 
YHKLFOH EODFN 7*)ȕ UHFHSWRU , LQKLELWRU /< EOXH JHPFLWDELQH RUDQJH RU WKH
FRPELQDWLRQ RI /< DQG JHPFLWDELQH LQ UHG 9ROume analysis of tumor growth by 3D 
abdominal ultrasound for animals receiving indicated treatments (N=8). Right; Kaplan-Meier 
DQDO\VLVRI.3DQLPDOVWUHDWHGYHKLFOH/<JHPFLWDELQHRUWKHFRPELQDWLRQRI/<
and gemcitabine (p<0.001; log-rank; 2-tailed) 
(2) Reduces immune evasive cues in the tumor microenvironment (Figure 6)
Figure 6 Flow cytometry analysis of immune cell populations from tumors in KP16 animals treated 
ZLWKYHKLFOHEODFN/<EOXHJHPFLWDELQHRUDQJHRUWKHFRPELQDWLRQRI/<DQG


Abbreviated Title: M7824/Gemcitabine for AAPC 
Version date: 03/20/2019 
16 
 
JHPFLWDELQHUHGIRUGD\VSULRUWRKDUYHVWDQGWXPRUGLJHVW7ȕ5-I blockade in combination with 
gemcitabine reduces CD4+FoxP3+ T regulatory cells (23.2% vs 11.0%; p=0.0010), increased 
LQWUDWXPRUDO&'H&'D7FHOOVYVS UHGXFHG&'E*U-1+ MDSCs 
YVS LQPXULQHSDQFUHDWLFFDQFHUV with no impact on CD206+F4/80+Gr1- 
WXPRUDVVRFLDWHGPDFURSKDJHVYVS FRPSDUHGWRYHKLFOH-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*)ȕEORFNDGHLQFRPELQDWLRQZLWKJHPFLWDELQHLQFUHDVHVDQWL-tumor cellular immunity in 
murine pancreatic cancers. Left top, Induction of IFN-ȖVHFUHWLRQE\LVRODWHGLQWUDWXPRUDO&'D7
cells from KP16 tumors treated with vehicle (EODFN/<EOXHJHPFLWDELQHRUDQJHRUWKH
FRPELQDWLRQRI/<DQGJHPFLWDELQHLQUHGIROORZLQJKRXUVFR-culture by KP16 pancreatic 
FHOOVDQGPHDVXUHGE\(/,6SRWDVVD\1VWLPXODWLRQRIVSOHQLF&'D7FHOOVVKRZQRQWKHULJKW
Increased expression of T cell activation markers 4-%%&'YVS DQG2;
(CD134) (4.2% vs 6.7%; p=0.014), and decreased PD-H[SUHVVLRQOHYHOVRQ&'DYV
S LQ/<LQFRPELQDWLRQZLWKJHPFLWDELQH-treated tumors (t test; 2-tailed; * p<0.05; ** 
p<0.01). 
M7824 with dual anti-PD-L1 and anti-7*)ȕDFWLRQPLJKWRYHUFRPHFRRSHUDWLYHO\LQGXFHG3'-
/XSUHJXODWLRQE\7*)ȕEORFNDGHDQGJHPFLWDELQH


Abbreviated Title: M7824/Gemcitabine for AAPC 
Version date: 03/20/2019 
17 
 
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-/SRVLWLYHFHOOVDV
in vehicle-WUHDWHGLQ/<LQJHPFLWDELQH-WUHDWHGDQGLQFHOOVWUHDWHG
with both (Figure 8). 
Figure 8 Cooperative upregulation of PD-L1 expression on human Panc1 pancreas cancer cells. Flow 
cytometry of PD-/H[SUHVVLRQRI3DQFFHOOVWUHDWHGZLWKYHKLFOHEODFN0/<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. 
 
Figure  7*)ȕEORFNDGHLQFRPELQDWLRQZLWKJHPFLWDELQHLQFUHDVHVH[SUHVVLRQRIWKHGHDWKUHFHSWRU
OLJDQGH[SUHVVLRQRQ&.-SRVLWLYHFDQFHUFHOOVLQ.3DXWRFKWKRQRXVSDQFUHDWLFWXPRUV 
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*)ȕIXQFWLRQRI0
LQWKLVFOLQLFDOSURWRFROPLJKWLPSURYHFOLQLFDORXWFRPHLVVKRZQLQ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) YHUVXV7*)ȕLQKLELWLRQSOXVJHPFLWDELQH(red 


Abbreviated Title: M7824/Gemcitabine for AAPC 
Version date: 03/20/2019 
18 
 
curve) suggesting that M7824 with dual PD-/DQG7*)ȕLQKLELWLRQPLJKWEHVXSHULRUWR7*)ȕ
inhibition alone. 
 
Figure 10 The addition of PD-/LQKLELWLRQH[WHQGVVXUYLYDORI.3PLFHWUHDWHGZLWKWKH7*)ȕ
LQKLELWRU/<LQFRPELQDWLRQZLWKJHPFLWDELQH 
 
1.2.6 Preclinical rationale using M7824 in combination with gemcitabine 
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[SHULPHQWDOVHULHVDUHSUHVHQWHGWRVXSSRUWWKHFRPELQDWLRQRI0ZLWKJHPFLWDELQH 
Reduction of primary tumor weight in the murine C57B/L Panc02 model: 
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.  
0
1 0
2 0
3 0
4 0
5 0
0
2 0
4 0
6 0
8 0
1 0 0
D a y s  e la p s e d
P e rc e n t s u rv iv a l
C o n t r o l
L Y 3 6 4 9 4 7
G e m c it a b in e
L Y + G e m
T G F E  in h ib ito r/G e m c ita b in e /D -P D -L 1  S u rv iv a l C u rv e
L Y + G e m + D -P D -L 1
** *
** *
*


Abbreviated Title: M7824/Gemcitabine for AAPC 
Version date: 03/20/2019 
19 
 
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 PXULQHPRGHORISDQFUHDVFDQFHU
Panc02 mice were only given one single dose of gemcitabine, M7824 was due to its immunogenic 
WR[LFLW\OLPLWHGWRLQMHFWLRQVDQGWXPRUVZHUHDOORZHGWRJURZEDFNIRU 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: 
,PPXQHFRPSHWHQW&%/-PLFHZHUHVXEFXWDQHRXVO\LQRFXODWHGZLWK0%FHOOV[ज़6 
per mouse) and when tumors reached 100mmज़WUHDWHGZLWKHLWKHU0ȝJi.e., day 2, 5, 
8), gemcitabine (120 mg/kg, day 0), or a combination of the tZR,VRW\SHFRQWUROȝJi.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 
Isotype conrol
133 ug, i.v.
day 5, 7, 9
Trap control
164ug i.v. 
day 5, 7, 9
Anti-PD-L1 (mut)/TGFb Trap 164ug i.v. 
day 5, 7, 9
Gemcitabine
120 mg/kg, i.p. day 3 


Abbreviated Title: M7824/Gemcitabine for AAPC 
Version date: 03/20/2019 
20 
 
M7824 (p<0.001, day 16) or gemcitabine (p<0.001) monotherapies (Figure 12). Furthermore, 
0DQGJHPFLWDELQHFRPELQDWLRQWKHUDS\PRGHVWO\H[WHQGHGWKHPHGLDQVXUYLYDORI0%
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 0LQFRRSHUDWLRQZLWKJHPFLWDELQHLPSURYHVFOLQLFDORXWFRPHLQWKH0%V\QJHQHLF
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. 
M7824 induces additional anti-tumor perturbations in the tumor immune landscape compared to 
its PD-L1 inhibitor component avelumab alone: 
Figure 4 has shown that gemcitabine cooperates with PD-/ LQKLELWLRQ WR H[WHQG VXUYLYDORI
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-/LQKLELWLRQWKURXJKWKHDYHOXPDEIXVLRQSOXV7*)ȕLQKLELWLRQVKRZVHQKDQFHG
changes reprogramming the tumor microenvironment towards an anti-tumor immune milieu 
(Table 10RVWQRWDEO\WUHDWPHQWZLWKWKHGXDO7*)ȕ-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-7*)ȕIXQFWLRQ 


Abbreviated Title: M7824/Gemcitabine for AAPC 
Version date: 03/20/2019 
21 
 
Table 1 The immuno-SKHQRW\SLFVLJQDWXUHVRIWKHGXDO7*)ȕ-PD-L1 inhibitor M7824 compared to 
anti-PD-L1 (with avelumab) alone are distinct in tumor-bearing mice. 
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 theUDSHXWLFSRWHQWLDORI0ZDVH[SORUHGLQFRPELQDWLRQZLWKYDULRXVVWDQGDUGRI-care 
therapies. In combination with the core components of the FOLFOX chemotherapy regimen 
R[DOLSODWLQIOXRURXUDFLODQGR[DOLSODWLQDQDGGLWLYHHQKDQFHPHQWLQHIILFDF\ZDV demonstrated 
against MC38 colorectal carcinoma. This finding is in line with results shown in Figure 5 where 
EORFNDGH RI 7*)ȕ VLJQDOLQJ LQKLELWLRQ YLD WKH XVH RI WKH 7ȕ5, VPDOO PROHFXOH LQKLELWRU
/<FRRSHUDWHVDVVKRZQZLWKJHPFLWDELQHWRVXSSUHVVWXPRUJURZWKDQGH[WHQGVXUYLYDO
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 ZKHUH7*)ȕEORFNDGHDQGJHPFLWDELQHV\QHUJLVWLFDOO\UHSURJUDPWKHLPPXQH
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 
QRWH7*)ȕVLJQDOLQJLQKLELWLRQLQFRPELQDWLRQZLWKJHPFLWDELQHQRWRQO\GHFUHDVHV7UHJXODWRU\
cells, it also decreases their anti-tumor immune evasive function. Figure 13 shows that intratumoral 
&'&'7UHJXODWRU\FHOOVLVRODWHGIURPPXULQH.3SDQFUHDWLFWXPRUVWUHDWHGZLWK7*)ȕ
inhibition and gemcitabine impair upon co-culture anti-tumor activity of CD8+ T cells 


Abbreviated Title: M7824/Gemcitabine for AAPC 
Version date: 03/20/2019 
22 
 
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 
WUHDWHGIRUGD\VZLWK/<LQFRPELQDWLRQZLWKJHPFLWDELQHKDYHUHGXFHGDQWL-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). 
7RVKRZWKDW7UHJXODWRU\FHOODQGP\HORLGLPPXQHSRSXODWLRQVFRRSHUDWLYHO\DIIHFWHGE\7*)ȕ
LQKLELWLRQDQGJHPFLWDELQHLQDERYHVWXGLHVDQGE\WKHGXDO7*)ȕ-PD-L1 inhibitor are connected 
WR7*)ȕVLJQDOLQJDQG7*)ȕOHYHOVLQKXPDQVDPSOHVZHFRUUHODWHGLQFOLQLFDOVSHFLPHQVIURP
The Cancer Genome Atlas (TCGA) and the International Cancer Genome Consortium (ICGC) 
GDWDVHWVH[SUHVVLRQOHYHOVRIDSUHYLRXVO\YDOLGDWHG7*)ȕUHVSRQVHVLJQDWXUe (TGRS) as well as 
7*)ȕJHQHH[SUHVVLRQOHYHOVZLWKH[SUHVVLRQOHYHOVRI 
x 7UHJXODWRU\FHOOPDUNHUFRPELQDWLRQ)R[3DQG&'7UHJXODWRU\FHOOV 
x Monocyte/macrophage-lineage cell marker combination CD11b and CD33 (Figure 14).  


Abbreviated Title: M7824/Gemcitabine for AAPC 
Version date: 03/20/2019 
23 
 
There was a strong association (p<1016) between TGFbeta-dependency measured by high 
H[SUHVVLRQOHYHOVRIWKH7*)ȕ5HVSRQVH6LJQDWXUH7%56DQGWRDOHVVHUGHJUHH7*)ȕOLJDQG 
OHYHOVDQGH[SUHVVLRQOHYHOVRIWKHLPPXQHFHOOSRSXODWLRQ-selective markers CD25high )R[3high 
(T regulatory cells) CD11bhigh CD33high (human MDSC markers) both in all cancers and in 
SDQFUHDWLFFDQFHUJHQHH[SUHVVLRQVHWV7KHVHILQGLQJVVXJJHVWWKDWLQWUDWXPRUDO7*)ȕVLJQDOLQJ
is connected to T regulatory cell and myeloid immune cell population levels and that these immune 
cell populatiRQVDUHLQGHHGUHJXODWHGE\7*)ȕZKLFKVXSSRUWVDERYHILQGLQJVRIDOWHUHG7UHJDQG
0'6&FHOOIUDFWLRQVXSRQ7*)ȕLQKLELWLRQ 


Abbreviated Title: M7824/Gemcitabine for AAPC 
Version date: 03/20/2019 
24 
 
Figure 14 Association of expression levels of T regulatory-specific markers CD25, FoxP3 (top) and 
myeloid-VHOHFWLYHPDUNHUV&'E&'ERWWRPZLWK7*)ȕ5HVSRQVH6LJQDWXUH7%56RULJLQDOO\
GHULYHGIURPODUJHFDQFHUFROOHFWLRQDVDPHDVXUHRIµGHSHQGHQW¶RQ7*)ȕELRORJ\DQG7*)ȕOLJDQG
1 expression (TGFB1) in TCGA and ICGC Pan-Cancer and pancreas cancer datasets. Cutoff of 


Abbreviated Title: M7824/Gemcitabine for AAPC 
Version date: 03/20/2019 
25 
 
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 LPPXQH-
mediated 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-UHJUDWLRVDQGUHGXFHG7*)ȕOLJDQG
levels [13]), and justify the pursuit of a cRPELQDWLRQLPPXQHWKHUDS\DSSURDFKRI7*)ȕVLJQDOLQJ
inhibition and gemcitabine. 
1.2.7 6DIHW\RIFRPELQHG7*)ȕDQG3'-/LQKLELWLRQE\WKHGXDO7*)ȕ-PD-L1 inhibitor 
M7824  
Targeting both, PD-1 / PD-/DQG7*)ȕVLJQDOLQJD[LVLVDWWUDFWLYHDVDQDQWLWXPRUDSSURDch. A 
UHFHQWUHSRUWIRXQGWKDWEORFNDGHRI7*)ȕVLJQDOLQJLQ7FHOOVRUGHOHWLRQRI7*)ȕIURP7FHOOV
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[SUHVVLRQRQ&'7FHOOVDQGWKDWDGGLWLRQDO3'-L1 blockade 
is ablHWRH[WHQGVXUYLYDOZKHQDGGHGWR7*)EHWDLQKLELWLRQDQGJHPFLWDELQH6LPLODUO\Ln a 
PXULQHPRGHORIKHSDWRFHOOXODUFDUFLQRPD7*)ȕDSSHDUHGWRLQFUHDVHWKHH[SUHVVLRQRI3'-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 
VXSSUHVVRUFHOOV0'6&VDVLJQLILFDQWVRXUFHRI7*)ȕDUHDVVRFLDWHGZLWKIDLOXUHWRUHVSRQGWR
anti-PD-1 therapy. Finally, the addition of PD-/LQKLELWLRQWR7*)ȕEORFNDGHLQFRPbination 
with gemcitabine as shown in Figure 10H[WHQGVVXUYLYDOLQWKHDXWRFKWKRQRXV.3SDQFUHDV
cancer model. 
6LPLODUO\WKHGXDO7*)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\DYHOXPDERU7*)ȕ5,,FRQWURODORQH7XPRUUH-FKDOOHQJHH[SHULPHQWVLQ
cured mice show durable protective immunity. In vivo studies showed that the antitumor effects 
ZHUHPHGLDWHGE\&'7FHOOVDVLQDERYHGHVFULEHG.3DQLPDOH[SHULPHQWVDQG1.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\EHWWHUHIILFDF\WKDQWKHFRPELQDWLRQRIDYHOXPDESOXV7*)ȕ7UDSFRQWUROVXSSRUWLQJ
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[SHFWHGWKDWWKHDQWL-PD-L1 function of 
M7824 suppresses the immune evasive signal of increased PD-/H[SUHVVLRQRQFDQFHUFHOOVDQG
KHQFHHQKDQFHHIILFDF\RIWKH7*)ȕLQKLELWLRQSOXVJHPFLWDELQHFRPELQDWLRQDSSURDFK 
$ 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 


Abbreviated Title: M7824/Gemcitabine for AAPC 
Version date: 03/20/2019 
26 
 
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-PHGLDWHGDGYHUVHUHDFWLRQVRFFXUULQJLQOHVVWKDQRISDWLHQWV,QDGGLWLRQDZDUQLQJ
IRU HPEU\RIHWDO WR[LFLW\ LV SURYLGHG )RU QLYROXPDE WKH VHFWLRQ RQ :DUQLQJ DQG 3UHFDXWLRQV
includes adverse reactions of immune-PHGLDWHGSQHXPRQLWLVZLWKIDWDOLPPXQH-mediated 
SQHXPRQLWLV LQ   LPPXQH-PHGLFDWHG FROLWLV  LPPXQH-mediated hepatitis 
 LPPXQH-PHGLDWHG QHSKULWLV DQG UHQDO G\VIXQFWLRQ  LPPXQH-mediated 
K\SHUWK\URLGLVPDQGK\SRWK\URLGLVPDQGDYDULHW\RIRWKHULPPXQH-mediated adverse 
UHDFWLRQVRFFXUULQJLQOHVVWKDQRISDWLHQWV,QDGGLWLRQDZDUQLQJIRUHPEU\RIHWDOWR[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 ,WULDOVWKHH[SHULHQFHZLWKDPROHFXOHZLWKDKLJKO\VLPLODUPHFKDQLVPWRWKHM7824 7*)ȕ
trap moiety, the anti-TGFE-and 3 antibody IUHVROLPXPDEVKRZHGQRGRVHOLPLWLQJWR[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-7ȕ0ZDVZHOOWROHUDWHGZKHQVWXGLHGDV
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 WKDWLQKLELWV7*)ȕH[SUHVVLRQ
was associated with thrombocytopenia that was moderate.[19]  
,QOLQHZLWKDERYHHDUO\FOLQLFDOH[SHULHQFHRIVLPLODUDQWL-7*)ȕDJHQWVWKHWR[LFLW\ profile of 
M7824 is predominantly benign and highly comparable to that of avelumaE LQ WKH UHFHQWO\
UHOHDVHGUHVXOWVRIWKHSKDVH,VWXG\1&7µ3KDVH7ULDORI0D%LIXQFWLRQDO)XVLRQ
Protein Targeting PD-/DQG7*)ȕLQ$GYDQFHG6ROLG7XPRUV¶ZLWKGRVHHVFDODWLRQFRKRUWVRI
DQGPJNJ H[FHHGLQJWKHPJIOat starting dose in this study) M7824 given 2-
weekly, the MTD was not reached: Data suggested overall good tolerance. One out of 16 patients 
GHYHORSHGDNHUDWRDFDQWKRPDZKLFKFRXOGEHUHODWHGWRWKH7*)ȕLQKLELWLRQPHFKDQLVPRI0
There was no grade 4-5 TEAEs. The only DLT observed was colitis. Overall, the MTD was not 
H[FHHGHG DW GRVHV XS WR  PJNJ IRU IXUWKHU GHWDLOV SOHDVH DOVR VHH Section 1.2.8.
 
Pharmacokinetic / Pharmacodynamic including human phase I findings of M7824). 
2QWKHRWKHUKDQGWR[LFRORJLFDOILQGLQJVZLWK0LQF\QRPROJXVPRQNH\LQGLFDWHGDGHFUHDVH
LQUHGEORRGFHOOVFRPSDUHGZLWKWKHFRQWUROJURXSYDOXHV and related parameters (Hgb and 
KHPDWRFULW 7KHVH GHFUHDVHV ZHUH UHYHUVLEOH GXULQJ WKH UHFRYHU\ SHULRG thus, anemia is 
FRQVLGHUHGDSRWHQWLDOULVNRIWKHFRPSRXQG'XHWRWKHLQYROYHPHQWRI7*)ȕLQUHSDLURIVNLQDQG
other tissue injuries, alterations in wound healing or repair of tissue damage is considered a 
potential risk. Overall, evidence suggests non-RYHUODSSLQJWR[LFLW\SURILOHVIRUDQWL-PD-L1 and 
anti-7*)ȕDJHQWFODVVHV7KHUHLVDWKHRUHWLFDOSRWHQWLDORILU$(VWKDWZRXOGEHWKHFRQVHTXHQFH


Abbreviated Title: M7824/Gemcitabine for AAPC 
Version date: 03/20/2019 
27 
 
of a GRXEOHEORFNDGHRIQHJDWLYHUHJXODWRU\ORRSVRIWKHLPPXQHV\VWHPKRZHYHUWKDWZDVQRW
seen in the several hundred of patients treated with 1,200mg M7824 to date.  
For full SUHFOLQLFDOWR[LFRORJ\DQGLQYLYRSKDUPDFRORJ\ILQGLQJVRI0LQFOXGLQJLQPice 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 
VDWXUDEOHFRPSRQHQW7KH7*)ȕELQGLQJZDVDVVHVVHGDnd showed suppression for prolonged 
SHULRGVEH\RQGGUXJH[SRVXUHDWDOOGRVHOHYHOV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 LVDSSUR[LPDWHO\GD\V 
x 6LPXODWLRQVSUHGLFWWKDWDPJNJGRVHZLOOSURYLGHDQDYHUDJHH[SRVXUHRIDSSUR[LPDWHO\
7 ȝJP/LQKXPDQV 
x Based on PK / PharmDyn modeling and human projections: 
o $W D KXPDQ GRVH RI  PJNJ  3'-L1 total occupancy at PD[LPXP VHUXP
concentration observed post-dose (CPD[) LVH[SHFWHGLQ3%0&VSURYLGLQJDSSUR[LPDWHO\
WRWDORFFXSDQF\LQWXPRU 
o $WDKXPDQGRVHRIPJNJPRUHWKDQRI3'-L1 total occupancy at CPD[ LVH[SHFWHG
in PBMCs and tumor 
o $W D KXPDQ GRVH RI  PJNJ  HIIHFW LV SURMHFWHG LQ WXPRU UHJUHVVLRQ LQ WKH
PK / 3KDUP'\QPRGHOFRPSDUHGZLWKDWPJNJ 
x Human projections indicate a dose of 7.5 mg/kg and higher (range 4 to 20 mg/kg), on a bi-
weekly 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 thrHH7*)ȕOLJDQGVE\VHYHUDORUGHUV
of magnitude to undetectable levels. PD-/HQJDJHPHQWDQGVXSSUHVVLRQRI7*)ȕOLJDQGOHYHOV
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).  


Abbreviated Title: M7824/Gemcitabine for AAPC 
Version date: 03/20/2019 
28 
 
1RVXEMHFWH[SHULHQFHGD'/7DQGQRVXEMHFWZDVGLVFRQWLQXHGIURPWUHDWPHQWIRUGUXJ-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´ZLWKWKH3UHIHUUHG7HUPVRIDEGRPLQDOSDLQS\UH[LD
and back pain. 
2YHUDOORIVXEMHFWVKDGGUXJ-related TEAEs. All drug related TEAEs were Grade 1 
or 2: mouth hemorrhaJH  VXEMHFWV  GU\ PRXWK HSLVWD[LV LQIOXHQ]D-like illness, 
PDFXORSDSXODUUDVKSUXULWLVVXEMHFWHDFK 
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,QDGGLWLRQ6'KDVEHHQUHSRUWHGVXEMHFWV
including 1 subject in the 1 mg/kg cohort, and 2 subjects in each of the 3 and 10 mg/kg cohorts. 
)LYHVXEMHFWVZHUHUHSRUWHGZLWKD%25RI3'$WWKHWLPHRIWKHGDWDFXWRIIVXEMHFWV
(UHPDLQHGRQWUHDWPHQW 
All subjects from the first 3 dose levels were evaluable for PK analysis showing at 3 and 10 mg/kg 
dose-OLQHDUSKDUPDFRNLQHWLFVDQGDQDSSUR[LPDWHW1/2 of 150 hours (6.25 days). Subjects from the 
1, 3, 10, and 20 mg/kg dose levels were evaluable for PD-L1 target occupancy.  
At 3 mg/kg and above, PD-L1 target occupancy was high throughout the entire dosing interval 
IURP&PD[WKURXJK&PLQ$OOVXEMHFWVIURPWKHILUVWGRVHOHYHOVZHUHHYDOXDEOHIRU7*)ȕ
SODVPDFRQFHQWUDWLRQV$IWHU0LQIXVLRQ7*)ȕDQGFRQFHQWUDWLRQVZHUHXQGHWHFWDEOH
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-/WDUJHWRFFXSDQF\DQGUHGXFWLRQRI7*)ȕOLJDQGVLQKXPDQVXEMHFWVWUHDWHGRQWKe 
‘Phase 1 Trial of M7824, a Bifunctional Fusion Protein Targeting PD-/DQG7*)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). 


Abbreviated Title: M7824/Gemcitabine for AAPC 
Version date: 03/20/2019 
29 
 
 
1.2.9 Summary of Clinical Findings of M7824 including Adverse Events (AEs) in Pancreas 
Cancer Patients to date 
As of March 21st, DWOHDVW1 SDWLHQWVZLWKDGLDJQRVLVKDYHUHFHLYHGDWOHDVWRQHRUPRre, 
doses of 1,200mg of M7824. Table 2 lists both drug-related and not-related AEs for items in which 
!RISDWLHQWVH[SHULHQFHWKHHYHQWRULIWKH 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 
FRKRUW2IQRWHDQHPLDZDVRXWZDVWKHPRVWJUDGHRUJUHDWHUWR[LFLW\7KHRQO\
other graGHWR[LFLWLHVRFFXUULQJLQPRUHWKDQSHUFHQWRIVWXG\VXEMHFWVZHUHIDWLJXHRXWRI
DQGDEGRPLQDOGLVFRPIRUWRXW7KHUHZHUHVXEMHFWVZLWKJUDGH
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 
Grade 
>=4 
Grade 5 
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 


Abbreviated Title: M7824/Gemcitabine for AAPC 
Version date: 03/20/2019 
30 
 
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 
Progression 
1 (2.8) 
1 (2.8) 
0 
0 
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 


Abbreviated Title: M7824/Gemcitabine for AAPC 
Version date: 03/20/2019 
31 
 
 
3UHOLPLQDU\FOLQLFDOHIILFDF\VLJQDORIWKH1 SDQFUHDWLFFDQFHU0PRQRWKHUDS\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 
EHGXHWR7*)EHWDLQKLELWLRQZKLFKKDVDQHIIHFWRQDQJLRJHQHVLVEOHHGLQJKDVDOVREHHQREVHUYHG
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[WHQGV survival 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-/XSRQ7*)ȕLQKLELWLRQis a mechanism of resistance to optimal efficacy 
RI7*)ȕEORFNDGHLQFRPELQDWLRQZLWKJHPFLWDELQHDQGWKe addition of PD-L1 inhibition to 
7*)ȕEORFNDGHDQGJHPFLWDELQHIXUWKHUH[WHQGVVXUYLYDOµWULSOHLPPXQRWKHUDS\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 :LWKWKHH[FHSWLRQRIDQHPLD0DQGJHPFLWDELQHKDYHQon-RYHUODSSLQJWR[LFLW\SURILOHV 
x &OLQLFDOH[SHULHQFHZLWK0WR-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. 


Abbreviated Title: M7824/Gemcitabine for AAPC 
Version date: 03/20/2019 
32 
 
1.2.11 5DWLRQDOHIRU0'RVH/HYHOVZLWKVSHFLDOFRQVLGHUDWLRQRIRYHUODSSLQJWR[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\VKRZLQJKLJKO\HIIHFWLYH7*)ȕVXSSUHVVLRQDQGQHDUFRPSOHWH3'-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, 
HIIHFWVH[FHSWDWUHQGRIUHYHUVLEOHUHGEORRGFHOOUHGXFWLRQZLWKDssociated 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
KXPDQPRXVHDQGF\QRPROJXVSULPDWHVLQFH7*)ȕLVDQH[WUHPHO\KLJKO\FRQVHUYHGJHQHZLWK
WKHPRXVHVHTXHQFHIRU7*)ȕGLIIHULQJE\RQO\RQHDPLQRDFLGDQGWKHcynomolgus monkey 
SUHGLFWHGWREHLGHQWLFDOWRKXPDQ)RU7*)ȕWKHDPLQRDFLGVHTXHQFHLVSUHGLFWHGWREH
LGHQWLFDODFURVVPRXVHKXPDQDQGcynomolgus 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 
LQH[SHFWHGLPPXQHIHDWXUHVZLWKDFXUUHQWO\DFFHSWDEOHVDIHW\SURILOHWKDWFRQWLQXHVWREHDVVHVVHG
(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[SHULHQFHKDVEHHQFROOHFWHGLQPRUHWKDQVXEMHFWVZLWKVROLGWXPRUVH[SRVHGWRWKHPJNJ
GRVHDVGHVFULEHGIXUWKHULQWKLVVHFWLRQ7KHH[SRVXUHRI0ZLOOOLNHOy be similar at the same 
dose strength since the molarity for PD-/ELQGLQJLVDSSUR[LPDWHO\OHVVRI0EXWWKH
half-OLIHLVSUHGLFWHGWREHDSSUR[LPDWHO\WRPRUH 
2QHRIWKHSRWHQWLDOFRQFHUQVRI7*)ȕOLJDQG-binding agents has been the unknown therapeutic 
window between tumor-selective effects in the microenvironment of cancer and systemic 
WR[LFLWLHV%LQGLQJRI0WRIUHH7*)E in the periphery is projected to be substantial since 
7*)ȕOHYHOVDUHYHU\ORZDSSUR[LPDWHO\QJP/[20] Human PK simulations suggest that a 1 
PJNJGRVHZRXOGSURYLGHDQDYHUDJHH[SRVXUHRIDSSUR[LPDWHO\ȝJP/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, IRUWKLVPROHFXOHZKLFKELQGV7*)ȕDWPRODUUDQJHV(&50 and IC50 
FDQQRWEHUHJDUGHGDVDIL[HGDIILQLW\FRQVWDQWDQGLVWKHUHIRUHGLIILFXOWWRHVWLPDWHLQ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 


Abbreviated Title: M7824/Gemcitabine for AAPC 
Version date: 03/20/2019 
33 
 
the local environment including tumor environment.[8] This lack of interference with essential 
WLVVXHKRPHRVWDVLVUHJXODWHGE\7*)ȕLVFRUURERUDWHGE\WKHODFNRIGUXJ-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 -PHGLDWHG7*)ȕLQKLELWLRQDWPJNJUDQJHWRPJNJEDVHGRQ
 YDULDELOLW\ EHWZHHQ VXEMHFWV LV SUHGLFWHG WR UHDFK HIIHFWLYH WXPRU JURZWK LQKLELWLRQ RI
DSSUR[LPDWHO\7DNHQWRJHWKHUthe 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 
RYHUODSSLQJWR[LFLWLHVEHWZHHQWKH3'-/DQG7*)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-RYHUODSSLQJWR[LFLW\SURILOHZLWKJHPFLWDELQH 
 
dose-adjustments or discontinuation of drug(s) for each drug – M7824 and gemcitabine - will be 
made / carried out separDWHO\EDVHGRQWKHREVHUYHGWR[LFLW\SURILOH 
1.2.12 Rationale for Gemcitabine Dose Selection and Safety Measures 
7RDFFRXQWIRUSRVVLEOHJHPFLWDELQHWR[LFLW\H[DFHUEDWHGWKURXJKWKHFRPELQDWLRQZLWK0
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 ZLWKWR[LFLW\RI

-GLIOXRUR
-
GHR[\F\WLGLQHJHPFLWDELne)-based chemoradiotherapy and possibly clinical outcome including 
KHPDWRORJLFWR[LFLW\DQGRYHUDOl survival.  
Gemcitabine enters the cell via facilitated transport of nucleoside transporters and becomes 
activated through ATP-UHTXLULQJSKRVSKRU\ODWLRQE\GHR[\F\WLGLQHNLQDVHG&.WRWKHDFWLYHWUL-
phosphatide 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 VWXGLHVH[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)RURWKHUSRO\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 


Abbreviated Title: M7824/Gemcitabine for AAPC 
Version date: 03/20/2019 
34 
 
polymorphism genotyping showed the KRPR]\JRXV ZLOG W\SH /\V/\V ZDV IRXQG LQ 
ZKHUHDVWKHKHWHUR]\JRXV/\V*OQDQGKRPR]\JRXVYDULDQW*OQ*OQZDVIRXQGLQDQG
 [21] There was a statistically significant increased riVNIRUVHYHUHKHPDWRORJLFDOWR[LFLW\
JUDGHLQSDUWLFXODUIRUWKHKRPR]\JRXVCDA Lys27Gln*OQYDULDQWRGGVUDWLR25 
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 
IURPWKH0'$QGHUVRQ&DQFHU&HQWHUH[DPLQHG613VLQJHPFLWDELQH-metabolizing genes and 
LPSDFWRQVXUYLYDODQGWR[LFLW\&'$&7DQGQRW&'$&!$.4ZDVDVVRFLDWHGZLWK
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 
SDWLHQWVRIWKHWZRH[DPLQHG&'$KDSORW\SHVKDUERULQJWKHQRQ-synonymous SNPs CDA 79A>C 
(Lys27Gln) and 208G>A (Ala70Thr) variants, 208G>A (Ala70Thr) was associated with higher drug-
UHODWHGWR[LFLWLHVEXW&'$79A>C (Lys27Gln) was not. [25] The recently released European FFCD-
&OLQLFDO7ULDOµ,mpact of Cytidine Deaminase Activity on Clinical Outcome in Gemcitabine-
Monotherapy Treated Patients¶ IURP WKH Fédération Francophone de Cancérologie Digestive 
DLPHGWRSURVSHFWLYHO\H[DPLQHLPSDFWRI&'$DFWLYLW\DIIHFWHGE\613LQSDWLHQWVZLWK
resected pancreatic cancer.[26] Surprisingly, only 5 out of 120 (4.65) of patients were found to 
have a CDA polymorphism and the study ultimately lacked statistical power to detect on impact 
oQ JHPFLWDELQH WR[LFLW\ )LQDOO\ ERWK µPHWD-DQDO\VHV¶ FRQGXFWHG RQ WKH VXEMHFW RI &'$
polymorphisms and outcome of gemcitabine to date, did demonstrate a moderate impact of CDA 
79A >C (CDA K27Q) SRO\PRUSKLVPRQKHPDWRORJLFDOWR[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] 
 
 


Abbreviated Title: M7824/Gemcitabine for AAPC 
Version date: 03/20/2019 
35 
 
 
Figure 16 .H\ JHPFLWDELQH G)G& WUDQVSRUWDWLRQ DQG PHWDEROLVP VWHSV (Q]\PHV NQRZQ WR EH
DIIHFWHGE\SRO\PRUSKLVPKLJKOLJKWHGLQUHGIURP2ND]DNL7HWDO 
 
Thus, to increase safety of patients treated with gemcitabine in combination of M7824, and in 
particular to account for any enhanced gemcitabine-GULYHQWR[LFLWLHVGXHWRWKHFRPELQDWLRQZLWK
gemcitabine, patients will be genotyped prior to study treatment with the Drug Metabolizing 
(Q]\PHVDQG7UDQVSRUWHU'0(73OXVJHQRW\SLQJSODWIRUP$II\PHWUL[SDWients will be co-
signed onto NCI 16-C-0076 “Prospective Screening for Patient Specific Genotypes and 
Phenotypes that Influence Drug Dosing and Trial Selection in Cancer Patients”, PI: Dr. William 
D. Figg). Depending on the genotyping results (turnaround time 1 – 2 weeks), patients will be 
VWUDWLILHG LQWR ORZ DQG KLJK JHPFLWDELQH WR[LFLW\ ULVN JURXSV DGPLQLVWHUHG VWDUWLQJ GRVH RI
JHPFLWDELQH'D\ZLOOEHDGMXVWHGDFFRUGLQJWRF\WLGLQHGHDPLQDVH&'$WKHPDMRUHQ]\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 
RIVWDQGDUGJHPFLWDELQHGRVHPJP2 weekly) 
Upon Day 43, start of cycle #5, after the initial 4 doses of gemcitabine, patients who have received 
OHVVWKDQRIWKHVWDQGDUGJHPFLWDELQHGose (initially tested positive for either heterozygous 
or homozygous CDA variants) and who have not shown any gemcitabine-UHODWHGWR[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 


Abbreviated Title: M7824/Gemcitabine for AAPC 
Version date: 03/20/2019 
36 
 
Molecular Diagnostics Laboratory, Frederick, MD (CLIA certificate 21D0947274) through Dr. 
:LOOLDP')LJJ¶V/DERUDWRU\&&5NCI.
1.2.13 Gemcitabine in Pancreas Cancer 
*HPFLWDELQH+&OLVDQXFOHRVLGHDQDORJXHWKDWH[KLELWVDQWLWXPRUDFWLYLW\*HPFLWDELQH+&OLV-
GHR[\--GLIOXRURF\WLGLQHPRQRK\GURFKORULGHȕ-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+\GURFKORULFDFLGDQGRUVRGLXPK\GUR[LGHPD\KDYHEHHQDGGHGIRUS+DGMXVWPHQW 
Clinical Pharmacokinetics
*HPFLWDELQHH[KLELWVFHOOSKDVHVSHFLILFLW\SULPDULO\NLOOLQJFHOOVXQGHUJRLQJ'1$V\QWKHVLV6-
phase) 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). 
Human Pharmacokinetics 
Gemcitabine disposition was studied in 5 patients who received a single 1,000 mg/m2 /30 minute 
infusion 
of 
radiolabeled 
drug 


Abbreviated Title: M7824/Gemcitabine for AAPC 
Version date: 03/20/2019 
37 
 
(https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/020509s077lbl.pdf). Within one (1) 
ZHHNWRRIWKHGRVHZDVUHFRYHUHGDOPRVWHQWLUHO\LQWKHXULQH*HPFLWDELQH
DQGWKHLQDFWLYHXUDFLOPHWDEROLWH-GHR[\--GLIOXRURXULGLQHG)G8DFFRXQWHGIRURI
WKHH[FUHWHGGRVH7KHPHWDEROLWHG)G8LVDOVRIRXQG in plasma. Gemcitabine plasma protein 
ELQGLQJLVQHJOLJLEOH7KHSKDUPDFRNLQHWLFVRIJHPFLWDELQHZHUHH[DPLQHGLQSDWLHQWVDERXW
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 
Table 3: PK parameters of gemcitabine in human subjects. 
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, 
LVQRWH[WHQVLYHO\GLVWULEXWHGLQWRWLVVXHV)RUORQJLQIXVLRQVWKHYROXPHRIGLVWULEXWLRQURVHWR
370 L/m2, reflecting slow equilibration of gemcitabine within the tissue compartment. The 
PD[LPXPSODVPDFRncentrations of dFdU (inactive metabolite) were achieved up to 30 minutes 
DIWHUGLVFRQWLQXDWLRQRIWKHLQIXVLRQVDQGWKHPHWDEROLWHLVH[FUHWHGLQXULQHZLWKRXWXQGHUJRLQJ
further biotransformation. The metabolite did not accumulate with weekly dosing, but its 
HOLPLQDWLRQLVGHSHQGHQWRQUHQDOH[FUHWLRQDQGFRXOGDFFXPXODWHZLWKGHFUHDVHGUHQDOIXQFWLRQ
The effects of significant renal or hepatic insufficiency on the disposition of gemcitabine have not 
been assessed. The active metabolite, gemcitabine triSKRVSKDWHFDQEHH[WUDFWHGIURPSHULSKHUDO
blood mononuclear cells. The half-life of the terminal phase for gemcitabine triphosphate from 
mononuclear cells ranges from 1.7 to 19.4 hours.  


Abbreviated Title: M7824/Gemcitabine for AAPC 
Version date: 03/20/2019 
38 
 
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 
PLQXWHVRQFHZHHNO\IRUXSWRZHHNVRUXQWLOWR[LFLW\QHFHVVLWDWHGKROGLQJDGRVHIROORZHG
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UHGXFWLRQLQSDLQLQWHQVLW\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 
39 
 
Table 4 5DQGRPL]HGWULDORIJHPFLWDELQHYHUVXV-fluorouracil in pancreas cancer (Burris H$
 
Figure 17 Overall survival by Kaplan-Meier analysis of Gemcitabine vs 5-FU systemic chemotherapy 
as first-line treatment in advanced pancreas cancer patients. 
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 


Abbreviated Title: M7824/Gemcitabine for AAPC 
Version date: 03/20/2019 
40 
 
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 RIJHPFLWDELQHLQFRPELQDWLRQZLWK7*)ȕLQKLELWLRQ to date. 
To date OLPLWHGGDWDRQ7*)ȕVLJQDOLQJLQKLELWLRQFRPELQHGwith F\WRWR[LFFKHPRWKHUDS\DUH
DYDLODEOH 7KH ODUJHVW FOLQLFDO H[SHULHQFH RI 7*)ȕ LQKLELWLRQ LQ FRPELQDWLRQ ZLWK V\VWHmic 
FKHPRWKHUDS\LQFOXGHVJHPFLWDELQHDQGFRPHVIURPWKH7*)ȕUHFHSWRU,VPDOOPROHFXOHLQKLELWRU
galunisertib (LY2157299 monohydrate), a small molecule inhibitor of transforming growth factor-
beta 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 
,KDGWKHH[SHFWHGPDQDJHDEOHWR[LFLW\RIJHPFLWDELQH 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 
GUXJDQGQRDGGLWLRQDOWR[LFLWLHVV\QHUJLVWLFDOO\LQGXFHGWhrough the combination. 
The most frequent CTC grade 3/4 adverse events possibly related to study treatment (GG vs GP) 
ZHUHDQHPLDYVQHXWURSHQLDYVDQGWKURPERF\WRSHQLDYV
 and are consistent with a gemcitabine-GULYHQWR[LFLW\SURILOHRIWKHcombination with no 
DGGLWLYHRUQHZWR[LFLW\ZLWKWKHDGGLWLRQRI7*)ȕLQKLELWLRQ. 
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). 
1.2.15 Clinical safety data of gemcitabine in combination with PD-L1 inhibition to date. 
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] $QWLJHQLFLW\LVWKHUHVXOWRILQFUHDVLQJWKHH[SUHVVLRQDQGRU
presentation of tumor-associated antigens on the cell surface of cancer cells. There are currently 
not less than 6 trials registered on clinicaltrials.gov combining gemcitabine with various immune 
checkpoint inhibitors. Several phase IB studies have shown safety of the combined immune 
FKHFNSRLQWLQKLELWRUDQGFKHPRWKHUDS\DSSURDFK$VH[DPSOHVDUHOLVWHG 
Pembrolizumab, in combination with gemcitabLQHJHPFLWDELQHDQGGRFHWD[HOJHPFLWDELQHDQG
nab-SDFOLWD[HORUJHPFLWDELQHDQGYLQRUHOELQHor 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


Abbreviated Title: M7824/Gemcitabine for AAPC 
Version date: 03/20/2019 
41 
 
including pancreas cancer.[33] More importantly, the recently released results of the KEYNOTE-
021 study in NSCLC show that RYHUDOO WR[LFLWLHV LQ patients in the pembrolizumab plus 
chemotherapy group ZDVVLPLODUEHWZHHQJURXSV>@RISDWLHQWVLQWKHSHPEUROL]XPDE
plus chemRWKHUDS\JURXSDQG>@RILQWKHFKHPRWKHUDS\DORQHJURXS[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
EHWZHHQDYHOXPDEDQGWKHF\WRWR[LFFKHPRWKHUDS\>(0'6HURQR@ 
1.2.16 Health-related Quality of Life 
It is conceivable that clinical benefit of the tested combined M7824 gemcitabine approach is 
limited to LPSURYHPHQWLQ4R/PHDVXUHVRIWUHDWHGSDWLHQWV)RUH[DPSOHRQHRIWKHLQLWLDOVWXGLHV
RIJHPFLWDELQHVKRZHGµRQO\¶LPSURYHPHQWLQSDLQVFRUHVDQG4R/SDUDPHWHUVEXWQRFKDQJHLQ
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&DQFHU7KHUDS\¶ZLWKWKH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). 
1.2.17 Justification of Research Studies 
1.2.17.1 Dynamic Contrast Enhanced MRI (DCE-MRI): 
As a possible stromal modulator µEUHDNLQJWKHEDUULHURIWKHGHQVHPLFURHQYLURQPHQWRISancreatic 
WXPRUVDQGHQDEOLQJLQFUHDVHGGUXJGHOLYHU\LQWRWKHVHWXPRUV¶, 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 


Abbreviated Title: M7824/Gemcitabine for AAPC 
Version date: 03/20/2019 
42 
 
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, 
WKDWWKHXQGHUO\LQJJHQRW\SHRISDQFUHDWLFFDQFHUVPLJKWJRYHUQERWUHVSRQVHWR7*)ȕDVZHOODV
LPPXQHFKHFNSRLQWEORFNDGH,QSDUWLFXODUYDULDQWVDIIHFWLQJWKH7*)ȕUHFHSWRU- 60$'D[LV
have been cited as potentially protective against an initial pro-WXPRUHIIHFWRI7*)ȕLQKLELWLRQGXH
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 
RISDWLHQWVIRUWKHGXDO7*)ȕµWUDS¶3'-L1 blockade in combination with gemcitabine approach 
as well as (2) improve understanding of the mechanism of action of M7824 in pancreas cancer. 
1.2.17.3 6HUXPF\WRNLQHVDQGVHUXP7*)ȕOHYHOV 
One of the least elaborate ways to confirm that the administered M7824 is active and is engaging 
LWVWDUJHWLVWRPHDVXUHVXSSUHVVLRQRI7*)ȕOHYHOVYLDµWUDSSLQJ¶DQGLQGXFHGFKDQJHVLQWKH
F\WRNLQHSURILOHV\VWHPLFDOO\)ROORZLQJ7*)ȕDQGF\WRNLQHOHYHOVORQJLWXGLQDOO\DFURVVWUHDWment 
course will allow detection of lack of M7824 activity and can trigger additional investigations 
(ADA development) into lack of efficacy. 
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 on-
treatment 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). 
1.2.17.6 Rationale for circulating free tumor DNA measures: 
Measures of copies of genomic tumor DNA released into the circulation has been shown to be an 
accurate measure of tumor burden in patients with solid organ cancers and to have value to follow 
response to anti-cancer treatment both for the early identification of responders as well as patients 
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: 


Abbreviated Title: M7824/Gemcitabine for AAPC 
Version date: 03/20/2019 
43 
 
AbbreviatHG3.PHDVXUHPHQWVRIERWK 0 DQG JHPFLWDELQH ZLOO EH WDNHQWR H[FOXGH WKDW
0DQGJHPFLWDELQHSKDUPDFRORJ\DUHLQWHUGHSHQGHQW0SODVPD&PD[DQG&Pin levels 
will be compared to PK PHDVXUHVWDNHQGXULQJ0PJIODWGRVHPRQRWKHUDS\H[SDQVLRQ
FRKRUWVJHPFLWDELQHSODVPD&PD[DQG&PLQOHYHOVZLOOEHcorrelated to initial DMET genotyping 
and compared between the two JHPFLWDELQHWR[LFLW\ULVNJURXSs). Gemcitabine PKs will be used 
to adjust gemcitabine schedule during the study, patients in the high-risk group who have not 
VKRZQDQ\WR[LFLW\DQGZKRVH3.VGRQ¶WVKRZDQ\HOHYDWHG&PD[DQG&PLQOHYHOVFDQKDYHWKHLU
doses increased to the standard 1,000 mg/m2 level. 
1.2.18 Amendment B 
With this amendment we want to update DLT definition. Originally, we inadvertently left out DLT 
definitions DQGGLGQRWH[FOXGHDGYHUVHHYHQWVZLWKFOHDUHYLGHQFHRIDQDOWHUQDWLYHFDXVDOLW\RU
H[SHFWHGDQGVKRUWO\UHVROYHG 
As a result, there were DLTs, that in the opinion of the PI, are not related to study treatment or 
H[SHFWHGDQGFDQEHH[FOXGHGEXWZHUHQRWPHQWLRQHGDVH[FOXVLRQV 
6RDGKHULQJWRWKHFXUUHQW'/7GHILQLWLRQLQWKHSURWRFROFDSWXULQJµ$Q\'/76HFWLRQ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 
ZDQWWRFDSWXUHDQ\SRVVLEOHDGGLWLYHWR[LFLW\VLJQDOZKHQFRPELQLQJ0DQGJHPFLWDELQHZH
also do not want to unnecessarily lower M7824 dose levels in a disease where the lack of sufficient 
LQWUDWXPRUDOH[SRVXUHOHYHOVGXHWRWKHXQLTXHQHVVRISDncreas cancer (high interstitial pressures, 
SRRUYDVFXODUL]DWLRQLVDPDMRULPSHGLPHQWWRWKHHIILFDF\RIDSSURYHGF\WRWR[LFWKHUDSLHV 
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EHHQWZRODUJHGURSV!LQWXPRUPDUNHUOHYHOVRFFXUULQJDIWHU!PRQWKVRI
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.  
 


Abbreviated Title: M7824/Gemcitabine for AAPC 
Version date: 03/20/2019 
44 
 
2 
ELIGBILITY ASSESSMENT AND ENROLLMENT 
 
2.1 
Eligibility Criteria 
2.1.1 Inclusion Criteria  
x Patient must be able to understand and willing to sign a written informed consent document 
x $JH\HDUV%HFDXVHQRGRVLQJRUDGYHUVHHYHQWGDWDDUHFXUUHQWO\DYDLODEOHRQWKHXVH
of M7824 in combination with gemcitabine in patients <18 years of age, children are 
H[FOXGHGIURPWKLVVWXG\EXWZLOOEHHOLJLEOHIRUIXWXUHSHGLDWULFWULDOV 
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 ZKLWHEORRGFHOO:%&FRXQWî9/L  
¾ ZLWKDEVROXWHQHXWURSKLOFRXQW$1&î9/L,  
¾ O\PSKRF\WHFRXQWî9/L,  
¾ SODWHOHWFRXQWî9/L, and  
¾ Hgb J dL (more than 48 hours post-completion of blood transfusion)) 
x Adequate hepatic function defined by: 
¾ DWRWDOELOLUXELQOHYHOîULN,  
¾ an AST levelî8/1 
¾ ALT OHYHOî8/1.  
x Adequate renal function defined by: 
¾ Creatinine up to 1.5-times upper institutional limits OR creatinine clearance (CrCl) 
>50 mL/min/1.73 m2 OR within normal as predicted by the Cockcroft-Gault 
formula: 
                 &U&O íDJH (y)[ZHLJKWLQNJ[LIIHPDOH [P2 
                                         [Serum Creatinine (mg/dL) [SW¶V%6$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EDUULHUPHWKRGRIELUWKFRQWURODEVtinence) 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. 


Abbreviated Title: M7824/Gemcitabine for AAPC 
Version date: 03/20/2019 
45 
 
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\RUH[SHULmental drug treatment with published half-life known to be 72 
hours within 14 days 
¾ H[SHULPHQWDOGUXJWUHDWPHQWZLWKXQSXEOLVKHGRUKDOI-life greater than 72 hours within 
28 days 
¾ radiotherapy for measurable lesions delivered in a normal organ-sparing technique 
within 21 days H[FHSWIRUpalliative 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 (IRUH[DPSOHK\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 
WUHDWHGZLWKFXUDWLYHLQWHQWDUH127H[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 
RUPHWDVWDVHVWKDWUHTXLUHWKHUDSHXWLFLQWHUYHQWLRQDUHH[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 ZLWKWKHH[FHSWLRQV: 
¾ diabetes type I, vitiligo, alopecia, psoriasis, hypo- or hyperthyroid disease not requiring 
immunosuppressive treatment are eligible 


Abbreviated Title: M7824/Gemcitabine for AAPC 
Version date: 03/20/2019 
46 
 
¾ subjects requiring hormone replacement with corticosteroids are eligible if the steroids 
are administered only for the purSRVHRIKRUPRQDOUHSODFHPHQWDQGDWGRVHVPJ
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 
v5.0DQ\KLVWRU\RIDQDSK\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 
WKHVXEMHFW¶VWolerance 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 DUHH[FOXGHGGXHWRthe absence of 
SUHYLRXVH[SHULHQFHwith 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 
The study will be posted on the CCR website and on clinicaltrials.gov. 
2.2 
Screening Evaluation 
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 Hematological profile: CBC with differential and platelet count  


Abbreviated Title: M7824/Gemcitabine for AAPC 
Version date: 03/20/2019 
47 
 
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&705,VFDQLIFOLQLFDOO\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. 
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): 
Cohorts 
Number Name 
Description 
1 
Phase 
IB 
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 
 
Arms 
Number Name 
Description 
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 
 
Arm assignment 
Subjects in Cohort 1 will be directly assigned to Arm 1. 


Abbreviated Title: M7824/Gemcitabine for AAPC 
Version date: 03/20/2019 
48 
 
Subjects in Cohort 2 will be directly assigned to Arm 2.   
2.4 
Baseline Evaluation 
Tests done at screening do not need to be repeated on baseline if performed in designated time 
frame prior to start of 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 
DVVHVVPHQWVWKHWKYHUVLRQRIWKHµ)XQFWLRQDO Assessment of Cancer Therapy with the 
hepatobiliary and pancreatic specific module (FACT-Hep Appendix B). (For English 
speaking subjects only).   
3 
STUDY IMPLEMENTATION 
3.1 
Study Design  
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 IBDQG
WRH[DPLQHWKHVDIHW\DQGefficacy 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 
SURILOLQJUHVXOWVSDWLHQWVZLWKORZULVNwild 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)).  


Abbreviated Title: M7824/Gemcitabine for AAPC 
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49 
 
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/LPLWLQJ7R[LFLW\
The DLT period is two cycles, 28 days. 
DLT is defined as follows: 
¾ Febrile neutropenia of any grade  
¾ $Q\*UDGHDGYHUVHHYHQW (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-UHODWHGWR[LFLW\WKDWFOLQLFDOO\UHVROYHWR*UDGH
within 7 days of initiating therapy  
x *UDGHGLDUUKHDRUVNLQWR[LFLW\WKDWUHVROYHVWR*UDGHLQOHVVWKDQGD\VDIWHU
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. 


Abbreviated Title: M7824/Gemcitabine for AAPC 
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50 
 
x 7UDQVLHQW24 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 
UHVROYHVWR*UDGHRU%DVHOLQHJUDGH 
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 
*UDGHZLWKLQWKHVXEVHTXHQWF\FOH14 days) 
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 6NLQOHVLRQUHODWHGWR7*)ȕLQKLELWLRQLHNHUDWRDFDQWKRPDVTXDPRXVFHOOFDUFLQRPD
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*UDGHZLWKLQGD\VZLWKDGHTXDWHPHGLFDOPDQDJHPHQW 
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, 
WKHQH[WJURXSRISDUWLFLSDQWVZLOOEHHQUROOHG,IQRPRUHWKDQ 1/6 H[SHULHQFHD'/7 during 
'/7SHULRGDFFUXDOPD\SURFHHGLQWKHSKDVH,,H[SDQVLRQFRKRUWDQG'/ 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'/7SHULRGWKHQWKHQH[WJURXSRI participants will be 
enrolled at DL-1. If no more than 1/6 H[SHULHQFHD DLT, then accrual may proceed to the phase II 
H[SDQVLRQFRKRUWDQG'/-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.  


Abbreviated Title: M7824/Gemcitabine for AAPC 
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51 
 
The dose de-escalation scheme in the safety run-in will use the following dose levels (Table 5): 
Table 5 Dose modification in safety run-in of the study (Phase IB). 
Dose 
level 
M7824, mg, IV every 2 
weeks  
Gemcitabine, mg/m2, IV every week* 
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 ZLWKSDWient having DLT and 28 days of observation 
have passed (completion of DLT period) after the first treatment of the 6th subject, patients can be 
DFFUXHGWRWKHSKDVH,,H[SDQVLRQFRKRUW 
The recommended phase 2 dose (RP2D) is the dose level of M7824 at which  LQGLYLGXDO
H[SHULHQFHGDDLT during the first 2 cycles of treatment (28 days). 
In case of DLT patients will be taken off study treatment (M7824 and gemcitabine) 
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[SHULHQFHGE\WKHSDWLHQW&OHDUDQFHLQZRPHQDQGWKHHOGHUO\LVUHGXFHGDQGZRPHQare 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. )DLOXUHWRUHVXPHJHPFLWDELQHDIWHUDKROGRIZHHNZLOOEHDQDO\]HGDVD'LT within 
respective dose level group. 


Abbreviated Title: M7824/Gemcitabine for AAPC 
Version date: 03/20/2019 
52 
 
For patients receiving 600 mg/m2 gemcitabine per dose gemcitabine dosage will not be reduced 
and gemcitabine will be withheld. 
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.  
3.2 
Study Stopping Rules  
For safety reasons, the protocol will be temporarily halted XQWLODQH[SHGLWHGVDIHW\UHSRUWis 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:  
2QHRFFXUUHQFHRIJUDGHWR[LFLW\ 
7ZRRFFXUUHQFHVRIJUDGHWR[LFLW\ 
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 0.2-
micron 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 
WRDQLQWHQVLYHFDUHXQLWRUHTXLYDOHQWHQYLURQPHQWDQGDGPLQLVWUDWLRQRIWKHUDS\IRUDQDSK\OD[LV
such as the ability to implement immediate resuscitation measureV6WHURLGVGH[DPHWKDVRQH


Abbreviated Title: M7824/Gemcitabine for AAPC 
Version date: 03/20/2019 
53 
 
mg), epinephrine (1:1,000 dilution), allergy medications (IV antihistamines), bronchodilators, or 
equivalents, DQGR[\JHQVKRXOGEHDYDLODEOHIRULPPHGLDWHDFFHVV 
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 
LIQRJUDGHWR[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 


Abbreviated Title: M7824/Gemcitabine for AAPC 
Version date: 03/20/2019 
54 
 
infusion. ,QFDVHRIORFDOLQIXVLRQUHDFWLRQVFRQWUDODWHUDOH[WUHPLWLHVRURWKHUDFFHVVURXWHVVKRXOG
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).  
 
Figure  Schedule of drug administration of M7824 and gemcitabine and assessments on treatment 
including DCE-MRI and tumor biopsies. 
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[FHSWIRU 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. 


Abbreviated Title: M7824/Gemcitabine for AAPC 
Version date: 03/20/2019 
55 
 
Any Grade 3 ADRs require treatment discontinuation except for any of the following:  
x 7UDQVLHQWKRXUV*UDGHIOX-like symptoms or fever, which is controlled with medical 
management. 
x 7UDQVLHQWKRXUV*UDGHIDWLJXHORFDOUHDFWLRQVKHDGDFKHQDXVHDHPHVLVWKDWUHVROYHV
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 *UDGH3 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 36LV 3 
on the day of planned M7824 administration DQGVKRXOGEHGHOD\HGXQWLO(&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PLVVHGdiscontinuation 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: 
Any Grade 2 ADR should be managed as follows: 
x ,ID*UDGH$'5UHVROYHVWR*UDGHE\WKHODVWGD\RIWKHFXUUHQWF\FOHWUHDWPHQWPD\
continue. 
x ,ID*UDGH$'5GRHVQRWUHVROYHWR*UDGHE\WKHODVWGD\RIWKHFXUUHQWF\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. 


Abbreviated Title: M7824/Gemcitabine for AAPC 
Version date: 03/20/2019 
56 
 
x Upon the second occurrence of the same Grade 2 ADR in the same subject H[FHSWIRUfatigue 
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 
Mild transient 
UHDFWLRQLQIXVLRQ
interruption not 
LQGLFDWHG
intervention not 
indicated. 
Decrease the M7824 
LQIXVLRQ UDWH E\ 
and monitor closely for 
any worsening. 
The total infusion time 
for M7824 should not 
H[FHHGPLQXWHV 
Increase monitoring of 
vital signs as 
medically indicated 
until the subject is 
medically stable. 
None 
Grade 2 – moderate 
Therapy or infusion 
interruption indicated 
but responds 
promptly to 
symptomatic 
treatment (for 
H[DPSOH
antihistamines, 
NSAIDs, narcotics, 
,9IOXLGV
prophylactic 
Stop M7824 infusion. 
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.). 
Otherwise dosing will 
be held until symptoms 
resolve and the subject 
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 pre-
medicated 1.5h (± 
30 minutes) prior 
to infusion of 
M7824 with: 
Diphenhydramine 
50 mg po (or 
equivalent dose of 
antihistamine). 
Acetaminophen 
500-1,000 mg PO 
(or equivalent 


Abbreviated Title: M7824/Gemcitabine for AAPC 
Version date: 03/20/2019 
57 
 
NCI-CTCAE Grade  
Infusion of M7824 
Treatment 
Premedication at 
subsequent 
dosing 
medications indicated 
for d 24 hours. 
should 
be 
pre-
PHGLFDWHG IRU WKH QH[W
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 Grade 3: 
Prolonged (for 
H[DPSOHQRW
rapidly 
responsive to 
symptomatic 
medication and / 
or brief 
interruption of 
LQIXVLRQ
recurrence of 
symptoms 
following initial 
LPSURYHPHQW
hospitalization 
indicated for 
clinical sequelae. 
x Stop the M7824 
infusion 
immediately and 
disconnect infusion 
tubing from the 
subject. 
If resolved within 6 
hours, infusion may 
be restarted by 
discretion of PI 
 
 
 
 
 
 
 
 
 
 
 
 
 
Therapy includes but is 
not limited to: 
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. 
Subjects who develop 
Grade 
3 
toxicity 
despite 
adequate 
premedication should 
be 
permanently 
discontinued 
from 
further 
trial 
Subject to be pre-
medicated 1.5h (± 
30 minutes) prior 
to infusion of 
M7824 with: 
Diphenhydramine 
50 mg po (or 
equivalent dose of 
antihistamine). 
Acetaminophen 
500-1,000 mg PO 
(or equivalent 
dose of 
antipyretic). 


Abbreviated Title: M7824/Gemcitabine for AAPC 
Version date: 03/20/2019 
58 
 
NCI-CTCAE Grade  
Infusion of M7824 
Treatment 
Premedication at 
subsequent 
dosing 
 
 
treatment 
administration. 
x Grade 4: Life-
threatening 
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: 
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. 
No subsequent 
dosing 
16$,'V QRQVWHURLGDODQWL-inflammatory drugs. 
Additional Modifications for Subjects with Grade 2 Infusion-related Reactions 
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,QYHVWLJDWRUPD\FRQVLGHUWUHDWPHQWZLWKFRUWLFRVWHURLGVDQGWKHLQIXVLRQRI M7824 
should be stopped for that day. $WWKHQH[WLQIXVLRQWKH,QYHVWLJDWRUPD\FRQVLGHUWKHDGGLWLRQRI
H2-blocker DQWLKLVWDPLQHVIRUH[DPSOHIDPRWLGLQHRUUDQLWLGLQHLQDGGLWLRQWRSUHPHGLFDWLRQ
for select subjects. However, prophylactic steroids are NOT permitted. If the subject has a second 
infusion-UHODWHGUHDFWLRQ*UDGHRQWKHVORZHULQIXVLRQUDWHZLWKRr 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 


Abbreviated Title: M7824/Gemcitabine for AAPC 
Version date: 03/20/2019 
59 
 
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 'HFUHDVHGR[\JHQVDWXUDWLRQ 
x Confusion 
x Lethargy 
x Hypotension 
x Pale / clammy skin 
x Cyanosis 
B. Management 
x (SLQHSKULQHLQMHFWLRQDQG,9GH[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 
)RUSURSK\OD[LVRIIOX-OLNHV\PSWRPVD16$,'IRUH[DPSOH ibuprofen 400 mg or comparable 
NSAID dose, may be administered 2 hours before and 8 hours after the start of each dose of M7824 
IV infusion. 
3.4.1.5 Immune-Related Adverse Events 
Since inhibition of PD-/DQG7*)ȕVLJQDOLQJVWLPXODWHVWKHLPPXQHV\VWHPLU$(VPD\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 


Abbreviated Title: M7824/Gemcitabine for AAPC 
Version date: 03/20/2019 
60 
 
Colitis: asymptomatic  
If worsens: 
Treat as Grade 2, 3 or 4.  
Grade 2  
Diarrhea: 4 to 6 stools per day over 
%DVHOLQH,9IOXLGVLQGLFDWHG
KRXUVQRWLQWHUIHULQJZLWK$'/ 
&ROLWLVDEGRPLQDOSDLQEORRGLQ
stool  
 
Withhold M7824 therapy 
Symptomatic treatment 
,ILPSURYHVWR*UDGH 
Resume M7824 therapy 
 
If persists > 5-7 days or recurs: 
Treat as Grade 3 or 4. 
Grade 3 to 4 
'LDUUKHD*UDGHVWRROVSHU
GD\RYHU%DVHOLQHLQFRQWLQHQFH,9
IOXLGV KLQWHUIHULQJZLWK$'/ 
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. 
 
1.0 to 2.0 mg/kg/day 
prednisone IV or equivalent 
Add prophylactic antibiotics 
for opportunistic infections  
Consider lower endoscopy  
If improves:  
&RQWLQXHVWHURLGVXQWLO*UDGHWKHQ
WDSHURYHUDWOHDVWPRQWKUHVXPH
M7824 therapy following steroids taper 
(for initial Grade 3).  
 
If worsens, persists > 3 to 5 days, or 
recurs after improvement: 
$GGLQIOL[LPDEPJNJLIQR
contrainGLFDWLRQ1RWHLQIOL[LPDEVKRXOG
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  
&RYHULQJERG\VXUIDFHDUHD 
Continue M7824 therapy 
Symptomatic therapy (for 
H[DPSOHDQWLKLVWDPLQHV
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\
VXUIDFHDUHD 
Grade 4: Life threatening 
consequences  
Withhold M7824 for 
Grade 3. 
Permanently discontinue for 
Grade 4 or recurrent Grade 3.  
Consider skin biopsy  
,ILPSURYHVWR*UDGH 
7DSHUVWHURLGVRYHUDWOHDVWPRQWK
resume M7824 therapy following steroids 
taper (for initial Grade 3). 


Abbreviated Title: M7824/Gemcitabine for AAPC 
Version date: 03/20/2019 
61 
 
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 
Radiographic changes only  
Consider withholding M7824 
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 
Mild to moderate new symptoms  
Withhold M7824 therapy 
Pulmonary and Infectious 
Disease consults 
0RQLWRUV\PSWRPVGDLO\
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:  
:KHQV\PSWRPVUHWXUQWR*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 
*UDGH6HYHUHQHZV\PSWRPV
1HZZRUVHQLQJK\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  
,ILPSURYHVWR*UDGH 
Taper steroids over at least 1 month  
If not improving after 48 hours or 
worsening:  
Add additional immunosuppression (for 
H[DPSOHLQIOL[LPDEF\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 
[8/1DQGRU7RWDOELOLUXELQ!
8/1WR[8/1 
Continue M7824 therapy 
Continue liver function monitoring  
If worsens:  
 Treat as Grade 2 or 3 to 4.  


Abbreviated Title: M7824/Gemcitabine for AAPC 
Version date: 03/20/2019 
62 
 
Grade 2 
$67RU$/7!WR[8/1
DQGRUWRWDOELOLUXELQ!WR[
ULN  
Withhold M7824 therapy 
Increase frequency of 
monitoring to every 3 days. 
 
,IUHWXUQVWR*UDGH 
5HVXPHURXWLQHPRQLWRULQJUHVXPH
M7824 therapy. 
If elevation persists > 5 to 7 days or 
worsens:  
Treat as Grade 3 to 4. 
Grade 3 to 4 
$67RU$/7![8/1DQGRUWRWDO
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  
,IUHWXUQVWR*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 
Grade 1 
&UHDWLQLQHLQFUHDVHG!8/1WR[
ULN 
Continue M7824 therapy 
 
Continue renal function monitoring 
If worsens: 
Treat as Grade 2 to 3 or 4. 
Grade 2 to 3 
&UHDWLQLQHLQFUHDVHG!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 
,IUHWXUQVWR*UDGH 
Taper steroids over at least 1 
month, and resume M7824 therapy 
following steroids taper. 
If worsens:  
Treat as Grade 4. 
 
 
Grade 4 
&UHDWLQLQHLQFUHDVHG![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 
,IUHWXUQVWR*UDGH 
Taper steroids over at least 1 
month. 
 
 
 
 
 
 
 


Abbreviated Title: M7824/Gemcitabine for AAPC 
Version date: 03/20/2019 
63 
 
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. 
Hospitalize. 
In the presence of life threatening cardiac 
decompensation, consider transfer to a 
IDFLOLW\ H[SHULHQFHG LQ DGYDQFHG KHDUW
failure and arrhythmia management. 
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. 
If 
symptoms 
improve 
and 
immune-mediated etiology is 
ruled 
out, 
re-start 
M7824 
therapy. 
 
If symptoms do not 
improve/worsen, viral 
P\RFDUGLWLVLVH[FOXGHGDQG
immune-mediated etiology is 
suspected or confirmed 
following cardiology consult, 
manage as immune-mediated 
myocarditis. 
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: 
KWWSSURIHVVLRQDOKHDUWRUJSURIHVVLRQDO*XLGHOLQHV6WDWHPHQWVVHDUFKUHVXOWVMVS"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 
 
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) 
Continue hormone 
replacement/suppression and 
monitoring of endocrine 
function as appropriate. 


Abbreviated Title: M7824/Gemcitabine for AAPC 
Version date: 03/20/2019 
64 
 
Grade 3 or Grade 4 
endocrinopathies 
(hypothyroidism, 
hyperthyroidism, adrenal 
insufficiency, type I diabetes 
mellitus) 
Withhold M7824 therapy 
Consider hospitalization 
Endocrinology consult 
 
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) 
Resume M7824 once symptoms 
and/or laboratory tests improve 
to Grade ZLWKRUZLWKRXW
hormone 
replacement/suppression). 
 
Continue hormone 
replacement/suppression and 
monitoring of endocrine 
function as appropriate.  
Hypopituitarism/Hypophysitis 
(secondary endocrinopathies) 
If secondary thyroid and/or adrenal 
insufficiency is confirmed (i.e. 
subnormal serum FT4 with 
inappropriately low TSH and/or low 
serum cortisol with inappropriately 
low ACTH): 
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 
ILHOGH[DPLQDWLRQDVLQGLFDWHG 
 
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. 
 
 
 
 
Resume M7824 once symptoms 
and hormone tests improve to 
Grade ZLWKRUZLWKRXW
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. 


Abbreviated Title: M7824/Gemcitabine for AAPC 
Version date: 03/20/2019 
65 
 
 
Other irAEs (not described above) 
Grade of other irAEs 
(NCI-CTCAE v5) 
Initial Management 
Follow-up Management 
Grade 2 or Grade 3 clinical signs 
or symptoms suggestive of a 
potential irAE 
Withhold M7824 therapy pending 
clinical investigation 
If irAE is ruled out, manage as 
appropriate according to the 
diagnosis and consider re-
starting M7824 therapy 
If irAE is confirmed, treat as 
Grade 2 or 3 irAE. 
Grade 2 irAE or first occurrence 
of Grade 3 irAE 
Withhold M7824 therapy 
1.0 to 2.0 mg/kg/day prednisone or 
equivalent  
Add prophylactic antibiotics for 
opportunistic infections  
Specialty consult as appropriate 
,ILPSURYHVWR*UDGH 
Taper steroids over at least 1 
month and resume M7824 
therapy following steroids taper. 
Recurrence of same Grade 3 
irAEs 
Permanently discontinue M7824 
therapy 
1.0 to 2.0 mg/kg/day 
prednisone or equivalent 
Add prophylactic antibiotics for 
opportunistic infections  
Specialty consult as appropriate 
,ILPSURYHVWR*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. 
,ILPSURYHVWR*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 
 
Persistent Grade 2 or 3 irAE 
lasting 12 weeks or longer 
Permanently discontinue M7824 
therapy 
Specialty consult 
 
 
 
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 


Abbreviated Title: M7824/Gemcitabine for AAPC 
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66 
 
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+JEUHGEORRGFHOOVDQGKHPDWRFULWDUHWREHFORVHO\PRQLWRUHG 
x ,IDVXEMHFWH[SHULHQFHVVLJQLILFDQWDnemia 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 
GHYHORSPHQWRIDQHPLDDQGH[SHGLWLRXVO\UHVWULFWEORRGGUDZVThe 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 PHGLFDOWUHDWPHQWXQWLOWKHQH[WWUHDWPHQWVHFRQG
cycle after the AE occurred) DFRQVLGHUDWLRQRIDSRVVLEOHH[WHQVLRQRIWKHGRVHLQWHUUXSWLRQIRUXS
to 3 additional cycles is allowed. 
If upon the resumed study treatment, WKHVXEMHFWH[SHULHQFHVWKHVDPH$(, 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[LFLWLHVDOLJQHGZLWKJHPFLWDELQHWR[LFLW\SURILOHZLOOOHDGWRGRVHreduction of the nucleoside 
analogue (of the selected starting dose according to DMET genotypingSOHDVHVHH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, 
x106/L 
% of selected 
starting dose 


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Version date: 03/20/2019 
67 
 
 
And 
 
 
500-999 
Or 
50,000-99,999 
 
<500 
Or 
<50,000 
Hold, 
restart 
gemcitabine 
after 
recover to Grade 1 at 
RIGRVH 
,I*UDGHKHPDWRORJLFWR[LFLW\SRVVLEO\UHODWHGWRgemcitabine, restart gemcitabine after recover 
to Grade DWRIWKHGRVH 
Dose Modifications for Non-Hematologic Adverse Reactions 
Permanently discontinue gemcitabine for any of the following: 
x 8QH[SODLQHGG\VSQHDRURWKHUHYLGHQFHRIVHYHUHSXOPRQDU\WR[LFLW\ 
x 6HYHUHKHSDWLFWR[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\XQWLOUHVROYHGFor 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. 
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-WUHDWPHQWWKHVXEMHFWPXVWQRWKDYHH[SHULHQFHGDQ\WR[LFLW\WKDWOHGWRSHUPDQHQW
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 


Abbreviated Title: M7824/Gemcitabine for AAPC 
Version date: 03/20/2019 
68 
 
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. 
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-of-
Treatment visit. The discontinuation visit consists of assessments indicated in Study Calendar, 
Section 3.7. 
3.5.2 Post-Treatment Follow-up 
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.  
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.  
3.6 
Questionnaires 
The rationale for questionnaires is discussed in Section 1.2.16 and timing is specified in Study 
Calendar 3.7. The average time to complete these instruments is 20 minutes. For English speaking 
subjects only. 


Abbreviated Title: M7824/Gemcitabine for AAPC 
Version date: 03/20/2019 
69 
 
3.7 
Study Calendar 
Procedure 
 
Screening Baseline 
Cycles 1 (14 days each cycle) 
EOT 
visit20 
28 Days 
FU20 
Long 
Term 
FU,20 
1 
2 
3 
4 
5 
6 
7 
8-N 
M7824 2 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Gemcitabine 3 
 
 
 
X 
X 
X 
X 
X 
X 
X 
 
 
 
NIH Advance Directives 
Form 4 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Confirmation of Pathology X 
 
 
 
 
 
 
 
 
 
 
 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
3K\VLFDO H[DP ZHLJKW
ECOG 5 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Vital signs 23 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
TB testing (if clinically 
indicated) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
EKG 
X 
 
X/X6  
 
 
 
 
 
 
 
X 
 
CBC with differential 7 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Biochemical profile 7, 8 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 


Abbreviated Title: M7824/Gemcitabine for AAPC 
Version date: 03/20/2019 
70 
 
Procedure 
 
Screening Baseline 
Cycles 1 (14 days each cycle) 
EOT 
visit20 
28 Days 
FU20 
Long 
Term 
FU,20 
1 
2 
3 
4 
5 
6 
7 
8-N 
Amylase / lipase  
 
 
X 
X 
 
X 
 
 
X 
X9 
X 
X 
 
Urinalysis  
 
 
X 
X 
 
X 
 
 
X 
X9 
X 
X 
 
Pregnancy testing (urine or 
serum) 
X 
 
X 
X 
 
X 
 
X 
 
X10 
 
X 
 
PT, INR, aPTT, fibrinogen  
 
X 
 
 
 
 
 
 
 
 
X 
 
T4 and TSH 
 
 
X 
X 
 
X 
 
 
X 
X9 
 
X 
 
Tumor 
evaluation 
(CT 
Scan / MRI)11 
X 
X 
 
 
 
X 
 
 
X 
X 
 
X 
X 
Brain CT/MRI 12 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant Medications 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Adverse events 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Research blood for PK 
sampling – M782413 
 
 
X/X 
X 
X/X 
 
 
X 
 
 
X 
 
 
Research blood for PK 
sampling – gemcitabine 14 
 
 
 
X 
X 
X 
X 
 
 
 
 
 
 
Research blood for ADA 
sampling 15 
 
 
X 
 
X 
 
 
X 
 
 
X 
 
 


Abbreviated Title: M7824/Gemcitabine for AAPC 
Version date: 03/20/2019 
71 
 
Procedure 
 
Screening Baseline 
Cycles 1 (14 days each cycle) 
EOT 
visit20 
28 Days 
FU20 
Long 
Term 
FU,20 
1 
2 
3 
4 
5 
6 
7 
8-N 
Research 
blood 
for 
Cytokines 15 
 
 
X 
X 
X 
 
X 
 
X 
 
 
 
 
5HVHDUFK EORRGIRU 7*)ȕ
1, 2 and 3 15 
 
 
X 
X 
X 
 
 
 
 
 
 
 
 
CEA, CA19-9, CA-125  
 
 
X 
 
X 
 
X 
 
X 
X16 
X 
X16 
 
Research 
blood 
for 
Circulating 
free 
tumor 
DNA (cftDNA) 
 
 
X 
X 
X 
 
X 
 
X 
 
X 
X 
 
Research blood for DMET 
pharmacogenomic 
screening22 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Research Tumor biopsy 17 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
Research 
Perfusion 
evaluation – DCE-MRI 21 
 
X 
 
X 
 
X 
 
 
 
X 
X 
 
 
FACT-Hep 18 
 
X 
 
 
 
X 
 
 
 
X 
 
X 
 
Phone call or e-mail for 
survival/new 
cancer 
treatments every 3 months 
for 1 year, every 6 months 
after that 
 
 
 
 
 
 
 
 
 
 
 
 
X 


Abbreviated Title: M7824/Gemcitabine for AAPC 
Version date: 03/20/2019 
72 
 
 
1 Cycle indicated procedures will be performed on Day 1 of each cycle. Cycle length is 2 weeks (+/- 3 days). If any Screening/Baseline 
procedures are conducted within 3 days prior to Day 1 of Cycle 1, the assessments scheduled on Day 1 of Cycle 1 do not need to be 
repeated. 
2 M7824 will be administered as a 1 hour (-10 minutes / +20 minutes) IV infusion on Day 1 of each cycle before gemcitabine when both 
drugs are given on the same day.  
3 Gemcitabine will be given starting on Day 1 of Cycle 2 at assigned dose over 30 (+/- 10) minutes once weekly for the 4 weeks (cycles 
2-3)). Starting on Cycle 4 once weekly for 3 weeks with one week without gemcitabine. Gemcitabine will be discontinued after Cycle 
13 (after a total of 6 months of gemcitabine therapy). 
4 As indicated in section 10.3, all subjects will be offered the opportunity to complete an NIH advanced directives form. This should be 
done preferably at baseline but can be done at any time during the study as long as the capacity to do so is retained. The completion of 
the form is strongly recommended, but is not required 
5 Assessed prior to trial treatment. (\HVLJQVDQGV\PSWRPVDQGDVVHVVPHQWRIVNLQVKRXOGEHLQFOXGHGLQWRSK\VLFDOH[DPRQEDVHOLQH
and following visits. If clinically indicated, ophthalmology and dermatology consults should be ordered. 
6 X/X means before and after infusion of M7824. Within 2 hours prior to M7824 infusion and within 2 hours after completion of M7824. 
7 Must be drawn and reviewed within 72 hours prior to drug administration. During screening within 28 days of enrollment.  
8 Biochemical profile: electrolytes, BUN, creatinine, AST, ALT, total bilirubin, calcium, phosphorus, albumin, magnesium, uric acid.  
9 Every 6 weeks  
 
10 Every 4 weeks  
11 CT or PET of chest, abdomen and pelvis (or MRI abdomen) with tumor measurements. For the purposes of this study, patients should 
be re-evaluated for response every 6 weeks. If a scan identifies objective response or PD, a confirmatory scan should be obtained 4 
weeks following initial documentation of objective response or PD. Allowed time window is 5 days prior to dosing (-5 days). For 
subjects continuing treatment beyond 12-month tumor evaluations should take place every 12 weeks.  
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) 
 


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Version date: 03/20/2019 
73 
 
12 Brain CT/MRI scan (either, with contrast preferred) only if clinically indicated at Screening (in case of neurological symptoms, 
previous history of brain metastases, or at the discretion of the Investigator). 
13 X/X means before and after infusion at Cycles 1 and 3. Pre-M7824 PK levels to be taken within 45 minutes prior M7824 infusion. 
Post-M7824 PK levels to be taken within 45 minutes after completion of M7824 infusion / as close as possible to completion of following 
gemcitabine infusion. Within 45 minutes prior to infusion at Cycles 2, 6 and EOT.  
14 Blood samples for the determination of gemcitabine (GEM) plasma levels will be obtained just prior to drug administration, end of 
infusion (EOI), and 0.5hr, 1hr, 2hr, and 4hr post EOI. These samples will be collected for the doses received on Day 1 of Cycles 2, 3, 4 
and 5. Blood draws will be permitted to have a window of +/- 5 minutes to accommodate logistical challenges.  
15 To be taken within 30 minutes prior to start of M7824 infusion.  
16 On Cycles 8-13 every 6 weeks and then every 12 weeks.  
17 Optional Research biopsies might be performed at baseline and within 7 days after the Day 1 Cycle 4 M7824 administration. 
18 Subject-reported outcomes / symptom severity assessmHQWVWKYHUVLRQRIWKHµ)XQFWLRQDO$VVHVVPHQWRI&DQFHU7KHUDS\ZLWKWKH
hepatobiliary and pancreatic specific module (FACT-Hep) will be completed at Baseline, after cycle 3, 7 and every 12 weeks after start 
of treatment. By English speaking subjects only. 
19 All SAEs ongoing at the 28-Day Safety Follow-up visit must be monitored and followed up by the Investigator until stabilization or 
until the outcome is known, unless the subject is documented as “lost to follow-up.” In addition, all trial drug-related SAEs occurring 
after 28 Day Safety Follow up visit and ongoing at the Safety Follow-up visit should be followed up in the same manner. 
20 If subjects are unable or not willing to come to NIH after treatment discontinuation for FU visits, they will be followed quarterly (± 
14 days) by phone call or e-mail for survival, adverse events and further tumor therapy 
21 At baseline, cycles 2, 4, 10 and EOT visit. Patients who have heart pacemakers, metal implants, or metal chips or clips in or around 
the eyeballs cannot be scanned with an MRI because of the risk that the magnet may move the metal in these areas. DCE-MRI in cycle 
2 should be obtained before first gemcitabine infusion, DCE-MRI at baseline and in cycles 2, 4 and 10 are mandatory, at EOT visit it is 
per PI discretion. If DCE-MRI is not obtained in cycle 2, it may be obtained in cycle 3, with the following DCE-MRI studies moving to 
cycle 5 and 11. 
22 Prior to study treatment, patients (under NCI 16-C-0076) will provide one peripheral blood sample to analyze genomic DNA via the 
'0(73OXVNLWIRUWKHDVVHVVPHQWRIWKHSDWLHQW¶VF\WLGLQHGHDPLQDVH&'$JHQRW\SH%DVHGRQWKH&'$JHQRW\SHSDWLHQWVZLOO be 
stratified into a specified dosing strategy (as per Section 3.1). 
23 During treatment vital signs must be measured within 1 hour before and 40 minutes following M7824 infusions. In addition, at least 
one time during the infusion of M7824.


Abbreviated Title: M7824/Gemcitabine for AAPC 
Version date: 03/20/2019 
74 
 
3.8 
Criteria for Removal from Protocol Therapy and Off Study Criteria 
3.8.1 Criteria for Removal from Protocol Therapy 
x Progressive disease. Subjects should continue treatment beyond the initial determination 
RI3'WKURXJKWKHLUQH[WWXPRUDVVHVVPent, which in this case should be in 4 weeks if:  
¾ 7KHUHDUHQRQHZ*UDGHRUJUHDWHUV\PSWRPVRUVLJQLILFDQWZRUVHQLQJRIH[LVWLQJ
symptoms. 
¾ There is no increase in ECOG. 
¾ In the opinion of the Investigator, the subject does not require new anticancer 
therapy. 
x Occurrence of DLT (see section 3.1.1) 
x ([FHVVLYHWR[LFLW\ (see section 3.4) 
x Necessity to administer a non-permitted concomitant drug 
x PI discretion 
x Positive pregnancy test 
3.8.2 Off -Study Criteria 
x Death 
x Patient request to be withdrawn from study 
x PI discretion 
x PI decision to end the study 
3.8.3 Off Protocol Therapy and Off-Study Procedure  
Authorized staff must notify Central Registration Office (CRO) when a subject is taken off 
protocol therapy and when a subject is taken off-study. A Participant Status Updates Form from 
the web site (http://home.ccr.cancer.gov/intra/eligibility/welcome.htm) main page must be 
completed and sent via encrypted email to: NCI Central Registration Office ncicentralregistration-
l@mail.nih.gov. 
4 
CONCOMITANT MEDICATIONS / MEASURES 
4.1 
Permitted Medicines 
Any medications RWKHUWKDQWKRVHH[FOXGHGE\ WKHFOLQLFDOWULDOSURWRFROthat are considered 
necessary to protect subject welfare and will not interfere with the trial medication may be given 
at thH,QYHVWLJDWRU¶VGLVFUHWLRQ 
Palliative radiotherapy delivered in a normal organ-sparing technique may be administered during 
the trial. The assessment of PD will not be based on the necessity for palliative radiotherapy.  


Abbreviated Title: M7824/Gemcitabine for AAPC 
Version date: 03/20/2019 
75 
 
4.2 
Prohibited Medicines 
The following treatments must not be administered during the trial: 
x Immunotherapy including interferons, immunosuppressive drugs (IRUH[DPSOH, chemotherapy 
RU V\VWHPLF FRUWLFRVWHURLGV H[FHSW IRU VKRUW WHUP WUHDWPHQW RI DOOHUJLF UHDFWLRQV, endocrine 
replacement therapy at low dose prednisone >PJGDLO\@or glucocorticoid equivalent doses, 
or for the treatment of irAEs or other appropriate short term steroid useRURWKHUH[SHULPHQWDO
pharmaceutical products. Short term administration of systemic steroid or other 
LPPXQRVXSSUHVVDQWVXFKDVLQIOL[LPDERUP\FRSKHQRODWH (that is, for allergic reactions or the 
management of irAEs) is allowed. Steroids with no or minimal systemic effect (topical, 
inhalation) are allowed.  
x Prophylactic use of corticosteroids for infusion related reactions is prohibited. 
x +HUEDOUHPHGLHVZLWKLPPXQRVWLPXODWLQJSURSHUWLHVIRUH[DPSOHPLVWOHWRHH[WUDFWRUNQRZQ
WRSRWHQWLDOO\LQWHUIHUHZLWKPDMRURUJDQIXQFWLRQIRUH[DPSOHK\SHULFLQ 
x Any live attenuated vaccine therapies for the prevention of infectious disease. Administration 
of inactivated vaccines is allowed (IRUH[DPSOH inactivated influenza vaccines). 
If the administration of a non-permitted concomitant drug becomes necessary during the trial, the 
subject will be withdrawn from trial treatment. 
5 
BIOSPECIMEN COLLECTION 
5.1. 
Correlative Studies for Research/Pharmacokinetic Studies 
Correlative studies rationale is discussed in detail in Section 1.2.17 Justification of Research 
6WXGLHVRIWKLVSURWRFRO,QJHQHUDOVWXGLHVZLOODGGUHVVWKHHIIHFWRQ7*)ȕFRQFHQWUDWLRQVDQG
other soluble factors in plasma upon response to the study drugs, DCE-MRI as a measure if impact 
on perfusion upon stromal modulation by M7824 and the impact of the somatic genotype on 
response to M7824. We also will evaluate intratumoral alterations of the immune milieu / stroma 
of pre- versus on-treatment biopsies as well as follow copies of circulating free tumor DNA levels 
during treatment. 
 
Test/assay 
Volume 
(approx.) 
Type of tube Collection point  
Location of 
specimen 
analysis 
50-cancer gene panel 
Tumor 
sample 
 
Before treatment 
Laboratory of Dr. 
M. Raffeld, 
Molecular 
Pathology 
0XOWLSOH[HG
immunohistochemical 
evaluation of immune 
cell populations 
Tumor 
sample 
 
Before and after 7 
weeks of treatment 
Dr. Raffeld, 
Laboratory of 
Pathology NCI 
 


Abbreviated Title: M7824/Gemcitabine for AAPC 
Version date: 03/20/2019 
76 
 
Test/assay 
Volume 
(approx.) 
Type of tube Collection point  
Location of 
specimen 
analysis 
M7824 
Pharmacokinetics 
Blood, 3.5 
mL 
Serum 
Separator 
Tubes 
(SST®) 
(gold 
capped) 
 
See Study calendar 
3.7 
EMD Serono * 
(Processed in Figg 
Lab) 
Gemcitabine 
Pharmacokinetics 
Blood, 4 
mL 
Sodium 
Heparin 
(green 
top) 
tube 
(pre-
treated with 
THU)  
 
See Study calendar 
3.7 
Dr. Figg Lab 
Cytokines 
by ELISA  
Blood, [ 
mL 
Gold top 
SST 
See Study calendar 
3.7 
EMD Serono* 
(Processed in Figg 
Lab) 
7*)ȕOLJDQG
concentrations 
by ELISA 
Blood, 4.5 
mL 
Blue top 
CTAD 
See Study calendar 
3.7 
EMD Serono* 
(Processed in Figg 
Lab) 
Circulating free 
tumor DNA 
(cftDNA) 
Blood, 3.5 
mL 
EDTA 
(purple top) 
tubes 
See Study calendar 
3.7 
Dr. Raffeld, 
Laboratory of 
Pathology NCI 
(Processed in Figg 
Lab) 
ADA by ELISA 
Blood, 2.5 
mL 
Gold top 
SST 
See Study calendar 
3.7 
EMD Serono* 
(Processed in Figg 
Lab) 
 
DMET 
pharmacogenomic 
screening 
Plasma, 
3.5 mL 
EDTA 
(purple top) 
tubes  
  
 
Baseline 
Dr. Figg Lab 
* Coded linked samples without key will be sent to EMD Serono: 


Abbreviated Title: M7824/Gemcitabine for AAPC 
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77 
 
Laureen Ojalvo, MD, PhD 
Associate Medical Director Immuno-Oncology 
(0'6HURQR5HVHDUFK	'HYHORSPHQW,QF 
0LGGOHVH[7XUQSLNH%LOOHULFD0$86$ 
+1 978 821 6144 
+1 978 294 1400 
laureen.ojalvo@emdserono.com 
Samples will be sent for barcoding and initial storage to Blood Processing Core (BPC). 
Patients will undergo blood and tissue sampling for research purposes on the time points outlined 
in the Study Calendar 3.7.  
5.1.1 Tumor and Tissue Collection 
Tumor samples might be collected at baseline and within 7 days after the Cycle 4 Day 1 M7824 
administration for flow cytometry and RNA evaluation.  
Of any tumor biopsy, one sample will always be sent to Laboratory of Pathology for disease 
evaluation first (confirmation of metastatic pancreatic cancer). Leftover samples will be used for 
research. 
It is preferable to QRWELRSV\DWDUJHWOHVLRQKRZHYHULIRQO\RQHOHVLRQLVDPHQDEOHIRUELRSV\, 
biopsy will be performed on this lesion.  
Tissue processing: Fresh tumor tissue obtained from subjects for research purposes and not used 
for surgical pathology evaluation should undergo a tumor digest and used for flow cytometry to 
study immune cell populations. Other parts of obtained cancer tissues should either be snap frozen 
DQGXVHGIRUODWHU51$H[WUDFWLRQDQGIL[HGLQQHXWUDOEXIIHUHGIRUPDOLQ1%) followed by 
paraffin-embedding or used for the generation of a tumor digest. Formalin substitutes are not suited 
DVIL[DWLYH 
Tissue storage: Fresh tumor tissue digest obtained from subjects for the evaluation of efficacy 
should be stored in defined cryopreservation mHGLXP FRQWDLQLQJ  GLPHWK\O VXOIR[LGH
[CryoStor® CS10].  
Prioritization of limited sample of fresh tumor biopsy for research purposes: First priority: fresh 
VDPSOHIRUWXPRUGLJHVWDQGIORZF\WRPHWU\DQG51$6HTDQDO\VLVVHFRQGSULRULW\WRIRUPDOLQ
IL[DQGJHQHUDWHDSDUDIILQHPEHGGHG))3(WLVVXHEORFNLIWKHDUFKLYDOWXPRUFRQWDLQLQJ))3(
tissue block cannot be provided, sections from the tumor biopsy used for FFPE should be provided 
which are freshly cut, 4 μm thick and mounted on positively-charged microscope slides. 
SuperFrost Plus glass slides are recommended for samples designated for IHC to reduce IHC assay 
failure. If the archival tumor block is available preferably 15 VOLGHVVKRXOGEHSURYLGHGLIQRW
possible a minimum of 5 slides is required. 
5.1.2 0XOWLSOH[HGLPPXQRKLVWRFKHPLFDOHYDOXDWLRQRILPPXQHFHOOSRSXODWLRQ in tumor 
samples 
0XOWLSOH[HGLPPXQRKLVWRFKHPLFDOHYDOXDWLRQRILPPXQHFHOOSRSXODWLRQ WRH[DPLQHWKHLPPXQH
ODQGVFDSH IRU 7*)ȕ VLJQDOLQJ-dependent immune cell populations like T cells including T 


Abbreviated Title: M7824/Gemcitabine for AAPC 
Version date: 03/20/2019 
78 
 
regulatory cells, MDSCs, or tumor-associated macrophages and will be done in the Laboratory of 
Pathology. 
5.1.3 Pharmacokinetics of M7824 and gemcitabine 
Pharmacokinetic parameters are limited to &PD[ (in μg/mL plasma)WLPHWRUHDFKPD[LPXP
concentraWLRQWPD[and minimum serum concentration (CminLQJP/SODVPD).  
Blood will be collected for PK assessments according to Study Calendar 3.7.  
Plasma M7824 PK measurements will be done at EMD Serono, plasma gemcitabine measurements 
in the Clinical Pharmacology Core (Dr. W. Figg). 
5.1.3.1 M7824 Pharmacokinetics (EMD Serono) 
Plasma M7824 PK measurements will be done at EMD Serono 
5.1.3.2 Gemcitabine Pharmacokinetics (Figg Lab) 
Blood samples for the determination of gemcitabine (GEM) plasma levels will be obtained from 
participating patients via 4 mL sodium heparin (green top) tube (BD, Franklin Lakes, NJ) collected 
according to Study Calendar 3.7. Bioanalytical measurements will be conducted on an ultra HPLC-
MS/MS system by the Clinical Pharmacology Program (CPP).  
Because GEM is rapidly deactivated by cytidine deaminase (CD), green top tubes will be fortified 
with 100 uM tetrahydrouridine (THU). These tubes will be prepared in advance by the CPP and 
provided to the clinic. In advance of PK samples being drawn, please notify the CPP at least 24 
hrs. prior to prepare fresh green top tubes with 100 uM THU. 
This data will be used to monitor GEM plasma concentrations to assess any drug interactions with 
M7834 and/or correlations with pharmacogenomics, adverse events, and clinical response.  
7KHVDPSOHVZLOOEHSODFHGLPPHGLDWHO\RQZHWLFHDQGUHIULJHUDWHG7KHGDWHDQGH[DFWWLPHRI
each blood draw should be recorded on the sample tube and the PK sheet. Please page 102-11964 
for immediate pick-up. CoQWDFW'U)LJJ¶V&OLQLFDO3KDUPDFRORJ\3URJUDP%ORRG3URFHVVLQJ
Core) in Bldg. 10/5A09 at 301-402-3622 or 301-594-6131 with any questions. 
Upon arrival in the Clinical Pharmacology Program, samples will be centrifuged and the plasma 
transferred into cryovials for storage at -80 C until the time of analysis. In addition, samples will 
be barcoded as described in Section 5.2.1. 
5.1.4 Soluble Factors Investigation 
Blood will be collected to analyze soluble factors including cytokines and T*)ȕligand 
concentrations according to Study Calendar 3.7. The investigation will be done by EMD Serono 
using ELISA.  
5.1.5 ADA Analysis. 
Blood will be collected to analyze ADA according to Study Calendar 3.7. Samples positive for 
ADAs will be re-analyzed to determine the titer. The investigation will be done by EMD Serono 
using ELISA.  


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5.2 
Sample Storage, Tracking and Disposition 
Samples will be ordered in CRIS and tracked through a Clinical Trial Data Management system. 
Should a CRIS screen not be available, the CRIS downtime procedures will be followed. All 
samples will be sent to Blood Processing Core (BPC) for processing and storage until they are 
distributed to Dr. Rudloff¶VODEVDPSOHDQDO\VLVDVGHVFULEHGLQWKHSURWRFRO Samples will not be 
sent outside NIH without ,5%QRWLILFDWLRQDQGDQH[HFXWHG07$. 
5.2.1  6DPSOHV0DQDJHGE\'U)LJJ¶V%ORRGProcessing Core (BPC)  
5.2.1.1 BPC contact information  
Please e-mail NCIBloodcore@mail.nih.gov at least 24 hours before transporting samples (the 
Friday before is preferred). 
For sample pickup, page 102-11964. 
For immediate help, call 240-760-6180 (main blood processing core number) or, if no answer, 
240-760-6190 (main clinical pharmacology lab number). 
For questions regarding sample processing, contact  NCIBloodcore@mail.nih.gov. 
5.2.2 Sample Data Collection 
All samples sent to the Blood Processing Core (BPC) will be barcoded, with data entered and 
stored in the LABrador (aka LabSamples) utilized by the BPC. This is a secure program, with 
access to LABrador limited to defined Figg lab personnel, who are issued individual user accounts. 
Installation of LABrador is limited to computers specified by Dr. Figg. These computers all have 
a password restricted login screen. All Figg lab personnel with access to patient information 
annually complete the NIH online Protection of Human Subjects course.  
LABrador FUHDWHVDXQLTXHEDUFRGH,'IRUHYHU\VDPSOHDQGVDPSOHER[ZKLFKFDQQRWEHWUDFHG
back to patients without LABrador access. The data recorded for each sample includes the patient 
ID, name, trial name/protocol number, time drawn, cycle time point, dose, material type, as well 
DV ER[ DQG IUHH]HU ORFDWLRQ 3DWLHQW GHPRJUDSKLFV DVVRFLDWHG ZLWK WKH FOLQLFDO FHQWHU SDWLHQW
number are provided in the system. For each sample, there are notes associated with the processing 
method (delay in sample processing, storage conditions on the ward, etc.).  
Sample bar-codes are linked to patient demographics and limited clinical information. This 
information will only be provided to investigators listed on this protocol, via registered use of the 
LABrador. It is critical that the sample remains linked to patient information such as race, age, 
dates of diagnosis and death, and histological information about the tumor, in order to correlate 
genotype with these variables. 
5.2.3 Sample Storage  
Barcoded saPSOHVDUHVWRUHGLQEDUFRGHGER[HVLQDORFNHGIUHH]HUDWHLWKHU-20 or -80qC according 
to stability requirements. These freezers are located onsite in the BPC and offsite at NCI Frederick 
Central Repository Services in Frederick, MD. Visitors to the laboratory are required to be 
accompanied by laboratory staff at all times.  
Access to stored clinical samples is restricted. Samples will be stored until requested by a 
researcher named on the protocol. All requests are monitored and tracked in LABrador. All 
researchers are required to sign a form stating that the samples are only to be used for research 


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80 
 
purposes associated with this trial (as per the IRB approved protocol) and that any unused samples 
must be returned to the BPC. It is the responsibility of the NCI Principal Investigator to ensure that 
the samples requested are being used in a manner consistent with IRB approval.  
Following completion of this study, samples will remain in storage as detailed above. Access to 
these samples will only be granted following IRB approval of an additional protocol, granting the 
rights to use the material. 
,IDWDQ\WLPHDSDWLHQWZLWKGUDZVIURPWKHVWXG\DQGGRHVQRWZLVKIRUWKHLUH[LVWLQJVDPSOHVWR
be utilized, the individual must provide a written request. Following receipt of this request, the 
samples will be destroyed (or returned to the patient, if so requested), and reported as such to the 
IRB. Any samples lost (in transit or by a researcher) or destroyed due to unknown sample integrity 
(i.e. broken free]HUDOORZVIRUH[WHQVLYHVDPSOHWKDZLQJetc.) will be reported as such to the IRB. 
5.2.4 Procedures for Storage of Tissue Specimens in the Laboratory of Pathology 
Tissues designated for clinical diagnostics are transported to the Laboratory of Pathology (LP) 
ZKHUH WKH\ DUH H[DPLQHG JURVVO\ DQG UHOHYDQW SRUWLRQV DUH IL[HG HPEHGGHG LQ SDUDIILQ DQG
sectioned and stained for diagnostic interpretation. 8QXWLOL]HGH[FHVVWLVVXHVDUHVWRUHGIRUXSWR
three months, in accordance with College of American Pathologists/Joint Commission on 
Accreditation of Healthcare Organizations (CAP/JCAHO) guidelines, and then discarded. 
Following completion of the diagnostic workup, the slides and tissue blocks are stored indefinitely 
LQWKH /3¶VFOLQLFDODUFKLYHV All specimens are catalogued and retrieved utilizing the clinical 
laboratory information systems, in accordance with CAP/JCAHO regulations. The use of any 
stored specimens for research purposes is only allowed when the appropriate IRB approval has 
been obtained. In some cases, this approval has been obtained via the original protocol on which 
the patient was enrolled. 
5.2.5 Protocol Completion/Sample Destruction 
All specimens obtained in the protocol are used as defined in the protocol. Any specimens that are 
remaining at the completion of the protocol will be stored in the conditions described in Section 
5.2.1. The study will remain open so long as sample or data analysis continues. Samples from 
consenting subjects will be stored until they are no longer of scientific value or if a subject 
withdraws consent for their continued use, at which time they will be destroyed. The PI will report 
any loss or destruction of samples to the NIH Intramural IRB as soon as he is made aware of such 
loss. If tKH SDWLHQW ZLWKGUDZV FRQVHQW WKH SDUWLFLSDQW¶V GDWD ZLOO EH H[FOXGHG IURP IXWXUH
distributions, but data that have already been distributed for approved research use will not be able 
to be retrieved. 
The PI will report destroyed samples to the IRB if samples become unsalvageable because of 
HQYLURQPHQWDOIDFWRUVH[EURNHQIUHH]HURUODFNRIGU\LFHLQDVKLSSLQJFRQWDLQHURULIDSDWLHQW
withdraws consent. Samples will also be reported as lost if they are lost in transit between facilities 
or misplaced by a researcher. Freezer problems, lost samples or other problems associated with 
samples will also be reported to the NIH Intramural IRB and to the NCI Clinical Director. 
5.3 
Samples for Genetic/Genomic Analysis 
5.3.1 Description of the scope of genetic/genomic analysis 


Abbreviated Title: M7824/Gemcitabine for AAPC 
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81 
 
x We will use baseline archival or fresh biopsy specimens for somatic tumor variant 
sequencing which will be performed by the CLIA-approved 50-cancer gene panel of the 
Molecular Pathology section (Dr. M. Raffeld lab).  
x We plan to characterize cfDNA from blood at baseline and during treatment. All samples 
will be subjected to targeted sequencing. This will allow us to characterize somatic point 
mutations, and copy-number changes DQGZLOOEHSHUIRUPHGLQ'U05DIIHOG¶VODERUDWRU\ 
x DMET genotyping (DMET samples will be drawn under 16-C-0076 and sent to the Clinical 
Pharmacology Program for processing and analysis to determine polymorphisms in genes 
involved in gemcitabine metabolism). Prior to study enrollment, patients will enroll on NCI 
16-C-0076 (Prospective Screening for Patient Specific Genotypes and Phenotypes that 
Influence Drug Dosing and Trial Selection in Cancer Patients, PI: William D. Figg). As 
per NCI 16-C-0076, one peripheral blood sample per patient will be collected in a EDTA 
(purple top) tube for pharmacogenetics studies to analyze the genomic DNA and assess 
genotype of the most relevant drug metabolizing enzymes and transporters (DMET). DNA 
ZLOOEHDQDO\]HGRQD'0(73OXV$II\PDWUL[JHQRW\SLQJSODWIRUPWKDWWHVWVIRU
genetic variations in 225 drug disposition genes, including 47 CYP (phase I metabolism) 
genes, 13 non-CYP (phase I metabolism) genes, 78 phase II metabolizing genes (including 
UGTs), 63 transporters, 4 genes involved in facilitation of drug transporters, 9 genes 
involved in global regulation of drug metabolizing/transporting proteins, 4 drug binding 
proteins, and 4 drug targets. The samples will be sent to the NCI Frederick National 
Laboratory for Cancer Research (CLIA certificate 21D0947274) for analysis via the 
'0(73OXVNLWIRUWKHSXUSRVHRIGHWHUPLQLQJWKHSDWLHQW¶V&'A genotype. 
5.3.2 Privacy and Confidentiality of medical information/biological specimens 
Fresh tumor samples will be stored in a minus 80-degree freezer. Initially the samples of each 
patient will be barcoded. $WQRWLPHZLOOSDWLHQW¶VQDPHVEHXVHGRQWKHEORRGDnd tissue samples. 
Sometimes, because a group collaboration or jouUQDOSROLF\UHTXLUHVLWDVXEMHFW¶VJHQHWLFGDWD
may be deposited in a database such as dbGaP. Although there is controlled access to such a 
database, such a submission carries theoretical risks of revealing the identity of the subject. This 
is discussed in the consent. 
5.3.3 Management of Results 
Subjects will be contacted if a clinically actionable gene variant is discovered. Clinically actionable 
findings for the purpose of this study are defined as disorders appearing in the American College 
of Medical Genetics and Genomics recommendations for the return of incidental findings that is 
current at the time of primary analysis. (A list of current guidelines is maintained on the CCR 
intranet: 
https://ccrod.cancer.gov/confluence/display/CCRCRO/Incidental+Findings+Lists). 
Subjects who still remain on the study will be contacted at this time with a request to provide a 
blood sample to be sent to a CLIA certified laboratory.  
5.3.4 Genetic counseling 
If the research findings are verified in the CLIA certified lab, the subject will be offered the 
RSSRUWXQLW\WRFRPHWR1,+DWRXUH[SHQVHWRKDYHJHQHWLFHGXFDWLRQDQGFRXQVHOLQJZLWK the 
1&,*HQHWLFV%UDQFKWRH[SODLQWKLVUHVXOW If the subject does not want to come to NIH, a referral 
WRDORFDOJHQHWLFKHDOWKFDUHSURYLGHUZLOOEHSURYLGHGDWWKHLUH[SHQVH This is the only time 


Abbreviated Title: M7824/Gemcitabine for AAPC 
Version date: 03/20/2019 
82 
 
during the course of the study that incidental findings will be returned. No interrogations regarding 
clinically actionable findings will be made after the primary analysis. 
6 
DATA COLLECTION AND EVALUATION  
6.1 
Data Collection 
The PI will be responsible for overseeing entry of data into an in-house password protected 
electronic system (C3D) and ensuring data accuracy, consistency and timeliness. The principal 
investigator, associate investigators/research nurses and/or data manager will assist with the data 
management efforts. All data obtained during the conduct of the protocol will be kept in secure 
network drives or in approved alternative sites that comply with NIH security standards. Primary 
and final analyzed data will have identifiers so that research data can be attributed to an individual 
human subject participant.  
All adverse events, including clinically significant abnormal findings on laboratory evaluations, 
regardless of severity, will be followed until return to baseline or stabilization of event. Patients 
will be followed for adverse events for 28 days after removal from study treatment or until off-
study, whichever comes first.  
An abnormal laboratory value will be recorded in the database as an AE only if the laboratory 
abnormality is characterized by any of the following: 
x 
Results in discontinuation from the study 
x 
Is associated with clinical signs or symptoms  
x 
Requires treatment or any other therapeutic intervention 
x 
Is associated with death or another serious adverse event, including hospitalization.  
x 
Is judged by the Investigator to be of significant clinical impact 
x 
If any abnormal laboratory result is considered clinically significant, the investigator will 
SURYLGHGHWDLOVDERXWWKHDFWLRQWDNHQZLWKUHVSHFWWRWKHWHVWGUXJDQGDERXWWKHSDWLHQW¶V
outcome. 
Grade 1 adverse events will not be collected 
+RVSLWDOL]DWLRQIRUVRFLDOUHDVRQZLOOQRWEHFRQVLGHUHG an SAE. 
6.1.1 Tumor data 
The tumor disease information that will be documented and verified at the Screening visit for each 
subject includes: 
x Detailed history of the tumor, including histopathological diagnosis, grading and staging in 
accordance with the Union Internationale Contre le Cancer Tumor Node Metastasis 
Classification at diagnosis (UICC TNM). 
o The M category (M0 or M1) of the tumor at the time of study entry, based on screening 
assessments 
x All therapy used for prior treatment of the tumor (including surgery, radiotherapy and 
chemotherapy, immunotherapy). 


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x Any other conditions that were treated with chemotherapy, radiation therapy, or 
immunotherapy. 
6.1.2 Concomitant Medications and Therapies 
All concomitant medications taken by the subject during the trial, from the date of signature of 
informed consent are to be recorded in the appropriate section of the eCRF, noting the name, dose, 
duration and indication of each drug. Nondrug interventions (other than vitamins) and any changes 
to a concomitant medication or other intervention should also be recorded in the eCRF. 
End of study procedures: Data will be stored according to HHS, FDA regulations and NIH 
Intramural Records Retention Schedule as applicable.  
Loss or destruction of data: Should we become aware that a major breach in our plan to protect 
subject confidentiality and trial data has occurred, the IRB will be notified.  
6.2 
Data Sharing Plans 
6.2.1 Human Data Sharing Plan 
What data will be shared? 
I will share human data generated in this research for future research as follows: 
x Coded linked data in an NIH-funded or approved public repository.  
x Coded linked data in BTRIS (automatic for activities in the Clinical Center) 
x Coded linked or identified data with approved outside collaborators under appropriate 
agreements. 
Data will be shared through: 
x An NIH-funded or approved public repository: clinicaltrials.gov. 
x BTRIS (automatic for activities in the Clinical Center) 
x Approved outside collaborators under appropriate individual agreements. 
x Publication and/or public presentations. 
Data will be shared:  
x Before publication. 
x At the time of publication or shortly thereafter. 
6.2.2 Genomic Data Sharing Plan 
Unlinked genomic data will be deposited in public genomic databases such as dbGaP in 
compliance with the NIH Genomic Data Sharing Policy. 
6.3 
Response Criteria 
For the purposes of this study, patients should be re-evaluated for response every 6 weeks for. In 
addition, if a scan identifies objective response, a confirmatory scan should be obtained 4 weeks 
following initial documentation of objective response. For subjects continuing treatment beyond 
12 months tumor evaluations should take place every 12 weeks 


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Response and progression will be evaluated in this study using the new international criteria 
proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline 
(version 1.1) [[36, 37]] and Modified Immune-related response criteria (Section 6.4). Changes in 
the largest diameter (unidimensional measurement) of the tumor lesions and the shortest diameter 
in the case of malignant lymph nodes are used in the RECIST criteria.  
6.3.1 Disease Parameters 
Measurable disease: Measurable lesions are defined as those that can be accurately measured in at 
least one dimension (longest diameter to be recorded) as:  
• 
%\FKHVW[-UD\!PP 
• 
By CT scan:  
o 
Scan slice thickness 5 mm or under as >10 mm with CT scan 
o 
Scan slice thickness >5 mm: double the slice thickness  
• 
:LWKFDOLSHUVRQFOLQLFDOH[DP!PP 
All tumor measurements must be recorded in millimeters (or decimal fractions of centimeters). 
Malignant lymph nodes. To be considered pathologically enlarged and measurable, a lymph node 
must be >PPLQVKRUWD[LVZKHQDVVHVVHGE\&7VFDQ&7VFDQVOLFHWKLFNQHVVUHFRPPHQGHG
to be no greater than 5 mm). At baseline and in follow-XSRQO\WKHVKRUWD[LVZLOOEHPHDVXUHG
and followed. 
Non-measurable disease. All other lesions (or sites of disease), including small lesions (longest 
diameter <10 mm or SDWKRORJLFDOO\PSKQRGHVZLWKWRPPVKRUWD[LVDUHconsidered 
non-measurable disease. Bone lesions, leptomeningeal disease, ascites, pleural/pericardial 
effusions, lymphangitis cutis/pulmonitis, inflammatory breast disease, and abdominal masses (not 
followed by CT or MRI), are considered as non-measurable. 
Note: Cystic lesions that meet the criteria for radiographically defined simple cysts should not be 
considered as malignant lesions (neither measurable nor non-measurable) since they are, by 
definition, simple cysts. 
µ&\VWLFOHVLRQV¶WKRXJKWWRUHSUHVHQWcystic metastases can be considered as measurable lesions, if 
they meet the definition of measurability described above. However, if non-cystic lesions are 
present in the same patient, these are preferred for selection as target lesions. 
Target lesions. AlOPHDVXUDEOHOHVLRQVXSWRDPD[LPXPRIOHVLRQVSHURUJDQDQGOHVLRQVLQ
total, representative of all involved organs, should be identified as target lesions and recorded and 
measured at baseline. Target lesions should be selected on the basis of their size (lesions with the 
longest diameter), be representative of all involved organs, but in addition should be those that 
lend themselves to reproducible repeated measurements. It may be the case that, on occasion, the 
largest lesion does not lend itself WRUHSURGXFLEOHPHDVXUHPHQWLQZKLFKFLUFXPVWDQFHWKHQH[W
largest lesion which can be measured reproducibly should be selected. A sum of the diameters 
(longest for non-QRGDOOHVLRQVVKRUWD[LVIRUQRGDOOHVLRQVIRUDOOWDUJHWOHVLRQVZLOOEHFDOFXODWHG
and reported as the baseline sum diameters. If lymph nodes are to be included in the sum, then 
RQO\WKHVKRUWD[LVLVDGGHGLQWRWKHVXP The baseline sum diameters will be used as reference to 
further characterize any objective tumor regression in the measurable dimension of the disease. 


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Non-target lesions. All other lesions (or sites of disease) including any measurable lesions over 
and above the 5 target lesions should be identified as non-target lesions and should also be 
recorded at baseline. Measurements of these lesions are not required, but the presence, absence, or 
in rare cases unequivocal progression of each should be noted throughout follow-up.  
6.3.2 Methods for Evaluation of Measurable Disease 
All measurements should be taken and recorded in metric notation using a ruler or calipers. All 
baseline evaluations should be performed as closely as possible to the beginning of treatment and 
never more than 4 weeks before the beginning of the treatment. 
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. Imaging-based evaluation is 
SUHIHUUHG WR HYDOXDWLRQ E\ FOLQLFDO H[DPLQDWLRQ XQOHVV WKH OHVLRQV EHLQJ IROORZHG FDQQRW EH
imaged but are assessable by clinicaOH[DP 
Clinical lesions: Clinical lesions will only be considered measurable when they are superficial 
(e.g., skin nodules and palpable lymph nodes) and t10 mm diameter as assessed using calipers 
(e.g., skin nodules). In the case of skin lesions, documentation by color photography, including a 
ruler to estimate the size of the lesion, is recommended.  
&KHVW[-ray: /HVLRQVRQFKHVW[-ray are acceptable as measurable lesions when they are clearly 
defined and surrounded by aerated lung. However, CT is preferable.  
Conventional CT and MRI: This guideline has defined measurability of lesions on CT scan based 
on the assumption that CT slice thickness is 5 mm or less. If CT scans have slice thickness greater 
than 5 mm, the minimum size for a measurable lesion should be twice the slice thickness. MRI is 
also acceptable in certain situations (e.g. for body scans).  
8VHRI05,UHPDLQVDFRPSOH[LVVXH 05,KDVH[FHOOHQWFRQWUDVWVSDWLDODQGWHPSRUDOUHVROXWLRQ
however, there are many image acquisition variables involved in MRI, which greatly impact image 
quality, lesion conspicuity, and measurement. Furthermore, the availability of MRI is variable 
globally. As with CT, if an MRI is performed, the technical specifications of the scanning 
sequences used should be optimized for the evaluation of the type and site of disease. Furthermore, 
as with CT, the modality used at follow-up should be the same as was used at baseline and the 
lesions should be measured/assessed on the same pulse sequence. It is beyond the scope of the 
RECIST guidelines to prescribe specific MRI pulse sequence parameters for all scanners, body 
parts, and diseases. Ideally, the same type of scanner should be used and the image acquisition 
protocol should be followed as closely as possible to prior scans. Body scans should be performed 
with breath-hold scanning techniques, if possible. 
6.3.3 Response Criteria 
All the scans performed at Baseline and other imaging performed as clinically required (other 
supportive imaging) need to be repeated at subsequent visits. In general, lesions detected at 
Baseline need to be followed using the same imaging methodology and preferably the same 
imaging equipment at subsequent tumor evaluation visits. 
Brain CT / MRI scan should be performed, if clinically indicated by development of new specific 
symptoms or on the discretion of the Principal Investigator. For each subject, the Investigator will 
designate 1 or more of the following measures of tumor status to follow for determining response: 
CT or MRI images of primary and / RUPHWDVWDWLFWXPRUPDVVHVSK\VLFDOH[DPLQDWLRQILQGLQJV


Abbreviated Title: M7824/Gemcitabine for AAPC 
Version date: 03/20/2019 
86 
 
and the results of other assessments. All available images collected during the trial period will be 
considered. The most appropriate measures to evaluate the tumor status of a subject should be 
used. The measure(s) to be chosen for sequential evaluation during the trial have to correspond to 
the measures used to document the progressive tumor status that qualifies the subject for 
enrollment. The tumor response assessment will be assessed and listed according to the Study 
Calendar 3.7. 
The foreseen treatment duration is until disease progression verified by a scan subsequent to the 
initial documentation of PDXQDFFHSWDEOHWR[LFLW\RUDQ\FULWHULRQIRUwithdrawal from the trial 
occurs (see Section 3.8). Before stopping the treatment, progressive disease should be 
confirmed by imaging 4 to 6 weeks (preferably 6 weeks, but not later) after progression has 
been diagnosed according to RECIST 1.1. If progression is based on the occurrence of a new 
lesion in an area not scanned at Baseline, a further on-study scan 6 weeks later should be 
considered before performing the 28-Day Safety Follow-up visit. Treatment may be continued 
despite progression according to RECIST 1.1 at any time if: 
x 7KHUHDUHQRQHZV\PSWRPVRUZRUVHQLQJRIH[LVWLQJV\PSWRPV 
x There is no decrease in ECOG PS. 
x The Investigator does not consider it necessary to administer a salvage therapy.  
The treatment should be stopped immediately, if the subject does not tolerate M7824 in 
combination with gemcitabine anymore or if therapeutic failure occurs, which requires urgent 
treatment with an additional drug or results in clinically significant progression / deterioration.  
Tumor responses to treatment will be assigned based on the evaluation of the response of target, 
non-target, and new lesions according to RECIST 1.1 (all measurements should be recorded in 
metric notation). 
x To assess objective response, the tumor burden at baseline will be estimated and used for 
comparison with subsequent measurements. At baseline, tumor lesions will be categorized in 
target and non-target lesions according to RECIST 1.1. 
Results for these evaluations will be recorded with as much specificity as possible so that pre- and 
post-treatment results will provide the best opportunity for evaluating tumor response.  
Any CR or PR should be confirmed according to RECIST 1.1 (Table ). In the case of a PR or 
CR, a confirmatory CT or MRI scan should be done no sooner than 4 weeks (preferably at 
the scheduled 6-week interval).  
The Investigator may perform scans in addition to a scheduled trial scan for medical reasons or if 
the Investigator suspects PD.  
Table . Response Criteria for Patients with Measurable Disease (i.e., Target Disease) 
Target 
Lesions 
Non-Target 
Lesions 
New 
Lesions 
Overall 
Response 
Best Overall Response when 
Confirmation is Required* 
CR 
CR 
No 
CR 
>4 wks. Confirmation** 


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


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SXEMHFWVZKRKDYHH[SHULHQFHGSD, PR, or CR should continue treatment through the end of 
24 months, although additional treatment is possible. If the Investigator believes that a subject may 
benefit from treatment beyond 24 months, it may be permissible.  
6.3.4 Responses 
6.3.4.1 Best overall response (BOR)  
The duration of best overall response is measured from the time measurement criteria are met for 
CR, PR or SD (whichever is first recorded) until the first date that recurrent or progressive disease 
is objectively documented (taking as reference for progressive disease the smallest measurements 
recorded since the treatment started). 
The duration of overall CR is measured from the time measurement criteria are first met for CR 
until the first date that progressive disease is objectively documented.  
6.3.4.2 Duration of stable disease  
Stable disease is measured from the start of the treatment until the criteria for progression are met, 
taking as reference the smallest measurements recorded since the treatment started, including the 
baseline measurements. Stable Disease (SD) when sum of all target lesions does not qualify for 
CR/PR/PD for Target Lesion Response and Persistence of non-target lesions on Non-Target 
Lesion Response. 
6.4 
Immune-related Response Criteria (irRECIST) 
Modified immune-related response criteria (irRECIST) will also be employed in this study. This 
new classification is based on the recent learning from clinical studies with cancer 
immunotherapies that even if some new lesions appear at the beginning of a treatment or if the 
total tumor burden does not increase substantially, tumor regressions or stabilizations might still 
occur later. For this trial, the concepts of the irRECIST are combined with RECIST 1.1. Please 
refer to Appendix C for further details. 
6.4.1 Immune-related BOR (irBOR)  
The duration of Immune-related best overall response is measured from the time measurement 
criteria are met for irCR or irPR (whichever is first recorded) until the first date that recurrent or 
progressive disease is objectively documented (taking as reference for progressive disease the 
smallest measurements recorded since the treatment started). irSD, not meeting criteria for irCR 
or irPR, in absence of irPD. 
The duration of overall irCR is measured from the time measurement criteria are first met for irCR 
until the first date that progressive disease is objectively documented. Confirmation of assessment 
might be delayed up to 12 weeks to confirm PD to account for flare. 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
* µ1RQ-CR/non-3'¶LVSUHIHUUHGRYHUµVWDEOHGLVHDVH¶IRUQRQ-target disease since SD is increasingly used as 
an endpoint for assessment of efficacy in some trials so to assign this category when no lesions can be 
measured is not advised 


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6.5 
Toxicity Criteria 
The following adverse event management guidelines are intended to ensure the safety of each 
patient while on the study. The descriptions and grading scales found in the revised NCI Common 
Terminology Criteria for Adverse Events (CTCAE) version 5.0 will be utilized for AE reporting. 
All appropriate treatment areas should have access to a copy of the CTCAE version 5.0. A copy 
of 
the 
CTCAE 
version 
5.0 
can 
be 
downloaded 
from 
the 
CTEP 
web 
site 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm#ctc_50).  
The safety assessments will be performed according to the Study Calendar, Section 3.7.  
7 
SAFETY REPORTING REQUIREMENTS / DATA AND SAFETY MONITORING 
PLAN 
7.1 
Definitions 
7.1.1 Adverse Event 
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abnorPDOSK\VLFDOH[DPRUODERUDWRU\ILQGLQJV\PSWRPRUGLVHDVHWHPSRUDOO\DVVRFLDWHGZLWK
WKH VXEMHFW¶V SDUWLFLSDWLRQ LQ UHVHDUFK ZKHWKHU RU QRW FRQVLGHUHG UHODWHG WR WKH VXEMHFW¶V
participation in the research. 
7.1.2 Suspected adverse reaction 
Suspected adverse reaction means any adverse event for which there is a reasonable possibility 
WKDWWKHGUXJFDXVHGWKHDGYHUVHHYHQW)RUWKHSXUSRVHVRI ,1'VDIHW\UHSRUWLQJµUHDVRQDEOH
SRVVLELOLW\¶PHDQVWKHUHLVHYLGHQFHWRVXJJHVWDFDXVDOUHODWLRQVKip between the drug and the 
adverse event. A suspected adverse reaction implies a lesser degree of certainty about causality 
than adverse reaction, which means any adverse event caused by a drug. 
7.1.3 8QH[SHFWHGDGYHUVHUHDFWLRQ 
An adverse event or suspected adYHUVHUHDFWLRQLVFRQVLGHUHG³XQH[SHFWHG´LILWLVQRWOLVWHGLQWKH
LQYHVWLJDWRUEURFKXUHRULVQRWOLVWHGDWWKHVSHFLILFLW\RUVHYHULW\WKDWKDVEHHQREVHUYHGRULIDQ
investigator brochure is not required or available, is not consistent with the risk information 
GHVFULEHGLQWKHJHQHUDOLQYHVWLJDWLRQDOSODQRUHOVHZKHUHLQWKHFXUUHQWDSSOLFDWLRQ8QH[SHFWHG´
also refers to adverse events or suspected adverse reactions that are mentioned in the investigator 
brochure as occurring with a class of drugs or as anticipated from the pharmacological properties 
of the drug but are not specifically mentioned as occurring with the particular drug under 
investigation. 
7.1.4 Serious 
An Unanticipated Problem or Protocol Deviation is serious if it meets the definition of a Serious 
Adverse Event or if it compromises the safety, welfare or rights of subjects or others. 
7.1.5 Serious Adverse Event 
An adverse event or suspected adverse reaction is considered serious if in the view of the 
investigator or the sponsor, it results in any of the following: 
x 
Death, 
x 
A life-WKUHDWHQLQJDGYHUVHGUXJH[SHULHQFH 


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90 
 
x 
,QSDWLHQWKRVSLWDOL]DWLRQRUSURORQJDWLRQRIH[LVWLQJKRVSLWDOL]DWLRQ 
x 
Persistent or significant incapacity or substantial disruption of the ability to conduct normal 
life functions 
x 
A congenital anomaly/birth defect.  
x 
Important medical events that may not result in death, be life-threatening, or require 
KRVSLWDOL]DWLRQPD\EHFRQVLGHUHGDVHULRXVDGYHUVHGUXJH[SHULHQFHZKHQEDVHGXSRQ
appropriate medical judgment, they may jeopardize the patient or subject and may require 
medical or surgical intervention to prevent one of the outcomes listed in this definition. 
7.1.6 Disability 
$VXEVWDQWLDOGLVUXSWLRQRIDSHUVRQ¶VDELOLW\WRFRQGXFWQRUPDOOLIHIXQFWLRQV 
7.1.7 Life-threatening DGYHUVHGUXJH[SHUience 
Any adverse event or suspected adverse reaction that places the patient or subject, in the view of 
the investigator or sponsor, at immediate risk of death from the reaction as it occurred, i.e., it does 
not include a reaction that had it occurred in a more severe form, might have caused death. 
7.1.8 Protocol Deviation (NIH Definition) 
Any change, divergence, or departure from the IRB-approved research protocol.  
7.1.9 Non-Compliance (NIH Definition) 
The failure to comply with applicable NIH Human Research Protections Program (HRPP) policies, 
IRB requirements, or regulatory requirements for the protection of human research subjects. 
7.1.10 Unanticipated Problem 
$Q\LQFLGHQWH[SHULHQFHRURXWFRPHWKDW 
x  ,VXQH[SHFWHGLQWHUPVRIQDWXUHVHYHULW\RUIUHTXHQF\LQUelation to  
(a) the research risks that are described in the IRB-approved research protocol and 
LQIRUPHGFRQVHQWGRFXPHQW,QYHVWLJDWRU¶V%URFKXUHRURWKHUVWXG\GRFXPHQWVDQG 
EWKHFKDUDFWHULVWLFVRIWKHVXEMHFWSRSXODWLRQEHLQJVWXGLHGAND 
x ,VUHODWHGRUSRVVLEO\UHODWHGWRSDUWLFLSDWLRQLQWKHUHVHDUFKAND 
x Suggests that the research places subjects or others at a greater risk of harm (including 
physical, psychological, economic, or social harm) than was previously known or 
recognized 
7.2 
NIH Intramural IRB and Clinical Director Reporting 
7.2.1 NIH Intramural IRB DQG1&,&'([SHGLWHG5HSRUWLQJRI8QDQWLFLSDWHG3UREOHPVDQG
Deaths 
The Protocol PI will report in the NIH Problem Form to the NIH Intramural IRB and NCI Clinical 
Director: 
x $OOGHDWKVH[FHSWGHDWKVGXHWRSURJUHVVLYHGLVHDVH 
x All Protocol Deviations 


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91 
 
x All Unanticipated Problems 
x All non-compliance 
Reports must be received within 7 days of PI awareness via iRIS. 
7.2.2 NIH Intramural IRB Requirements for PI Reporting at Continuing Review 
The protocol PI will report to the NIH Intramural IRB:  
1. A summary of all protocol deviations in a tabular format to include the date the deviation 
occurred, a brief description of the deviation and any corrective action. 
2. A summary of any instances of non-compliance 
3. A tabular summary of the following adverse events: 
x All Grade 2 unexpected events that are possibly, probably or definitely related to the 
UHVHDUFK 
x All Grade 3 and 4 events that are possibly, probably or definitely related to tKHUHVHDUFK 
x All Grade 5 events regardless of attribution.  
x All Serious Events regardless of attribution.  
NOTE: Grade 1 events are not required to be reported.  
7.2.3 NIH Intramural IRB Reporting of IND Safety Reports 
Only IND Safety Reports that meet the definition of an unanticipated problem will need to be 
reported to the NIH Intramural IRB. 
7.3 
IND Sponsor Reporting Criteria  
From the time of the first study treatment through  the first 28 days after the subject receives the 
last investigational agent/intervention, the investigator must immediately report to the sponsor, 
using the mandatory MedWatch form 3500a or equivalent, any serious adverse event, whether or 
not considered drug related, including those listed in the protocol or investigator brochure and 
must include an assessment of whether there is a reasonable possibility that the drug caused the 
event. For events that occur more than 28 days after the last administration of investigational 
agent/intervention, only report serious adverse events that have an attribution of at least possibly 
related to the agent/intervention. 
Required timing for reporting per the above guideline: 
x Deaths H[FHSWGHDWKGXHWRSURJUHVVLYHGLVHDVHPXVWEHUHported via email within 24 
hours. A complete report must be submitted within one business day.  
x Other serious adverse events including deaths due to progressive disease must be reported 
within one business day 
Events will be submitted to Center for Cancer Research (CCR) at: 
CCRsafety@mail.nih.gov and to the CCR PI and study coordinator. 
7.3.1 Reporting Pregnancy  
7.3.1.1 Maternal H[SRVXUH 


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92 
 
If a patient becomes pregnant during the course of the study, the study treatment should be 
discontinued immediately, and the pregnancy reported to the Sponsor. The potential risk of 
H[SRVXUH RI WKH IHWXV WR WKH LQYHVWLJDWLRQDO DJHQWV RU FKHPRWKHUDS\ DJHnts (s) should be 
GRFXPHQWHGLQER[%RIWKH0HG:DWFKIRUP³'HVFULEH(YHQWRU3UREOHP´ 
Pregnancy itself is not regarded as an SAE. However, as patients who become pregnant on study 
ULVNLQWUDXWHULQHH[SRVXUHRIWKHIHWXVWRDJHQWVZKLFKPD\EHWHUDWRJHQLc, the CCR is requesting 
WKDWSUHJQDQF\VKRXOGEHUHSRUWHGLQDQH[SHGLWHGPDQQHUDVGrade 3 “Pregnancy, puerperium 
and perinatal conditions - Other (pregnancy)” under the Pregnancy, puerperium and perinatal 
conditions SOC.  
Congenital abnormalities or birth defects and spontaneous miscarriages should be reported and 
handled as SAEs. Elective abortions without complications should not be handled as AEs. The 
outcome of all pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, 
normal birth, or congenital abnormality) should be followed up and documented. 
If any pregnancy occurs in the course of the study, then the investigator should inform the Sponsor 
within 1 day, i.e., immediately, but no later than 24 hours of when he or she becomes aware of 
it. 
The designated Sponsor representative will work with the investigator to ensure that all relevant 
information is provided to the Sponsor within 1 to 5 calendar days for SAEs and within 30 days 
for all other pregnancies. 
The same timelines apply when outcome information is available. 
7.3.1.2 Paternal H[SRVXUH 
Male patients should refrain from fathering a child or donating sperm during the study and for 4 
months after the last treatment with M7824 or gemcitabine whichever occurs later. Pregnancy of 
WKHSDWLHQW¶VSDUWQHULVQRWFRQVLGHUHGWREHDQ$(+RZHYHUWKHRXWFRPHRIDOOSUHJQDQFLHV
(spontaneous miscarriage, elective termination, ectopic pregnancy, normal birth, or congenital 
abnormality) occurring from the date of the first dose until 4 months after the last treatment with 
M7824 or gemcitabine whichever occurs later should, if possible, be followed up and documented. 
7.4 
 Reporting Criteria to the Pharmaceutical Collaborators 
All events listed below must be reported in the defined timelines to CCRsafety@mail.nih.gov.  
The CCR Office of Regulatory Affairs will send all reports to the manufacturer as described below, 
H[FHSWDVQRWHG. 
7.4.1 EMD-Serono  
The following reportable events must be submitted to EMD Serono within 2 business days or 3 
calendar days (whichever comes first) using the Medwatch form or equivalent. The Sponsor will 
assume responsibility for submitting the reportable event(s) to EMD Serono as well as ensuring 
that any local reporting requirements are completed in parallel. 
x Serious Adverse Events 
x ([SRVXUHGXULQJ3UHJQDQF\RU%UHDVWIHHGLQJHYHQLIQRWDVVRFLDWHGZLWKDQDGYHUVH
event) 
x 2FFXSDWLRQDOH[SRVXUHHYHQLIQRWDVVRFLDWHGZLWKDQDGYHUVHHYHQW 


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93 
 
x Potential drug-LQGXFHGOLYHULQMXU\+\¶V/DZFDVHV7KHVHHYHQWVDUHFRQVLGHUHG
important medical events and should be reported as SAEs. 
x In addition, all AEs will be collected in tabulated form and reported to EMD Serono as 
outlined in the Collaborative Agreement. Note: The PI and Research Team will be 
responsible for reporting the AEs that are not specifically listed above. 
7.4.1.1 Reporting of Overdose of M7824  
$QRYHUGRVHLVGHILQHGDVDQ\GRVHJUHDWHUWKDQWKHKLJKHVWGRVHLQFOXGHGLQWKHFOLQLFDOWULDO
protocol. Any overdose must be recorded in the trial medication section of the eCRF. 
For monitoring purposes, any case of overdose, whether or not associated with an AE (serious or 
non-serious), must be reported to the sponsor. 
There are no known symptoms of M7824 overdose to date. The Investigator should monitor 
closely for AEs should an overdose occur and use his or her clinical judgment in providing 
symptomatic / supportive care as medically indicated. There is no known antidote for M7824. 
Contact information for submission of reportable events to EMD Serono: 
E-mail: ICSR_CT_GPS@merckgroup.com 
Specifying: 
PROTOCOL Number and/or Title 
EMD Serono assigned Study Number (MS200647_0015) 
SUBJECT Number 
PI Name 
SAE/ONSET DATE. 
7.5 
Data and Safety Monitoring Plan 
7.5.1 Principal Investigator/Research Team 
The clinical research team will meet on a regular basis (every two weeks by teleconference with 
the pharmaceutical collaborator) when patients are being actively treated on the trial to discuss 
each patient, enrollment and data management issues. Decisions about dose level enrollment and 
GRVHHVFDODWLRQZLOOEHPDGHEDVHGRQWKHWR[LFLW\GDWDIURPSULRUSDWLHQWV 
All data will be collected in a timely manner and reviewed by the principal investigator or a lead 
associate investigator. Adverse events will be reported as required above. Any safety concerns, 
new information that might affect either the ethical and or scientific conduct of the trial, or protocol 
deviations will be immediately reported to the IRB using iRIS.  
The principal investigator will review adverse event and response data on each patient to ensure 
safety and data accuracy. The principal investigator will personally conduct or supervise the 
investigation and provide appropriate delegation of responsibilities to other members of the 
research staff.  
7.5.2 Sponsor Monitoring Plan 
As a sponsor for clinical trials, FDA regulations require the CCR to maintain a monitoring 
SURJUDP7KH&&5¶VSURJUDPDOORZVIRUFRQILUPDWLRQRIVWXG\GDWDVSHFLILFDOO\GDWDWKDWFRXOG


Abbreviated Title: M7824/Gemcitabine for AAPC 
Version date: 03/20/2019 
94 
 
affect the interpretation of prLPDU\VWXG\HQGSRLQWVDGKHUHQFHWRWKHSURWRFROUHJXODWLRQVDQG
623VDQGKXPDQVXEMHFWVSURWHFWLRQ7KLVLVGRQHWKURXJKLQGHSHQGHQWYHULILFDWLRQRIVWXG\GDWD
with source documentation focusing on: 
x Informed consent process 
x Eligibility confirmation 
x Drug administration and accountability 
x Adverse events monitoring 
x Response assessment. 
7KHPRQLWRULQJSURJUDPDOVRH[WHQGVWRPXOWL-site research when the CCR is the coordinating 
center. 
This trial will be monitored by personnel employed by a CCR contractor. Monitors are qualified 
E\WUDLQLQJDQGH[SHULHQFHWRPRQLWRUWKHSURJUHVVRIFOLQLFDOWULDOV3HUVRQQHOPRQLWRULQJWKLV
study will not be affiliated in any way with the trial conduct.  
8 
STATISTICAL CONSIDERATIONS 
8.1 
 Statistical Considerations 
8.1.1 Primary efficacy endpoints 
The primary objectives of this trial are to determine the safety and tolerability, measured by 
number, severity and duration of treatment-related AEs for the combination treatment M7824 and 
gemcitabine according to CTCAE v5.0, and the occurrence, severity, and duration of Treatment-
Emergent Adverse Events (TEAEs) for the combination treatment M7824 and gemcitabine 
according to the NCI-CTCAE v5.0. and the efficacy, as measured by Best Objective Response 
(BOR) rate according to RECIST 1.1 
8.1.2 Secondary efficacy endpoints 
The secondary endpoints are the following: 
x Progression-free Survival (PFS) 
x Overall survival (OS)  
x Immune-related BOR (irBOR) using the immune-related RECIST (irRECIST) 
8.2 
6DPSOHVL]HGHWHUPLQDWLRQ 
Prior to amendment B, the protocol enrolled 6 evaluable patients into safety run-in and according 
to DLT definition, DLTs were recorded. We want to change DLT definition and the results from 
these initial 6 patients will be reported as a separate group, and accrual will begin again using the 
same phase IB design as initially proposed, but with new DLT definition described in amendment 
B. Total amount of patient on trial will be the same as with this amendment we are removing 200 
mg M7824 dose level.  
Phase IB:  
This combination will be first given to 6 patients as a safety run-in: the doses are 1,200 mg for 
M7824 and an assigned gemcitabine dose: 600 or 1,000 mg/m2 weekly according to baseline 


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95 
 
pharmacogenomic profiling. If there are 0-1 grade 3 and 4 DLTs, the study will proceed to the 
phase 2 cohorts,IWKHUHDUHJUDGHDQG'/7VWKHUHZLOOEHDGRVHUHGXFWLRQWR mg 
M7824 and the safety run-in in 6 patients will be repeated. With these 6 patients who have 0-1 
DLTs in 6 patients at the reduced level of M7824, the trial will then be carried out in the phase 2 
cohorts,IRUPRUHJUDGHRUJUHDWHUWR[LFLWLHVDUHVHHQLQWKLVVHFRQGUXQ-in of 6 patients,  the 
study will be halted. 
Thus, no more than 12 evaluable patients will be enrolled in the phase IB cohort with Amendment 
B. 
Phase II: 
The study will be conducted using a Simon two-VWDJHSKDVHPLQLPD[GHVLJQ The objective of 
the trial will be to determine whether this novel combination can be associated with a response 
UDWH35&55(&,67WKDWFDQUXOHRXWS LQIDYRURIDQLPSURYHGUHVSRQVHUDWHRI
 S  8VLQJ DOSKD  SUREDELOLW\ RI DFFHSWLQJ D SRRU DJHQW DQG EHWD 
(probability of rejecting a good agent), initially 13 evaluable patients will be enrolled into the phase 
II study, including up to 6 patients from the completed safety cohort if they are completely eligible 
for the phase II portion of the trial. 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 
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. If 1 to 2 of the 20 has a clinical response, then this will be considered 
LQDGHTXDWHIRUIXUWKHULQYHVWLJDWLRQRIWKLVUHJLPHQ,IRUPRUHRIUHVSRQGWKHQWKLV
will warrant further investigation in a subsequent trial. Under the null h\SRWKHVLVUHVSRQVH
UDWHWKHSUREDELOLW\RIHDUO\WHUPLQDWLRQLV  
Although participants who are in the phase II cohort will receive different levels of gemcitabine 
based on their genetic results, the participants will have their outcomes combined and will be 
evaluated using a single two-stage design with up to 20 participants. This will then assess the 
ability of the treatment strategy of gemcitabine (regardless of dose 600 or 1000 mg/m2) and M7824 
at a consistent dose to act together and produce responses. 
Thus, with 6 patients enrolled prior to Amendment B, up to 12 participants in the phase IB cohort 
starting with Amendment B and up to 20 evaluable participants in phase II, the trial may require 
up to 38 participants to be treated. This number may be reduced by up to 6 participants treated at 
the RP2D in the phase IB portion of the study. To allow for a small number of inevaluable patients, 
the accrual ceiling will be set at 41 participants. With an anticipated accrual rate of 10-12 patients 
SHU\HDULWLVH[SHFWHGWKDWWKHWULDOPD\FRPSOHWHDFFUXDOZLWKLQWR\HDUV 
8.2.1 Populations for analysis 
Evaluable for objective response: all patients who receive at least one dose of M7824 in 
combination with gemcitabine at the dose level determined to be safe in the initial safety run-in in 
6 patients will be included in the statistical analyses performed.) 
Evaluable Non-Target Disease Response: all patients who receive at least one dose of M7824 in 
combination with gemcitabine at the dose level determined to be safe in the initial safety run-in in 
6 patients will be included in the statistical analyses performed. The response assessment is based 
on the presence, absence, or unequivocal progression of the lesions.  


Abbreviated Title: M7824/Gemcitabine for AAPC 
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(YDOXDEOH IRU WR[LFLW\: $OO SDWLHQWV ZLOO EH HYDOXDEOH IRU WR[LFLW\ IURP WKH WLPH RI WKHLU ILUVW
treatment with M7824. 
Evaluable for RP2D: Subject enrolled to the safety run in portion of the study are evaluable. 
However, subjects who do not complete the DLT observation period for reasons other than a DLT 
will be replaced and not included in the evaluation. 
8.3 
Description of Statistical Analyses 
8.3.1 General Considerations 
Patients who are in the safety evaluation will have the number of patients with a DLT determined. 
Patients who are in the efficacy evaluation and patients from the safety run-in administered the 
0GRVHXVHGLQWKHSKDVH,,H[SDQVLRQZLOOKDYHWKHIUDFWLRQRIFOLQLFDOUHVSRQVHVGHWHUPLQHG 
8.3.2 Analysis of the primary efficacy endpoints 
Patients who are in the efficacy evaluation will have the fraction of clinical responses determined 
DQGUHSRUWHGDORQJZLWKWZRVLGHGDQGFRQILGHQFHLQWHUYDOV. 
8.3.3 Analysis of the secondary efficacy endpoints 
Overall survival and PFS will be determined in all patients treated at the RP2D of the combination 
of M7824 and gemcitabine using Kaplan-Meier curves. Any comparisons with published results 
ZLOOEHLQWHUSUHWHGDVEHLQJH[SORUDWRU\7KHLPPXQH-related BOR (irBOR) rate will be determined 
by dividing the number of patients with an immune-related response by the number of evaluable 
patients who are treated at the RP2D. The fraction with irBOR will be reported along with two-
VLGHGDQGFRQILGHQFHLQWHUYDOV 
At the end of the trial, as a secondary analysis, a retrospective evaluation will be performed to 
GHWHUPLQHWKHLQGLYLGXDOUHVSRQVHUDWHVEDVHGRQWKHSDUWLFLSDQWV
JHQHWLFWUHDWPHQWUHVXOWV7KLV
HYDOXDWLRQZLOOLQFOXGHDQGWZR-sided confidence intervals for each of the treatment 
arms within the phase II cohort. 
8.3.4 Safety analyses 
3DWLHQWVLQWKHSKDVH,SRUWLRQRIWKHWULDOZLOOEHDVVHVVHGIRUWR[LFLW\E\UHSRUWLQJWKHJUDGHVRI
WR[LFLW\DQGWKHW\SHRIWR[LFLW\REVHUYHGIRUDOOSDWLHQWV3DWLHQWVZLOOEHHQUROOHGDQGHYDOXDWHG
in the phase IB cohort of the trial as described in the phase IB sample size determination section. 
Patients will continue to be enrolled onto the phase II cohort if the cumulative fraction of patients 
with greater or equal grade 3 DLT is less than 1/3. 
8.3.5 Baseline descriptive statistics 
Limited demographic and clinical characteristics of all patients will be reported, separately for the 
phase IB and the phase II cohorts. 
8.3.6 Planned interim analyses: 
7R[LFLW\ ZLOO EH DVVHVVHG ZLWKLQ HDFK group of 6 patients accrued in the phase IB cohort. An 
evaluation of the fraction of patients who respond in the phase IB part will be included in the phase 
II cohort, as indicated in the phase II sample size determination section.  
8.3.7 ([SORUDWRU\ analyses 


Abbreviated Title: M7824/Gemcitabine for AAPC 
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([SORUDWRU\objectives of the study are to compare each of following parameters between patients 
in the phase II cohorts of the trial who are clinical responders vs. non-responders, using the approach 
described below for each: 
Tumor perfusion measured by Dynamic Contrast Enhanced MRI (DCE-05,WKLVZLOOSULPDULO\
compare the Houndsfield units obtained between responders and non-UHVSRQGHUVXVLQJDQH[DFW
:LOFR[RQUDQNVXPWHVW 
Impact of baseline somatic genomic profile of advanced pancreatic cancers on clinical response to 
M7824 in combination with gemcitabine. The number of somatic mutations obtained for each 
patient will be compared between responders and non-responders. This will be done using either a 
)LVKHU¶VH[DFWWHVW&RFKUDQ-Armitage trend test, oUH[DFW:LOFR[RQUDQNVXPWHVWGHSHQGLQJRQWKH
distributions of values.  
Determination of circulating free tumor DNA (cftDNA) levels to correlate with clinical course of 
SDQFUHDWLFFDQFHUSDWLHQWVWUHDWHGZLWK0LQFRPELQDWLRQZLWKJHPFLWDELQHthe levels will be 
compared between responders and non-UHVSRQGHUVXVLQJDQH[DFW:LOFR[RQUDQNVXPWHVW 
Measures of intra-tumoral immune cell fractions to evaluate the intra-tumoral immunogenicity of 
0LQFRPELQDWLRQZLWKJHPFLWDELQHWKHVH fractions per patient will be compared between 
responders and non-responders using an appropriate non-parametric test.  
Health-related Quality of Life (HRQoL) scores measuring patient-reported disease-specific 
symptoms and treatment-UHODWHGFRQFHUQVWKHVHZLOOEHFRPSDUed between responders and non-
UHVSRQGHUVXVLQJDQH[DFW:LOFR[RQUDQNVXPWHVW  
 
COLLABORATIVE AGREEMENTS 
 
Cooperative Research and Development Agreement (CRADA) 
A CRADA (02666) is in place with EMD Serono for the supply of M7824. 
10 HUMAN SUBJECTS PROTECTIONS  
10.1 Rationale For Subject Selection 
Subjects from all racial and ethnic groups are eligible for this trial if they meet the eligibility criteria. 
(IIRUWVZLOOEHPDGHWRH[WHQGWKHDFFUXDOWRDUHSUHVHQWDWLYHSRSXODWLRQ. 
10.2 Participation of Children 
Individuals under the age of 18 will not be eligible to participate in this study because they are 
unlikely to have pancreatic cancerDQGEHFDXVHRIXQNQRZQWR[LFLWLHVLQSHGLDWULFSDWLHQWV 
10.3 Participation of subjects unable to give consent 
Adults XQDEOHWRJLYHFRQVHQWDUHH[FOXGHGIURPHQUROOLQJLQWKHSURWRFRO However, re-consent may 
be necessary and there is a possibility, though unlikely, that subjects could become decisionally 
impaired. For this reason and because there is a prospect of direct benefit from research participation 
(Section 10.4.2), all subjects will be offered the opportunity to direct their wishes for research and 
care to a surrogate, and assign a substitute decision maker on the “NIH Advance Directive for Health 
Care and Medical Research Participation” form so that another person can make decisions about 
their medical care in the event that they become incapacitated or cognitively impaired during the 
course of the study. Note: The PI or AI will contact the NIH Ability to Consent Assessment Team 
(ACAT) for evaluation as needed for the following: an independent assessment of whether an 


Abbreviated Title: M7824/Gemcitabine for AAPC 
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individual has the capacity to provide FRQVHQWDVVLVWDQFHLQLGHQWLI\LQJDQGDVVHVVLQJDQDSSURSULDWH
VXUURJDWHZKHQLQGLFDWHGDQGRUDQDVVHVVPHQWRIWKHFDSDFLW\WRDSSRLQWDVXUURJDWH. For those 
subjects that become incapacitated and do not have pre-determined substitute decision maker, the 
procedures described in MEC Policy 87-4 and NIH HRPP SOP 14E for appointing a surrogate 
decision maker for adult subjects who are (a) decisional impaired, and (b) who do not have a legal 
guardian or durable power of attorney, will be followed. 
10.4 Evaluation of Benefits and Risks/Discomforts 
The primary ULVNWRSDWLHQWVSDUWLFLSDWLQJLQWKLVUHVHDUFKVWXG\LVIURPWKHWR[LFLty of M7824 and 
gemcitabine, or both drugs. M7824 is an investigational agent designed to enhance antitumor 
efficacy of standard treatment. Gemcitabine is an approved agent for treatment of pancreatic cancer. 
7KH SURWRFROSURYLGHVIRUGHWDLOHGDQG FDUHIXO PRQLWRULQJ RI DOO SDWLHQWV WR DVVHVV IRU WR[LFLW\
7R[LFLW\GDWDIURPWKHphases I and II dose levels will be collected and reviewed to ensure that there 
ZHUHQRVHYHUHWR[LFLWLHVWKDWZRXOGSUHFOXGHIXUWKHUSDWLHQWHQUROOPHQW3DWLHQWVZLOOEHWUHDWHGZLWK
therapeutic intent and response to the therapy will be closely monitored. 
10.4.1 Risks 
10.4.1.1 Risk of Biopsies  
All care will be taken to minimize risks that may be incurred by tumor sampling. Biopsies will be 
taken by Interventional Radiology sampling the lesion which is most accessible and can be sampled 
with the least morbidity. Up to 6 passages are allowed if deemed safe by the Interventional 
Radiologist. All procedure-related risks (such as bleeding, infection and visceral injury) that will be 
H[SODLQHGIXOO\GXULQJLQIRUPHGFRQVHQW. 
10.4.1.2 5LVNVRIH[SRVXUHWRLRQL]LQJUDGLDWLRQ 
This research study involves two optional CT guided biopsies collected for research purposes. 
Subjects undergoing two biopsies FROOHFWLRQVZLOOEHH[SRVHGWR6 rem. This amount of radiation 
is below the guideline of 5 rem per year allowed for adult research subjects by the NIH Radiation 
Safety Committee. 
10.4.1.3 Risks of Dynamic Contrast Enhanced MRIs (DCE-MRI) 
This research study involves up to 5 Dynamic Contrast Enhanced MRIs (DCE-MRI) performed for 
research purposes. The main risk is allergic reaction to IV administered contrast agent. This risk is 
in the range of 1 to 1.  
10.4.1.4 Research Blood Collection Risks 
Risks of blood draws include pain and bruising in the area where the needle is placed, 
lightheadedness, and rarely, fainting. When large amounts of blood are collected, low red blood cell 
count (anemia) can develop.  
10.4.1.5 Other Risks 
Risks include the possible occurrence of any of a range of side effects which are listed in the Consent 
Document or this protocol document. Frequent monitoring for adverse effects will help to minimize 
the risks associated with administration of the study agents. 
10.4.1.6 Non-Physical Risks of Genetic Research 
Risk of receiving unwanted information 


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$Q[LHW\DQGVWUHVVPD\DULVHDVDUHVXOWRIWKHDQWLFLSDWLRQWKDWXQZDQWHGLQIRUPDWLRQUHJDUGLQJ
disease related DNA sequencing or disease tendencies, or misattributed paternity. Patients will be 
clearly informed that the data related to DNA sequencing and genetic analysis is coded, 
investigational and will not be shared with patients, family members or health care providers. 
Risk related to possibility that information may be released 
This includes the risk that data related to genotype, DNA sequencing or risk for disease tendency or 
trait can be released to members of the public, insurers, employers, or law enforcement agencies. 
Although there are no plans to release results to the patients, family members or health care 
providers, this risk will be included in the informed consent document. 
10.4.2 Benefits 
The potential benefit to a patient that goes onto study is a reduction in the bulk of their tumor which 
may or may not have favorable impact on symptoms and/or survival.  
10.5 Risks/Benefits Analysis for All Participants 
For patients with advanced pancreas cancer, median survival is in the range of 6 months. It is 
possible that treatment on this protocol may reduce tumor burden or lessen symptoms caused by the 
cancer. While treatment on this protocol may not individually benefit subjects, the knowledge 
gained from this study may help others in the future who have pancreatic cancer. Potential risks 
include the possible occurrence of any of a range of side effects listed. If patients suffer any physical 
LQMXU\DVDUHVXOWRIWKHELRSVLHVLPPHGLDWHPHGLFDOWUHDWPHQWLVDYDLODEOHDWWKH1,+¶V&OLQLFDO
Center in Bethesda, Maryland. Although no compensation is available, any injury will be fully 
evaluated and treated in keeping with the benefits or care to which patients are entitled under 
applicable regulations. 
10.6 Consent Process and Documentation 
The investigational nature and research objectives of this trial, the procedures and treatments 
involved and their attendant risks and discomforts and benefits, and potential alternative therapies 
ZLOOEHFDUHIXOO\H[SODLQHGWRWKHSDWLHQWDQGDVLJQHGLQIRUPHGFRQVHQWGRFXPent will be obtained 
by a study investigator prior to entry onto the study. 
The PI or associate investigator will meet with the patient to discuss the protocol treatment and 
alternative options in detail. It will be stated clearly that participation in the research study is 
voluntary and that participants can withdraw from the study without losing benefits they would 
otherwise be entitled to. The patient will be encouraged to ask questions, and additional meetings to 
discuss the treatment options will be arranged as necessary. 
10.6.1 Re-Consent via Telephone 
The informed consent document will be sent to the subject. $QH[SODQDWLRQRIWKHVWXG\ZLOOEH
provided over the telephone after the subject has had the opportunity to read the consent form. The 
subject will sign and date the informed consent. 
The original informed consent document will be sent back to the consenting investigator who will 
sign and date the consent form with the date the consent was obtained via telephone.  
$IXOO\H[HFXWHGFRS\ZLOOEHUHWXUQHGYLDPDLOIRUWKHVXEMHFW¶VUHFRUGV. 


Abbreviated Title: M7824/Gemcitabine for AAPC 
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11 PHARMACEUTICAL INFORMATION 
11.1  M7824  
Other names: Anti PDL-1 TGF Beta-Trap, “TRAP”, MSB0011359C 
The finished injectable dosage form is manufactured by EMD 6HURQR5HVHDUFK	'HYHORSPHQW
Institute, Inc. 
11.1.1 Status: 
For Investigational Use Only. 
11.1.2 Brief Mechanism of Action/Drug Classification: 
M7824 is a fully human antibody of the IgG1 isotype designed as a single molecule that blocks 
the following two major immune escape mechanisms (negative immunoregulatory pathways) 
simultaneously: PD-L1/PD1 signaling and TGF-EHWDVLJQDOLQJ3'/LVKLJKO\H[SUHVVHGLQWXPRU
cells, which strongly correlates with poor prognosis in a variety of human cancers. TGF-beta is 
associated with malignant progression, evasion of immune surveillance, invasion and metastasis. 
Elevated levels of TGF-beta correlate with poor outcome in many different human cancers. 
11.1.3 How Supplied: 
M7824 is supplied in two different formulations: a sterile lyophilized powder and a sterile liquid. 
Lyophilized (freeze-dried) formulation: 
Supplied as a Type 1 glass vial containing a white lyophilized powder. Each vial contains 45 mg 
RI0DQGZYWUHKDORVHGLK\GUDWHP0VRGLXPFKORULGHP0/-methionine and 
ZYSRO\VRUEDWH7ZHHQDQGP0/-histidine at pH 5.5. 
Liquid formulation: 
6XSSOLHGDVD7\SHJODVVYLDOFRQWDLQLQJDQH[WUDFWDEOHYROXPHRIP/RIDVWHULOHFOHDU
cRORUOHVVVROXWLRQ(DFKP/FRQWDLQVPJRI0DQGZ/v) trehalose dihydrate, 40 mM 
sodium chloride, 5 mM L-PHWKLRQLQHDQGZYSRO\VRUEDWH7ZHHQDQGP0/-
histidine at pH 5.5. 
11.1.4 Storage: 
Store intact vials, both lyophilized and liquid formulations, in the refrigerator (2°C – 8°C). Do 
NOT freeze the vials. The vials must be stored in the original packaging and protected from light 
until use. 
Store reconstituted lyophilized vials and diluted infusion solutions at room temperature. 
11.1.5 Reconstitution: 
For lyophilized formulation only: 
Allow each vial to equilibrate to room temperature preferably for 10 to 20 minutes. 
Reconstitute each 45 mg vial with 4.5 mL of Sterile Water for Injection, USP (SWI) using a sterile 
syringe and needle. An 18 gauge needle is suggested. Avoid forceful impact of the SWI on the 
powder and avoid foaming. Slowly and gently add the SWI to the vial, aiming the flow of water 
towards the vial wall and NOT directly onto the lyophilized powder cake. Start the clock at this 
SRLQW*HQWO\LQYHUWHDFKYLDOVHYHUDOWLPHVWRPL['RQRWshake or agitate vigorously. Stop the 


Abbreviated Title: M7824/Gemcitabine for AAPC 
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clock after the product is completely dissolved. The reconstitution time MUST be no more than 
120 seconds. When reconstituted as recommended, each mL will contain 10 mg of M7824 as a 
clear, colorless solution. 
NOTE: If the reconstitution time is greater than 120 seconds, put the vial aside to return to IDMRS 
and get a new vial to prepare the dose. 
11.1.6 Stability: 
Reconstituted lyophilized vials, if not used immediately, are stable at room temperature for up to 
24 hours. 
When GLOXWHGZLWK6RGLXP&KORULGH,QMHFWLRQ863WRDFRQFHQWUDWLRQRIPJP/WR
mg/mL, chemical and physical in-use stability has been demonstrated for 72 hours when stored at 
room temperature. 
11.1.7 Administration: 
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 0.2 
micron polyethersulfone (PES) in-line filter is mandatory for administration. 
11.1.8 Compatibility: 
M7824 is coPSDWLEOHZLWK6RGLXP&KORULGH,QMHFWLRQ863 
M7824 is compatible with DEHP-free infusion bags composed of polyethylene and/or 
SRO\SURS\OHQH $FFHSWDEOH EDJV LQFOXGH % %UDXQ (;&(/ FRQWDLQHUV SUHILOOHG ZLWK 
6RGLXP&KORULGH,QMHFWLRQ863%D[WHU INTRAVIA™ empty containers and AVIVA pre-filled 
bags may also be used. 
M7824 is compatible with DEHP-free polyvinylchloride (PVC) and polyurethane (PUR) infusion 
lines. A polyethersulfone (PES) 0.2 micron in-line filter is required during administration. 
11.1.9 Preparation of Infusion: 
1. If using the liquid formulation, allow each vial to equilibrate to room temperature preferably for 
10 to 20 minutes. If using the lyophilized formulation, first follow reconstitution instructions 
above. 
2. Gently invert the vial(s) several times before use. Do NOT shake or agitate vigorously. 
 &DOFXODWH WKH YROXPH RI 0  PJP/ UHTXLUHG WR SUHSDUH D SDWLHQW¶V GRVH 1RWH
Pharmacy will add 25 mL overfill (fluid plus drug). 
4. Prepare DEDJFRQWDLQLQJWKHDPRXQWRI Sodium Chloride Injection, USP required to dilute 
the dose to a total volume of 250 mL. Note: Pharmacy will add 25 mL overfill (fluid plus drug). 
5. With a syringe and sterile 18 gauge needle, withdraw from the vials containing the M7824 the 
volume calculDWHGLQ6WHSDQGLQMHFWWKHGUXJLQWRWKHEDJFRQWDLQLQJWKH6RGLXP&KORULGH
Injection, USP. 
6. GeQWO\PL[WKHVROXWLRQE\VORZO\LQYHUWLQJWKHFRQWDLQHUWLPHVWRHQVXUHDKRPRJHQHRXV
clear solution free of visible particles. Do NOT shake the adPL[WXUHWRPL[ 
7. Purge all air from the container. 


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8. Attach to the container an administration set for ambulatory pump with an integral 0.2 micron 
filter. Prime the tubing close to its distal end and cap the administration set with a Luer-locking 
cap. 
9. The prescription label will identify the total volume to infuse: “Volume to Infuse is 250 mL” 
and will state the product contains overfill (25 mL fluid + drug). 
11.1.10Hazards and Precautions: 
M7824 should be handled and labeled as a hazardous drug 
11.1.11Labeled:  
M7824 AAPC. 
11.2 Gemcitabine  
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. Gemcitabine will be provided and 
prepared by the Clinical Center Pharmacy Department. The clinical formulation is supplied in a 
sterile form for intravenous use only. Vials of gemcitabine contain either 200 mg or 1 g of 
JHPFLWDELQH+&OH[SUHVVHGDVIUHHEDVHIRUPXODWHGZLWK mannitol (200 mg or 1 g, respectively) 
and sodium acetate (12.5 mg or 62.5 mg, respectively) as a sterile lyophilized powder. 
+\GURFKORULFDFLGDQGRUVRGLXPK\GUR[LGHPD\KDYHEHHQDGGHG for pH adjustment 
11.2.1 7R[LFLW\ 
Data in Table 10 are based on 979 patients receiving gemcitabine as a single-agent administered 
weekly as a 30-minute infusion for treatment of a wide variety of malignancies. The gemcitabine 
starting doses ranged from 800 to 1250 mg/m2. The frequency of all grades and severe (WHO 
Grade 3 or 4) adverse events were generally similar in the single-agent safety database of 979 
patients and the subset of patients with pancreatic cancer. Adverse reactions reported in the single-
agent safety database resulted in discontinuation of gemcitabine WKHUDS\LQDERXWRISDWLHQWV
In the comparative trial in pancreatic cancer, the discontinuation rate for adverse reactions was 
IRUWKHJHPFLWDELQHDUPDQGIRUWKe 5-FU arm. All WHO-graded laboratory events 
are listed in Table 10, regardless of causality. Non-laboratory adverse events were reported, 
regardless oIFDXVDOLW\IRUDWOHDVWRIDOOSDWLHQWVH[FHSWWKHFDWHJRULHVRI([WUDYDVDWLRQ
Allergic, and Cardiovascular and certain specific events under the Renal, Pulmonary, and Infection 
categories 
(from 
https://www.accessdata.fda.gov/drugsatfda_docs/label/2005/020509s033lbl.pdf). 


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Table 10. Selected WHO-graded AEs in patients receiving single-agent gemcitabine (from 
KWWSVZZZDFFHVVGDWDIGDJRYGUXJVDWIGDBGRFVODEHOV
lbl.pdf)  
 
Most adverse events are reversible and do not need to result in discontinuation, although doses 
may need to be withheld or reduced. There was a greater tendency in women, especially older 
ZRPHQQRWWRSURFHHGWRWKHQH[WF\FOH*HPFLWDELQHFOHDUDQFHLVDIIHFWHGE\DJH7KHUHLVQR
evidence, however, that unusual dose adjustments are necessary in patients over 65 years of age, 
and in general, adverse reaction rates in the single-agent safety database of 979 patients were 
similar in patients above and below 65 years. Grade 3/4 thrombocytopenia was more common in 
the elderly. Gemcitabine clearance is affected by gender: in the single-agent safety database 
1 SDWLHQWVKRZHYHUWKHUHLVQRHYLGHQFHWKDWXQXVXDOGRVHDGMXVWPHQWVDUHQHFHVVDU\LQ
women. In general, in single-agent studies of gemcitabine, adverse reaction rates were similar in 
men and women, but women, especially older women, were more likely not to proceed to a 


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VXEVHTXHQWF\FOHDQGWRH[SHULHQFH*UDGHQHXWURSHQLDDQGWKURPERF\WRSHQLD*HPFLWDELQH
VKRXOGEHXVHGZLWKFDXWLRQLQSDWLHQWVZLWKSUHH[LVWLQJUHQDOLPSDLUPHQWRUhepatic insufficiency. 
Gemcitabine has not been studied in patients with significant renal or hepatic impairment. 
11.2.2 Formulation 
Gemcitabine 200 mg white, lyophilized powder in a 10-mL size sterile single use vial (No. 7501) 
NDC 0002-7501-01 1 gram white, lyophilized powder in a 50-mL size sterile single use vial (No. 
7502) NDC 0002-7502-01 Store at controlled room temperature (20° to 25°C) (68° to 77°F).  
(from https://www.accessdata.fda.gov/drugsatfda_docs/label/2005/020509s033lbl.pdf). 
11.2.3 Preparation 
7KHUHFRPPHQGHGGLOXHQWIRUUHFRQVWLWXWLRQRI*HP]DULV6RGLXP&KORULGH,QMHFWLRQZLWKRXW
SUHVHUYDWLYHV 'XH WR VROXELOLW\ FRQVLGHUDWLRQV WKH PD[LPXP FRQFHQtration for Gemzar upon 
reconstitution is 40 mg/mL. Reconstitution at concentrations greater than 40 mg/mL may result in 
LQFRPSOHWH GLVVROXWLRQ DQG VKRXOG EH DYRLGHG 7R UHFRQVWLWXWH DGG  P/ RI  6RGLXP
Chloride Injection to the 200-mg vial or 25 mL RI6RGLXP&KORULGH,QMHFWLRQWRWKH-g vial. 
Shake to dissolve. These dilutions each yield a gemcitabine concentration of 38 mg/mL which 
includes accounting for the displacement volume of the lyophilized powder (0.26 mL for the 200-
mg vial or 1.3 mL for the 1-g vial). The total volume upon reconstitution will be 5.26 mL or 26.3 
mL, respectively. Complete withdrawal of the vial contents will provide 200 mg or 1 g of 
gemcitabine, respectively. The appropriate amount of drug may be administered as prepared or 
IXUWKHU GLOXWHGZLWK 6RGLXP&KORULGH ,QMHFWLRQ WR FRQFHQWUDWLRQV DV ORZ DV  PJP/
Reconstituted Gemzar is a clear, colorless to light straw-colored solution. After reconstitution with 
6RGLXP&KORULGH,QMHFWLRQWKHS+RIWKHUHVXOWLQJVolution lies in the range of 2.7 to 3.3. 
The solution should be inspected visually for particulate matter and discoloration, prior to 
administration, whenever solution or container permit. If particulate matter or discoloration is 
found, do not administer.  
(from https://www.accessdata.fda.gov/drugsatfda_docs/label/2005/020509s033lbl.pdf). 
&DXWLRQVKRXOGEHH[HUFLVHGLQKDQGOLQJDQGSUHSDULQJJHPFLWDELQHVROXWLRQV7he use of gloves 
is recommended. If Gemcitabine solution contacts the skin or mucosa, immediately wash the skin 
thoroughly with soap and water or rinse the mucosa with copious amounts of water. Although 
acute dermal irritation has not been observed in animDOVWXGLHVRIUDEELWVH[KLELWHGGUXJ-
UHODWHGV\VWHPLFWR[LFLWLHVGHDWKK\SRDFWLYLW\QDVDOGLVFKDUJHVKDOORZEUHDWKLQJGXHWRGHUPDO
absorption. 
(from https://www.accessdata.fda.gov/drugsatfda_docs/label/2005/020509s033lbl.pdf). 
11.2.4 Stability and Storage 
When prepared as directed, gemcitabine solutions are stable for 24 hours at controlled room 
temperature 20° to 25°C (68° to 77°F). Discard unused portion. Solutions of reconstituted 
gemcitabine should not be refrigerated, as crystallization may occur. The compatibility of 
gemcitabine with other drugs has not been studied. No incompatibilities have been observed with 
infusion bottles or polyvinyl chloride bags and administration sets. Unopened vials of gemcitabine 
DUH VWDEOH XQWLO WKH H[SLUDWLRQ GDWH LQGLFDWHG RQ WKH SDFNDJH ZKHQ VWRUHG DW FRQWUolled room 
temperature 20° to 25°C (68° to 77°F). 


Abbreviated Title: M7824/Gemcitabine for AAPC 
Version date: 03/20/2019 
105 
 
(from https://www.accessdata.fda.gov/drugsatfda_docs/label/2005/020509s033lbl.pdf). 
11.2.5 Administration Procedures 
See Section 3.3.2. 
11.2.6 Incompatibilities and Overdose 
The compatibility of gemcitabine with other drugs has not been studied. No incompatibilities have 
been observed with infusion bottles or polyvinyl chloride bags and administration sets. There is 
no known antidote for overdoses of gemcitabine. Myelosuppression, paresthesias, and severe rash 
ZHUHWKHSULQFLSDOWR[LFLWLHVVHHQZKHQDVLQJOHGRVHDVKLJKDV,700 mg/m2 was administered by 
I.V. infusion over 30 minutes every 2 weeks to several patients in a Phase 1 study. In the event of 
suspected overdose, the patient should be monitored with appropriate blood counts and should 
receive supportive therapy, as necessary. 
 
 
 


Abbreviated Title: M7824/Gemcitabine for AAPC 
Version date: 03/20/2019 
106 
 
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$OHVVDQGUR00HUULPDQ%/HH+6]HYHUHQ\L,$YHU\62
&RQQRU%'
Nelson SF, Coats SE, Stewart A et al: Multiple self-healing squamous epithelioma is 
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Farrell JJ, Bae K, Wong J, Guha C, Dicker AP, Elsaleh H: Cytidine deaminase single-
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22. 
Okazaki T, Javle M, Tanaka M, Abbruzzese JL, Li DH: Single Nucleotide 
Polymorphisms of Gemcitabine Metabolic Genes and Pancreatic Cancer Survival 
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Serdjebi C, Gagniere J, Desrame J, Fein F, Guimbaud R, Francois E, Andre T, Seitz JF, 
Monterymard C, Arsene D et al: FFCD-1004 Clinical Trial: Impact of Cytidine 


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Deaminase Activity on Clinical Outcome in Gemcitabine-Monotherapy Treated 
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Int J Biol Marker 2014, (3):E224-E232. 
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Rothenberg ML, Moore MJ, Cripps MC, Andersen JS, Portenoy RK, Burris HA, 3rd, 
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Langer CJ, Gadgeel SM, Borghaei H, Papadimitrakopoulou VA, Patnaik A, Powell SF, 
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:ROFKRN-'+RRV$2
'D\6:HEHU-6+DPLG2/HEEH&0DLR0%LQGHU0
Bohnsack O, Nichol G et al: Guidelines for the evaluation of immune therapy activity 
in solid tumors: immune-related response criteria. Clin Cancer Res 2009, 
15(23):7412-7420. 


Abbreviated Title: M7824/Gemcitabine for AAPC 
Version date: 03/20/2019 
109 
 
13 APPENDICES 
13.1 Appendix A Performance Status Criteria 
ECOG Performance Status Scale 
 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Description 
0 
Normal activity. Fully active, able 
to 
carry 
on 
all 
pre-disease 
performance without restriction. 
100 
Normal, 
no 
complaints, 
no 
evidence of disease. 
90 
Able to carry on QRUPDODFWLYLW\
minor signs or symptoms of 
disease. 
1 
Symptoms, 
but 
ambulatory. 
Restricted in physically strenuous 
activity, but ambulatory and able 
to carry out work of a light or 
sedentary 
nature 
(e.g., 
light 
housework, office work). 
80 
Normal activity ZLWKHIIRUWVRPH
signs or symptoms of disease. 
70 
Cares for self, unable to carry on 
normal activity or to do active 
work. 
2 
,Q EHG  RI WKH WLPH 
Ambulatory and capable of all 
self-care, but unable to carry out 
any work activities. Up and about 
PRUHWKDQRIZDNLQJKRXUV 
60 
Requires occasional assistance, 
but is able to care for most of 
his/her needs. 
50 
Requires considerable assistance 
and frequent medical care. 
3 
,QEHG!RIWKHWLPH Capable 
of only limited self-care, confined 
to EHGRUFKDLUPRUHWKDQRI
waking hours. 
40 
Disabled, requires special care 
and assistance. 
30 
Severely disabled, hospitalization 
indicated. Death not imminent. 
4 

EHGULGGHQ 
Completely 
disabled. Cannot carry on any self-
care. Totally confined to bed or 
chair. 
20 
Very 
sick, 
hospitalization 
indicated. Death not imminent. 
10 
Moribund, 
fatal 
processes 
progressing rapidly. 
5 
Dead. 
0 
Dead. 
 
 
 


Abbreviated Title: M7824/Gemcitabine for AAPC 
Version date: 03/20/2019 
110 
 
13.2 Appendix B Fact-Hep 
 
 


Abbreviated Title: M7824/Gemcitabine for AAPC 
Version date: 03/20/2019 
111 
 
 
 
 
 


Abbreviated Title: M7824/Gemcitabine for AAPC 
Version date: 03/20/2019 
112 
 
 
 
 
 
 
 
 


Abbreviated Title: M7824/Gemcitabine for AAPC 
Version date: 03/20/2019 
113 
 
13.3 Appendix C: Modified Immune-related Response Criteria (irRECIST) 
This new classification is based on the recent learning from clinical studies with cancer 
immunotherapies that even if some new lesions appear at the beginning of a treatment or if the 
total tumor burden does not increase substantially, tumor regressions or stabilizations might still 
occur later. The irRC were created using bi-dimensional measurements (as previously widely used 
in the World Health Organization criteria). For this trial, the concepts of the irRC are combined 
with RECIST 1.1 to come up with the modified irRC.  
For modified irRC, only target and measurable lesions are taken into account. In contrast to the 
RECIST 1.1 criteria, the modified irRC criteria (a) require confirmation of both progression and 
response by imaging at 6 weeks after initial imaging and (b) do not necessarily score the 
appearance of new lesions as progressive disease if the sum of lesion diameters of target lesions 
(minimum of 10 PPSHUOHVLRQPD[LPXPRIWDUJHWOHVLRQVPD[LPXPRISHURUJDQDQG
PHDVXUDEOHQHZOHVLRQVGRHVQRWLQFUHDVHE\ 
The same method of assessment and the same technique should be used to characterize each 
identified and reported target lesion(s) at baseline, during the trial, and at the end of trial visit. All 
measurements should be recorded in metric notation. The modified irRC based on RECIST 1.1 are 
displayed below.  
 
 
 
 
 


Abbreviated Title: M7824/Gemcitabine for AAPC 
Version date: 03/20/2019 
114 
 
Overall Responses Derived from Changes in Index, Non-Index, and New Lesions 

ICF_001.pdf: 
MEDICAL RECORD
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY
•
Adult Patient or•Parent, for Minor Patient
INSTITUTE:
National Cancer Institute
STUDY NUMBER:
18-C-0061
PRINCIPAL INVESTIGATOR:
Udo Rudloff, M.D.
STUDY 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.
Continuing Review Approved by the IRB on 02/12/19
Amendment Approved by the IRB on 04/18/19 (C)
Date posted to web: 04/24/19
Standard
PATIENT IDENTIFICATION
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY
•
Adult Patient or
•Parent, for Minor Patient
NIH-2514-1 (07-09)
P.A.: 09-25-0099
File in Section 4: Protocol Consent (1)
INTRODUCTION
We invite you to take part in a research study at the National Institutes of Health (NIH).
First, we want you to know that:
Taking part in NIH research is entirely voluntary. 
You may choose not to take part, or you may withdraw from the study at any time. In 
either case, you will not lose any benefits to which you are otherwise entitled. However, 
to receive care at the NIH, you must be taking part in a study or be under evaluation for 
study participation.
You may receive no benefit from taking part. The research may give us knowledge that 
may help people in the future.
Second, some people have personal, religious or ethical beliefs that may limit the kinds of 
medical or research treatments they would want to receive (such as blood transfusions). If you 
have such beliefs, please discuss them with your NIH doctors or research team before you agree 
to the study.
Now we will describe this research study. Before you decide to take part, please take as much 
time as you need to ask any questions and discuss this study with anyone at NIH, or with family, 
friends or your personal physician or other health professional. 
Why is this study being done? 
In this study we will investigate safety of using M7824 given in combination with gemcitabine 
and whether this combined treatment will cause your tumors to shrink. 
M7824 is an investigational (has not been approved by the FDA) agent that targets and blocks a 
pathway that prevents your immune system from effectively fighting your cancer. 
Gemcitabine is an FDA approved standard treatment recommended for pancreatic cancer.


MEDICAL RECORD
CONTINUATION SHEET for either:
NIH 2514-1, Consent to Participate in A Clinical Research Study
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study
STUDY NUMBER: 18-C-0061
CONTINUATION: page 2 of 16 pages
PATIENT IDENTIFICATION
CONTINUATION SHEET for either:
NIH-2514-1 (07-09)
NIH-2514-2 (10-84)
P.A.: 09-25-0099
File in Section 4: Protocol Consent
Different people have different sensitivity to gemcitabine. In this study we are planning to 
evaluate your sensitivity to gemcitabine first and assign you to a dosage of gemcitabine 
according to your sensitivity. Some people are at higher risk to side effects of gemcitabine. 
Pharmacogenomic blood tests can determine if you are in the low risk or high-risk category. If 
you are in the high-risk category you will receive the reduced dose of gemcitabine instead of the 
standard dose. 
This study has two parts:  safety and efficacy.
First, we are going to evaluate the safety of using M7824 in combination with gemcitabine. 
Decreasing doses of M7824 will be given to participants in the study to find the tolerated dose of 
M7824  when given in combination with gemcitabine. 
Secondly, we will compare how well the recommended dose of M7824 in combination with 
gemcitabine works in making your tumors shrink.
Why are you being asked to take part in this study?
You are being asked to take part in this study because you have been diagnosed with pancreatic 
cancer already treated with standard therapies.
How many people will take part in this study? 
Up to 41 subjects will take part in this study. Approximately 18 participants will be enrolled in 
the safety part and approximately 23 participants will be enrolled in the efficacy part.
Description of Research Study
For your safety, some medications and therapies are not allowed during the study. You should 
tell the study doctor before you take any new medications (includes prescription, herbal, and 
over-the-counter remedies) or start a new therapy during the study.
Before you begin the study
Before you begin this study, you will need to have the following exams and tests to make sure 
you are eligible for this study. The exams and tests are part of regular cancer care. These tests 
will be done under a separate consent. 

A review of any past or current medical conditions, medicines you are taking and cancer 
history.

Physical examination, including height, weight, and vital signs.

Electrocardiogram (EKG – a record of your heartbeat) to evaluate your heart.

Review of your symptoms and your ability to perform your normal activities.

Imaging Assessments – a computed tomographic scan (CT) that produces a picture of 
your body using a small amount of radiation or magnetic resonance imaging (MRI) that 
uses a magnetic field to produce an image of your body. These will be used to examine 
your chest, abdomen, pelvis, and brain (if your doctor thinks this is needed). 


MEDICAL RECORD
CONTINUATION SHEET for either:
NIH 2514-1, Consent to Participate in A Clinical Research Study
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study
STUDY NUMBER: 18-C-0061
CONTINUATION: page 3 of 16 pages
PATIENT IDENTIFICATION
CONTINUATION SHEET for either:
NIH-2514-1 (07-09)
NIH-2514-2 (10-84)
P.A.: 09-25-0099
File in Section 4: Protocol Consent

You will have blood drawn for:
o
routine blood tests to find out if you are anemic, have low blood counts, and if your 
liver, kidneys, and other organs are working well,
o
TB testing if your doctor thinks this is needed

Pregnancy test if you are a woman who can have children

You will be asked to provide confirmation of your diagnosis. If a pathology report or 
tumor sample from a previous surgery/biopsy is not available, we will perform a biopsy 
(collect a sample of your tumor) to confirm your diagnosis.
During the study
M7824 will be administered to you through an IV (intravenous catheter, a small plastic tube that 
is put into a vein, usually in your arm) once every 2 weeks (2 weeks = 1 Cycle).
Gemcitabine will be administered to you through an IV once weekly for seven weeks. After a 
rest of one week, it will be given once a week for three weeks followed by a rest of one week. 
The three weeks on and one week off schedule may continue until you have received 
gemcitabine for no more than 6 months. 
You will continue treatment with M7824 alone unless your disease gets worse or you have 
unacceptable side effects.
Ongoing Procedures before treatment on the first day of each cycle 

Physical exam and vital signs measured

Review of your symptoms and your ability to perform your normal activities

Routine blood tests to find out if you are anemic, have low blood counts, , and if your 
liver, kidneys, and other organs are working well
Additional Procedures before treatment on first day of cycles:

Blood tests to evaluate:
the gemcitabine dose for first 4 gemcitabine infusions
if your blood is clotting normally – on cycle 1
if your thyroid and pancreas are working well – on cycles 1, 2, 4, 7, every 6 weeks 
after that
tumor markers – on cycles 1, 3, 5, 7, every 6 weeks after that for up to one year, then 
every 12 weeks

Pregnancy test – on cycles 1, 2, 4, 6, every 4 weeks after that

Routine urine tests – on cycles 1, 2, 4, 7, every 6 weeks after that


MEDICAL RECORD
CONTINUATION SHEET for either:
NIH 2514-1, Consent to Participate in A Clinical Research Study
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study
STUDY NUMBER: 18-C-0061
CONTINUATION: page 4 of 16 pages
PATIENT IDENTIFICATION
CONTINUATION SHEET for either:
NIH-2514-1 (07-09)
NIH-2514-2 (10-84)
P.A.: 09-25-0099
File in Section 4: Protocol Consent

Electrocardiogram (EKG) to evaluate your heart – on Day 1 of Cycle 1  before and after 
the M7824 infusion. 

Imaging Assessments – a CT scan or MRI of chest, abdomen and pelvis – every 6 weeks 
for up to one year, then every 12 weeks. If a scan identifies objective response, a 
confirmatory clinical PET or CT or MRI will be obtained 4 weeks following initial 
documentation of objective response.
Research tests
In addition to the tests that we will conduct to determine whether you are having side effects or if 
you are responding to the study therapy, we will also collect samples from you for purposes of 
research only. These studies include:

Blood samples to study 
the effects of therapy on your immune system will be collected on Day 1 of cycles 1, 
2, 3, 5, 6, 7 and after discontinuation of treatment;
drugs levels in your blood on Day 1 of cycles 1, 2, 3, 4, 5, 6, and after discontinuation 
of treatment;
markers of tumor activity including collecting and testing tumor DNA that we find in 
your bloodstream on Day 1 of cycles 1, 2, 3, 5, 7 and after discontinuation of 
treatment

Two optional tumor biopsies might be collected before and after you have completed 3 
cycles of therapy. Please see page 9 for the risks of biopsy. You will be asked to sign a 
separate consent each time you agree to have an optional biopsy. You can participate in 
the study even if you decide not to undergo the biopsy procedures. Although it is not 
clinically needed, samples will be used for disease evaluation first; leftover samples will 
be used to study the response of your immune system and do genetic testing.

MRI to evaluate how well the drugs circulate in your tumor before start of treatment, on 
Day 1 of cycles 2, 4, 10 and after discontinuation of treatment. 

You will be asked to complete questionnaires to determine you general well-being and 
function - before start of treatment on cycles 4, 8, every 12 weeks after that. It will take 
you about 20 minutes and will only be done if you can complete the surveys in English.

Genetic testing – Your tissue samples contain genes, which are made up of DNA 
(deoxyribonucleic acid) which serves as the "instruction book" for the cells that make up 
our bodies. We will use the tissue samples and blood you provided to learn about how the 
genes in your tumor compare to genes in normal tissue. Your tissue will help us study 
how genes might play a role in pancreatic cancer and other diseases. We will not share 
the results of these research tests with you.


MEDICAL RECORD
CONTINUATION SHEET for either:
NIH 2514-1, Consent to Participate in A Clinical Research Study
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study
STUDY NUMBER: 18-C-0061
CONTINUATION: page 5 of 16 pages
PATIENT IDENTIFICATION
CONTINUATION SHEET for either:
NIH-2514-1 (07-09)
NIH-2514-2 (10-84)
P.A.: 09-25-0099
File in Section 4: Protocol Consent
When we are conducting the above genetic tests, it is possible that we could identify changes in 
other parts of your DNA that are not related to this research. These are known as “incidental 
medical findings”.
However, the analyses that we perform in our laboratory are for research purposes only; they are 
not nearly as sensitive as the tests that are performed in a laboratory that is certified to perform 
genetic testing. Changes that we observe unrelated to our research may or may not be valid. 
Therefore, we do not plan to inform you of the results of testing on your tissue and blood that is 
performed in our research lab. However, in the unlikely event that we discover a finding that is 
believed to be clinically important based on medical standards at the time that we first analyze 
your results, we will contact you. This could be many years in the future. We will ask you to 
have an additional tube of blood drawn to verify the findings we have seen in our lab. If the 
results are verified, you will be re-contacted and offered a referral to a genetic healthcare 
provider to discuss the results.
When you are finished taking the drugs
About 4 – 5 weeks after you have finished taking the study drugs, you will be asked to return for 
a safety follow up visit. At this visit, your will be asked questions about your health, get a 
physical exam, undergo blood and urine tests and might have a CT scan. If you are unable to 
return for this visit, we will obtain the information from you by telephone or e-mail.
If your disease did not get worse, but you finished taking M7824, we will invite you for imaging 
studies every 12 weeks. Also, if in the opinion of the investigator you can get benefit from more 
treatment, we might re-start treatment with M7824, but not gemcitabine.
If your disease got worse, after the safety visit, we will call or e-mail you or your physician 
approximately once every 3 months for 1 year and once every 6 months after that to ask about 
your health and about any other medications you may have taken for your cancer. If you still 
have unresolved health issues, caused by study drug, you will be invited to NIH for additional 
tests and treatment. 
Birth Control
If you are a woman who is breast feeding or pregnant, you will not take part in the study because 
we don’t know how this medicine would affect your baby or your unborn child. If you are a 
woman who can become pregnant or are the partner of a woman who can become pregnant, you 
will need to practice an effective form of birth control at least 28 days before starting study 
treatment, during study treatment, and for 4 months after the last drug infusion. If you think that 
you or your partner is pregnant, you should tell your study doctor or nurse at once. 
Effective forms of birth control include: 
•
abstinence 

intrauterine device (IUD)
•
hormonal [birth control pills, injections, or implants]


MEDICAL RECORD
CONTINUATION SHEET for either:
NIH 2514-1, Consent to Participate in A Clinical Research Study
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study
STUDY NUMBER: 18-C-0061
CONTINUATION: page 6 of 16 pages
PATIENT IDENTIFICATION
CONTINUATION SHEET for either:
NIH-2514-1 (07-09)
NIH-2514-2 (10-84)
P.A.: 09-25-0099
File in Section 4: Protocol Consent
•
tubal ligation
•
vasectomy
Risks or Discomforts of Participation
If you choose to take part in this study, there is a risk that:

You may lose time at work or home and spend more time in the hospital or doctor’s 
office than usual

You may be asked sensitive or private questions which you normally do not discuss

If test shows you are more sensitive to gemcitabine, you will receive less than the 
approved weekly dose of gemcitabine.

Because of combined therapy used on this study, you also might receive less than the 
approved weekly dose of gemcitabine.
The M7824 and chemotherapy used in this study may affect how different parts of your body 
work such as your liver, kidneys, heart, and blood. The study doctor will be testing your blood 
and will let you know if changes occur that may affect your health.
There is also a risk that you could have side effects from the study drug(s). 
Here are important points about side effects:

The study doctors do not know who will or will not have side effects.

Some side effects may go away soon, some may last a long time, or some may never go 
away.

Some side effects may interfere with your ability to have children.

Some side effects may be serious and may even result in death.
Here are important points about how you and the study doctor can make side effects less of a 
problem:

Tell the study doctor if you notice or feel anything different so they can see if you are 
having any symptoms.

The study doctor may be able to treat some side effects.

The study doctor may adjust the study drugs to try to reduce side effects.
Late side effects of the investigational agents may affect your ability to tolerate subsequent 
regimens of standard of care chemotherapy.
Below we show the most common and the most serious side effects that researchers know about. 
There might be other side effects that researchers do not yet know about. If important new side 
effects are found, the study doctor will discuss these with you.


MEDICAL RECORD
CONTINUATION SHEET for either:
NIH 2514-1, Consent to Participate in A Clinical Research Study
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study
STUDY NUMBER: 18-C-0061
CONTINUATION: page 7 of 16 pages
PATIENT IDENTIFICATION
CONTINUATION SHEET for either:
NIH-2514-1 (07-09)
NIH-2514-2 (10-84)
P.A.: 09-25-0099
File in Section 4: Protocol Consent
Risks from study therapy
M7824
Common (occurring in more than 5 % of patients)

Fatigue (tiredness) 

Nausea 

Diarrhea

Decreased appetite

Infusion-related reaction

Chills (feeling cold)
Occasional (occurring in less than 5% of patients)

Shortness of breath

Rash

Abdominal pain

Non-cardiac chest pain
Allergic reactions or reactions in the context with the infusions might occur during treatment. 
Although M7824 is a fully human protein the risk cannot be completely excluded. In general, 
these reactions are mild to moderate and can be handled with appropriate drugs, but in very rare 
cases severe to life-threatening and even fatal reactions might occur, which require advanced 
cardiac life support. 
For the prevention of infusion-related adverse effects and possible allergic reactions you will 
receive a premedication of an antihistamine drug (so-called H1 blocker) and acetaminophen 60 
to 120 minutes before the 1st and 2d infusion.
In addition, immune-mediated side effects might be possible. These are:

joint pain

arthritis (inflammatory disease of the joint)

pneumonitis (inflammatory disease of the lung)

hypothyroidism (decreased function of the thyroid gland)

hyperthyroidism (increased function of thyroid gland)

thyroiditis (inflammatory disease of the thyroid gland)

autoimmune hepatitis (inflammatory disease of the liver caused by the body’s immune 
system)


MEDICAL RECORD
CONTINUATION SHEET for either:
NIH 2514-1, Consent to Participate in A Clinical Research Study
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study
STUDY NUMBER: 18-C-0061
CONTINUATION: page 8 of 16 pages
PATIENT IDENTIFICATION
CONTINUATION SHEET for either:
NIH-2514-1 (07-09)
NIH-2514-2 (10-84)
P.A.: 09-25-0099
File in Section 4: Protocol Consent

thrombocytopenia (decrease of the blood platelets)

dry eyes

inflammatory eye disease 

diabetes mellitus (high blood sugar levels)

decreased function of the adrenal glands

inflammatory disease of muscles characterized by pain and tenderness

colitis (inflammatory disease of the large intestine)

impairment of the brain function

psoriasis 

nerve irritation

autoimmune disorder (body’s immune system approaches own cells)

myocarditis 
There is a risk of tumor lysis syndrome due to tumor shrinkage. This complication is caused by 
the breakdown products of dying cells and includes elevated blood potassium, elevated blood 
phosphorus, elevated blood uric acid and elevated urine uric acid, low blood calcium, and 
consequent acute kidney failure.
Risk of increased bleeding with M7824 administration.
Bleeding has been frequently observed in patients receiving the drug M7824. Patients may 
experience bleeding including, but not limited to: gum bleeding, nose bleeds, blood in their 
urine, blood in their stool, or coughing up blood. Occasionally, this bleeding can be serious and 
potentially life threatening. If you experience any bleeding on this trial, please tell the study team 
immediately.
Tell your doctor if you've had a life-long problem of frequent or excessive bleeding or bruising, 
or if you take aspirin or prescription medication to thin your blood.
If any of these side effects occur, you must inform your study doctor immediately.
Gemcitabine
Common (occurring in more than 20% of patients)
Diarrhea, loss of appetite, nausea, vomiting
Liver enzymes increase
Fever
Rash


MEDICAL RECORD
CONTINUATION SHEET for either:
NIH 2514-1, Consent to Participate in A Clinical Research Study
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study
STUDY NUMBER: 18-C-0061
CONTINUATION: page 9 of 16 pages
PATIENT IDENTIFICATION
CONTINUATION SHEET for either:
NIH-2514-1 (07-09)
NIH-2514-2 (10-84)
P.A.: 09-25-0099
File in Section 4: Protocol Consent
Occasional (occurring in 4-20% of patients)
Anemia which may require blood transfusions
Low blood counts
Blood loss from any cause
Difficulty breathing
Swelling of the body
Flu-like Symptoms
Infection, especially when white blood cell count is low
Hair loss
Feeling of "pins and needles" in arms and legs
Rare and serious (occurring in fewer than 4% of patients) 
Allergic reaction which may cause rash, low blood pressure, wheezing, shortness of breath, 
swelling of the face or throat
Damage to the heart
Blood infection (sepsis)
Damage to the liver
Damage to the kidney
Risks from Blood Collection 
Side effects of blood draws include pain and bruising in the area where the needle was placed, 
lightheadedness, and rarely, fainting. When large amounts of blood are collected, low red blood 
cell count (anemia) can develop.
Risks from Biopsy 
This procedure usually causes only brief discomfort at the site from which the biopsy is taken. 
Rarely, infection or bleeding may occur at the needle site.
Tumor biopsies may be done by a specialist using the CT scanner or ultrasound machine to guide 
the biopsy needle into the tumor to ensure accuracy. To collect the optional research biopsies, 
you may be exposed to 2 CT scans. This radiation exposure is not required for your medical care 
and is for research purposes only. The amount of radiation you might receive in these procedures 
is 1.6 rem which is below the guideline of 5 rem per year allowed for research subjects by the 
NIH Radiation Safety Committee. The average person in the United States receives a radiation 
exposure of 0.3 rem per year from natural sources, such as the sun, outer space, and the earth's 


MEDICAL RECORD
CONTINUATION SHEET for either:
NIH 2514-1, Consent to Participate in A Clinical Research Study
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study
STUDY NUMBER: 18-C-0061
CONTINUATION: page 10 of 16 pages
PATIENT IDENTIFICATION
CONTINUATION SHEET for either:
NIH-2514-1 (07-09)
NIH-2514-2 (10-84)
P.A.: 09-25-0099
File in Section 4: Protocol Consent
air and soil. If you would like more information about radiation, please ask the investigator for a 
copy of the pamphlet, An Introduction to Radiation for NIH Research Subjects.
Privacy Risks:
The following general points are indirectly related to your participation in the research study.
1.
Unanticipated medical information: During the course of this investigation, it is possible 
(although not likely) that we will obtain unanticipated information about your health or genetic 
background. 
2.
Release of medical records. In the course of applying for certain types of insurance (e.g., 
medical insurance, life insurance, or disability insurance), people are often asked to sign forms 
that authorize insurance companies to obtain their medical records. If you sign such a release 
form at some point in the future, it is possible that the insurance company would present this 
signed release form to the Clinical Center of the National Institutes of Health. In that event, the 
National Institutes of Health would comply with your request to provide the insurance company 
with your medical record. It is possible that information contained in your medical record might 
affect (either favorably or unfavorably) the willingness of the insurance company to sell you 
insurance. Your employability may also be affected.
3.
Release of genetic information: 
•
Your privacy is very important to us and we will use many safety measures to protect 
your privacy. However, in spite of all of the safety measures that we will use, we cannot 
guarantee that your identity will never become known. Although your genetic information is 
unique to you, you do share some genetic information with your children, parents, brothers, 
sisters, and other blood relatives. Consequently, it may be possible that genetic information from 
them could be used to help identify you. Similarly, it may be possible that genetic information 
from you could be used to help identify them. 
•
While the controlled-access databases developed for this project will not contain 
information that is traditionally used to identify you, such as your name, address, telephone 
number, or social security number, people may develop ways in the future that would allow 
someone to link your genetic or medical information in our databases back to you. For example, 
someone could compare information in our databases with information from you (or a blood 
relative) in another database and be able to identify you (or your blood relative). It also is 
possible that there could be violations to the security of the computer systems used to store the 
codes linking your genetic and medical information to you.
•
Since some genetic variations can help to predict the future health problems of you and 
your relatives, this information might be of interest to health providers, life insurance companies, 
and others. Patterns of genetic variation also can be used by law enforcement agencies to identify 
a person or his/her blood relatives. Therefore, your genetic information potentially could be used 
in ways that could cause you or your family distress, such as by revealing that you (or a blood 
relative) carry a genetic disease.


MEDICAL RECORD
CONTINUATION SHEET for either:
NIH 2514-1, Consent to Participate in A Clinical Research Study
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study
STUDY NUMBER: 18-C-0061
CONTINUATION: page 11 of 16 pages
PATIENT IDENTIFICATION
CONTINUATION SHEET for either:
NIH-2514-1 (07-09)
NIH-2514-2 (10-84)
P.A.: 09-25-0099
File in Section 4: Protocol Consent
•
There also may be other privacy risks that we have not foreseen.
There are state and federal laws that protect against genetic discrimination. There is also a 
federal law called the Genetic Information Nondiscrimination Act (GINA). In general, this law 
makes it illegal for health insurance companies, group health plans, and most employers to 
discriminate against you based on your genetic information. However, it does not protect you 
against discrimination by companies that sell life insurance, disability insurance, or long-term 
care insurance. GINA also does not apply to members of the United States military, to veterans 
obtaining health care through the Veteran’s Administration or the Indian Health Service. Lastly, 
GINA does not forbid insurance medical underwriting based on your current health status.
Potential Benefits of Participation
Are there benefits to taking part in this study? 
The aim of this study is to find out whether the experimental treatment will cause your tumors to 
shrink. We do not know if you will receive personal, medical benefit from taking part in this 
study. Potential benefits could include shrinking of your tumor or lessening of your symptoms, 
such as pain, that are caused by the cancer. Because there is not much information about the 
drug’s effect on your cancer, we do not know if you will benefit from taking part in this study, 
although the knowledge gained from this study may help others in the future who have cancer. 
Alternative Approaches or Treatments
Instead of being in this study, you have these options:

Getting standard FDA approved treatment or care for your cancer without being in a 
study

Taking part in another study

Getting comfort care, also called palliative care. This type of care helps reduce pain, 
tiredness, appetite problems and other problems caused by the cancer. It does not treat the 
cancer directly. Instead, it tries to improve how you feel. Comfort care tries to keep you 
as active and comfortable as possible.
Please talk to your doctor about these and other options.
Stopping Therapy
Your doctor may decide to stop your therapy for the following reasons:

if he/she believes that it is in your best interest

if your disease comes back during treatment

if you need to take medication that is not allowed on the study

if you become pregnant

if you have side effects from the treatment that your doctor thinks are too severe


MEDICAL RECORD
CONTINUATION SHEET for either:
NIH 2514-1, Consent to Participate in A Clinical Research Study
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study
STUDY NUMBER: 18-C-0061
CONTINUATION: page 12 of 16 pages
PATIENT IDENTIFICATION
CONTINUATION SHEET for either:
NIH-2514-1 (07-09)
NIH-2514-2 (10-84)
P.A.: 09-25-0099
File in Section 4: Protocol Consent

if new information shows that another treatment would be better for you

if the investigator decides to end the study
In this case, you will be informed of the reason therapy is being stopped.
You can stop taking part in the study at any time. However, if you decide to stop taking part in 
the study, we would like you to talk to the study doctor and your regular doctor first.
If you decide at any time to withdraw your consent to participate in the trial, we will not collect 
any additional medical information about you. However, according to FDA guidelines, 
information collected on you up to that point may still be provided to EMD Serono or designated 
representatives. If you withdraw your consent and leave the trial, any samples of yours that have 
been obtained for the study and stored at the NCI can be destroyed upon request. However, any 
samples and data generated from the samples that have already been distributed to other 
researchers or placed in the research databases cannot be recalled and destroyed.
Research Subject’s Rights
What are the costs of taking part in this study? 
If you choose to take part in the study, the following will apply, in keeping with the NIH policy:

You will receive study treatment at no charge to you. This may include 
surgery, medicines, laboratory testing, x-rays or scans done at the 
Clinical Center, National Institutes of Health (NIH), or arranged for you 
by the research team to be done outside the Clinical Center, NIH if the 
study related treatment is not available at the NIH. 

There are limited funds available to cover the cost of some tests and 
procedures performed outside the Clinical Center, NIH. You may have to 
pay for these costs if they are not covered by your insurance company.

Medicines that are not part of the study treatment will not be provided or 
paid for by the Clinical Center, NIH.

Once you have completed taking part in the study, medical care will no 
longer be provided by the Clinical Center, NIH.
Will your medical information be kept private? 
We will do our best to make sure that the personal information in your medical record will be 
kept private. However, we cannot guarantee total privacy. Organizations that may look at and/or 
copy your medical records for research, quality assurance, and data analysis include:

The National Cancer Institute (NCI) and other government agencies, like the Food and 
Drug Administration (FDA), which are involved in keeping research safe for people.

National Institutes of Health Intramural Institutional Review Board


MEDICAL RECORD
CONTINUATION SHEET for either:
NIH 2514-1, Consent to Participate in A Clinical Research Study
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study
STUDY NUMBER: 18-C-0061
CONTINUATION: page 13 of 16 pages
PATIENT IDENTIFICATION
CONTINUATION SHEET for either:
NIH-2514-1 (07-09)
NIH-2514-2 (10-84)
P.A.: 09-25-0099
File in Section 4: Protocol Consent

Qualified representatives from EMD Serono, the pharmaceutical company who produces 
M7824.
Portions of your samples, genomic data, and health information will be stored for an unlimited 
period of time to be used in future research. Your individual genomic data and health 
information will be put in a controlled-access database. This means that only researchers who 
apply for and get permission to use the information for a specific research project will be able to 
access the information. Your genomic data and health information will not be labeled with your 
name or other information that could be used to identify you. Researchers approved to access 
information in the database have agreed not to attempt to identify you.
A description of this clinical trial will be available on http://www.Clinicaltrials.gov, as required 
by U.S. Law. This Web site will not include information that can identify you. At most the 
Web site will include a summary of the results. You can search this Web site at any time.
Certificate of Confidentiality
To help us protect your privacy, we have obtained a Certificate of Confidentiality. The 
researchers can use this Certificate to legally refuse to disclose information that may identify you 
in any federal, state, or local civil, criminal, administrative, legislative, or other proceedings, for 
example, if there is a court subpoena. The researchers will use the Certificate to resist any 
demands for information that would identify you, except as explained below.
You should also know that there are several circumstances in which the Certificate does not 
provide coverage. These include when information: 

will be used for auditing or program evaluation internally by the NIH; or 

must be disclosed to meet the legal requirements of the federal Food and Drug 
Administration (FDA). 

is necessary for your medical treatment and you have consented to this disclosure; 

is for other research. 
In addition, identifiable, sensitive information protected by this Certificate cannot be admissible 
as evidence or used for any purpose in any action, suit, or proceeding without your consent. 
You should understand that a Certificate of Confidentiality does not prevent you or a member of 
your family from voluntarily releasing information about yourself or your involvement in this 
research. If an insurer, employer, or other person obtains your written consent to receive research 
information, then the researchers will not use the Certificate to withhold that information.
The Certificate of Confidentiality will not protect against the required reporting by hospital staff 
of information on suspected child abuse, reportable communicable diseases, and/or possible 
threat of harm to self or others.
Conflict of Interest
The National Institutes of Health (NIH) reviews NIH staff researchers at least yearly for conflicts 
of interest. This process is detailed in a Protocol Review Guide. You may ask your research team 


MEDICAL RECORD
CONTINUATION SHEET for either:
NIH 2514-1, Consent to Participate in A Clinical Research Study
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study
STUDY NUMBER: 18-C-0061
CONTINUATION: page 14 of 16 pages
PATIENT IDENTIFICATION
CONTINUATION SHEET for either:
NIH-2514-1 (07-09)
NIH-2514-2 (10-84)
P.A.: 09-25-0099
File in Section 4: Protocol Consent
for a copy of the Protocol Review Guide or for more information. Members of the research team 
who do not work for NIH are expected to follow these guidelines but they do not need to report 
their personal finances to the NIH.
Members of the research team working on this study may have up to $15,000 of stock in the 
companies that make products used in this study. This is allowed under federal rules and is not a 
conflict of interest. 
The National Institutes of Health and the research team for this study are using therapies 
developed by EMD Serono through a joint study with your researchers and the companies. The 
company also provide financial support for this study. 
Use of Specimens and Data for Future Research
To advance science, it is helpful for researchers to share information they get from studying 
human samples. They do this by putting it into one or more scientific databases, where it is 
stored along with information from other studies. A researcher who wants to study the 
information must apply to the database and be approved. Researchers use specimens and data 
stored in scientific databases to advance science and learn about health and disease. 
These specimens and data will be used for future research and shared with other researchers. We 
will not contact you to ask about each of these future uses. These specimens and data will be 
stripped of identifiers such as name, address or account number, so that they may be used for 
future research on any topic and shared broadly for research purposes. Your specimens and data 
will be used for research purposes only and will not benefit you. It is also possible that the stored 
specimens and data may never be used. Results of research done on your specimens and data will 
not be available to you or your doctor. It might help people who have cancer and other diseases 
in the future. 
If you do not want your stored specimens and data used for future research, please contact us in 
writing and let us know that you do not want us to use your specimens and/or data. Then any 
specimens that have not already been used or shared will be destroyed and your data will not be 
used for future research. However, it may not be possible to withdraw or delete materials or data 
once they have been shared with other researchers.


MEDICAL RECORD
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY
•
Adult Patient or•Parent, for Minor Patient
STUDY NUMBER: 18-C-0061
CONTINUATION: page 15 of 16 pages
PATIENT IDENTIFICATION
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH 
STUDY (Continuation Sheet)
•
Adult Patient or
•Parent, for Minor Patient
NIH-2514-1 (07-09)
P.A.: 09-25-0099
File in Section 4: Protocol Consent
OTHER PERTINENT INFORMATION
1.
Confidentiality. When results of an NIH research study are reported in medical journals 
or at scientific meetings, the people who take part are not named and identified. In most cases, 
the NIH will not release any information about your research involvement without your written 
permission. However, if you sign a release of information form, for example, for an insurance 
company, the NIH will give the insurance company information from your medical record. This 
information might affect (either favorably or unfavorably) the willingness of the insurance 
company to sell you insurance.
The Federal Privacy Act protects the confidentiality of your NIH medical records. However, you 
should know that the Act allows release of some information from your medical record without 
your permission, for example, if it is required by the Food and Drug Administration (FDA), 
members of Congress, law enforcement officials, or authorized hospital accreditation 
organizations.
2.
Policy Regarding Research-Related Injuries. The Clinical Center will provide short-
term medical care for any injury resulting from your participation in research here. In general, no 
long-term medical care or financial compensation for research-related injuries will be provided 
by the National Institutes of Health, the Clinical Center, or the Federal Government. However, 
you have the right to pursue legal remedy if you believe that your injury justifies such action.
3.
Payments. The amount of payment to research volunteers is guided by the National 
Institutes of Health policies. In general, patients are not paid for taking part in research studies at 
the National Institutes of Health. Reimbursement of travel and subsistence will be offered 
consistent with NIH guidelines.
4.
Problems or Questions. If you have any problems or questions about this study, or about 
your rights as a research participant, or about any research-related injury, contact the Principal 
Investigator, Udo Rudloff, M.D., Building 10, Room 2B38D, phone 240-760-6238. You may 
also call the Clinical Center Patient Representative at 301-496-2626. If you have any questions 
about the use of your specimens or data for future research studies, you may also contact the 
Office of the Clinical Director, Telephone: 240-760-6187. 
5.
Consent Document. Please keep a copy of this document in case you want to read it 
again.


MEDICAL RECORD
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY
•
Adult Patient or•Parent, for Minor Patient
STUDY NUMBER: 18-C-0061
CONTINUATION: page 16 of 16 pages
PATIENT IDENTIFICATION
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH 
STUDY (Continuation Sheet)
•
Adult Patient or
•Parent, for Minor Patient
NIH-2514-1 (07-09)
P.A.: 09-25-0099
File in Section 4: Protocol Consent
COMPLETE APPROPRIATE ITEM(S) BELOW:
A. Adult Patient’s Consent
B. Parent’s Permission for Minor Patient.
I have read the explanation about this study 
and have been given the opportunity to discuss 
it and to ask questions. I hereby consent to 
take part in this study.
I have read the explanation about this study 
and have been given the opportunity to discuss 
it and to ask questions. I hereby give 
permission for my child to take part in this 
study. 
(Attach NIH 2514-2, Minor’s Assent, if 
applicable.)
Signature of Adult Patient/
Legal Representative
Date
Signature of Parent(s)/ Guardian
Date
Print Name
Print Name
C. Child’s Verbal Assent (If Applicable)
The information in the above consent was described to my child and my child agrees to 
participate in the study.
Signature of Parent(s)/Guardian
Date
Print Name
THIS CONSENT DOCUMENT HAS BEEN APPROVED FOR USE 
FROM FEBRUARY 12, 2019 THROUGH FEBRUARY 15, 2020.
Signature of Investigator
Date
Signature of Witness
Date
Print Name
Print Name