A Phase Ib/II Trial of M7824 in Solid Tumors With Microsatellite Instability With Consensus Molecular Subtype 4 Metastatic Colorectal Cancer in Combination With Radiation, or in Colorectal Cancer Patients With Detectable Circulating Tumor DNA Following Definitive Therapy
Phase: PHASE1
Conditions: Colon Adenocarcinoma, High-Frequency Microsatellite Instability, Metastatic Malignant Solid Neoplasm, Rectal Adenocarcinoma, Refractory Colorectal Carcinoma, Stage IV Colon Cancer AJCC v8, Stage IV Rectal Cancer AJCC v8, Stage IVA Colon Cancer AJCC v8, Stage IVA Rectal Cancer AJCC v8, Stage IVB Colon Cancer AJCC v8, Stage IVB Rectal Cancer AJCC v8
Sponsor: M.D. Anderson Cancer Center

MD Anderson IND Sponsor Cover Sheet 
Protocol ID 
2017-0339 
Protocol Title 
A phase Ib/II trial of M7824 in solid tumors with microsatellite 
instability, with Consensus Molecular Subtype 4 metastatic colorectal 
cancer in combination with radiation, or in colorectal cancer patients with 
detectable circulating tumor DNA following definitive therapy 
Phase 
Ib/II 
Protocol Version 
9.0 
Version Date 
June 25, 2020 
Protocol PI 
Van Morris, MD 
Department 
GI Medical Oncology 
IND Sponsor 
MD Anderson Cancer Center 
IND # 
137789 
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Clinical Trial Protocol 
Clinical Trial Protocol Number 
MDA # 2017-0339 
Title 
A phase Ib/II trial of M7824 in solid tumors with 
microsatellite instability, with Consensus Molecular 
Subtype 
4 
metastatic 
colorectal 
cancer 
in 
combination with radiation, or in colorectal cancer 
patients with detectable circulating tumor DNA 
following definitive therapy 
Phase 
Ib/II 
IND Number 
137789 
Principal Investigator 
Van Morris, MD 
The University of Texas – MD Anderson Cancer 
Center 
Houston, TX USA 
  
Sponsor 
MD Anderson Cancer Center, Houston, TX USA 
 
Clinical Trial Protocol Version 
 June 25, 2020/ Version 9.0 
Replaces Version 
May 23, 2019/Version 8.0 
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Protocol Table of Contents 
 
Protocol Table of Contents ..................................................................................................2 
List of Abbreviations ...........................................................................................................6 
1 
Sponsor, Investigators and Trial Administrative Structure ................27 
2 
Background Information .....................................................................27 
2.1 
Investigational Product .......................................................................27 
2.1.1 
Safety ..................................................................................................28 
2.2 
Non-Clinical Findings for M7824 ......................................................32 
2.2.1 
In Vitro and in Vivo Pharmacology Findings .....................................32 
2.2.2 
Pharmacokinetics / Immunogenicity Findings ...................................34 
2.2.3 
Toxicology ..........................................................................................35 
2.2.4 
Brief Summary of the Clinical Findings for M7824 ..........................35 
2.2.5 
Rationale for Cohorts ..........................................................................36 
2.2.6 
Summary of the Overall Benefit and Risk ..........................................39 
3 
Trial Objectives ..................................................................................42 
3.1 
Primary Objective ...............................................................................42 
3.2 
Secondary Objectives .........................................................................42 
3.3 
Exploratory Objectives .......................................................................43 
4 
Investigational Plan ............................................................................44 
4.1 
Overall Trial Design and Plan ............................................................44 
4.1.2 
Planned number of subjects ................................................................45 
4.1.3 
Planned treatment duration .................................................................46 
4.1.4 
Dose Modification and ADRs Requiring Treatment 
Discontinuation ...................................................................................46 
4.1.5 
Analysis Cut-Off Dates .......................................................................48 
4.2 
Discussion of Trial Design .................................................................48 
4.2.2 
Inclusion of Special Populations ........................................................50 
4.3 
Selection of Trial Population ..............................................................50 
4.3.1 
Inclusion criteria .................................................................................50 
4.3.2 
Exclusion criteria ................................................................................51 
4.4 
Criteria for Initiation of Trial Treatment ............................................53 
4.5 
Criteria for Subject Withdrawal ..........................................................53 
4.5.1 
Withdrawal from Trial Treatment ......................................................53 
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4.5.2 
Withdrawal from the Trial ..................................................................54 
4.6 
Premature Termination of the Trial ....................................................54 
4.7 
Definition of End of Trial ...................................................................55 
5 
Investigational Medicinal Product and Other Drugs Used in the 
Trial .....................................................................................................55 
5.1 
Description of the Investigational Medicinal Product ........................55 
5.2 
Dosage and Administration ................................................................55 
5.3 
Assignment to Treatment Groups .......................................................56 
5.4 
Noninvestigational Medicinal Products to be Used ............................56 
5.5 
Concomitant Medications and Therapies ...........................................57 
5.5.1 
Permitted Medicines ...........................................................................57 
5.5.2 
Prohibited Medicines ..........................................................................57 
5.5.3 
Special Precautions .............................................................................59 
5.6 
Packaging and Labeling of the Investigational Medicinal Product ....64 
5.7 
Preparation, Handling, and Storage of the Investigational 
Medicinal Product ...............................................................................64 
5.8 
Investigational Medicinal Product Accountability .............................65 
5.9 
Assessment of Investigational Medicinal Product Compliance .........66 
5.10 
Medical Care of Subjects after End of Trial .......................................67 
6 
Trial Procedures and Assessments ......................................................67 
6.1 
Schedule of Assessments ....................................................................67 
6.1.1 
Screening and Baseline Procedures and Assessments ........................67 
6.1.2 
Treatment period .................................................................................68 
6.1.3 
End of Treatment ................................................................................70 
6.1.4 
Post Treatment Follow Up ..................................................................71 
6.1.5 
Blood Consumption for Clinical Assessments ...................................72 
6.2 
Demographic and Other Baseline Characteristics ..............................72 
6.2.1 
Demographic Data ..............................................................................72 
6.2.2 
Diagnosis of Tumor ............................................................................73 
6.2.3 
Medical History ..................................................................................73 
6.2.4 
Vital Signs and Physical Examination ................................................73 
6.2.5 
CT or MRI Scans for Tumor Assessment at Baseline ........................74 
6.2.6 
Cardiac Assessments ..........................................................................74 
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6.2.7 
Clinical Laboratory Tests ...................................................................74 
6.3 
Efficacy Assessments .........................................................................77 
6.4 
Assessment of Safety ..........................................................................78 
6.4.1 
Adverse Events ...................................................................................79 
6.4.2 
Pregnancy and In Utero Drug Exposure .............................................86 
6.4.3 
Clinical Laboratory Assessments .......................................................86 
6.4.4 
Vital Signs, Physical Examinations, and Other Assessments .............88 
6.4.5 
Biomarkers ..........................................................................................89 
7 
Statistics ..............................................................................................95 
7.1 
Sample Size Calculations ...................................................................95 
7.1.1 
Cohort A-C .........................................................................................95 
7.1.2 
Cohort B ..............................................................................................95 
7.1.3 
Cohort C .............................................. Error! Bookmark not defined. 
7.2 
Randomization ....................................................................................95 
7.3 
Endpoints ............................................................................................96 
7.3.1 
Primary Endpoints ..............................................................................96 
7.3.2 
Secondary Endpoints ..........................................................................96 
7.3.3 
Exploratory Endpoints ........................................................................96 
7.4 
Analysis sets .......................................................................................96 
7.5 
Description of Statistical Analyses .....................................................96 
7.5.1 
General Considerations .......................................................................96 
7.5.2 
Analysis of Primary Endpoint ............................................................97 
7.5.3 
Analysis of Endpoints .........................................................................97 
7.6 
Interim safety monitoring ...................................................................99 
8 
References Cited in the Text .............................................................101 
 
 
 
 
 
 
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Table of In-Text Tables 
 
Table 1: Schedule of Assessments (Cohort A-C) ................................................................8 
Table 2: Schedule of Assessments (Cohort B) ..................................................................16 
Table 3: Schedule of Assessments (Cohort D) ..................................................................22 
Table 4: Overview of TEAEs for the Dose Escalation Cohorts of M7824 .......................31 
Table 5: Adverse Events in Dose Expansion Cohort for CRC of M7824………………..33 
Table 6: Treatment Modification for Symptoms of Infusion-related Reactions Caused 
by M7824 ............................................................................................61 
Table 7: Required Laboratory Panel Tests .........................................................................92 
Table 8: Toxicity stopping boundaries for Cohort A-C ...................................................103 
Table 9: Operating Characteristics for Toxicity Monitoring in Cohort A-C ...................104 
Table 10: Toxicity stopping boundaries for Cohort B .....................................................104 
Table 11: Operating Characteristics for Toxicity Monitoring in Cohort B .....................104 
 
 
 
 
 
 
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List of Abbreviations 
 
ADR 
Adverse Drug Reaction 
AE 
Adverse Event 
ALT 
Alanine Aminotransferase 
AST 
Aspartate Aminotransferase 
CIMP 
CpG Island Methylator Phenotype  
CMS 
Consensus Molecular Subtype 
CRF 
Case Report Form 
CR 
Complete Response 
CTCAE 
Common Terminology Criteria for Adverse Events 
ctDNA 
Circulating Tumor DNA 
DFS 
Disease-Free Survival 
DLT 
Dose Limiting Toxicity 
EKG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
GCP 
Good Clinical Practice 
Hgb 
Hemoglobin 
IB 
Investigator’s Brochure 
ICH 
International Conference on Harmonization 
iCPD 
Immune Confirmed Progressive Disease 
IEC 
Independent Ethics Committee 
IHC 
Immunohistochemistry 
IMP 
Investigational Medicinal Product 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
ITT 
Intention To Treat 
iUPD 
Immune Unconfirmed Progressive Disease 
IV 
Intravenous 
IVRS 
Interactive Voice Response System 
LA 
Locally advanced 
mCRC 
Metastatic Colorectal Cancer 
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MoA 
Mechanism of Action 
MSI 
Microsatellite Instability 
MSI-L 
Microsatellite Instability – Low 
MSI-H 
Microsatellite Instability - High 
MSS 
Microsatellite Stable 
NCI 
National Cancer Institute 
NFkB 
Nuclear Factor Kappa Light Chain Enhanced of Activated B cells 
NK 
Natural Killer 
OS 
Overall Survival 
ORR 
Objective Response Rate 
PCR 
Polymerase Chain Reaction 
PD 
Progressive Disease 
PD-1 
Programmed Death - 1 
PD-L1 
Programmed Death Ligand 1 
PDx 
Pharmacodynamics 
PGx 
Pharmacogenetics/Pharmacogenomics 
PFS 
Progression Free Survival 
PK 
Pharmacokinetics 
PO 
Per Os 
PR 
Partial Response 
PS 
Performance Status 
RECIST 
Response Evaluation Criteria in Solid Tumors  
ROS 
Reactive oxygen species 
RR 
Response Rate 
SAE 
Serious Adverse Event 
SBRT 
Stereotactic Body Radiation Therapy 
Treg 
T-regulatory 
TGF-β 
Transforming Growth Factor β 
WBC 
White Blood Cell 
ULN 
Upper Limit of Normal 
UR 
Unresectable 
 
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Table 1: Schedule of Assessments (Cohort A-C) 
Test 
Cycle  1 
Cycle  2 
Cycle 3 (and all 
subsequent cycles) 
End-of-
Treatment 
28-day
follow up
after 
progression 
Long 
term 
follow up 
Measure 
Day -28 to 
treatment 
Day 1 
Day 15 
Day 1 
Day 15 
Day 1 
Day 15 
Day of dis-
continuation 
or within 7 
days after 
Every 3 
months 
after 28 
day 
follow up 
Inclusion/exclusion 
criteria 
X 
X 
Demographic data 
X 
Medical history 
X 
Cancer disease history 
X 
Prior anticancer drug/ 
radiotherapy/ 
procedures 
X 
Concurrent medications 
X 
Written informed 
consent 
X 
Enrollment (if eligible)a 
X 
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Test 
Cycle  1 
Cycle  2 
Cycle  3(and all 
subsequent cycles) 
End of 
Treatment 
28day 
follow-up 
after 
progression 
Long-
term 
follow-up 
Measure 
Day -28 
to 
treatment 
Day 
1 
Day 15 
Day 1 
Day 15 
Day 1 
Day 15 
Day of 
discontinuati
on or within 
7 days after 
Every 3 
months 
after 28-
day 
follow up 
Physical examinationb,p 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital signs including 
weightp and height 
(latest height on record 
acceptable; height is 
only performed at 
screening) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ECOG PSp 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Toxicity assessmentp 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xr 
12-lead EKGc,d, p
X 
X 
X 
Full serum chemistrye, p 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Complete blood counte,
p
X 
X 
X 
X 
X 
X 
X 
X 
X 
Free T4, TSHe, f, p 
X 
X 
X 
ANA, RFe,  
X 
X 
Urinalysis (dipstick)e, p 
X 
X 
X 
X 
X 
X 
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β-HCG pregnancy test, 
FSH e, f,p 
X 
X 
X 
X 
Xo 
Test 
Cycle  1 
Cycle  2 
Cycle  3 (and all 
subsequent cycles) 
End of 
treatment 
28 day 
follow up 
after 
progression 
Long-
term 
follow-up 
Measure 
Day -28 
to 
treatment 
Day 
1 
Day 15 
Day 1 
Day 15 
Day 1 
Day 15 
Day of 
discontinuati
on or within 
7 days after 
Every 3 
months 
after 28-
day 
follow up 
HIV, HBV, HCV 
testing  
X 
Documentation of AEs, 
concomitant 
medications, and 
procedures q 
X 
X 
X 
X 
X 
X 
X 
Xq 
Xq 
X 
M7824 Administration p 
Xt 
Xt 
X 
X 
X 
X 
Patient-reported 
outcomes p 
X 
X 
X 
X 
X 
X 
X 
Tumor biopsy g,p 
X 
X 
X 
MSI testing h 
X 
Tumor evaluation by 
imaging (w/collection 
of available staging 
imaging prior to study 
enrollment)  l,j,p 
X 
X 
Xu 
Xq 
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Verification of available 
specimen for mutation 
profiling k 
X 
Test 
Cycle  1 
Cycle  2 
Cycle 
 
3 
(and 
all 
subsequent cycles) 
End 
of 
Treatment 
28 
day 
follow 
up 
after 
progression 
Long-
term 
follow-
upr 
Measure 
Day -28 
to 
treatment 
Day 
1 
Day 15 
Day 1 
Day 15 
Day 1 
Day 15 
Day of 
discontinuati
on or within 
7 days after 
Every 3 
months 
after 28-
day 
follow up 
Verification of available 
specimen for TGFβ 
1,2,3 analysis p 
X 
X 
X 
X 
Xs 
X 
Blood biomarkers 
(including circulating 
cytokines)  l,p 
X 
X 
X 
X 
X 
X 
Collection of buccal 
and fecal swabs for 
microbiome testingp 
X 
X 
Xs 
X 
Verification of available 
specimen for PD-L1 
expression m 
X 
X 
Collection of specimens 
for analysis of 
pharmacokinetics of 
M7824  n,p 
X 
X 
X 
X 
aEnrollment will be done after the confirmation of fulfilling all screening inclusion criteria without matching any exclusion criterion. 
bPhysical examination should include a dermatological examination.  If abnormal skin findings are observed, patient should be 
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referred to a dermatologist for biopsy of suspicious lesions. An ophthalmology examination including slit lamp evaluation inclusive of 
the anterior segment and with visual acuity should be conducted at Screening. At subsequent visits, eye signs and symptoms should be 
checked. If there are any clinically relevant findings then an appropriate ophthalmology examination including slit lamp evaluation 
inclusive of the anterior segment and with visual acuity should be obtained within 2 days. Starting with C1D15, a focused examination 
may be performed centered around patient’s symptoms at an assigned visit.  
c12-lead EKG should be performed as soon after completion of infusion as possible.   
dEKGs are to be performed every 6 weeks. 
eLaboratory draws may be performed up to 72 hours before a scheduled treatment. 
fFor women of child-bearing potential.  FSH should be drawn if clarification of post-menopausal state is warranted.  Refer to 
Appendix 2 for further details. 
gMandatory fresh tumor biopsies will be collected prior to treatment and prior to dose 3.  An optional tumor biopsy following 
progression may be offered to the patient. 
hPerformed on archival tissue or fresh biopsy. MSI testing performed in a CLIA certified laboratory is acceptable and does not need to 
be repeated (see section 6.4.5) 
iTumor measurements should occur with CT imaging or MRI.  Ideally the same methodology would be used over the course of the 
study for a given patient. Bone scan should be done at screening if clinically indicated. For collection of those prior imaging studies 
prior to informed consent, readily available imaging studies since the onset of metastatic/unresectable disease are to be prioritized for 
collection.  If the results of a CT scan or MRI performed within 4 weeks prior to first treatment are available, the screening CT and/or 
MRI does not need to be performed. 
jTumor measurements are to be assessed every 8 weeks (+/- 5 days).  For subjects continuing treatment beyond 12 months, tumor 
evaluations should take place every 12 weeks (+/- 5 days). 
kTo be performed on archival tissue or fresh biopsy either via hotspot next general sequencing panel in CLIA certified molecular 
diagnostics laboratory at MD Anderson.  
lPlasma will be sent for markers including, but not limited to, interleukin (IL) IL-1α, IL-1β, IL-2, IL-5, IL-6, IL-8, IL-13, TNF-α, 
MCP, MIP-1β, G-CSF, GM-CSF, IFN-γ via a cytokine assay ((Meso Scale Discovery (MSD), 40 Plex). Leukocyte subpopulations and 
immune activation status will be assessed by flow cytometry (fluorescence-activated cell sorter [FACS]) on PBMC from heparinized 
blood samples (10 mL, tubes). Additional time points to include for collection after cycle 3, day 1 include C4D1, C5D1, and C6D1.  
No additional biomarker samples for this analysis will be collected while the patient is receiving treatment on study. 
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mPD-L1 expression by immunohistochemistry on fresh biopsy. Repeat IHC on FRESH biopsy prior to dose 3 of M7824 
nOne 10 mL vial of blood will be drawn prior to M7824 infusion and immediately following completion of M7824 infusion for doses 
1 and 3 (cycle 1 day 1 and cycle 2 day 1) for analysis of pharmacokinetics.  One 10 mL vial of blood will be drawn prior to M7824 
infusion of M7824 infusion for doses 2 (cycle 1 day 15) and dose 6/end of treatment (whichever comes first).  Refer to Section 6.4.3 
for details on processing of PK samples. 
oβ-hCG (no FSH) at post-progression follow-up visit 
pWindow of +/- 7 days is allowed 
qAdverse events are recorded and assessed continuously throughout the trial (see Section 6.4.1.3) and are assessed for final outcome at 
the End of Treatment visit. After the End of Treatment visit only AEs that are deemed attributable to trial drug by the Investigator 
should be documented until the Safety Follow-up visit. 
rFor up to one year following discontinuation of treatment on study.  
sCycle 3, Day 1 collection only.  
tPatients must remain at the CTRC for two hours of observation following the first two doses of therapy.   
uOnly to be performed if no disease progression was documented previously. 
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Table 2: Schedule of Assessments (Cohort B) 
Test 
Cycle  1 
Cycle  2 
Cycle 3 (and all 
subsequent cycles) 
End-of-
Treatment 
28 day 
follow up 
after 
progression 
Long 
term 
follow up 
Measure 
Day -28 to 
treatment 
Day 1 
Day 15 
Day 1 
Day 15 
Day 1 
Day 15 
Day of dis-
continuation 
or within 7 
days after 
Every 3 
months 
after 28 
day 
follow up 
Inclusion/exclusion 
criteria 
X 
X 
Demographic data 
X 
Medical history 
X 
Cancer disease history 
X 
Prior anticancer drug/ 
radiotherapy/ 
procedures 
X 
Concurrent medications 
X 
Written informed 
consent 
X 
Enrollment (if eligible)a 
X 
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Test 
Cycle  1 
Cycle  2 
Cycle  3 (and all 
subsequent cycles) 
End of 
Treatment 
28 day 
follow-up 
after 
progression 
Long-
term 
follow-up 
Measure 
Day -28 
to 
treatment 
Day 
1 
Day 15 
Day 1 
Day 15 
Day 1 
Day 15 
Day of 
discontinuati
on or within 
7 days after 
Every 3 
months 
after 28-
day 
follow up 
Physical examinationb,q 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital signs including 
weight and height 
(latest height on record 
acceptable)q 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ECOG PSq 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Toxicity assessmentq 
X 
X 
X 
X 
X 
X 
X 
Xs 
Xs 
X 
12-lead EKGc,d, q
X 
X 
X 
Full serum chemistrye, q 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Complete blood counte,
q
X 
X 
X 
X 
X 
X 
X 
X 
X 
Free T4, TSHe, f, q 
X 
X 
X 
ANA, RFe,  
X 
X 
Urinalysis (dipstick)e, q 
X 
X 
X 
X 
X 
X 
β-HCG pregnancy test, 
FSH e,  f,q 
X 
X 
X 
X 
Xp 
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Test 
Cycle  1 
Cycle  2 
Cycle  3 (and all 
subsequent cycles) 
End of 
treatment 
28 day 
follow up 
after 
progression 
Long-
term 
follow-up 
Measure 
Day -28 
to 
treatment 
Day 
1 
Day 15 
Day 1 
Day 15 
Day 1 
Day 15 
Day of 
discontinuati
on or within 
7 days after 
Every 3 
months 
after 28-
day 
follow up 
HIV, HBV, HCV 
testing  
X 
Documentation of AEs, 
concomitant 
medications, and 
procedures q 
X 
X 
X 
X 
X 
X 
X 
Xr 
Xr 
X 
M7824 Administration q 
Xu 
Xu 
X 
X 
X 
X 
SBRT Administrationw 
X 
Patient-reported 
outcomes q 
X 
X 
X 
X 
X 
X 
X 
Tumor collection g,q 
X 
Xx 
X 
X 
MSI testing h 
X 
Confirmation of CMS 
statusi 
X 
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Test 
Cycle  1 
Cycle  2 
Cycle 
 
3 
(and 
all 
subsequent cycles) 
End 
of 
Treatment 
28 
day 
follow 
up 
after 
progression 
Long-
term 
follow-ups 
Measure 
Day -28 
to 
treatment 
Day 1 
Day 15 
Day 1 
Day 15 
Day 1 
Day 15 
Day of 
discontinuati
on or within 
7 days after 
Every 3 
months 
after 28-
day 
follow up 
Verification of available 
specimen for analysis of 
TGFβ 1,2,3 q 
X 
X 
X 
X 
Xt 
X 
Tumor evaluation by 
imaging (w/collection 
of available staging 
imaging prior to study 
enrollment) j,k,q 
X 
X 
Xv 
Xr 
Verification of available 
specimen for mutation 
profiling l 
X 
Blood biomarkers 
(including circulating 
cytokines)  m,q 
X 
X 
X 
X 
X 
X 
Collection of buccal 
and fecal swabs for 
microbiome testingq 
X 
X 
Xt 
X 
Verification of available 
specimen for PD-L1 
expression n 
X 
X 
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Collection of samples 
for pharmacokinetics of 
M7824o,q 
X 
X 
X 
X 
aEnrollment will be done after the confirmation of fulfilling all screening inclusion criteria without matching any exclusion criterion. 
bPhysical examination should include a dermatological examination.  If abnormal skin findings are observed, patient should be 
referred to a dermatologist for biopsy of suspicious lesions. An ophthalmology examination including slit lamp evaluation inclusive of 
the anterior segment and with visual acuity should be conducted at Screening. At subsequent visits, eye signs and symptoms should be 
checked. If there are any clinically relevant findings then an appropriate ophthalmology examination including slit lamp evaluation 
inclusive of the anterior segment and with visual acuity should be obtained within 2 weeks, unless an urgent necessity is determined 
by the treating provider that requires a sooner evaluation. Starting with C1D15, a focused examination may be performed centered 
around patient’s symptoms at an assigned visit.  
c12-lead EKG should be performed as soon after completion of infusion as possible.   
dEKGs are to be performed every 6 weeks. 
eLaboratory draws may be performed up to 72 hours before a scheduled treatment. 
fFor women of child-bearing potential.  FSH should be drawn if clarification of post-menopausal state is warranted.  Refer to 
Appendix 2 for further details. 
gMandatory fresh tumor biopsies will be collected prior to treatment and prior to dose 2 (i.e., on cycle 1, day 15) and prior to dose 3.  
An optional tumor biopsy following progression may be offered to the patient. 
hMSI testing performed in a CLIA certified laboratory is acceptable and does not need to be repeated (see section 6.4.5) 
iCMS on FFPE at CLIA testing laboratory on archival primary tissue or fresh biopsy. 
jTumor measurements should occur with CT imaging or MRI.  Ideally the same methodology would be used over the course of the 
study for a given patient. Bone scan should be done at screening if clinically indicated. For collection of those prior imaging studies 
prior to informed consent, readily available imaging studies since the onset of metastatic/unresectable disease are to be prioritized for 
collection.  If the results of a CT scan or MRI performed within 4 weeks prior to first treatment are available, the screening CT and/or 
MRI does not need to be performed. 
kTumor measurements are to be assessed every 8 weeks (+/- 5 days).  For subjects continuing treatment beyond 12 months, tumor 
evaluations should take place every 12 weeks (+/- 5 days). 
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lTo be performed on archival tissue or fresh biopsy either via hotspot next general sequencing panel in CLIA certified molecular 
diagnostics laboratory at MD Anderson.  
mPlasma will be sent for markers including, but not limited to, interleukin (IL) IL-1α, IL-1β, IL-2, IL-5, IL-6, IL-8, IL-13, TNF-α, 
MCP, MIP-1β, G-CSF, GM-CSF, IFN-γ via a cytokine assay ((Meso Scale Discovery (MSD), 40 Plex). Leukocyte subpopulations and 
immune activation status will be assessed by flow cytometry (fluorescence-activated cell sorter [FACS]) on PBMC from heparinized 
blood samples (10 mL, tubes).  Additional time points to include for collection after cycle 3, day 1 include C4D1, C5D1, and C6D1.  
No additional biomarker samples for this analysis will be collected while the patient is receiving treatment on study. 
nPD-L1 expression by immunohistochemistry on fresh biopsy. Repeat IHC on FRESH biopsy prior to dose 3 of M7824 
oOne 10 mL vial of blood will be drawn prior to M7824 infusion and immediately following completion of M7824 infusion for doses 
1 and 3 (cycle 1 day 1 and cycle 2 day 1) for analysis of pharmacokinetics.  One 10 mL vial of blood will be drawn prior to M7824 
infusion of M7824 infusion for doses 2 (cycle 1 day 15) and  dose 6/end of treatment (whichever comes first).  Refer to Section 6.4.3 
for details on processing of PK samples. 
pβ-hCG (no FSH) at post-progression follow-up visit 
qWindow of +/- 7 days is allowed 
rAdverse events are recorded and assessed continuously throughout the trial (see Section 6.4.1.3) and are assessed for final outcome at 
the End of Treatment visit. After the End of Treatment visit only AEs that are deemed attributable to trial drug by the Investigator 
should be documented until the Safety Follow-up visit. 
sFor up to one year following discontinuation of treatment on study.  
tCycle 3, Day 1 collection only.  
uPatients must remain at the CTRC for two hours of observation following the first two doses of therapy.   
vOnly to be performed if no disease progression was documented previously. 
wSBRT administration (total 24 Gy over 3 consecutive business days at a daily fraction of 8Gy to start within 7 days following cycle 
1, day 15 and completed prior to cycle 2, day 1).  While SBRT is preferred, Intensity-modulated radiation therapy (IMRT) or 3D 
conformal techniques may be utilized at the discretion of the treating radiation oncologist depending on the dose to surrounding 
normal tissues.  Patient will receive a total dose of 24Gy over three days with one of the following modalities, at the discretion of the 
treating radiation oncologist: SBRT, IMRT and 3D conformal.     
xBiopsy to be performed cycle 1, day 15   
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Table 3: Schedule of Assessments (Cohort D) 
Test 
Cycle  1 
Cycle  2 
Cycle  3 
Cycle 4x (and all 
subsequent cycles) 
End of 
treatment 
Long term 
follow up 
Measure 
Day 
-28 
to 
treatmen
t 
Day 1 
Day 15 
Day 1 
Day 15 
Day 1 
Day 15 
Day 1 
Day 15 
Day of dis-
continuation or 
within 7 days 
after 
28 
day 
follow 
up 
after 
progr
ession 
Every 
3 
months 
after 
28 day 
follow 
up 
Inclusion/exclusion 
criteria 
X 
X 
Demographic data 
X 
Cancer disease history 
X 
Prior anticancer drug/ 
radiotherapy/ 
procedures 
X 
Medical history 
X 
Concurrent medications 
X 
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Vital signs including 
weightq and height 
(latest height on record 
acceptable; height is 
only performed at 
screening) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Test 
Cycle  1 
Cycle  2 
Cycle  3 
Cycle 4x (and all 
subsequent cycles) 
End of 
treatment 
Long term 
follow up 
Measure 
Day 
-28 
to 
treatmen
t 
Day 1 
Day 15 
Day 1 
Day 15 
Day 1 
Day 15 
Day 1 
Day 15 
Day of dis-
continuation or 
within 7 days 
after 
28 
day 
follow 
up 
after 
progr
ession 
Every 
3 
months 
after 
28 day 
follow 
up 
Written informed 
consent 
X 
Enrollment (if eligible)a 
X 
Physical examinationb,q 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ECOG PSq 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
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Toxicity assessmentq 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xs 
Xs 
Test 
Cycle  1 
Cycle  2 
Cycle  3 
Cycle 4y (and all 
subsequent cycles) 
End of 
treatment 
Long term 
follow up 
Measure 
Day 
-28 
to 
treatmen
t 
Day 1 
Day 15 
Day 1 
Day 15 
Day 1 
Day 15 
Day 1 
Day 15 
Day of dis-
continuation or 
within 7 days 
after 
28 
day 
follow 
up 
after 
progr
ession 
Every 
3 
months 
after 
28 day 
follow 
up 
Documentation of AEs, 
concomitant 
medications, and 
procedures q 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xs 
12-lead EKGc,d, q
X 
X 
X 
X 
X 
Full serum chemistrye, q 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Complete blood counte,
q
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Free T4, TSHe, f, q 
X 
X 
ANA, RFe,  
X 
Urinalysis (dipstick)e, q 
X 
X 
X 
X 
X 
X 
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β-HCG pregnancy test, 
FSH e, t,q 
X 
X 
X 
X 
X 
HIV, HBV, HCV 
testing  
X 
Test 
Cycle  1 
Cycle  2 
Cycle  3 
Cycle 4x (and all 
subsequent cycles) 
End
of 
treatment 
Long 
term 
follow 
up 
Measure 
Day 
-28 
to 
treatmen
t 
Day 1 
Day 15 
Day 1 
Day 15 
Day 1 
Day 15 
Day 1 
Day 15 
Day 
of 
dis-
continuation or 
within 7 days 
after 
28 day 
follow 
up 
after 
progr
ession 
Every 
3 
months 
after 
28 day 
follow 
up 
M7824 Administration 
q
Xu 
Xu 
X 
X 
X 
X 
X 
X 
Tumor biopsy g 
Xn 
Patient-reported 
outcomes q 
X 
X 
X 
X 
X 
X 
X 
X 
X 
MSI testing h 
X 
Verification of 
available specimen for 
mutation profiling m 
X 
Tumor evaluation by 
imaging (w/collection 
of available staging 
X 
X 
Xv 
Xs 
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imaging prior to study 
enrollment) j,k,q 
Verification of 
available specimen for 
TGFβ 1,2,3 q 
X 
X 
X 
X 
X 
X 
Xt 
X 
Test 
Cycle  1 
Cycle  2 
Cycle  3 
Cycle 4x (and all 
subsequent cycles) 
End of 
treatment 
Long term 
follow up 
Measure 
Day 
-28 
to 
treatmen
t 
Day 1 
Day 15 
Day 1 
Day 15 
Day 1 
Day 15 
Day 1 
Day 15 
Day of dis-
continuation or 
within 7 days 
after 
28 
day 
follow 
up 
after 
progr
ession 
Every 
3 
months 
after 
28 day 
follow 
up 
Verification of 
available specimen for 
PD-L1 expression n 
X 
Collection of buccal 
and fecal swabs for 
microbiome testingq 
X 
X 
X 
X 
Verification of 
available specimen for 
testing of 
pharmacokinetics of 
M7824  o,q 
X 
X 
X 
X 
X 
Blood for collection of 
ctDNA 
X 
Xy
X 
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aEnrollment will be done after the confirmation of fulfilling all screening inclusion criteria without matching any exclusion criterion. 
bPhysical examination should include a dermatological examination.  If abnormal skin findings are observed, patient should be 
referred to a dermatologist for biopsy of suspicious lesions. An ophthalmology examination including slit lamp evaluation inclusive of 
the anterior segment and with visual acuity should be conducted at Screening. At subsequent visits, eye signs and symptoms should be 
checked. If there are any clinically relevant findings then an appropriate ophthalmology examination including slit lamp evaluation 
inclusive of the anterior segment and with visual acuity should be obtained within 2 days. Starting with C1D15, a focused examination 
may be performed centered around patient’s symptoms at an assigned visit.  
c12-lead EKGs should be performed as soon after completion of infusion as possible.   
dEKGs are to be performed every 6 weeks. 
eLaboratory draws may be performed +/- 7 days of  a scheduled treatment. 
fFor women of child-bearing potential.  FSH should be drawn if clarification of post-menopausal state is warranted.  Refer to 
Appendix 2 for further details. 
gAn optional tumor biopsy following progression may be offered to the patient. 
hPerformed on archival tissue or fresh biopsy. MSI testing performed in a CLIA-certified laboratory is acceptable and does not need to 
be repeated (see section 6.4.5) 
iBlood for ctDNA collection to be drawn after14 days of completion of standard treatment. 
jTumor measurements should occur with CT imaging or MRI.  Ideally the same methodology would be used over the course of the 
study for a given patient. Bone scan should be done at screening if clinically indicated. For collection of those prior imaging studies 
prior to informed consent, readily available imaging studies since the onset of metastatic/unresectable disease are to be prioritized for 
collection.  If the results of a CT scan or MRI performed within 4 weeks prior to first treatment are available, the screening CT and/or 
MRI does not need to be performed. 
kTumor measurements are to be assessed every 12 weeks (+/- 5 days).  For subjects continuing treatment beyond 12 months, tumor 
evaluations should take place every 12 weeks (+/- 5 days). 
lTo be performed on archival tissue or fresh biopsy either via hotspot next general sequencing panel in CLIA certified molecular 
diagnostics laboratory at MD Anderson. TGFβR2, ACVR2A, SMAD2 and SMAD4 will need to be performed if not done previously. 
mPlasma will be sent for markers including, but not limited to, interleukin (IL) IL-1α, IL-1β, IL-2, IL-5, IL-6, IL-8, IL-13, TNF-α, 
MCP, MIP-1β, G-CSF, GM-CSF, IFN-γ via a cytokine assay ((Meso Scale Discovery (MSD), 40 Plex). Leukocyte subpopulations and 
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immune activation status will be assessed by flow cytometry (fluorescence-activated cell sorter [FACS]) on PBMC from heparinized 
blood samples (10 mL, tubes). 
nPD-L1 expression by immunohistochemistry on archival tumor specimen or fresh tumor tissue (if available).  
oOne 10 mL vial of blood will be drawn prior to M7824 infusion and immediately following completion of M7824 infusion for doses 
1 and 3 (cycle 1 day 1 and cycle 2 day 1) for analysis of pharmacokinetics.  One 10 mL vial of blood will be drawn prior to M7824 
infusion of M7824 infusion for doses 2 (cycle 1 day 15) and dose 6/end of treatment (whichever comes first).  Refer to Section 6.4.3 
for details on processing of PK samples. 
pβ-hCG (no FSH) at post-progression follow-up visit 
qWindow of +/- 7 days is allowed 
rAdverse events are recorded and assessed continuously throughout the trial (see Section 6.4.1.3) and are assessed for final outcome at 
the End of Treatment visit. After the End of Treatment visit only AEs that are deemed attributable to trial drug by the Investigator 
should be documented until the Safety Follow-up visit. 
sFor up to one year following discontinuation of treatment on study.  
tCycle 4, Day 1 collection only.  
uPatients must remain at the CTRC for two hours of observation following the first two doses of therapy.   
vOnly to be performed if no disease progression was documented previously. 
wIncluding confirmation of R0 resection of metastatic disease 
xAt the discretion of the treating provider and patient in the absence of recurrence or progression 
yCycle 4 Day 1, and every 12 weeks (+/1 14 days) thereafter as long as the patient continues study treatment. 
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1 
Sponsor, Investigators and Trial Administrative Structure 
This clinical trial will be sponsored by: 
The University of Texas - MD Anderson Cancer Center. 
The trial will be conducted within the Department of Gastrointestinal Medical Oncology at the 
University of Texas - MD Anderson Cancer Center in Houston, TX.  All clinical assessments will 
be performed in the outpatient clinic setting.  Study drug will be administered in the Cancer 
Therapy and Research Center (CTRC), an outpatient infusion center at MD Anderson.   
The Principal Investigator represents all Investigators for decisions and discussions regarding this 
trial, consistent with the International Conference on Harmonisation (ICH) Topic E6 Good Clinical 
Practice (GCP; hereafter referred to as ICH GCP). The Coordinating Investigator will provide 
expert medical input and advice relating to trial design and execution and is responsible for the 
review and signoff of the clinical trial report.   
The trial will appear in the following clinical trial registry: www.clinicaltrials.gov 
2 
Background Information 
2.1 
Investigational Product 
The Investigational Medicinal Product (IMP) for the present trial is  M7824. 
M7824 is a bifunctional fusion protein that combines an anti-programmed death ligand 1 (PD-
L1) antibody and the soluble extracellular domain of transforming growth factor beta (TGFβ 
receptor type II as a TGFβ neutralizing “trap,” into a single molecule. This anti-PD-L1 / TGFβ-
Trap molecule is designed to target 2 major mechanisms of immunosuppression in the tumor 
microenvironment. The anti-PD-L1 moiety of M7824 is identical to avelumab, except for three 
amino acid substitutions in the heavy chain constant regions, which result in a different human 
IgG1 allotype, and one amino acid substitution in the heavy chain for antibody stability. As of 
June 2017, FDA has granted accelerated approval to avelumab for metastatic Merkel cell 
carcinoma (MCC) and locally advanced or metastatic urothelial carcinoma whose disease 
progressed during or following platinum-containing chemotherapy. 
Combining these pathways, PD-1 / PD-L1 and TGFβ, is attractive as an antitumor approach. A 
recent report found that blockade of TGFβ signaling in T cells or deletion of TGFβ1 from T cells 
in a mouse model led to diminished PD-1 expression in tumor-infiltrating CD8+ T cells1. 
Concomitant PD-1 and TGFβ blockade can restore pro-inflammatory cytokines2. In a murine 
model of hepatocellular carcinoma, TGFβ appeared to increase the expression of PD-L1 in 
dendritic cells, which in turn promoted T-cell apoptosis and increased percentage of CD25+, 
Foxp3+ T regulatory cells3. Higher levels of circulating myeloid-derived suppressor cells 
(MDSCs), a significant source of TGFβ, are associated with failure to respond to anti-PD-1 
therapy4. 
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Experiments demonstrate that M7824 strongly enhances antitumor activity and prolongs survival 
in mouse tumor models above the effect of either the anti-PD-L1 antibody, avelumab, or 
TGFβRII control alone. Tumor rechallenge experiments in cured mice show durable protective 
immunity. In vivo studies showed that the antitumor effects were mediated by CD8+ T cells and 
NK cells. CD8+ T-cell tumor infiltrates were observed and, overall, the CD8+ response was 
associated with long term protective immunity. Importantly, in the MC38 model, M7824 showed 
significantly better efficacy than the combination of avelumab plus TGFβ Trap control, 
supporting the rationale of combining the 2 active moieties in 1 molecule. 
M7824, is comprised of an extracellular domain of the human TGFβ receptor TGFβRII 
covalently joined via a glycine / serine linker to the C terminus of each heavy chain of the fully 
human IgG1 anti-PD-L1 antibody, avelumab. 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 
cotargeting a complementary immune modulation step will improve tumor response. A similar 
TGF-targeting agent, fresolimumab, which is a monoclonal antibody targeting TGFβ1, 2, and 3, 
showed initial evidence of tumor response in a Phase I trial in subjects with melanoma. The 
objective response was observed in 1 of 28 subjects with 6 subjects showing stable disease5. 
Internal data shows that the TGFβRII portion of M7824 has dose dependent antitumor activity 
in a mouse pharyngeal carcinoma xenograft model, similar to antitumor findings with soluble 
receptor reported elsewhere6. Given the preclinical and clinical evidence of both pathways, it is 
anticipated that M7824 may have enhanced antitumor activity compared with avelumab. 
2.1.1 
Safety 
A reasonable safety profile is anticipated when targeting these pathways. The safety of the PD-1 
/ PD-L1 class continues to emerge but appears to be substantially less adverse compared with 
the CTLA-4 class of T cell checkpoint inhibitors7,8. Two TGFβ inhibiting biologics have been 
administered in clinical trials and showed an acceptable human safety profile in humans. 
Fresolimumab was studied in Phase I trial in subjects with cancer (28 with melanoma, 1 with renal 
cell carcinoma). No DLTs were observed and 15 mg/kg, the highest dose tested, was determined 
to be safe5. The major AE was emergent skin tumors and hyperkeratosis. In a small trial of 
idiopathic pulmonary fibrosis, the most common AE was fatigue9. In a study of 16 subjects with 
focal segmental glomerulosclerosis, the only AE was pustular rash in 2 subjects10. TβM1, an 
antibody inhibiting the TGFβII receptor, was well tolerated when studied at doses as high as 240 
mg with diarrhea as the only DLT event11. Notably, one event of low hemoglobin (Hgb) was 
observed in the high dose group. Importantly, the preclinical profile of M7824 is 
predominantly benign and highly comparable to that of avelumab. Overall, evidence suggests 
non-overlapping toxicity profiles for anti-PD-L1 and anti-TGFβ agent classes. There is a 
theoretical potential of immune-related adverse events (irAEs) that would be the consequence of 
a double blockade of negative regulatory loops of the immune system; however, taken together, 
the preclinical profile of M7824 and clinical evidence of each pathway suggests a low risk of 
synergistic toxicity stemming from the dual-functionality of M7824. 
An irAE is defined as off target side effects associated with exposure of immunogenic drug and is 
consistent with an immune mechanism. In the process of identification of irAEs, any possible 
etiology of neoplastic, infectious, metabolic, toxin, or any other factor should be ruled out. 
Serological, histological (biopsy), immunological data should be obtained to support immune 
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mediation of occurrence of adverse event. Immune-related AEs are AESIs for M7824 and 
important identified risks (adverse reactions) for M7824, and the precautions and management are 
discussed in Section 5.5.3.3. 
Important identified irAE risks for M7824 include colitis, pneumonitis/interstitial lung disease, 
endocrinopathies, 
hyperthyroidism, 
hypothyroidism, 
autoimmune 
thryroiditis, 
adrenal 
insufficiency, Type 1 diabetes mellitus), nephritis, hepatitis, retinal microvasculitis, uveitis, 
myositis, and skin reactions like rash (generalized, maculo-papula, erythematous, bullous 
pemphigoid). Management algorithms include steroids, other immune-suppressants, study drug 
interruption / discontinuation, and supportive management. Anti-PDL1 has shown an overall 
rate of infusion reactions of approximately 10% (Grade 3 / 4 approximately 0.4% [fell to 0.2% 
with mandatory premedication]; no Grade 5. 
A brief summary of safety experience with the PD-1 inhibitors nivolumab (Opdivo®) and 
pembrolizumab (Keytruda®) is given here, based on prescribing information (refer to current label 
information for updated information). For pembrolizumab the section on Warnings and 
Precautions includes adverse reactions of immune-mediated pneumonitis (2.9%), immune-
mediated colitis (1%), immune-mediated hepatitis (0.5%), immune-mediated hypophysitis 
(0.5%), renal failure (0.5%) and immune-mediated nephritis (0.7%), immune-mediated 
hyperthyroidism (1.2%) and hypothyroidism (8.3%), and a variety of other immune-mediated 
adverse reactions occurring in less than 1% of patients. In addition, a warning for embryofetal 
toxicity is provided. For nivolumab the section on Warning and Precautions includes adverse 
reactions of immune-mediated pneumonitis (2.2%) with fatal immune-mediated pneumonitis in 
0.9% (5/574), immune-medicated colitis (2.2%), immune-mediated hepatitis (1.1%), immune-
mediated nephritis and renal dysfunction (0.7%), immune-mediated hyperthyroidism (3%) and 
hypothyroidism (8%) and a variety of other immune-mediated adverse reactions occurring in less 
than 1% of patients. In addition, a warning for embryofetal toxicity is provided. 
Safety experience with various TGFβ 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 I trials, the experience with a molecule with a highly similar mechanism to the M7824 
TGFβ trap moiety, the anti-TGFβ-1 and 3 antibody fresolimumab, showed no dose limiting 
toxicity up to 15 mg/kg and no immune related events5. 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 TGFβ is associated with 
the formation of keratoacanthomas, similar to the findings described for fresolimumab12. 
Therefore, it is plausible that skin tumors observed during fresolimumab treatment may be 
related to TGFβ inhibition. A neutralizing antibody against TGFβ-1, TβM1, was well tolerated 
when studied as 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 oligonucelotide that 
inhibits TGFβ2 expression, was associated with thrombocytopenia that was moderate13. Finally, 
TGFβ is known to play a role in wound repair14. 
In the recently released initial phase I dose escalation cohort of M7824 (MSB0011359C), 19 
subjects had enrolled in the dose-escalation part of the study with 3 subjects treated at each dose 
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level of M7824 (MSB0011359C): 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).  
As of the data cutoff date (Oct 3rd, 2016), the overview of treatment emergent adverse events 
(TEAEs) for the M7824 dose escalation cohort is provided in Table 4. 
Table 4: Overview of TEAEs for the Dose Escalation Cohorts of M7824 
 
Dose Level 
0.3 mg/kg 
N = 3 
(%) 
Dose Level 
1 mg/kg 
N = 3 
(%) 
Dose Level 
3 mg/kg 
N = 3 
(%) 
Dose Level 
10 mg/kg 
N = 3 
 (%) 
Dose Level 
20 mg/kg 
N = 7 
(%) 
Overall 
N = 19 
(%) 
Any TEAE 
2 (66.7) 
3 (100.0) 
3 (100.0) 
3 ( 100) 
7 (100.0) 
18 ( 94.7) 
TEAE, Grade ≥ 3 
2 (66.7) 
3 (100.0) 
1 ( 33.3) 
0 (  0.0) 
4 ( 57.1) 
10 ( 52.6) 
Related TEAE  
1 (33.3) 
0 ( 0.0) 
2 ( 66.7) 
1 (  33.3) 
5 ( 71.4) 
9 ( 47.4) 
Related 
TEAE, 
Grade ≥ 3 
0 (0.0) 
0 (  0.0) 
1 ( 33.3) 
0 (  0.0) 
2 ( 28.6) 
3 ( 15.8) 
TEAE Leading to 
Treatment 
Discontinuation 
0 (0.0) 
1 ( 33.3) 
1 ( 33.3) 
0 (  0.0) 
2 ( 28.6) 
4 (  21.1) 
Any TEAE leading 
to Infusion Rate 
Reduction 
0 (0.0) 
0 (  0.0) 
0 (  0.0) 
0 (  0.0) 
1 (  14.3) 
1 (  5.3) 
Serious TEAE 
1 (33.3) 
2 ( 66.7) 
1 ( 33.3) 
0 (  0.0) 
5 ( 71.4) 
9 ( 47.4) 
Related 
Serious 
TEAE 
0 (0.0) 
0 (  0.0) 
1 ( 33.3) 
0 (  0.0) 
3 (  42.9) 
4 (  21.1) 
TEAE Leading to 
Death 
0 (0.0) 
0 (  0.0) 
0 (  0.0) 
0 (  0.0) 
0 (  0.0) 
0 (  0.0) 
Any 
TEAE 
of 
Special 
Interest: 
Infusion-Related 
Reaction 
0 (0.0) 
0 (  0.0) 
0 (  0.0) 
0 (  0.0) 
1 (  14.3) 
1 (  5.3) 
Any 
TEAE 
of 
Special 
Interest: 
Immune-Related 
1 (33.3) 
0 (  0.0) 
0 (  0.0) 
1 (  33.3) 
2 (  28.6) 
4 (  21.1) 
Note: Reporting of infusion-related reactions is being amended at the time this document was being prepared. 
TEAE: treatment emergent adverse events. 
18 out of 19 subjects experienced at least one TEAE of any grade. The most frequently observed 
TEAEs in more than 3 subjects were gastrointestinal disorders reported in 14 subjects (nausea in 
9 subjects, vomiting in 7 subjects and abdominal pain in 4 subjects), followed by general disorders 
and administration site conditions in 8 subjects (fatigue in 5 subjects, localized edema in 4 subjects 
and fever in 4 subjects), skin and subcutaneous tissue disorders in 7 subjects, anemia in 6 subjects, 
infections and infestations in 5 subjects, metabolism and nutrition disorders in 5 subjects, 
musculoskeletal and connective tissue disorders in 4 subjects and respiratory, thoracic and 
mediastinal disorders in 4 subjects. 
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Most of the TEAEs are of Grade 1 or 2. Ten subjects experienced at least 1 Grade ≥ 3 TEAE, 
including Grade 4 cerebrovascular accident (CVA) in 1 subject, Grade 4 anemia in 1 subject, Grade 
3 anemia in 4 subjects, cerebrovascular accident (CVA) in 1 subject, nausea in 3 subjects, vomiting 
in 2 subjects, abdominal pain in 2 subjects, colitis in 1 subject, rectal bleeding in 1 subject, 
hematuria in 1 subject, decreased urine output in 1 subject, skin infection in 1 subject, soft tissue 
infection in 1 subject, hypertension in 1 subject, dehydration in 1 subject, back pain in 1 subject, 
skin squamous cell carcinoma in 1 subject. Grade 3 laboratory abnormalities include decreased 
lymphocyte counts in 2 subjects, prolonged APTT in 1 subject, acidosis in 1 subject, hypokalemia 
in 1 subject. 
9 out of 19 subjects experienced at least one trial drug related TEAE. 3 subjects experienced at 
least 1 Grade ≥ 3 trial drug related TEAE, including grade 3 anemia in 1 subject, grade 3 colitis in 
1 subject, grade 3 skin infection in 1 subject, grade 3 skin squamous cell carcinoma in 1 subject. 
All of the other trial drug related TEAEs are of Grade 1 or 2, including hyperthyroidism in 2 
subjects, hypothyroidism in 2 subjects, maculopapular rashes in 2 subjects, bullous dermatitis in 1 
subject, acneiform dermatitis in 1 subject, pruritus in 1 subject, infusion related reaction in 1 
subject, nausea in 1 subject, vomiting in 1 subject, dry mouth in 1 subject, exertional dyspnea in 1 
subject. 
At the 20 mg/kg dose level, 2 subjects experienced TEAE leading to treatment discontinuation. 
The maximum tolerated dose (MTD) level was not reached at the highest so far at investigated 
dose of 20 mg/kg. One subject had a dose limiting toxicity (DLT) with colitis with subsequent 
bleeding and anemia at the 20 mg/kg dose level. Overall, the TEAE profile was similar across 
different dose escalation cohorts and the incidences of TEAEs by TEAE category did not increase 
significantly with increasing dose. 
The safety summary of the M7824 expansion cohort in colorectal patients is listed as below. As of 
April 21 2017, 32 patients with a diagnosis of colorectal cancer have received at least one, or more, 
doses of 1,200mg of M7824. Table 5 list both drug-related and not-related AEs for items in which 
> 10% of patients experience the event, or if the events was recurrent Grade 3 or any Grade 4 or 
higher. Overall, the drug was well tolerated at the 1,200mg dose level with a typical AE profile for 
an advanced cancer patient cohort. Of note, the grade 3 toxicities occurring in more than 10 percent 
of study subjects were anemia (4 out of 32, 12.5%), hyponatremia (4 out of 32, 12.5%) and dyspnea 
(4 out of 32, 12.5%).  There were 4 subjects with Grade 3 events listed as related to M7824. These 
include anemia (1 event), blood bilirubin increased (1 event), enteritis (1 event) and adrenal 
insufficiency (1 event). No Grade 4 or Grade 5 events have been reported as related to M7824. 
Table 5. Adverse Events (AEs) in Dose Expansion cohort of colorectal cancer patients on 
EMR200647-001 dosed with 1,200mg M7824 (cut-off date 21 April 2017; n=32). Both drug-
related and not drug-related AEs for items in which > 10% of patients experience the event, or if 
the event was recurrent Grade 3 or any Grade 4 or higher, are listed. 
 
Primary System Organ Class 
Any Grade 
Grade 
>=3 
Grade 
>=4 
Grade 
5 
Preferred Term 
n (%) 
n (%) 
n (%) 
n (%) 
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Anemia 
8 (25.0) 
4 (12.5) 
1 (3.1) 
0 
Abdominal Pain 
10 (31.3) 
1 (3.1) 
0 
0 
Constipation 
12 (37.5) 
0 
0 
0 
Diarrhea 
8 (25.0) 
0 
0 
0 
Nausea 
11 (34.4) 
3 (9.4) 
0 
0 
Vomiting 
7 (19.4) 
2 (6.3) 
0 
0 
Fatigue 
10 (31.3) 
2 (6.3) 
0 
0 
Pyrexia 
8 (25.0) 
1 (3.1) 
0 
0 
Cholangitis 
1 (3.1) 
1 (3.1) 
1 (3.1) 
0 
Sepsis 
3 (9.4) 
3 (9.4) 
2 (6.3) 
1 (3.1) 
UTI 
7 (21.9) 
1 (3.1) 
0 
0 
Infusion related reaction 
5 (15.6) 
0 
0 
0 
Blood bilirubin increased 
2 (6.3) 
2 (6.3) 
0 
0 
GGT increased 
3 (9.4) 
3 (9.4) 
0 
0 
Weight decreased 
4 (12.5)  
0 
0 
0 
Decreased Appetite 
10 (31.3) 
1 (3.1) 
0 
0 
Dehydration  
4 (12.5) 
0 
0 
0 
Hyperglycemia  
3 (9.4) 
3 (9.4) 
1 (3.1) 
0 
Hyperkalemia  
1 (3.1) 
1 (3.1) 
1 (3.1) 
0 
Hyponatremia 
6 (18.8) 
4 (12.5) 
0 
0 
Back pain 
7 (21.9) 
0 
0 
0 
Myalgia 
5 (15.6) 
0 
0 
0 
Headache 
4 (12.5) 
1 (3.1) 
0 
0 
Anxiety 
4 (12.5) 
0 
0 
0 
Cough 
5 (15.6) 
0 
0 
0 
Dyspnea 
9 (28.1) 
4 (12.5) 
1 (3.1) 
0 
Pleural Effusion 
5 (15.6) 
0 
0 
0 
Respiratory Failure 
1 (3.1) 
1 (3.1) 
1 (3.1) 
0 
Hypotension 
2 (6.3) 
1 (3.1) 
1 (3.1) 
0 
 
 
2.2 
Non-Clinical Findings for M7824 
2.2.1 
In Vitro and in Vivo Pharmacology Findings 
Avelumab, a fully human anti-PD-L1 IgG1 antibody, recently entered Phase III clinical 
development by EMD Serono R&D, Billerica, MA. Preclinical pharmacology investigations have 
shown that avelumab functionally enhances T cell activation in vitro and significantly inhibits the 
growth of PD-L1 expressing tumors in vivo; thus avelumab serves as a benchmark for the 
preclinical proof of principle studies of the anti-PD-L1 / TGFβ Trap (M7824). In addition, M7824, 
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which consists of the TGFβ trap covalently linked to an inactive anti-PD-L1, was generated to 
evaluate the effect of inhibition of TGFβ only. 
M7824 binds recombinant and cell surface expressed PD-L1 with an affinity similar to that of 
the parental anti-PD-L1 antibody (avelumab), and binds recombinant human TGFβ1 with high 
affinity. Importantly, M7824 can bind simultaneously to PD-L1 and TGFβ1 as demonstrated by 
a two-step binding assay. M7824 potently attenuated TGFβ signaling in cell assays and enhanced 
interleukin-2 production by T cells stimulated with a super antigen, Staphylococcal enterotoxin 
A. M7824 is capable of mediating antibody-dependent cell-mediated cytotoxicity (ADCC) in 
vitro, but at a significantly reduced level compared with the parental avelumab antibody. M7824 
was shown to be internalized by PD-L1-expressing cells in vitro with kinetics similar to those of 
the parental avelumab antibody. In summary, the dual functionalities of M7824 were confirmed 
by in vitro studies: the fusion protein retains the biological activities of the parental anti-PD-L1 
avelumab antibody, but possesses the added modality of effective TGFβ binding and 
neutralization. 
M7824 is cross-reactive with murine PD-L1 and TGFβ1; therefore, its in vivo antitumor efficacy 
and the immunological response during the course of treatment can be evaluated in syngeneic 
models; however, since this therapeutic agent is a recombinant human protein with two 
mechanisms of action aimed at blocking immunosuppression, it caused an augmented mouse 
antibody against human antibody (MAHA) response in immunocompetent mice, which limits the 
dosing to a 3- or 6-day window, depending on the strain of mice. To avoid a MAHA response, 
2 B cell deficient strains of mice were employed in a series of studies designed to assess the optimal 
antitumor efficacy of M7824 treatment in cancer models. Homozygous Jh mice (Igh-Jtm1Dhu; 
Balb/C) lack normal B lymphocyte numbers and have no detectable IgM or IgG antibody titers 
due to the absence of the Jh gene segments responsible for genetic recombination of the Ig heavy 
chain. Likewise, B6.129S2-Ighmtm1Cgn/J mice (C57BL/6) lack mature B cells due to a 
targeted Ighmtm1Cgn mutation. The use of Jh and B6.129S mice allowed clinically-relevant 
repeat dosing schedules of the M7824 treatment in the in vivo pharmacology studies. To ensure 
the results obtained were not artifacts due to the B cell deficiency, efficacy and associated 
immunological responses of M7824 in wild type mice were also demonstrated, although to a 
lesser extent for efficacy due to the limited dosing window and interference by MAHA. 
M7824 possesses superior antitumor activities relative to monotherapy with either PD-L1 
blockade or TGFβ sequestration, resulting in complete tumor regression and long-term survival 
in the EMT-6 breast cancer model and MC38 colorectal cancer model. Dose-dependent efficacy 
was observed in multiple models, and the effective dose range was between 25 to 492 μg per 
mouse (approximately 1.25 to 25 mg/kg) depending on the model. Importantly, M7824 therapy 
induced antitumor activities that conferred a durable, protective immunity in those mice eradicated 
of their primary tumor. Moreover, the antitumor effect of M7824 was associated with 
modulations in T cell and NK cell phenotypes, increase in dendritic cell maturation, and reduction 
in MDSCs in the tumor microenvironment. M7824 was also shown to be capable of activating 
both adaptive and innate immune responses that included favorable changes in tumor immune 
infiltrates. Furthermore, tumor antigen-specific CD8+ T cell responses were enhanced with 
M7824 therapy. 
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In a trial to further elucidate the mechanisms of action, tumor-bearing mice were systemically 
depleted of CD4+ T cells, CD8+ T cells or NK cells during treatment. The therapeutic efficacy 
of M7824 was completely abrogated by the depletion of either CD8+ T cells or NK cells, but not 
by the depletion of CD4+ T cells. Consistent with the reduced ADCC in vitro, the effector 
function of M7824 did not play an important role in the antitumor effect in vivo. Furthermore, 
the dominant role of CD8+ T cells in maintaining long-term protective immunity following 
M7824 induced tumor eradication has been demonstrated. 
The therapeutic potential of M7824 was explored in combination with various standard-of-care 
therapies. In combination with the core components of the FOLFOX chemotherapy regimen 
(oxaliplatin, 5-fluorouracil and oxaliplatin), an additive enhancement in efficacy was 
demonstrated against MC38 colorectal carcinoma. 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. 
These data suggest that M7824 can be explored as a combination partner in different clinical 
settings for the treatment of cancer patients. 
Refer to the Investigator’s Brochure for full details of the preclinical pharmacology of M7824. 
2.2.2 
Pharmacokinetics / Immunogenicity 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 saturable component. The TGFβ1 binding was assessed and showed suppression for prolonged 
periods beyond drug exposure at all dose levels; however, 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: 
• The predicted human terminal half-life (t1/2) for M7824 is approximately 6 days 
• Simulations predict that a 1 mg/kg dose will provide an average exposure of 
approximately 7 μg/mL in humans 
• Based on PK / PharmDyn modeling and human projections: 
o At a human dose of 0.1 mg/kg, 95% PD-L1 total occupancy at maximum serum 
concentration observed post-dose (Cmax) is expected in PBMCs, providing 
approximately 60% total occupancy in tumor 
o At a human dose of 1.0 mg/kg, more than 95% of PD-L1 total occupancy at Cmax is 
expected in PBMCs and tumor 
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o At a human dose  of  1.0  mg/kg,  20%  effect  is  projected  in  tumor  regression  in  the 
PK / PharmDyn model compared with 95% at 7.5 mg/kg 
• Human projections indicate a dose of 7.5 mg/kg and higher (range 4 to 20 mg/kg), on a 
biweekly schedule is needed to achieve full efficacy based on a mouse tumor model in which 
complete tumor regressions were observed. 
Anti-drug  antibodies  were  observed  in  some  animals;  however,  the  impact  on  PK  or PK / 
PharmDyn is not known. Preclinical antidrug antibody formation is not predictive of human 
antibodies. 
2.2.3 
Toxicology 
The toxicological profile of M7824 was investigated in vivo in mice and cynomolgus 
monkeys. In addition, an optimized in vitro cytokine release assay in human PBMCs as well as 
tissue cross-reactivity studies in normal human and cynomolgus monkey tissues were performed. 
Investigations of local tolerance were integrated in the repeat-dose toxicity studies. The 
investigation of safety pharmacology relevant parameters (CNS, respiratory, cardiovascular) was 
included in the pivotal 4-week intravenous (IV) repeat-dose toxicity study in cynomolgus 
monkeys. Please refer to the investigator brochure for M7824 for further details. 
2.2.4 
Brief Summary of the Clinical Findings for M7824 
As of October 2016, 19 subjects had enrolled in the dose-escalation part of the dose escalation 
study with M7824. Please see Table 4 for further details. 
No subject experienced a DLT and no subject was discontinued from treatment for drug-related 
TEAEs. No subject was reported with a TEAE with a Preferred Term of infusion-related reaction; 
however using a post-reporting analysis according to criteria outlined in the Statistical Analysis 
Plan, 3 subjects were reported with TEAEs that were classified as “infusion-related reactions,” 
with the Preferred Terms of abdominal pain, pyrexia, and back pain (Note: these events are 
undergoing further review). 
The safety summary of the M7824 expansion cohort in colorectal patients is listed in Table 5. As 
of April 21 2017, 32 patients with a diagnosis have received at least one, or more, doses of 1,200mg 
of M7824. Table 5 list both drug-related and not-related AEs for items in which > 10% of patients 
experience the event, or if the events was recurrent Grade 3 or any Grade 4 or higher. Overall, the 
drug was well tolerated at the 1,200mg dose level with a typical AE profile for an advanced cancer 
patient cohort. Of note, the grade 3 toxicities occurring in more than 10 percent of study subjects 
were anemia (4 out of 32, 12.5%), hyponatremia (4 out of 32, 12.5%) and dyspnea (4 out of 32, 
12.5%). There were 4 subjects with Grade 3 events listed as related to M7824. These include 
anemia (1 event), blood bilirubin increased (1 event), enteritis (1 event) and adrenal insufficiency 
(1 event). No Grade 4 and Grade 5 events have been reported as related to M7824. Please see 
Table 5 for further details. 
 
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2.2.5 
Rationale for Cohorts 
The programmed death 1 (PD-1) protein/ PD ligand-1 (PD-L1) interaction is important for immune 
evasion. PD-L1 is expressed on many cells including tumor cells. The PD-1/PD-L1 interaction 
results in peripheral T effector cell exhaustion and promotes conversion of T cells towards a T-
regulatory (Treg) phenotype. Other cell types express PD-L1 such as natural killer (NK) cells, 
myeloid cells and dendritic cells. These cells all contribute to the tumor microenvironment (TME) 
and have the potential to upregulate PD-L1. Evidence for disrupting this interaction via checkpoint 
inhibitors has been shown in melanoma and non-small cell lung cancer. PD1 antibodies, nivolumab 
and pembrolizumab tested in phase III trials versus standard of care chemotherapy have 
demonstrated better clinical outcomes in melanoma4,15,16, non-small cell lung cancer17-19. Initial 
data suggests anti-PD-1 therapy may have efficacy in MSI-H mCRC20.  
TGFβ is a cytokine with multiple functions21. It is produced by various cell types including 
platelets22, various myeloid populations, fibroblasts and T regulatory (Treg) cells23. TGFβ has dual 
roles in cancer24. In early stage disease, TGFβ promotes differentiation and apoptosis acting as a 
tumor suppressor. In late stage cancer, TGFβ has a tumor promoter function. TGFβ enhances 
epithelial mesenchymal transition (EMT) by the control of genes like ZEB1,2, TWIST, SNAIL 
and SLUG that control expression of cell surface markers that mediate epithelial cell-cell contacts 
such as E-cadherin25. TGFβ has autocrine and paracrine functions in fibroblasts, macrophages and 
myeloid derived suppressor cells (MDSC)26. These cells have direct and indirect effects on the 
overall inflammatory/immune state of the tumor microenvironment (TME).  
TGFβ also contributes to an immunosuppression within the TME. Cancers secrete various 
cytokines and chemokines that stimulate myelopoiesis and attract immature myeloid cells towards 
the tumor. Granulocyte (PMN-MDSC) and monocyte (M-MDSC) can be recruited and under TME 
specific conditions such as hypoxia, cause differentiation of these precursors into tumor associated 
macrophages and neutrophils (TAMs and TANs)26-28. TGFβ forms one of the many cytokines that 
forms autocrine feedback to sustain immunosuppressive signaling at the TME level29. In addition, 
these immature precursors are highly immunosuppressive while the TAMs are polarized towards 
alternatively activated forms such as the immunosuppressive M2 phenotype. Together, MDSC and 
M2 macrophages promote downregulation of tumor immunity through direct mechanisms on 
cytotoxic T cells. These include substrate metabolism (arginine) or sequestration (L-cystine), 
direct effects of reactive oxygen species (ROS) or reactive nitrogen species on T-cell receptor 
subunits and through the secretion of cytokines that promote Treg differentiation. TGFβ has 
downregulatory effects on cytotoxic T cells and natural killer (NK) cells26. In the bloodstream, 
TGFβ released from platelets after contact with circulating tumor cells downregulates NK 
tumorilytic activity in vitro30,31 and downregulates NKG2D receptors on NK cells32, providing 
another immune escape mechanism.   
TGFβ has pleotropic effects extend beyond the immune regulation. Through effects on local innate 
immune cells, endothelial cells and activated fibroblasts, TGFβ is a central component of the 
cytokine milieu that also promotes angiogenesis25.  TGFβ also mediates an environment of matrix 
remodeling via cancer associated fibroblasts (CAFs) and immune cells. The induction of these 
cells results secretion of matricellular proteins.  
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Modulation of the extracellular matrix (ECM) is a dynamic process. The ECM forms the structural 
components holding cells together in a tissue architecture but it has several functions beyond the 
cytoskeletal capacity. It serves as a reservoir for growth factors such as TGFβ, provides survival 
signals and inhibition signals via cell surface molecules such as integrins. TGFβ is secreted and 
bound to latent factors that are bound to the ECM until activated and liberated33. Integrins may 
also modulate TGFβ release34. Active signaling in this way is crucial in embryonic development, 
morphogenesis and wound healing35.  
In cancer, the extracellular signals that result in apoptosis or growth suppression from the ECM 
are perturbed. Growing tumors resist inhibitory growth signals and the local ECM is disrupted. 
Liberated factors and danger signals now available for recognition by innate immune cells cause 
a cascade of events analogous to wound healing23. Inflammation via activated macrophages set off 
a cascade inflammatory molecules that recruit further infiltration of neutrophils and immature 
myeloid cells to the area. Fibroblasts are also activated in this process and secrete TGFβ through 
autocrine and paracrine pathways. TGFβ induces production of ECM related genes including 
metalloproteinases (MMPs)36. Chronic remodeling without removal of the cancer trigger results 
in a perpetual cycle of remodeling. TGFβ secretion begets further TGFβ production and as a result, 
the TME is primed for angiogenesis, invasion, ECM breakdown and immune escape. 
The relationship between immune infiltrates and MSI-H in CRC is well established37. 
Immunotherapy with anti-PD1 therapy may have efficacy in this population38. Nivolumab and 
ipilumumab was well tolerated with a response rate of 33% in metastatic MSI-H CRC39. TGFβ, 
being a central determinant of an immune suppressive TME may be a key resistance mechanism 
in PDL1 therapy strategies40. It does so both directly on T cells to differentiate into Tregs or 
indirectly via attraction of immunosuppressive immature myeloid and MDSCs into the TME. 
Upregulation of TGF-β signaling has been associated with de novo resistance to anti-PD-1 
treatment in patients with metastatic melanoma and following development of acquired resistance 
to these agents following an initial response to therapy.  Given the ability of M7824 to sequester 
TGF-β in the circulation away from the TME, we hypothesize that M7824 may promote T cell 
effector function via disruption of PD-1/PD-L1 axis to enhance anti-tumor response following 
resistance to anti-PD-1/PD-L1 therapy in patients with MSI-H mCRC.  
The consensus molecular subtypes (CMS) are the best representation of the variation seen within 
CRC on the basis of gene expression41. Briefly, CMS1 is characterized by hypermutated tumors 
with immune infiltrates and often associated with MSI-H. Notably, MSI-H is a subset of CMS1 
and there is a proportion within this group that current biomarkers do not capture. CMS4 is a 
mesenchymal phenotype and is associated with a number of features associated with poor 
prognosis. Hallmark features of CMS4 include TGFβ activation, immune infiltration, EMT, matrix 
remodeling, and angiogenesis41. In contrast to CMS1, the immune infiltration displays a relative 
absence of cytotoxic T cells but a high proportion of tumor associated macrophages (TAMs)42. 
TGFβ signaling and immune suppression in the microenvironment are contributory factors to the 
aggressive biology that is reflected in the poor overall survival within this group. TGFβ activation 
conditions stroma at other sites to form metastatic niches that promote a receptive environment for 
circulating tumor cells or increases tumor initiating cell capacity in conjunction with fibroblast 
activation43. TGFβ inhibition with LY215299 in the TME prevented metastasis formation in 
patient derived tumor organoids44. Blocking TGFβ signaling may help reverse a number of key 
processes in the CMS4 poor prognosis group which include: reversing fibroblast activation, 
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removing tumor initiating capacity, reversing immature myeloid and MDSC infiltration and 
downregulating EMT. Given the role of inflammatory cells and TGFβ, M7824 may reprogram an 
inflammatory response that is immune suppressive to an immunogenic response.  
In a recent pilot study of patients with mCRC treated with M7824 monotherapy45, there were 22 
patients with adequate tumor tissue available for CMS subtyping.  Patients here had been permitted 
to enroll without prior knowledge of CMS status.  In this cohort, there were 10 patients with CMS4 
mCRC.  Only one of these ten patients demonstrated a radiographic response, which remained > 
6 months in duration.  Conclusions from this CMS4 cohort however were limited by the lack of 
available fresh paired tissue biopsies in order to understand better the intratumoral 
pharmacodynamics activity of M7824. 
Given the lack of activity noted with single-agent M7824 in the CMS4 CRC setting, additional 
interventions may boost the immunogenicity of these tumors in order to improve the anti-tumor 
responses.  Radiotherapy has been shown to induce tumor cell damage through apoptosis- and 
necrosis-induced mechanisms46-48, and augment exposure of more tumor-associated antigens for 
recognition by antigen-presenting cells and tumor attack by effector T cells49.  Radiated tumor 
cells promote release of danger-associated molecular patterns50, which likewise recruit more 
activated T cells to the tumor microenvironment.  In preclinical MC38 and CT26 models of 
colorectal cancer using immunocompetent mice, concomitant stimulation by immune checkpoint 
blockade agents may render these tumors more susceptible to disrupting the PD-1:PD-L1 axis in 
combination with radiotherapy51-54. 
TGF-β activation within the tumor microenvironment by cancer-associated fibroblasts promotes 
T cell exclusion in preclinical models of CRC akin to the CMS4 subtype55.  This may render 
immunotherapy agents ineffective in certain patients with MSS CRC if activated T cells are unable 
to penetrate intratumorally.  Indeed, knockdown of TGF-β activity microscopically in these 
preclinical models did not eradicate established MSS tumors, although T cells reflexively 
increased PD-L1 expression on the surface in response to TGF-β inhibition.  However, treatment 
with anti- TGF-β agents in the pre-metastatic setting (i.e., prior to development of exclusionary 
TGF-β activated stroma) decreased the onset of metastatic tumors for these models.  Recently, 
identification of micrometastases in patients with CRC has become more feasible due to the advent 
of circulating tumor DNA (ctDNA) technology.  Series of patients with non-metastatic and 
metastatic CRC alike have demonstrated resoundingly the strong association between CRC 
recurrence and the presence of ctDNA following curative resection56-58, with (+) ctDNA bearing a 
90-100% positive predictive value for the event of recurrent CRC, a surrogate for the presence of 
micrometastatic disease.  Applying these findings, it is possible then to treat patients with (+) 
ctDNA following resection of oligometastatic CRC and completion of standard-of-care 
chemotherapy in the absence of clinically/radiographically macroscopic disease elsewhere, who 
may have remnant microscopic disease that can be eradicated by dual PD-L1: TGF-β targeted 
therapies. 
Following on from the high response rates seen with PD-1 blockade in MSI-H mCRC, subsequent 
phase 2 studies have demonstrated impressive response rates in MSI-H tumors, irrespective of site 
of origin. A tumor agnostic phase 2 study enrolling patients with MSI-H metastatic tumors 
demonstrated an ORR of 53% and disease control rate of 77% with median PFS and OS not yet 
reached59. The cohort of 86 patients included CRC, neuroendocrine, ampulla of Vater, gastric, 
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pancreatic, prostate and cholangiocarcinomas. Predictive analysis using NGS from known 
databases across 32 different tumors suggests that the most common adenocarcinomas with a MSI-
H signature include endometrial, gastric, small intestinal, colon, rectum, cervical, prostate and 
neuroendocrine tumors. Ovarian and uterine sarcomas are the non-epithelial tumors expected to 
contain subsets of MSI-H. While only 4% of these tumors are stage IV, the number of tumors that 
display the MSI-H phenotype has led to an estimation of 20,000 patients in the US who would 
derive benefit in the advanced setting with PD-1 and immunotherapy treatments59.  
This clinical trial will be conducted in compliance with the clinical trial protocol, ICH GCP and 
any additional applicable regulatory requirements.  Based on the available nonclinical and clinical 
data to date, the conduct of the trial specified in this protocol is considered justifiable.  
2.2.6 
Summary of the Overall Benefit and Risk 
The risk-benefit ratio has been carefully considered in the planning of the trial. Based on the 
preclinical data available to date, the conduct of the trial is considered justifiable using the dose 
and schedule of M7824 as specified in this protocol. The trial will be discontinued in the event 
of any new findings that indicate a relevant deterioration of the risk-benefit ratio and would render 
continuation of the trial unjustifiable. The following are considered potential risks of exposure 
to M7824: 
• Infusion-related reactions including hypersensitivity 
• irAEs / autoimmune disorders 
• Anemia 
• Rash with hyperkeratosis, keratoacanthoma, and squamous cell carcinoma of the skin 
• Alterations in wound healing or repair of tissue damage 
• Embryofetal toxicities 
Respective safety measures that comprise inclusion / exclusion criteria for participation in clinical 
trials with M7824, guidance for prevention, monitoring, and medical management of potential 
risks, as well as guidance on study treatment interruption or discontinuation.  See Section 2.2.4 
for a summary of clinical safety findings. 
2.2.6.1 
Infusion-related Reactions / Hypersensitivity 
Infusion-related reactions hypersensitivity are a risk inherent to the administration of any 
recombinant protein to humans. Incidence of immunogenicity and character or severity of 
immunogenicity-induced side effects cannot be predicted by animal models because humanized 
or fully human proteins usually provoke a much stronger immune-response in rodents or non- 
human primates than in humans. The parent antibody (avelumab) caused lethal immune-mediated 
anaphylactic hypersensitivity reactions in mice after repeated application, while a control antibody 
lacking pharmacological activity only triggered a moderate immune reaction. However, in 
primates (cynomolgus monkeys), as a species closer to human, neither in the pilot 4-week IV 
repeat-dose toxicity trial nor in the pivotal 13-week IV infusion repeat-dose toxicity trial, clinical 
signs of hypersensitivity have been seen at dose levels of 20, 60, and 140 mg/kg, respectively. 
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As of 05 November 2014, from the EMR100070-001 trial with the parent avelumab antibody, 
1 subject (2.0%) in the dose-escalation cohort reported an infusion-related reaction event (Grade 2) 
and 49 (10.2%) of the 480 subjects in the expansion cohorts experienced at least 1 episode of an 
infusion-related reaction when receiving avelumab monotherapy. Most of the events were Grade 
1 (8 subjects, 1.7%) or Grade 2 (36 subjects, 7.5%) in intensity, and Grade 3 (3 subjects, 0.6%) 
or Grade 4 events (2 subjects, 0.4%) were less frequent. No Grade 5 events have been reported. 
Most of the infusion-related reaction events had an onset after the first (30 subjects, 6.3%) or 
second (16 subjects, 3.3%) avelumab infusion. In 8 subjects (1.7%), avelumab treatment was 
discontinued because of infusion-related reaction events. 
2.2.6.2 
Immune-related Adverse Events / Autoimmune Disorders 
Since inhibition of PD-L1 and TGFβ signaling stimulates the immune system, irAEs may occur.  
Treatment of irAEs is mainly dependent upon severity (NCI-CTCAE grade): 
• Grade 1 to 2:  treat symptomatically or with moderate dose steroids, more frequent monitoring 
• Grade 1 to 2 (persistent):  manage similar to high grade AE (Grade 3 to 4) 
• Grade 3 to 4:  treat with high dose corticosteroids 
Treatment of irAEs should follow guidelines set forth in Section 5.5.3.3:  
• Instructions for trial treatment discontinuation or interruption in case of irAEs / autoimmune 
disorders (see Section 5.5.3.3). 
 
• Guidance for the medical management of irAEs / autoimmune disorders including specific 
guidance with regard to the affected organ / body system (see Section 5.5.3.3). 
• irAEs / autoimmune disorders (any grade) are considered as AESIs requiring expedited 
reporting from the Investigator to Merck/EMD Serono. For non-serious AESIs, an AESI 
Report Form has to be completed; for serious events, an SAE Report Form has to be used. 
• Regular laboratory tests on parameters indicative for autoimmune disorders will be 
performed as detailed in the Schedules of Assessments (see Tables 1-3). 
• To help monitor for autoimmune effects, baseline ophthalmology examination including slit 
lamp inclusive of the anterior segment and including visual acuity. If clinically relevant eye 
signs or symptoms during the study, appropriate ophthalmology examination within 2 
days including slit lamp inclusive of the anterior segment and including visual acuity. 
2.2.6.3 
Anemia 
As the 4-week toxicology studies in cynomolgus monkeys demonstrated reversible decreases in 
red blood cell counts, as well as corresponding Hgb and hematocrit, anemia is considered a 
potential risk. Inclusion criteria for the study will require adequate entry Hgb value. Risk 
management measures are provided in Section 5.5.3.4. The amount of blood drawn during the 
study for non-essential biomarkers will be carefully considered, especially given the preclinical 
finding of reduced Hgb levels. 
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2.2.6.4 
Alterations in Wound Healing or Repair of Tissue Damage 
Alternations of wound healing and tissue damage repair are considered a potential risk given the 
TGFβ mechanism. Management should be discussed with the principal investigator on a case-
by-case basis. 
2.2.6.5 
Rash with Hyperkeratosis / Keratoacanthoma / Squamous 
Cell Carcinoma of the Skin 
Phase I information from a TGF antibody showed excess acanthomas, some with atypical features, 
and one confirmed squamous cell carcinoma5. A genetic disorder in the TGF pathway is also 
known to be associated with skin tumors12. Based on this information, skin tumors are considered 
a potential risk. Monitoring will include skin assessments as defined in the schedule of 
assessments (see Tables 1-3). Management should be discussed with the on a case-by-case basis. 
Dermatological consults should be requested as needed. Rash with hyperkeratosis / 
keratoacanthoma / squamous cell carcinoma of the skin are considered as AESIs requiring 
expedited reporting from the Investigator to the Merck/EMD Serono. Any suspicious lesion 
should be biopsied. For non-serious AESIs, an AESI Report Form has to be completed; for serious 
events, an SAE Report Form has to be used (see Section 6.4.1.2). 
2.2.6.6 
Embryofetal Toxicity 
Embryofetal toxicities are a known risk of the PD-1 / PD-L1 targeting class. Animal models link 
the PD-1 / PD-L1 signaling pathway with maintenance of pregnancy through induction of maternal 
immune tolerance to fetal tissue. Based on its mechanism of action (MoA), M7824 may cause 
fetal harm when administered to a pregnant female. An appropriate contraception warning is 
provided in this clinical protocol. Subjects with pregnancy or in lactation period are prohibited 
from being enrolled in clinical trials. 
2.2.6.7 
Potential Benefit 
In cohort A-C, patients will be selected based on MSI-H status and progression on prior immune 
checkpoint therapy on trial entry. Single agent responses to nivolumab in MSI-H mCRC have 
been updated in early key studies and range from 31%60 and 50%38. In a population in whom the 
anticipated response rate is high but who have progressed on therapy, M7824, which targets a 
possible immunotherapy resistance mechanism in the form of TGFβ upregulation, appears 
promising.  Beyond CRC, patients with MSI-H tumors who have progressed on prior 
immunotherapy will be enrolled. ORR and DCR to single agent pembrolizumab was 52% and 
77% respectively in a population that contained ampulla of Vater, duodenal, pancreatic, 
neuroendocrine, cholangiocarcinoma, gastric, ovarian cancers and uterine sarcomas59. Many of 
the these tumors lack effective salvage treatments and when considered in context of the response 
rates to single agent PD-1 blockade, targeting a potential resistance mechanism for potential 
durable responses with M7824 is a promising option. 
 
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In cohort B, patients with treatment-refractory CMS4 mCRC who have progressed on at least 
two standard-of-care options will be studied. M7824 has limited benefit as monotherapy in this 
setting. SBRT will be administered after a one dose lead-in of M7824.  Given the paucity of 
effective available therapies for patients with mCRC who have progressed on prior oxaliplatin-
based and irinotecan-based chemotherapy, the risk-benefit ratio in this population for M7824 is 
also favorable given the prognosis in this population and studies showing that SBRT to metastatic 
tumors have demonstrated ability to increase tumor-associated antigens and augment 
immunogenicity.  While SBRT is preferred, IMRT or 3D conformal techniques may be utilized 
at the discretion of the treating radiation oncologist depending on the dose to surrounding normal 
tissues.  Patient will receive a total dose of 24Gy over three days with one of the following 
modalities, at the discretion of the treating radiation oncologist: SBRT, IMRT and 3D conformal. 
In Cohort D, patients with MSS mCRC who have completed therapy following R0 resection with 
or without chemotherapy for removal of all clinically and radiographically evident macroscopic 
disease will be tested for the presence of ctDNA.  Given the correlation between detectable 
ctDNA and the presence of minimal residual disease, patients in this cohort are at high risk for 
recurrence. 
This clinical trial will be conducted in compliance with the clinical trial protocol, GCP (ICH Topic 
E6), and the applicable national regulatory requirements. 
3 
Trial Objectives 
3.1 
Primary Objective 
The primary objectives of this study are to estimate efficacy of M7824 with: 
o Objective response rate (ORR) in microsatellite instability-high (MSI-H) patients who 
have progressed on immune checkpoint blockade therapy (Cohort A-C). 
OR 
o ORR in patients with treatment-refractory, consensus molecular subtype 4 (CMS4) mCRC 
patients coadmnistered SBRT (Cohort B). While SBRT is preferred, IMRT or 3D 
conformal techniques may be utilized at the discretion of the treating radiation oncologist 
depending on the dose to surrounding normal tissues.  Patient will receive a total dose of 
24Gy over three days with one of the following modalities, at the discretion of the treating 
radiation oncologist: SBRT, IMRT and 3D conformal. 
OR 
o Clearance of ctDNA in ctDNA(+) patients with resected mCRC following completion of 
standard-of-care therapy (Cohort D). 
 
3.2 
Secondary Objectives 
To estimate progression-free survival (PFS) for M7824 in patients with: 
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o MSI-H solid tumors whose disease has progressed on prior immune checkpoint 
blockade therapy (Cohort A-C). 
OR 
o Treatment-refractory, CMS4 mCRC coadministered SBRT (Cohort B).  While SBRT 
is preferred, IMRT or 3D conformal techniques may be utilized at the discretion of the 
treating radiation oncologist depending on the dose to surrounding normal tissues.  
Patient will receive a total dose of 24Gy over three days with one of the following 
modalities, at the discretion of the treating radiation oncologist: SBRT, IMRT and 3D 
conformal. 
To estimate overall survival (OS) for M7824 in patients with: 
o MSI-H solid tumors who are refractory to prior immune checkpoint blockade therapy 
(Cohort A-C). 
OR 
o Treatment-refractory, CMS4 mCRC coadministered SBRT (Cohort B).  While SBRT 
is preferred, IMRT or 3D conformal techniques may be utilized at the discretion of the 
treating radiation oncologist depending on the dose to surrounding normal tissues.  
Patient will receive a total dose of 24Gy over three days with one of the following 
modalities, at the discretion of the treating radiation oncologist: SBRT, IMRT and 3D 
conformal. 
OR 
o ctDNA(+) resected mCRC following completion of standard-of-care therapy (Cohort 
D). 
To estimate disease-free survival (DFS) in patients with resected mCRC following standard-of-
care treatment (cohort D). 
To evaluate safety and tolerability of treatment with M7824 in patients with: 
o MSI-H mCRC who are refractory to prior immune checkpoint blockade therapy 
(Cohort A-C). 
OR 
o Treatment-refractory, CMS4 mCRC (Cohort B) 
OR 
o ctDNA(+) resected mCRC following completion of standard-of-care therapy (Cohort 
D). 
. 
3.3 
Exploratory Objectives 
 
1.  To evaluate intratumoral pharmacodynamic changes in immune populations using paired 
biopsies from patients with MSI-H solid tumors (Cohort A-C) or CMS4 mCRC treated with 
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M7824 and SBRT (Cohort B).  While SBRT is preferred, IMRT or 3D conformal techniques may be 
utilized at the discretion of the treating radiation oncologist depending on the dose to surrounding normal 
tissues.  Patient will receive a total dose of 24Gy over three days with one of the following modalities, at 
the discretion of the treating radiation oncologist: SBRT, IMRT and 3D conformal. 
2.  To characterize circulating immune cell populations and cytokine profiles in tumor and 
circulation following treatment with M7824.  
3.  To describe changes in levels of TGF-β following treatment with M7824. 
4.  To correlate the presence of microsatellite instability with CMS1 profile. 
5.  To correlate MSI-H and CMS4 to CpG island methylator phenotype (CIMP) status, KRAS and 
BRAF mutation status. 
6.  To quantify correlation with CMS4 and immune populations within tumor infiltrate. 
7.  To correlate anti-tumor response to M7824 with PD-L1 expression. 
8.  To conduct RNAseq, RNA Scope, WES targeted sequencing and tissue IO gene expression by 
Nanostring.   
9.  To evaluate novel markers in blood by liquid biopsy including, but not limited to, circulating-
free DNA (cfDNA), exosomes, and circulating tumor cells (CTC).   
10. To describe changes in microbiome profiling upon treatment with M7824 (with or without 
radiation). 
4 
Investigational Plan 
4.1 
Overall Trial Design and Plan 
4.1.1.1 
Cohort A-C – MSI-H solid tumors 
This is a phase Ib expansion study to assess efficacy of M7824 in patients with MSI-H solid tumors 
who have progressed on prior anti-PD-1/PD-L1 therapy. The hypothesis is that these patients will 
demonstrate anti-tumor response upon treatment with M7824.  Patients successfully enrolled will 
have had at least two doses of prior immune checkpoint therapy (anti-PD1, anti-PDL1 or anti-
CTLA4) with documented progression on CT or MRI imaging.  
M7824 will be administered intravenously at a dose of 1200mg every 14 days (-3/+1 day). M7824 
will be administered until documented PD, unacceptable toxicity, or withdrawal of informed 
consent. Tumor assessments will be performed every 8 weeks. Progressive disease, stable disease, 
partial response, and complete response will be defined by iRECIST 1.1.  Patients who discontinue 
due to toxicity will continue to be assessed via imaging until documented PD.  
4.1.1.2 
Cohort B – CMS4 mCRC 
This is a phase 2, single arm, Simon’s optimal two-stage design to assess ORR in treatment-
refractory CMS4 mCRC receiving M7824 with SBRT. The hypothesis is that efficacy of M7824 
coadministered with SBRT will be demonstrated in patients with CMS4 mCRC  
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Patients successfully enrolled will have had CMS4 classification after characterization of their pre-
treatment primary tissue biopsy.  M7824 will be administered intravenously at a dose of 1200mg 
every 14 days (+/- 7 days).  The first dose of M7824 will be administered alone.  After the second 
dose of M7824, patients will receive SBRT for a total dose of 24Gy over three days, with first 
treatment of radiotherapy administered within 7 days of completion of the second dose of M7824 
(cycle 1, day 15).  Radiotherapy must be completed prior to the third dose of M7824.  While SBRT 
is preferred, IMRT or 3D conformal techniques may be utilized at the discretion of the treating 
radiation oncologist depending on the dose to surrounding normal tissues.  Patient will receive a 
total dose of 24Gy over three days with one of the following modalities, at the discretion of the 
treating radiation oncologist: SBRT, IMRT and 3D conformal.  
M7824 will be continued until documented PD or unacceptable toxicity. Tumor assessments will 
be performed every 8 weeks. Progressive disease, stable disease, partial response, and complete 
response will be defined by iRECIST 1.1. Patients who discontinue due to toxicity will continue 
to be assessed via imaging until documented PD.  
4.1.1.3 
Cohort D – ctDNA(+) MSS mCRC following resection of 
metastatic disease 
This is a pilot study to assess the clearance of ctDNA with M7824 following R0 resection of 
metastatic disease in patients with MSS mCRC.  Patients with oligometastatic colorectal cancer 
must have undergone an R0 resection with no remnant clinically or radiographically evident 
disease.  The primary tumor must have also been resected, and patients must have completed all 
standard-of-care treatment for the primary tumor (e.g., chemoradiation for primary rectal cancer, 
adjuvant chemotherapy, etc) at the discretion of the treating physician. 
Following at least 14 days of completion of standard therapy, patients will be tested for the 
presence or absence of ctDNA.  Patients with a confirmed (+) ctDNA result will be allowed to 
proceed with M7824 treatment.   
M7824 will be administered intravenously at a dose of 1200 mg every 14 days (+/- 7 days).  ctDNA 
and CT scans will be repeated at 12 weeks.  Patients without evidence of clinical or radiographic 
progression will have the option to continue on treatment every 2 weeks with M7824, until the 
time of disease recurrence and/or progression, either radiographically or clinically.  Radiographic 
assessments will occur every 12 weeks thereafter, until disease progression or patient 
discontinuation on study. 
 
4.1.2 
Planned number of subjects 
4.1.2.1 
Cohort A-C – MSI-H solid tumors 
The planned number of subjects for this trial is 15 patients with MSI-H metastatic solid tumors. 
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4.1.2.2 
Cohort B – CMS4 mCRC 
In this Simon two-stage design, the planned number of subjects is 15 in the first stage. Should at 
least 2 patients demonstrate radiographic response (i.e. CR + PR), then 14 additional patients will 
be treated in the second stage, for a total of 29 patients.  If there is an anti-tumor signal in the 29 
patients with CMS4 metastatic CRC who are treated with this combination, then the study may be 
amended to expand patient selection across all CMS subgroups. 
. 
4.1.2.3 
Cohort D -- ctDNA(+) MSS mCRC following resection of 
metastatic disease  
The planned number of subjects for this cohort is 15 patients. 
4.1.3 
Planned treatment duration 
The trial duration for a subject is estimated to be up to 2 years. This includes an 28-day screening 
period (decision will be made in this period for subject’s trial inclusion if all eligibility criteria are 
met), a treatment duration until confirmed PD, unacceptable toxicity, or any criterion for 
withdrawal from the trial or IMP occurs (see Section 4.5) and an 28-Day Safety Follow-up visit 4 
weeks after the last dose of M7824 administration. 
Subjects who have experienced a durable, confirmed PR or CR may continue treatment for a 
maximum of 12 months, although additional treatment is possible. If the Investigator believes that 
a subject may benefit from treatment beyond 12 months, it may be permissible after discussion 
with the principal investigator. In the case of pseudoprogression, subjects should continue 
treatment through one additional tumor assessment, if they meet the criteria described in Section 
4.5.1. 
Adverse events (AEs) and adverse drug reactions (ADRs) should be followed until they resolve, 
return to baseline, or are irreversible (see Section 6.1.4 for details). 
In both cohorts, it is anticipated to enroll the first planned subject by October 2017, and the final 
subject enrolled by October 2018.  
4.1.4 
Dose 
Modification 
and 
ADRs 
Requiring 
Treatment 
Discontinuation 
4.1.4.1 
Dose Modification 
The dose of M7824 is 1200mg. Further details about discontinuation, withholding and restarting 
M7824 based on ADRs and AEs are presented in further detail in Section 5.5.3. 
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4.1.4.2 
Adverse 
Drug 
Reactions 
Requiring 
Treatment 
Discontinuation 
The following ADRs, defined as any AE assessed as related to M7824 by the Investigator and 
/ or Merck/EMD Serono, require permanent treatment discontinuation: 
Any Grade 4 ADRs require treatment discontinuation except for single laboratory values out of 
normal range that do not have any clinical correlate, and resolve to Grade ≤ 1 or Baseline grade 
within 14 days with adequate medical management. 
Any Grade 3 ADRs require treatment discontinuation except for any of the following: 
• Transient (≤ 6 hours) Grade 3 flu-like symptoms or fever, which is controlled with medical 
management. 
• Transient (≤ 24 hours) Grade 3 fatigue, local reactions, headache, nausea, emesis that 
resolves to ≤ Grade 1 or Baseline grade. 
• Tumor flare phenomenon defined as local pain, irritation, or rash localized at sites of known 
or suspected tumor. 
• Any Grade ≥ 3 drug-related amylase or lipase abnormality that is not associated with 
symptoms or clinical manifestations of pancreatitis. The study principal investigator should 
be consulted for such Grade ≥ 3 amylase or lipase abnormalities. 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 doses (28 days), the subject should 
permanently discontinue treatment with M7824. 
• 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.  
• Increases in Eastern Cooperative Oncology Group performance status (ECOG PS) ≥ 3 that 
resolves to ≤ 2 by Day 1 of the next cycle (infusions should not be given if the ECOG PS 
is ≥ 3 on the day of IMP administration and should be delayed until ECOG PS ≤ 2). 
Any Grade 2 ADR should be managed as follows: 
 
• If a Grade 2 ADR resolves to Grade ≤ 1 by the last day of the current cycle, treatment may 
continue. 
• If a Grade 2 ADR does not resolve to Grade ≤ 1 by the last day of the current cycle but it 
is manageable and / or not clinically relevant, the ADR should be discussed with the 
principal investigator and based upon discussion 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, discussion should be had with the principal investigator about permanently discontinuing 
treatment with M7824. 
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• Upon the second occurrence of the same Grade 2 ADR in the same subject (except for 
fatigue and hormone insufficiencies that can be managed by replacement therapy), 
continuation of treatment with M7824 has to be discussed with the principal investigator 
and might be permanently discontinued. 
• Infusion-related reactions and hypersensitivity reactions (Grades 1 to 4) should be handled 
according to the guidelines provided in Sections 5.5.3.1 and 5.5.3.2, respectively. 
• Anemia should be handled according to the guidelines provided in Section 5.5.3.4. 
4.1.5 
Analysis Cut-Off Dates 
4.1.5.1 
Cohort A-C 
The primary data cut-off for the analysis will be after 24 weeks after the last subject received 
M7824. 
The final data cut-off will be 1 year after the last subject has received the last dose of M7824. 
4.1.5.2 
Cohort B 
The first data cut-off for the interim analysis will be 12 weeks after the 15th subject enrolled has 
received study treatment. A decision to continue on to the target 29 patients will be based on the 
number of responses observed. If 2 or more confirmed responses are observed, the primary data 
cut-off for the analysis will be 24 weeks after the last subject (n=29) received study treatment. 
The final data cut-off will be 1 year after the last subject has received the last dose of M7824. 
4.1.5.3 
Cohort D 
The primary data cut-off for the analysis will be after 24 weeks after the last subject received 
M7824. 
The final data cut-off will be 1 year after the last subject has received the last dose of M7824. 
4.2 
Discussion of Trial Design 
4.2.1.1 
Cohort A-C 
This is a Phase Ib, open-label trial in patients with MSI-H metastatic solid tumors who have 
progressed on prior checkpoint inhibitor treatment. 
The study focuses on the subset of patients with metastatic solid tumors that has displayed higher 
responses rates to immune checkpoint blockade. Microsatellite instability is associated with higher 
immune infiltration61-63 .  One early study demonstrated that responders to the anti-PD-1 antibody, 
pembrolizumab, were restricted to MSI-H mCRC patients in comparison to non-MSI-H CRC38. 
Updated results from this study demonstrated RR of 50% and disease-control rate (DCR) of 89% 
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seen in MSI-H, compared to 0% and 16% in non-MSI-H mCRC patients, respectively59. 
Pembrolizumab has since received breakthrough designation by the FDA for approval in MSI-H 
solid tumors (including mCRC). In addition, PD-L1 expression was not associated with OS in this 
study and preliminary results from the Checkmate-142 trial, in which patients with mCRC were 
treated with the anti-PD-1 antibody nivolumab60. Therefore, using MSI-H as the current selection 
biomarker for this study is appropriate. 
MSI-H non-CRC tumors have demonstrated impressive ORR of 53% with PD-1 blockade in a 
variety of tumors was 53% and DCR of 77% with median PFS and OS not being met59. Given the 
mechanism of M7824, use of MSI-H as a biomarker as already demonstrated is appropriate to 
enrich for likely responders while selection based on prior progression following checkpoint 
immunotherapy approaches ensures targeting of a potential resistance mechanism.   
 
4.2.1.2 
Cohort B 
This is a phase II, single arm, Simon two-stage design to assess efficacy of M7824 as an abscopal 
phenomenon with radiation to a single metastatic lesion in patients with treatment-refractory, 
CMS4 mCRC receiving M7824. Tumors ≥ 7.0 cm in largest diameter should be excluded from 
receiving radiation as part of this study. As previously described, TGFβ represents an immune 
resistance mechanism via recruitment of immunosuppressive cells and downregulation of existing 
anti-tumoral responses within the TME. TGF-β signaling may also promote resistance to an 
abscopal phenomenon in patients with mCRC administered immunotherapy with radiation.  The 
trial design is also justified based on pre-clinical evidence that CMS4 mCRC demonstrate an 
intrinsically inflamed, immunosuppressive phenotype mediated by upregulation of TGF-β 
signaling.  
Restriction in this study to CMS4 comes from a number of preclinical studies implicating it with 
upregulation of TGF-β activation43,64,65. Several of the hallmark features including EMT, stromal 
infiltration, angiogenesis and matrix remodeling are explained by some of the pleotropic effects of 
TGF-β. TGFβ represents an immune resistance mechanism via recruitment of immunosuppressive 
cells and downregulation of existing anti-tumoral responses within the TME26,66. CMS4 is 
associated with poorer cancer specific outcomes and non-benefit to current adjuvant chemotherapy 
strategies3, and therefore novel effective therapies ae needed for this subpopulation of mCRC.   
4.2.1.3 
Cohort D 
This is a pilot study of M7824 in patients with MSS mCRC who have detectable ctDNA following 
R0 resection of metastatic disease.  The inevitability of disease recurrence for patients with 
colorectal cancer, as seen in the presence of ctDNA following resection of CRC,suggests existence 
of micrometastatic minimal residual disease in these cases.  Given that macroscopic metastases 
may use TGF-β signaling to exclude anti-tumor immune cells from the microenvironment, limiting 
selection of patients with micrometastatic disease may identify a subpopulation of mCRC patients 
that selectively benefit from immunotherapy. 
 
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4.2.2 
Inclusion of Special Populations 
Not applicable. 
4.3 
Selection of Trial Population 
4.3.1 
Inclusion criteria  
 
1. Histologically or cytologically confirmed adenocarcinoma of the colon or the rectum that 
is metastatic or unresectable (cohort B); or histologically or cytologically confirmed 
adenocarcinoma of the colon or the rectum following resection of the primary tumor and 
metastatic disease, following completion of standard-of-care perioperative therapy at the 
discretion of the treating provider (cohort D). 
2. Confirmation of: 
a. Cohort A-C: microsatellite instability  
b. Cohort B: CMS4 CRC classification on pretreatment primary tumor. 
c. Cohort D: microsatellite stability 
3. Age >18 years at time of study entry. 
4. Ability to provide written informed consent. 
5. Documented progression to prior therapies (Cohorts A-C and B): 
a. Cohort A-C: Disease progression following prior immune checkpoint blockade 
therapy  
b. Cohort B: Progression or intolerance to at least 2 prior lines of standard therapy 
for unresectable or metastatic CRC 
6. Available primary tumor tissue for CMS4 biomarker assessment (cohort B) 
7. Life expectancy ≥12 weeks as judged by the treating physician. 
8. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. 
9. Measurable disease according to iRECIST v1.1 (Cohorts A-C and B). For cohort B, 
measureable lesions must be identified apart from the irradiated tumor lesion.  Patients in 
cohort D must have no evidence of radiographically evident disease at the time of study 
entry. 
10. Adequate hematological function, defined by ANC ≥ 1.0 × 109/L, lymphocyte count ≥ 
0.5 × 109/L, platelet count ≥100 × 109/L, and Hgb ≥ 9 g/dL (in absence of blood 
transfusion). 
11. Adequate hepatic function defined by a total bilirubin level ≤ 1.5 × the upper limit of 
normal (ULN), an AST level ≤ 2.5 × ULN, and an ALT level ≤ 2.5 × ULN.  If liver 
metastases are present, then it is acceptable for AST level ≤ 5.0 × ULN, and an ALT level 
≤ 5.0 × ULN. 
12. International normalized ratio (INR) < 1.5 
13. Adequate renal function defined by an estimated creatinine clearance >30 mL/min 
according to the Cockcroft-Gault formula or be measure for creatinine clearance from 24 
hour urine collection. 
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14. Highly effective contraception for both male and female subjects if the risk of conception 
exists. Highly effective contraception must be used 30 days prior to first trial 
administration, for the duration of trial treatment, and at least for 4 months after stopping 
trial treatment (see Appendix 2 for further details). Should a woman become pregnant or 
suspect she is pregnant while she or her partner is participating in this trial, the treating 
physician should be informed immediately. 
15. Ability to tolerate receipt of radiotherapy to a metastasis not adjacent to a normal dose-
limiting structure, at the discretion of the treating radiation oncologist (cohort B). 
16. Presence of detectable ctDNA following completion of R0 resection with or without 
perioperative therapy (cohort D only). 
17. Completion of all standard-of-care adjuvant therapy (cohort D). 
4.3.2 
Exclusion criteria 
1. Concurrent treatment with non-permitted drugs and other interventions. 
2. Anticancer treatment within 14 days before the start of trial treatment [e.g., cytoreductive 
therapy, radiotherapy (with the exception of palliative radiotherapy delivered in a normal 
organ-sparing technique), immune therapy, or cytokine therapy]. 
3. Major surgery as determined by the investigator within 28 days before the start of trial 
treatment (prior diagnostic biopsy is permitted).  
4. Systemic therapy with immunosuppressive agents within 7 days before the start of 
treatment; or use of any investigational drug within 28 days before the start of trial 
treatment. 
5. Cohort A-C only: Intolerance or serious adverse immune related adverse events (irAEs) 
[refer to section 5.5.3.3] that were symptomatic or required or continues to require 
ongoing immunosuppression to previous immune checkpoint therapy. 
6. Cohorts B and D: prior exposure to any immune checkpoint blockade agent or any other 
immunomodulatory agent used for antineoplastic therapy for mCRC. 
7. Previous malignant disease (other than the target malignancy to be investigated in this 
trial) within 3 years prior to study treatment initiation. Other Lynch syndrome cancers do 
not exclude patients from participating on study, at the discretion of the Principal 
Investigator.  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 
treated with curative intent are NOT excluded. Subjects with other localized malignancies 
treated with curative intent need to be discussed with the Principal investigator. 
8. Subjects with active central nervous system (CNS) metastases are excluded. Subjects 
with a history of treated CNS metastases (by surgery or radiation therapy) are not eligible 
unless they have fully recovered from treatment, demonstrated no progression for at least 
2 months, and do not require continued steroid therapy. 
9. Receipt of any organ transplantation, including allogeneic stem-cell transplantation, but 
with the exception of transplants that do not require immunosuppression (e.g., corneal 
transplant, hair transplant). 
10. Significant acute or chronic infections including, among others:  
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a. Known history of testing positive test for human immunodeficiency virus (HIV) 
or known acquired immunodeficiency syndrome. 
b. HBV or HCV infection (HBV surface antigen positive and HBV core antibody 
positive with reflex to positive HBV DNA or HBV core antibody positive alone 
with reflex to positive HBV DNA or positive HCV antibody with reflex to 
positive HCV RNA). 
c. Subjects with active tuberculosis (history of exposure or history of positive 
tuberculosis test plus presence of clinical symptoms, physical or radiographic 
findings). 
11. Active autoimmune disease that might deteriorate when receiving an immunostimulatory 
agent: 
a. Subjects with type I diabetes, vitiligo, alopecia, psoriasis, hypo- or hyperthyroid 
disease not requiring immunosuppressive treatment are eligible 
b. Subjects requiring hormone replacement with corticosteroids are eligible if the 
steroids are administered only for the purpose of hormonal replacement and at 
doses ≤ 10mg of prednisone or equivalent per day. 
c. Administration of steroids for other conditions through a route known to result in 
a minimal systemic exposure (topical, intranasal, intro-ocular, or inhalation) is 
acceptable. 
12. Known severe hypersensitivity reactions to monoclonal antibodies (Grade ≥ 3 NCI-
CTCAE v4.03), any history of anaphylaxis, or recent (within 5 months) history of 
uncontrolled asthma. 
13. Persisting toxicity (except alopecia and vitiligo) related to prior oncologic therapy Grade 
>1 NCI-CTCAE v4.03, however, sensory neuropathy Grade ≤ 2 is acceptable. 
14. 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. 
15. Clinically relevant diseases (for example, inflammatory bowel disease) and / or 
uncontrolled medical conditions, which, in the opinion of the Investigator, might impair 
the subject’s tolerance or ability to participate in the trial. 
16. Vaccine administration within 4 weeks of M7824 administration. Vaccination with live 
vaccines while on trial is prohibited. Administration of inactivated vaccines is allowed 
(for example, inactivated influenza vaccines). 
17. Cohort D: peritoneal carcinomatosis. 
 
4.3.3 
Screening Eligibility (cohort B) 
Patients are eligible for screening for CMS subtyping prior to enrollment on cohort B provided 
that the following elibility criteria are met: 
• Histologically or cytologically confirmed adenocarcinoma of the colon or the rectum that 
is metastatic or unresectable. 
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• Progression on at least one prior line of systemic therapy for metastatic disease.  
• Prior tissue sampling of primary tumor with core biopsy, endoscopic biopsy, or surgical 
resection to be used for CMS subtype testing. 
4.4 
Criteria for Initiation of Trial Treatment 
The inclusion and exclusion criteria will be checked at the Screening visit. Eligible subjects will 
be enrolled before treatment start after verification of fulfilling all inclusion criteria and satisfy no 
exclusion criteria. Documentation of satisfaction of eligibility criteria for each patient will be 
performed within CORe. 
4.5 
Criteria for Subject Withdrawal 
4.5.1 
Withdrawal from Trial Treatment  
 
Subjects will be withdrawn from trial treatment for any of the following reasons: 
• PD as defined by iRECIST 1.1 
o Patients may continue on M7824 until immune confirmed PD (iCPD) provided they 
meet the criteria for pseudoprogression (see 5.5.1.1 below) 
• Therapeutic failure requiring urgent additional cancer therapy 
• Occurrence of any Grade ≥ 3 ADRs or repetitive Grade 2 ADRs as defined in Section 
5.5.3.3. 
• Occurrence of AEs, at the Investigator’s discretion 
• Pregnancy 
• Use of prohibited concomitant drug, as defined in Section 5.5.2, where the predefined 
consequence is withdrawal from the IMP 
• Non-adherence / non-compliance to the trial protocol or trial requirements (see Section 5.9) 
• Withdrawal of consent 
• Participation in any other trial 
4.5.1.1 
Pseudoprogression 
Pseudoprogression is defined as an initial disease flare followed by a delayed disease response. At 
the time of progression, there is no definitive way to distinguish this from true progressive disease 
without a confirmatory scan. 
 
To account for pseudoprogression, patients will have PD, SD, PR or CR recorded as defined by 
iRECIST 1.1. However, PD will require a subsequent scan at the next planned tumor assessment 
in 8 weeks or earlier if clinically indicated. Patients will be allowed to continue on M7824 despite 
first documentation of PD if: 
o No new Grade 2 or greater severity of symptoms or significant worsening of existing 
symptoms 
o No decrease in ECOG PS 
o In the opinion of the Investigator, the subject does not require new anticancer therapy. 
 
Failure to satisfy all of these conditions results in discontinuation of M7824.  
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Confirmed PD on the subsequent scan also results in study discontinuation.  
 
The time point for PD will be taken from the first noted date and not the time of the confirmation 
scan. 
 
4.5.2 
Withdrawal from the Trial  
Subjects may withdraw from the trial at any time without giving a reason. Withdrawal of consent 
will be considered withdrawal from the trial. If a subject withdraws participation while on study, 
survival information may still be collected via phone calls, electronic communication, letters or 
publically available records.  
A subject must be withdrawn if any of the following occur during the trial: 
• Withdrawal of the subject’s consent 
• Participation in any other therapeutic trial during the treatment duration of this trial; 
however, subjects will continue to be followed for survival 
If a subject fails to attend scheduled trial assessments, the Investigator must determine the reasons 
and the circumstances as completely and accurately as possible. 
In case of withdrawal from the trial, the assessments scheduled for the last visit (28-Day Safety 
Follow-up visit) should be performed (see Section 6.1.3), if possible, with focus on the most 
relevant assessments. In any case, the appropriate 28-Day Safety Follow-up electronic case report 
form (eCRF) in the Prometheus database visit must be completed. In case of withdrawal, subjects 
will be asked to continue safety and survival follow-up, which includes the collection of data on 
survival and subsequent anticancer therapy. After completion of the Follow-up period or after the 
End of Treatment visit, whatever is applicable, the appropriate eCRF section for Trial Termination 
must be completed in the Prometheus database. 
If a subject is withdrawn prior to PD for any reason the subject will not be replaced.  
4.6 
Premature Termination of the Trial 
For either cohort, the trial may be discontinued prematurely in the event of any of the following: 
New information leading to unfavorable risk-benefit judgment of the IMP, for example, due to 
1. Evidence of inefficacy of the IMP, 
2. Occurrence of significant previously unknown adverse reactions or unexpectedly high 
intensity or incidence of known adverse reactions, or  
3. Other unfavorable safety findings. 
(Note: Evidence of inefficacy may arise from this trial or from other trials; unfavorable 
safety findings may arise from clinical or non-clinical examinations, for example, 
toxicology.) 
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• Merck/EMD Serono or the IND Office’s decision that continuation of the trial is 
unjustifiable for medical or ethical reasons. 
• Poor enrollment of subjects making completion of the trial within an acceptable time frame 
unlikely. 
• Discontinuation of development of the Merck/EMD Serono’s IMP. 
Health Authorities and Independent Ethics Committees (IECs) / Institutional Review Boards 
(IRBs) will be informed about the discontinuation of the trial in accordance with applicable 
regulations. 
The whole trial may be terminated or suspended upon request of Health Authorities. 
4.7 
Definition of End of Trial 
If the trial is not terminated for a reason given in Section 4.6, the end of the trial is defined as 1 
year after the last subject receives the last dose of M7824. 
5 
Investigational Medicinal Product and Other Drugs Used in 
the Trial 
The term “Investigational Medicinal Product” (IMP) refers to an active substance or a placebo 
being tested or used as a reference therapy in a clinical trial, including products that have a 
marketing authorization but are formulated, packaged, or administered differently from the 
authorized form, used for an unauthorized indication, or used to gain further information about the 
authorized form. The only IMP used in this trial is M7824. 
5.1 
Description of the Investigational Medicinal Product 
M7824 drug product is a sterile, freeze-dried formulation presented at a concentration of 600 
mg/vial in United States Pharmacopeia (USP) type I glass vial closed with a rubber stopper and 
sealed with an aluminum plastic crimping cap. 
Each vial contains 600 mg of M7824 as a preservative-free histidine-buffered solution (pH=5.5) 
containing trehalose dihydrate, sodium chloride, L-methionine and polysorbate 20 (Tween 20). 
Only excipients that conform to the current USP are used for M7824 drug product. 
5.2 
Dosage and Administration 
5.2.1 
M7824 Administration 
Subjects will receive IV infusion of M7824 over 1 hour (-10 minutes / +20 minutes) once every 2 
weeks as detailed in the Schedules of Assessments (see Tables 1-3). Modifications of the infusion 
rate due to infusion-related reactions are described in Section 5.5.3.1.  
The dose for M7824 is 1200mg. In cohorts A-C and B, subjects will receive M7824 once every 2 
weeks until confirmed progression, unacceptable toxicity, or any criterion for withdrawal from the 
trial or IMP occurs (see Section 4.5). Subjects who have experienced a persistent, confirmed PR 
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or CR may continue treatment through the end of 12 months, although additional treatment is 
possible. If the Investigator believes that a subject may benefit from treatment beyond 12 months, 
it may be permissible after discussion with the principal investigator.  In cohort D, patients will 
receive M7824 for 6 doses.  After 6 doses, the patient will have blood checked for ctDNA 
clearance.  If there is no evidence of radiographic or clinical progression, then the patient may 
continue on study at the discretion of the investigator. 
For subjects who achieve a PR or CR on M7824 therapy and then subsequently develop disease 
progression after stopping therapy, but prior to the end of the trial, a re-initiation course of 
treatment at the same dose and schedule and treatment duration up to 12 months is allowed at the 
discretion of the Investigator and agreement of the trial principal investigator. Subjects re-initiating 
treatment should be assessed according to the Schedules of Assessment of the trial starting at Week 
1, Day 1 (see Tables 1-3). 
5.2.2 
Radiotherapy (cohort B only) 
Radiation therapy will be delivered to a single metastatic lesion, with total dose of 24 Gy in 3 daily 
fractions of 8 Gy each.  Radiation therapy will be delivered on consecutive business days.  All 3 
fractions will be administered after the second dose of M7824 and prior to the administration of 
the third dose of M7824. 
Patients will undergo CT simulation, with or without IV contrast.   The gross tumor volume (GTV) 
will include a single metastatic lesion.  The metastatic lesion to be irradiated must not be adjacent 
to a dose-limiting normal structure (e.g., heart, bowel) at the discretion of the treating radiation 
oncologist.  The planning target volume (PTV) will include the GTV with a 5-7 mm margin in all 
directions.  For lesions affected by respiratory motion, appropriate motion management techniques 
should be used, such as inspiratory breathhold.  Daily volumetric imaging with cone beam CT 
(CBCT) or CT on rails (CTOR) will be used for image guidance.   
 
5.3 
Assignment to Treatment Groups 
Not applicable 
5.4 
Noninvestigational Medicinal Products to be Used 
In order to mitigate potential infusion-related reactions, premedication with an antihistamine (e.g., 
25-50 mg PO at the discretion of the investigator) and with acetaminophen (e.g., 325-650 mg PO 
at the discretion of the investigator) approximately 30 to 60 minutes prior to each dose of M7824 
is mandatory for the first 2 infusions and is optional and at the discretion of the Investigator starting 
with the third infusion. If Grade ≥ 2 infusion reactions are seen during the first two infusions, then 
premedications should not be stopped. Steroids as premedication are not permitted. Special 
precautions for monitoring of subjects and management of infusion-related reactions / 
hypersensitivity including modifications of the infusion rate and stopping of trial drug are 
described in Section 5.5.3 and subsections. As with all monoclonal antibody therapies, there is a 
risk of allergic reaction including anaphylactic shock. M7824 should be administered in a setting 
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that allows for immediate access to an intensive care unit or equivalent environment and 
administration of therapy for anaphylaxis, such as the ability to implement immediate resuscitation 
measures. Steroids (dexamethasone 10 mg IV), epinephrine (1:1,000 dilution), allergy medications 
(IV antihistamines), bronchodilators, or equivalents, and oxygen should be available for immediate 
access in the event of an anaphylactic reaction. Infusion of M7824 will be stopped in case of Grade 
≥ 2 infusion-related, allergic, or anaphylactic reactions. Following M7824 infusions, subjects must 
be observed for a minimum of 2 hours post end of infusion for potential infusion-related reactions. 
Please see the guidelines for handling of infusion-related reaction in Section 5.5.3.1. 
If an allergic reaction occurs, the subject must be treated according to the best available medical 
practice. Guidelines for management of infusion-related reactions and severe hypersensitivity 
reaction according to the National Cancer Institute are found in Section 5.5.3. 
Further precautions are provided in Section 5.5.3.2. For prophylaxis of flu-like symptoms, a non-
steroidal anti-inflammatory drug (NSAID) for example, 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. 
5.5 
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 (Prometheus) and 
medical record, 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 (Prometheus) and medical record. 
5.5.1 
Permitted Medicines 
Any medications (other than those excluded by the clinical trial protocol) that are considered 
necessary to protect subject welfare and will not interfere with the trial medication may be given 
at the Investigator’s discretion. 
Other drugs to be used for prophylaxis, treatment of anaphylactic reactions, infusion-related 
reactions, and severe hypersensitivity reactions / flu-like symptoms and irAEs are described in 
Section 5.5.3. 
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. 
5.5.2 
Prohibited Medicines 
As stated for the exclusion criteria in Section 4.3.2, subjects must not have had chemotherapy, 
radiotherapy (other than palliative radiotherapy delivered in a normal organ-spearing technique as 
described in Section 5.5.1), major surgery, or received another investigational agent within 28 days 
before the start of trial treatment. 
The following treatments must not be administered during the trial: 
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• Immunotherapy 
including 
interferon, 
immunosuppressive 
drugs 
(for 
example, 
chemotherapy or systemic corticosteroids except for short term treatment of allergic 
reactions, endocrine replacement therapy at low dose prednisone [≤ 10 mg daily] or 
equivalent, or for the treatment of irAEs or other appropriate short term steroid use), or 
other experimental pharmaceutical products. Short term administration of systemic steroid 
or other immunosuppressant such as infliximab or mycophenolate (that is, for allergic 
reactions or the management of irAEs) is allowed. Steroids with no or minimal systemic 
effect (topical, inhalation) are allowed. Note: for subjects with glioblastoma, steroid use is 
allowed. 
• Adefovir. 
• Prophylactic use of corticosteroids for infusion related reactions is prohibited. 
• Any live vaccine therapies for the prevention of infectious disease. Administration of 
inactivated vaccines is allowed (for example, inactivated influenza vaccines). 
• Blood transfusions and erythroid growth factors are permitted for Hgb ≤ less 7 g/dL and/or 
for life threatening bleeding 
If the administration of a non-permitted concomitant drug becomes necessary during the trial, the 
subject will be withdrawn from trial treatment (the Principal investigator may be contacted to 
discuss whether the IMP must be discontinued). 
Medications other than those specifically excluded in this trial (as outlined in this section) may be 
administered for the management of symptoms associated with the administration of M7824 as 
required. These might include analgesics, anti-emetics, antihistamines, diuretics, anti-anxiety 
medications, and medication for pain management, including narcotic agents. 
Any additional concomitant therapy that becomes necessary during the trial and any change to 
concomitant drugs must be recorded in the corresponding section of the eCRF (Prometheus) and 
medical record, noting the name, dose, duration, and indication of each drug. 
The following non-drug therapies must not be administered during the trial (and within 28 days 
before the start of trial treatment): 
• Major surgery (excluding prior diagnostic biopsy). 
• Herbal remedies with immunostimulating properties (for example, mistletoe extract) or 
known 
• to potentially interfere with major organ function (for example, hypericin) 
• Subjects should not abuse alcohol or other illicit drugs during the trial 
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5.5.3 
Special Precautions 
As a routine precaution, subjects all enrolled in this trial must be observed for 2 hours in the CTRC 
post end of infusion, in an area with resuscitation equipment and emergency agents at least for the 
first two doses of treatment with M7824. If no medical problems arise during the first two 
treatments, then the 2 hour observation period does not need to continue starting with the third 
dose of treatment. At all times during M7824 treatment, immediate emergency treatment of an 
infusion-related reaction or a severe hypersensitivity reaction according to institutional standards 
must be assured. In order to treat possible anaphylactic reactions, for instance, dexamethasone 10 
mg and epinephrine in a 1:1000 dilution or equivalents should always be available along with 
equipment for assisted ventilation. 
Infusion of M7824 will be stopped in case of Grade ≥ 2 hypersensitivity, inflammatory response, 
or anaphylactic reaction. The treatment recommendations for infusion-related reactions and severe 
hypersensitivity reactions according to the NCI are outlined in Sections 5.5.3.1 and 5.5.3.2, 
respectively. 
Investigators should also monitor subjects closely for potential irAEs (described in Section 
5.5.3.3), 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. 
5.5.3.1 
Infusion-related reactions 
IRRs are defined as any signs or symptoms experienced by participants during the infusion of 
pharmacologic or biologic agents or any event occurring during or within 1 day of drug 
administration. IRRs are common ADRs with monoclonal antibodies timely related to drug 
administration and have been reported as anaphylaxis, anaphylactoid reactions, and cytokine 
release syndrome, among other terms used. IRRs are important identified risks (adverse reactions) 
for M7824, and the precautions and management are provided in Table 46 
A. Signs and symptoms of infusion related reactions (IRRs) including hypersensitivity include 
but not limited to pyrexia, chills, flushing, hypotension, dyspnea, wheezing, back pain, 
abdominal pain, and urticaria, were reclassified as important identified risks (adverse 
reactions). 
B. Management  
Table 6: Treatment Modification for Symptoms of Infusion-related Reactions Caused by 
M7824 
NCI-CTCAE Grade 
Treatment Modification for M7824 
Grade 1 – mild 
• 
Mild transient reaction; infusion interruption 
not indicated intervention not indicated. 
• 
Decrease the M7824 infusion rate by 50% and 
monitor closely for any worsening. 
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• 
The total infusion time for M7824 should not 
exceed 120 minutes 
Grade 2 – moderate 
• 
Therapy or infusion interruption indicated but 
responds promptly to symptomatic treatment 
(for 
example, 
antihistamines, 
NSAIDs, 
narcotics, IV fluids); prophylactic medications 
indicated for ≤ 24 hours. 
• 
Stop M7824 infusion. 
• 
Resume infusion at 50% of previous rate once 
infusion-related reaction has resolved or 
decreased to at least Grade 1 in severity, and 
monitor closely for any worsening 
Grade 3 or Grade 4 – severe or life-threatening 
• 
Grade 3: Prolonged (for example, not rapidly 
responsive to symptomatic medication and / or 
brief interruption of infusion); recurrence of 
symptoms following initial improvement; 
hospitalization indicated for clinical sequelae. 
• 
Grade 
4: 
Life-threatening 
consequences; 
urgent intervention indicated. 
• 
Stop the M7824 infusion immediately and 
disconnect infusion tubing from the subject.  
• 
Subjects have to be withdrawn immediately 
form M7824 treatment and must not receive 
any further M7824 treatment 
IV = intravenous; NCI-CTCAE = National Cancer Institute – Common Terminology Criteria for Adverse Event; 
NSAIDs = nonsteroidal anti-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 7 (including reducing the infusion rate by 
50%), the Investigator may consider treatment with corticosteroids and the infusion of IMP should 
be stopped for that day. At the next infusion, the Investigator may consider the addition of H2-
blocker antihistamines (for example, famotidine or ranitidine), in addition to premedication, for 
select subjects. However, prophylactic steroids are NOT permitted. If the subject has a second 
infusion-related reaction Grade ≥ 2 on the slower infusion rate, with or without the addition of 
further medication to premedication, the infusion should be stopped and the subject removed from 
M7824 treatment. 
5.5.3.2 
Severe Hypersensitivity Reactions and Flu-like Symptoms 
If a hypersensitivity reaction occurs, the subject must be treated according to the best available 
medical practice. A complete guideline for the emergency treatment of anaphylactic reactions 
according to the Working Group of the Resuscitation Council (United Kingdom) and can be found 
at https://www.resus.org.uk/pages/reaction.pdf. Subjects should be instructed to report any 
delayed reactions to the Investigator immediately. 
A. Symptoms 
• Impaired airway 
• Decreased oxygen saturation (< 92%) 
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• Confusion 
• Lethargy 
• Hypotension 
• Pale / clammy skin 
• Cyanosis 
B. Management 
1. Epinephrine injection and IV dexamethasone 
2. Patient should be placed on cardiac, blood pressure, heart rate, and oxygen saturation 
monitor immediately 
3. Alert intensive care unit for possible transfer if required 
For prophylaxis of flu-like symptoms, a NSAID, for example, 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. 
5.5.3.3 
Immune-Related Adverse Events 
For reporting irAE severity/toxicity grading, refer to CTCAE v4.03 toxicity grading system. 
For treatment management of irAE per CTCAE v4.03 criteria, refer to American Society of 
Clinical Oncology (ASCO) Clinical Practice Guidelines and National Comprehensive Cancer 
Network irAE Management Guidelines. 
Treatment of irAEs is mainly dependent upon severity as defined by NCI-CTCAE v4.03. In 
general, management by CTCAE v4.03 grading, as per ASCO, is listed below: 
• Grade 1: study treatment should be continued with close monitoring, with the exception of some 
neurologic, hematologic, and cardiac toxicities.  
• Grade 2: study treatment may be suspended for most Grade 2 toxicities, with consideration of 
resuming when symptoms revert to Grade 1 or less. Corticosteroids may be administered (initial 
dose of 0.5 to 1 mg/kg/day of prednisone or equivalent).  
• Grade 3: study treatment is generally suspended and the high-dose corticosteroids (prednisone 
1 to 2 mg/kg/day or methylprednisolone 1 to 2 mg/kg/day) treatment should be initiated. 
Corticosteroids should be tapered over the course of at least 4 to 6 weeks. Some refractory cases 
may require infliximab or other immunosuppressive therapy.  
• Grade 4: in general, permanent discontinuation of study treatment is recommended, with the 
exception of endocrinopathies that have been controlled by hormone replacement. 
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Since inhibition of PD-L1 stimulates the immune system, irAEs may occur. Treatment of irAEs is 
mainly dependent upon severity (NCI-CTCAE grade): 
• Grade 1 to 2: treat symptomatically or with moderate dose steroids, more frequent 
monitoring 
• Grade 1 to 2 (persistent): manage similar to high grade AE (Grade 3 to 4) 
• Grade 3 to 4: treat with high dose corticosteroids 
Treatment of irAEs should follow guidelines set forth in the ASCO/NCCN Management of 
Immunotherapy-Related Toxicities 
(https://www.nccn.org/professionals/physician_gls/pdf/immunotherapy.pdf). 
5.5.3.4 
Anemia 
Anemia is considered a potential risk based on toxicological findings with M7824 in cynomolgus 
monkey indicating a decrease in Hgb, RBCs, and hematocrit that was fully reversible or showed a 
substantial trend toward recovery. Notably, there are many reasons for anemia in patients with advanced 
cancer, which is why a thorough investigation of new anemia cases of unspecified etiology is requested.  
 Risk management measures in addition to routine laboratory tests will include: 
• Subjects must enter the study with Hgb values at least 9 g/dL, independent of recent (≤ 28 
days) packed red blood cell transfusion and/or use of an erythropoietin-stimulating agent. 
• Routine monitoring of Hgb will be performed every 2 weeks (prior to treatment). 
o Instructions for study treatment discontinuation or modification in case of anemia 
will be provided, briefly described here: 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); Hgb and hematocrit are to be closely monitored. 
 
• 
For new anemia events assessed as treatment-related, items queried may include but are not 
limited to detailed relevant past medical and treatment history, bruising tendency, history of 
blood transfusions and/or dependency, and a request for an updated eCRF including details such 
as concomitant medications, all laboratory data, updated dosing information and recent tumor 
evaluation scans. 
• If a subject experiences significant anemia, then the amount of blood to be drawn may be 
reduced by not taking blood at selected time points for PD-L1 target occupancy, 
immunomonitoring, soluble factors, and TGFβ. The decision to reduce the time points for 
these biomarkers will be taken by the Investigator in consultation with the principal 
investigator.  
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• 
Evaluation Guidance of  baseline anemia and Suspected Treatment-related Anemia AEs 
Baseline anemia evaluation (prior to transfusion, if feasible) 
Hb and CBC with differential (e.g. MCV, RDW, ANC, hematocrit, reticulocytes counts) 
Peripheral blood smear for cell morphological assessment 
Complete metabolic panel including liver panel-LFTs, bilirubin, LDH, renal function, and serum folate, B12 
values and other chemistries 
Coagulation factors (PT, PTT, INR) 
Urinalysis including culture 
Iron panel (TIBC, ferritin, Fe) 
TSH/hormonal panel 
Fecal-occult blood testing 
Peripheral blood smear 
haptoglobin 
Further recommendation based on suspected etiology (in addition to baseline anemia testing) 
Unknown etiology, 
suspect possible hemolysis 
Coombs test, fibrinogen, d-dimer 
Consider hematology consultation. 
Consider blood transfusion at clinical discretion. 
Unknown etiology, 
suspect possible bleeding 
Consider blood transfusion at clinical discretion. 
Consider surgical/interventional radiology consultation. 
Consider imaging, as clinically indicated (e.g. FAST scan, CT scan, MRI, 
angiography). 
Consider endoscopy (upper/lower)  
Unknown etiology despite 
above work-up 
Hematology consultation 
Consider bone marrow aspiration/morphologic evaluation 
•  
5.5.3.5 
Rash with Hyperkeratosis / Keratoacanthoma / Squamous 
Cell Carcinoma of the Skin 
Treatment-related skin lesions with hyperkeratosis, keratoacanthoma, cutaneous squamous cell 
carcinoma possibly due to TGFβ inhibition as important identified risks (adverse reactions) for 
M7824. They have been manageable and did not lead to permanent discontinuations in M7824 
studies. Patients with known Lynch Syndrome who develop keratoacanthomas on study are 
encouraged to be evaluated for Muir Torre syndrome.  Monitoring will include skin assessments 
as defined in the Schedules of Assessments (Tables 1-3), with biopsy of suspicious lesions. 
Management should be discussed with the principal investigator on a case-by-case basis. 
Dermatological consults should be requested as needed in the event that possible drug-related skin 
toxicity is suspected by the investigator. 
5.5.3.6 
Alterations in Wound Healing or Tissue Damage Repair 
Due to the involvement of TGFβ in repair of skin and other tissue injuries, alterations in wound 
healing or repair of tissue damage is considered a potential risk. No AEs have been reported in 
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Phase I studies. For any surgeries conducted post-treatment initiation, surgical wound healing will 
be closely monitored. Management should be discussed with the principal investigator on a case-
by-case basis. Dermatological consults should be requested as needed. 
5.5.3.7 
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 in spite of medical treatment until the next treatment (second 
cycle after the AE occurred) a discussion with the principal investigator should occur and 
consideration of a possible extension of the dose interruption for up to 1 additional cycle or a 
permanent withdrawal from the study treatment should be considered. 
If upon the resumed study treatment the subject experiences the same AE this should be re-
discussed with the principal investigator to assess permanent withdrawal from the study treatment. 
Grade 3 and 4 laboratory abnormalities that do not have clinical significance do not require dose 
interruption. 
5.6 
Packaging and Labeling of the Investigational Medicinal 
Product 
M7824 drug product is a sterile freeze-dried formulation presented at a concentration of 600 
mg/vial in USP type I glass vial closed with a rubber stopper and sealed with an aluminum plastic 
crimping cap. 
Packaging and labeling will be in accordance with applicable local regulatory requirements and 
applicable Good Manufacturing Practice guidelines. M7824 will be packed in boxes containing a 
suitable number of vials. The information on the medication will be in accordance with approved 
submission documents. 
M7824 will be shipped in transport cool containers (2°C to 8°C) that are monitored with 
temperature control devices. 
All IMPs will be packaged and labeled in accordance with all applicable regulatory requirements 
and Good Manufacturing Practice Guidelines. 
5.7 
Preparation, Handling, and Storage of the Investigational 
Medicinal Product 
M7824 drug product must be stored at 2°C to 8°C until use. The storage condition is based on data 
from ongoing long term stability studies with M7824. 
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M7824 drug product stored at room (23°C to 27°C) or higher temperatures for extended periods 
of time might be subject to degradation. M7824 must not be frozen. Rough shaking of the 
reconstituted solution must be avoided. 
For application in clinical trials, M7824 drug product must be reconstituted with 4.5 mL of Water 
for Injection and diluted with 0.9% saline solution (sodium chloride injection). The chemical and 
physical in-use stability for the infusion solution of M7824 in 0.9% saline solution has been 
demonstrated for a total of 72 hours at room temperature; however, from a microbiological point 
of view, the diluted solution should be used immediately and is not intended to be stored unless 
dilution has taken place in controlled and validated aseptic conditions. If not used immediately, 
in-use storage times and conditions prior to administration are the responsibility of the user. No 
other drugs should be added to the infusion containers containing M7824. 
Detailed information on infusion bags and medical devices to be used for the preparation of the 
dilutions and subsequent administration will be provided in the manual of preparation. 
M7824 must not be used for any purpose other than the study. The administration of IMPs to 
subjects who have not been enrolled into the study is not covered by the study insurance. 
The contents of the M7824 vials are sterile and nonpyrogenic, and do not contain bacteriostatic 
preservatives. Any spills that occur should be cleaned up using the facility’s standard cleanup 
procedures for biologic products. 
Any unused portion of the solution should be discarded in biohazard waste disposal with final 
disposal by accepted local and national standards of incineration. 
5.8 
Investigational Medicinal Product Accountability 
The Investigational Pharmacy is responsible for ensuring IMP accountability, including 
reconciliation of drugs and maintenance of records. 
• Upon receipt of IMP, the responsible person will check for accurate delivery and 
acknowledge receipt by signing or initialing and dating the appropriate documentation and 
returning it to the location specified. A copy will be archived for the Investigator Site File. 
• IMP dispensing will be recorded on the appropriate drug accountability forms so that 
accurate records will be available for verification at each monitoring visit. 
• IMP accountability records will include the following: 
o Confirmation of IMP receipt, in good condition and in the defined temperature 
range. 
o The inventory of IMP provided for the clinical trial and prepared at the site. 
o The use of each dose by each subject. 
o The disposition (including return, if applicable) of any unused IMP. 
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o  
o Dates, quantities, batch numbers, vial numbers, expiry dates, formulation (for IMP 
prepared at the site), and the individual subject trial numbers. 
The Investigator site should maintain records, which adequately document that subjects were 
provided the doses specified in this protocol, and all IMPs provided were fully reconciled. 
Unused IMP must not be used for any purpose other than the present trial. No IMP that is dispensed 
to a subject may be redispensed to a different subject. 
The clinical trial monitor will periodically collect and review the IMP accountability forms and 
where applicable, will check all returns (both unused and used containers) before arranging for 
their return or authorizing their destruction by the trial site. 
At the conclusion or termination of this trial, trial site personnel and the IND Office will conduct 
a final product supply inventory on the Investigational Drug Accountability Forms and all unused 
containers will be destroyed. Instructions for destruction of product will be provided to the site. 
The Clinical Trial Monitor will be supplied with a copy for filing of the Investigational Drug 
Accountability Forms. This documentation must contain a record of clinical supplies used, unused, 
and destroyed and shall include information on 
• all administered units, 
• all unused units, 
• all destroyed units (during the trial), 
• all destroyed units at the end of the trial, 
• date of destruction(s), 
• name and signature of the Investigator / pharmacist. 
It must be ensured at each trial site that the IMP is not used 
• after the expiration date, and 
• after the retest date unless the IMP is reanalyzed and its retest date extended. 
 This is to be closely monitored by the Clinical Trial Monitor. 
5.9 
Assessment of Investigational Medicinal Product Compliance 
In this trial, subjects will receive M7824 IV infusions at the investigational site. Well-trained 
medical staff will monitor and perform the IMP administration. The information of each IMP 
administration including the date, time, and dose of IMP will be recorded in Prometheus. The 
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Investigator will make sure that the information entered into Prometheus regarding IMP 
administration is accurate for each subject. Any reason for noncompliance should be documented. 
Noncompliance is defined as a subject missing > 1 administration of trial treatment for nonmedical 
reasons. If 1 treatment administration was missed and the interval between the subsequent 
treatment and the last administered treatment is longer than 4 weeks for nonmedical reasons, the 
criteria of insufficient compliance are met as well. Continuation of treatment should be discussed 
with the principal investigator. 
5.10 
Medical Care of Subjects after End of Trial 
After a subject has completed the trial or has withdrawn early, usual treatment will be 
administered, if required, in accordance with the trial site’s standard of care and generally accepted 
medical practice and depending on the subject’s individual medical needs. 
Upon withdrawal from the trial, subjects may receive whatever care they and their physicians agree 
upon. Subjects will be followed for survival and AEs as specified in Section 6.1.4. 
6 
Trial Procedures and Assessments 
6.1 
Schedule of Assessments 
A complete schedule of assessments is provided in Tables 1-3, including sample collection for 
tumor biopsies and plasma samples.  
Prior to performing any trial assessments not part of the subject’s routine medical care, the 
Investigator will ensure that the subject or the subject’s legal representative has provided written 
informed consent according to the procedure described in Section 7.2. 
6.1.1 
Screening and Baseline Procedures and Assessments 
There is a 28-day washout / recovery period for prior anticancer treatment (for example, 
cytoreductive therapy, radiotherapy [with the exception of palliative radiotherapy delivered in a 
normal organ-spearing technique], immune therapy, or cytokine therapy except for erythropoietin) 
and major surgery before the start of trial treatment (Section 4.3.2). Hematology and chemistry 
laboratory samples must be drawn and reviewed within 72 hours prior to dose administration. 
During the screening period and before any trial related investigations and assessments are started, 
the subjects will be asked to sign the relevant ICFs. The subjects’ information that will be 
documented during screening includes the demographic information (birth date, sex, ethnicity, and 
race) and the complete medical history, including the history of the tumor disease and prior 
anticancer therapies, previous medications (prior 30 days to signing of ICF), concomitant 
medications, and baseline medical condition (the information of concomitant medications and AEs 
will be monitored throughout the trial treatment period).  
During screening, subjects will undergo a complete physical examination, dermatological 
assessments (assessments for skin lesions or rash with biopsy of suspicious lesions), recording 
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vital signs, including body weight and height (height only at screening), 12-lead electrocardiogram 
(EKG), and a determination of the ECOG PS (Appendix 1).The screening laboratory examination 
includes hematology, full serum chemistry and full urinalysis. Antinuclear antibody (ANAs), 
rheumatoid factor (RF), free thyroxine (T4), and TSH will also be assessed at screening. 
During screening, a serum β-human chorionic gonadotropin (β-HCG) pregnancy test will be 
performed for females of child bearing potential and blood.  HIV, HBV, and HCV testing will be 
performed for all screening subjects as these conditions are trial entry exclusion criteria. A female 
is considered of childbearing potential (that is fertile) following menarche and until becoming 
postmenopausal unless permanently sterile. Permanent sterilization methods include 
hysterectomy, bilateral salpingectomy, and bilateral oophorectomy. A postmenopausal state is 
defined as no menses for 12 months without an alternative medical cause. A high follicle-
stimulating hormone (FSH) level (> 40 mIU/mL) in the postmenopausal range may be used to 
confirm a postmenopausal state in females not using hormonal contraception or hormonal 
replacement therapy. 
For Cohort D, patients will be screened for the presence or absence of ctDNA in the screening 
period prior to treatment initiation. 
Additional blood will be collected during screening for exploratory blood biomarkers including 
circulating cytokines and leukocyte subpopulations (Section 6.4.5). 
The tumor evaluation (type / staging, etc.) will be performed using CT scan or MRI (if MRI is 
used, CT of chest is mandatory.  
Collection of tumor biopsies or archived surgical specimen will also be done during this period, if 
applicable and at 4 weeks into the study (prior to dose 3) for cohort A-C. For cohort B, tumor 
biopsies will be collected pretreatment, prior to dose 2, and prior to dose 4.  ]Pretreatment and/or 
post-treatment biopsies will be subjected to assessment of immune infiltration, expression of PD-
L1, and CMS classification by FFPE RNA analysis.  
6.1.2 
Treatment period 
For this protocol, a cycle is defined as 28 days. M7824 will be given until confirmed progression, 
unacceptable toxicity, or any criterion for withdrawal from the trial or IMP occurs (see Section 
4.5). Subjects who have experienced a PR or CR should continue treatment through the end of 12 
months, although additional treatment is possible. If the Investigator believes that a subject may 
benefit from treatment beyond 12 months, it may be permissible after discussion with the principal 
investigator. In the case of PD, subjects should continue treatment through their next tumor 
assessment, if they meet the criteria described in Section 4.5.1. 
For subjects who achieve a PR or CR on M7824 therapy and then subsequently develop disease 
progression after stopping therapy, but prior to the end of the trial, a re-initiation course of 
treatment at the same dose and schedule and treatment duration up to 12 months is allowed at the 
discretion of the Investigator and agreement of the trial principal investigator. In order to be 
eligible for retreatment, the subject must not have experienced any toxicity that led to treatment 
discontinuation of the initial M7824 therapy. Prior to re-initiation of the study treatment, malignant 
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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 of treatment.  
Subjects will be asked to visit the investigational site according to the Schedules of Assessments 
(see Tables 1-3). In addition, the tumor evaluation (see Section 6.3) has a tumor assessment 
visiting time window of 5 days prior to dosing (-5 days). Furthermore, if any Screening procedures 
are conducted within 3 days prior to Day 1 of trial treatment (Cycle 1, Day 1), the assessments 
scheduled on Cycle 1, Day 1 do not need to be repeated except for the evaluation of AEs and 
concomitant medications. 
During the treatment period, the following assessments will be performed (see Tables 1-3 for the 
detailed schedule): 
• AEs and concomitant medications will be documented in each study visit 
• ECOG PS will be assessed prior to trial treatment on Day 1 (unless the Screening ECOG 
PS was performed within 3 days prior to Day 1) 
• Physical examination will be performed prior to trial treatment on Day 1 (Cycle  1) and 
then prior to trial treatment according to Tables 1-3 
• Eye signs and symptoms should be checked. If clinically relevant findings then an 
appropriate ophthalmology examination including slit lamp evaluation inclusive of the 
anterior segment and with visual acuity should be obtained within 2 days 
• Dermatological assessments (assessments for skin lesions or rash with biopsy of suspicious 
lesions according to Tables 1-3) 
• Vital signs, including body weight, will be assessed prior to trial treatment according to 
Tables 1-3. 
• The 12-lead EKG will be assessed according to Tables 1-3. 
• The laboratory hematology tests will be assessed prior to trial treatment according to 
Tables 1-3. Complete blood count results must be drawn and reviewed within 72 hours 
prior to dose administration. 
• Full serum chemistry will be assessed prior to trial treatment according to Tables 1-3. 
Samples for full chemistry results must be drawn and reviewed within 72 hours prior to 
dose administration. 
• A basic urinalysis will be performed prior to trial treatment every according to Tables 1-
3. 
• Samples for ANAs and RF according to Tables 1-3. 
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• A serum HCG pregnancy test will be required at Screening, urine or serum β-HCG 
pregnancy test will be performed prior to each administration of the study drug (if 
applicable). 
• The tumor evaluation (see Section 6.3) will be performed prior to treatment at week 8, and 
then once every 8 weeks, with a tumor assessment visiting time window of 5 days prior to 
dosing. For subjects continuing treatment beyond 12 months (in consultation with the 
principal investigator), tumor evaluations should take place every 12 weeks. 
• Tumor biopsies at Week 4, prior to the third treatment dose (-7 day window permitted). 
Archival tissue may be used in place of a fresh pretreatment biopsy if adequate tumor is 
available for analysis.  If insufficient tissue is available for analysis for pretreatment tumor, 
then a mandatory fresh biopsy must be obtained. In cohort A, the site of tumor tissue for 
the pretreatment sample, whether archival or fresh, may be from the primary tumor or the 
metastasis. In cohort B, the site of tumor for the pretreatment sample, in order to classify 
the CMS subtype, must come from the primary tumor.  The week 4, on-treatment biopsy 
for both cohorts may come from the primary tumor or from a metastatic site. 
• Free T4, and TSH will be measured prior to trial treatment according to Tables 1-3. 
• The exploratory blood biomarkers including circulating cytokines and leukocyte 
subpopulations will be performed as detailed in Tables 1-3 as described in Section 6.4.5.2 
• Samples for TGFβ determination will be drawn as detailed in Tables 1-3. 
6.1.3 
End of Treatment 
6.1.3.1 
End of Treatment Visit 
All subjects must undergo an End-of-Treatment visit after discontinuation of M7824 for any 
reason. This visit should be performed on the day of or within 7 days after the decision to 
discontinue trial treatment but before any new antineoplastic therapy is started (if possible), 
whichever occurs earlier (see Tables 1-3). 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. For all these subjects, the 
discontinuation visit consists of: 
• Documentation of AEs and concomitant medication. 
• Physical examination including vital signs and body weight. 
• Eye signs and symptoms should be checked. If clinically relevant findings then an 
appropriate ophthalmology examination including slit lamp evaluation inclusive of the 
anterior segment and with visual acuity should be obtained within 2 days. 
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• Dermatological assessments (assessments for skin lesions or rash with biopsy of suspicious 
lesions). 
• Laboratory hematology, full serum chemistry, and basic urinalysis. 
• ECOG performance status will be assessed. 
6.1.4 
Post Treatment Follow Up 
6.1.4.1 
28-Day Safety Follow Up 
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. 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 28-Day Safety Follow-up visit will comprise a full assessment for safety, 
immunogenicity, and tumor response as appropriate, which will include the following (refer to 
Tables 1-3): 
• AEs, concomitant medications. 
• Vital signs and body weight. 
• Physical examinations. 
• Eye signs and symptoms should be checked by the treating investigator. If clinically 
relevant findings then an appropriate ophthalmology examination including slit lamp 
evaluation inclusive of the anterior segment and with visual acuity should be obtained 
within 2 days. 
• Dermatological assessments (assessments for skin lesions or rash with biopsy of suspicious 
lesions) by the treating investigator. 
• The 12-lead EKG. 
• Complete blood count, full serum chemistry. 
• Full urinalysis. 
• ECOG performance status will be assessed. 
• The β-HCG pregnancy test (in females of childbearing potential). 
• The tumor evaluation (only to be performed, if no disease progression was documented 
previously). 
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• Free T4, and TSH. 
• Samples for ANAs and RF.  
• The exploratory blood biomarkers including circulating cytokines and leukocyte 
subpopulations will be performed as detailed in Tables 1-3 as described in Section 6.4.5.2. 
• Samples for TGFβ determination. 
• Blood samples for gene expression evaluation for subjects with PD. 
• An optional tumor biopsy following progression may be offered to the patient. 
6.1.4.2 
Long-term Follow-up / Trial Termination 
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 up for disease 
progression (CT / MRI scans every 12 weeks) until PD. 
After the 28-Day Safety Follow-up visit, subjects will be followed quarterly (± 14 days) for 
survival (including assessment of any further anticancer therapy). The survival follow-up will 
continue until 1 year after the last subject receives the last dose of M7824. 
6.1.5 
Blood Consumption for Clinical Assessments 
The overall amount of blood to be drawn from a single subject must not exceed 120 mL/day and 
550 mL in an 8-week period for safety laboratory testing, pregnancy testing, exploratory biomarker 
investigation, and antibody evaluation. 
6.2 
Demographic and Other Baseline Characteristics 
The assessments and procedures described in this section must be performed during the Screening 
period. 
6.2.1 
Demographic Data 
The following demographic data will be recorded: 
• Subject identifier 
• Date of birth 
• Sex 
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• Ethnicity 
• Race 
6.2.2 
Diagnosis of Tumor 
The tumor disease information that will be documented and verified at the Screening visit for each 
subject includes: 
• Detailed history of the tumor, including histopathological diagnosis, grading and staging 
in accordance with the American Joint Cancer Committee (7th Edition) Tumor Node 
Metastasis Classification at diagnosis (AJCC TNM). 
o The M category (M0 or M1) of the tumor at the time of study entry, based on 
screening assessments. 
• All therapy used for prior treatment of the tumor (including surgery, radiotherapy and 
chemotherapy, immunotherapy, etc.). 
• Any other conditions that were treated with chemotherapy, radiation therapy, or 
immunotherapy. 
• Current cancer signs and symptoms and side effects from current and / or previous 
anticancer treatments. 
• Current cancer disease status. 
6.2.3 
Medical History 
In order to determine the subject’s eligibility to the trial, a complete medical history of each subject 
will be collected and documented during Screening, which will include, but may not be limited to, 
the following: 
• Past and concomitant non-malignant diseases and treatments. 
• All medications taken and procedures carried out within 30 days prior to Screening. 
For the trial entry, all the subjects must fulfill all inclusion criteria described in Section 4.3.1, and 
none of the subjects should have any exclusion criterion from the list described in Section 4.3.2. 
6.2.4 
Vital Signs and Physical Examination 
Vital signs including body temperature, respiratory rate, heart rate (after 5-minute rest), and arterial 
blood pressure (after 5-minute rest), body weight and height will be recorded at study entry. 
Physical examinations will be performed according to Tables 1-3. An ophthalmology examination 
including slit lamp evaluation inclusive of the anterior segment and with visual acuity should be 
conducted. 
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The ECOG PS will be documented during the Screening phase. 
6.2.5 
CT or MRI Scans for Tumor Assessment at Baseline 
A CT scan or MRI (if MRI is used, CT of chest is mandatory) of the chest, abdomen, and pelvis 
will be performed within 28 days prior to trial treatment start in order to document the baseline 
status of the tumor disease using iRECIST 1.1 target and non-target lesions. However, if the results 
of a CT scan or MRI performed within 4 weeks prior to first treatment are available, the Screening 
CT / MRI does not need to be performed. 
A bone scan should be done at Screening as clinically indicated. 
6.2.6 
Cardiac Assessments 
A 12-lead EKG will be recorded at Screening. The EKG will be recorded after the subject has been 
in a supine position breathing quietly for 5 minutes. The EKG results will be used to evaluate the 
heart rate, atrial-ventricular conduction, QR, QT, and corrected QT intervals, and possible 
arrhythmias. 
The EKGs will be documented by recording date and time of collection. All EKG results must be 
reviewed at the site by the Investigator or a medically qualified designee for clinical management 
of the subject. EKGs are to be performed according to local procedures and will NOT be digitally 
uploaded. 
The Investigator will judge the overall interpretation as normal or abnormal. If abnormal, it will 
be decided if the abnormality is clinically significant or not clinically significant and the reason 
for the abnormality will be recorded on the eCRF (Prometheus). Abnormal values will not be 
recorded as AEs unless they are the reason for discontinuation of the trial IMP due to AEs or are 
SAEs. 
6.2.7 
Clinical Laboratory Tests 
Blood samples will be collected at screening for clinical laboratory parameter evaluations. These 
clinical laboratory test results will serve not only as the baseline values for subsequent safety 
clinical laboratory evaluations during the trial, but also help to make sure that each enrolled subject 
fulfills all the trial entry criteria as listed in Section 4.3.1 and does not meet any of the trial 
exclusion criteria for laboratory parameters as listed in Section 4.3.2. Detailed description of 
laboratory assessments is provided in Section 4.4.3. 
6.2.8 
ctDNA testing 
Guardant360 is a next-generation sequencing (NGS) panel of 70 clinically actionable onco- and 
tumor suppressor genes utilizing digital sequencing of cell-free circulating tumor DNA (cfDNA) 
isolated from a simple, non-invasive blood draw. It is medically indicated for the prevention of a 
repeat invasive biopsy in advanced cancer patients when the initial biopsy is insufficient (QNS) or 
unavailable/unobtainable as well as when cancer has progressed or recurred despite treatment. The 
test detects single nucleotide variants via complete exon sequencing in 70 genes, copy number 
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amplifications in 16 genes, small indels in EGFR, ERBB2 and MET exon 14 skipping, and fusions 
in ALK, FGFR2, FGFR3, RET, ROS1 and NTRK1. The genes are selected because mutations in 
these genes have FDA-approved matched therapies or are eligible for late phase clinical trials, as 
well as non-druggable genes with high prevalence alterations that may be helpful in monitoring 
for molecular response/non-response such as TP53.  
Guardant360 is an advanced diagnostic laboratory test (ADLT) offered by a sole source laboratory 
certified by the Clinical Laboratory Improvement Amendments (CLIA) for high complexity 
(molecular pathology) testing and accredited by the College of American Pathology (CAP). Due 
to high rates of false positives with traditional NGS assays when tumor DNA is in low 
concentrations, the majority of “liquid biopsy” methods interrogating cell-free DNA have been 
limited to hotspot analyses. In contrast, the ultra-high specificity (> 99.9999%) of the digital 
sequencing method enables the sequencing of long, targeted regions (146,000 base pairs) without 
false positives. Complete exons are sequenced for all exons in 30 genes and the critical exons 
(those reported as having a somatic mutation in COSMIC) in 40 additional genes. Thus, its key 
differentiating characteristic from other “liquid biopsy” methods is the ability to sequence 
complete exons in many genes, in contrast to gene hotspot testing. 
Advantages of the Guardant360 cell-free DNA NGS methodology versus solid tumor tissue-based 
NGS are: 
1. 
An invasive needle or surgical biopsy is avoided with ctDNA, reducing 
costs and complications. 
2. 
CtDNA provides a quantitative measure (concentration or mutant allele 
frequency) of mutations present whereas solid tumor biopsy typically 
provides a qualitative result (mutation either present or not detected). The 
quantitative cfDNA result may be followed over time to monitor response 
to treatment and evolution of acquired resistance. 
3. 
CtDNA sequencing identifies both germline and somatic mutations in the 
same sample. 
4. 
The assay failure rate is for ctDNA is less than 0.5% (in the first 9,000+ 
samples) compared to 15%-25% failure rates of tissue-based NGS related 
to insufficient quantity of tissue (QNS). 
 
Guardant360 utilizes algorithmic methods to encode and ultimately decode inputs and outputs 
from massively parallel deep sequencing analysis. By leveraging signal transduction processing 
technology where voice or image data is digitally encoded before transmission and then decoded 
post-transmission, this NGS method, known as Digital SequencingTM, enables signal interference 
to be reduced by two orders of magnitude or more (88).  Four validation studies have been published 
with concordance to tissue biopsy-based genomic testing (88-91). With high enough sensitivity and 
specificity to robustly quantitate ctDNA from blood, this approach has the potential to evaluate the 
multiple genomic targets required in NCCN guidelines, to act as a “summary” of the different 
tumor clones in patients with intra-tumor and inter-tumor heterogeneity, and to prevent the time 
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delays, costs and complications inherent in invasive biopsies. The analytical and clinical validation 
of Guardant360 is conducted in conformance with evidentiary standards established by the 
Standards for Reporting of Diagnostic Accuracy (STARD), REporting of tumor MARKer Studies 
(REMARK), Evaluation of Genomic Applications in Practice and Prevention (EGAPP), and the 
recent Next-generation Sequencing: Standardization of Clinical Testing (Nex-StoCT) biomarker 
guidelines (92-95). 
Methodology 
The gene panel was selected to focus on those genomic alterations that are currently actionable 
defined as being targets of sensitivity or resistance to an FDA-approved matched therapy and/or a 
targeted therapy in clinical trials. The test simultaneously sequences the 70 cancer-related genes 
to an average depth of coverage of greater than 8,000X. To summarize, cell-free DNA is extracted 
from plasma and genomic alterations are analyzed by massively parallel paired end synthesis-by-
sequencing of amplified target genes utilizing an Illumina Next-Seq platform complemented by 
systematic end-to-end process optimization including conversion of cell-free DNA fragments into 
digital sequences, improvements in the Illumina next generation sequencing process itself, 
followed by bioinformatics algorithms which enable ctDNA to be measured as a quantitative 
percentage of total cell-free DNA.  
Two 10mls of whole blood are collected in Streck Cell-Free DNA Blood Collection (Streck) tubes, 
which contain a proprietary formaldehyde-free preservative in that stabilizes white blood cells, 
preventing the release of genomic DNA and allowing shipping and stability for seven days without 
need for refrigeration, cold bricks or preliminary centrifugation prior to shipping.  
After digital libraries are produced, the sample is sequenced and post-sequencing data is processed 
using bioinformatics algorithms to quantify the absolute number of unique DNA fragments at a 
given nucleotide position. This proprietary process is referred to as Digital SequencingTM and 
enables reporting of the fractional concentration (mutant allele frequency) of a given SNV. 
Circulating cell-free DNA is mostly derived from leukocyte lysis (germline) and generally a much 
smaller amount of tumor DNA is derived from cancer cell apoptosis/necrosis. All of the cell-free 
DNA fragments, including leukocyte-derived and tumor-derived, are simultaneously sequenced 
with up to single molecule sensitivity. In other words, both tumor DNA and “normal”/germline 
DNA are sequenced and measured in the same sequencing assay. The fractional concentration or 
mutant allele frequency for a given mutation is calculated as the fraction of circulating tumor DNA 
harboring that mutation in a background of wild-type cell-free DNA fragments. The analytic 
sensitivity reaches detection of 1-2 single mutant cell-free DNA molecules from a 10 ml blood 
sample. 
 
Gene list and genomic alterations in the Guardant360 Panel 
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6.3 
Efficacy Assessments 
For all subjects, tumor response assessment will be performed by CT scan or MRI (if MRI is used, 
CT of chest is mandatory. 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. 
Skin metastasis can be used as target lesions according to iRECIST 1.1 using measurements by 
caliper, if they fulfill iRECIST 1.1 for target lesions as described below. The presence of new 
cutaneous lesions will be considered diagnostic of progression for iRECIST 1.1, even if not 
imaged. For each subject, the Investigator will designate 1 or more of the following measures of 
tumor status to follow for determining response: CT or MRI images of primary and / or metastatic 
tumor masses, physical examination findings, and the results of other assessments. All available 
images collected during the trial period will be considered. The most appropriate measures to 
evaluate the tumor status of a subject should be used. The measure(s) to be chosen for sequential 
evaluation during the trial have to correspond to the measures used to document the progressive 
tumor status that qualifies the subject for enrollment. The tumor response assessment will be 
assessed and listed according to the Schedule of Assessments (refer to Tables 1-3). 
The foreseen treatment duration is until documentation of PD, unacceptable toxicity, or any 
criterion for withdrawal from the trial or IMP occurs (see Section 4.5).  
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The treatment should be stopped immediately, if the subject does not tolerate M7824 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 iRECIST 1.1 (all measurements should be recorded in 
metric notation). 
• To assess objective response, the tumor burden at baseline will be estimated and used for 
comparison with subsequent measurements. At baseline, tumor lesions will be categorized 
in target and non-target lesions according to iRECIST 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 iRECIST 1.1.  
The Investigator may perform scans in addition to a scheduled trial scan for medical reasons or if 
the Investigator suspects PD. 
As outlined in Section 4.1, treatment should continue with M7824 if the patient has PD provided: 
• There are no new Grade 2 or greater symptoms or significant worsening of existing 
symptoms. 
• There is no decrease in ECOG PS. 
• In the opinion of the Investigator, the subject does not require new anticancer therapy. 
PD and any of the above conditions not satisfied results in study discontinuation.  
Subjects who have experienced a confirmed PR or CR should continue treatment through the end 
of 12 months, although additional treatment is possible. If the Investigator believes that a subject 
may benefit from treatment beyond 12 months, it may be permissible after discussion with the 
principal investigator.  
6.4 
Assessment of Safety 
The safety profile of the IMP will be assessed through the recording, reporting and analysis of 
baseline medical conditions, AEs, physical examination findings including vital signs and eyes 
signs and symptoms, and laboratory tests. 
Comprehensive assessment of any apparent toxicity experienced by each subject will be performed 
from the time of giving informed consent and throughout the trial. The Investigator will report any 
AEs, whether observed by the Investigator or reported by the subject (see Section 6.4.1.2). Given 
the intended MoA, particular attention will be given to AEs that may follow the enhanced T-cell 
activation such as persistent rash, diarrhea and colitis, autoimmune hepatitis, arthritis, 
glomerulonephritis, cardiomyopathy, uveitis and other inflammatory eye conditions, or other 
immune-related reactions. Ophthalmologic examinations should be considered, when clinically 
indicated, for signs or symptoms of uveitis. Furthermore, due to the anti-TGFβ activity, particular 
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attention will also be given to events associated with, anemia, and rash with hyperkeratosis / 
keratoacanthoma and squamous cell carcinoma of the skin. 
The reporting period for AEs is described in Section 6.4.1.3. 
The safety assessments will be performed according to the Schedules of Assessments (see Tables 
1-3). 
6.4.1 
Adverse Events 
6.4.1.1 
Adverse Event Definitions 
Adverse Event 
An AE is any untoward medical occurrence in a subject or clinical investigation subject 
administered a pharmaceutical product, regardless of causal relationship with this treatment. An 
AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory 
finding), symptom, or disease temporally associated with the use of a medicinal product, whether 
or not considered related to the medicinal product. 
For surgical or diagnostic procedures, the condition / illness leading to such a procedure is 
considered as the AE rather than the procedure itself. 
In case of a fatality, the cause of death is considered as an AE, and the death is considered as its 
OUTCOME. 
The investigator (or physician designee) is responsible for verifying and providing source 
documentation, grading the severity and assigning the attribution for all adverse events. 
Investigators will reference the NCI-CTCAE v4.03 (publication date: 17 November 2017), a 
descriptive terminology that can be used for AE reporting. 
A general grading (severity / intensity; hereafter referred to as severity) scale is provided at the 
beginning of the above referenced document, and specific event Grades are also provided. 
If a particular AE’s severity is not specifically graded by the guidance document, the Investigator 
is to use the general NCI-CTCAE definitions of Grade 1 through Grade 5 following his or her best 
medical judgment. 
Grade 1: Mild 
Grade 2:  Moderate 
Grade 3: Severe 
Grade 4: Life-threatening 
Grade 5:  Death  
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Recommended Adverse Event Recording Guidelines 
Attribution 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Grade 5 
Unrelated 
Phase I 
Phase I 
Phase I 
Phase II   
 
Phase I 
Phase II   
Phase III 
Phase I  
Phase II   
Phase III 
Unlikely 
Phase I 
Phase I 
Phase I  
Phase II   
Phase I 
Phase II   
Phase III 
Phase I 
Phase II   
Phase III 
Possible 
Phase I 
Phase II   
Phase I 
Phase II   
Phase III 
Phase I 
Phase II   
Phase III 
Phase I 
Phase II   
Phase III 
Phase I 
Phase II   
Phase III 
Probable 
Phase I 
Phase II  
 
Phase I 
Phase II   
Phase III 
Phase I 
Phase II   
Phase III 
Phase I 
Phase II   
Phase III 
Phase I 
Phase II   
Phase III 
Definitive 
Phase I 
Phase II  
  
Phase I 
Phase II   
Phase III 
Phase I 
Phase II   
Phase III 
Phase I 
Phase II  
Phase III  
Phase I 
Phase II   
Phase III 
 
Any clinical AE with severity of Grade 4 or 5 must also be reported as an SAE as per Section 
6.4.1.4; however, a laboratory abnormality of Grade 4, such as anemia or neutropenia, is 
considered serious only if the condition meets one of the serious criteria described below. 
If death occurs, the primary cause of death or event leading to death should be recorded and 
reported as an SAE. “Fatal” will be recorded as the outcome of this specific event and death will 
not be recorded as separate event. Only, if no cause of death can be reported (for example, sudden 
death, unexplained death), the death per se might then be reported as an SAE. 
Investigators must also systematically assess the causal relationship of AEs to the IMP using the 
following definitions. Decisive factors for the assessment of causal relationship of an AE to the 
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M7824 include, but may not be limited to, temporal relationship between the AE and the M7824, 
the known safety profile of M7824, medical history, concomitant medication, course of the 
underlying disease, trial procedures. 
Unrelated: Not reasonably related to the IMP. The AE could not medically (pharmacologically / 
clinically) be attributed to the IMP under study in this clinical trial protocol. A reasonable 
alternative explanation must be available. 
Related: Reasonably related to the IMP. The AE could medically (pharmacologically / clinically) 
be attributed to the IMP under study in this clinical trial protocol. 
Abnormal Laboratory Findings and Other Abnormal Investigational Findings 
Abnormal laboratory findings and other abnormal investigational findings (for example, on an 
EKG trace) should not be reported as AEs unless they are associated with clinical signs and 
symptoms, lead to treatment discontinuation or are considered otherwise medically important by 
the Investigator. If a laboratory abnormality fulfills these criteria, the identified medical condition 
(for example, anemia, increased ALT) must be reported as the AE rather than the abnormal value 
itself. 
6.4.1.1.1 
Serious Adverse Event (SAE) Reporting 
An adverse event or suspected adverse reaction is considered “serious” if, in the view of either the 
investigator or Merck/EMD Serono, it results in any of the following outcomes: 
• 
Death 
• 
A life-threatening adverse drug experience – any adverse experience that places the patient, 
in the view of the initial reporter, at immediate risk of death from the adverse experience as it 
occurred. It does not include an adverse experience that, had it occurred in a more severe form, 
might have caused death. 
• 
Inpatient hospitalization or prolongation of existing hospitalization 
• 
A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions. 
• 
A congenital anomaly/birth defect. 
Important medical events that may not result in death, be life-threatening, or require hospitalization 
may be considered a serious adverse drug experience when, based upon appropriate medical 
judgment, they may jeopardize the patient or subject and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition. Examples of such medical 
events include allergic bronchospasm requiring intensive treatment in an emergency room or at 
home, blood dyscrasias or convulsions that do not result in inpatient hospitalization, or the 
development of drug dependency or drug abuse (21 CFR 312.32). 
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• 
Important medical events as defined above, may also be considered serious adverse events. 
Any important medical event can and should be reported as an SAE if deemed appropriate by the 
Principal Investigator or the IND Office. 
• 
All events occurring during the conduct of a protocol and meeting the definition of a SAE 
must be reported to the IRB in accordance with the timeframes and procedures outlined in “The 
University of Texas M. D. Anderson Cancer Center Institutional Review Board Policy for 
Investigators on Reporting Serious Unanticipated Adverse Events for Drugs and Devices”.  Unless 
stated otherwise in the protocol, all SAEs, expected or unexpected, must be reported to the IND 
Office, regardless of attribution (within 5 working days of knowledge of the event). 
• 
All life-threatening or fatal events, that are unexpected, and related to the study drug, must 
have a written report submitted within 24 hours (next working day) of knowledge of the event to 
the Safety Project Manager in the IND Office.   
• 
Unless otherwise noted, the electronic SAE application (eSAE) will be utilized for safety 
reporting to the IND Office and MDACC IRB.  
• 
Serious adverse events will be captured from the time of the first protocol-specific 
intervention, until 90 days after the last dose of drug, unless the participant withdraws consent. 
Serious adverse events must be followed until clinical recovery is complete and laboratory tests 
have returned to baseline, progression of the event has stabilized, or there has been acceptable 
resolution of the event. 
• 
Additionally, any serious adverse events that occur after the 90 day time period that are 
related to the study treatment must be reported to the IND Office. This may include the 
development of a secondary malignancy. 
 
Reporting to FDA: 
• 
Serious adverse events will be forwarded to FDA by the IND Office (Safety Project Manager 
IND Office) according to 21 CFR 312.32. 
 
It is the responsibility of the PI and the research team to ensure serious adverse events are 
reported according to the Code of Federal Regulations, Good Clinical Practices, the protocol 
guidelines, Merck/EMD Serono’s guidelines, and Institutional Review Board policy. 
6.4.1.1.2 
Events Not to Be Considered as AEs / SAEs 
Medical conditions present at the initial trial visit that do not worsen in severity or frequency during 
the trial are defined as Baseline Medical Conditions, and are not to be considered AEs. 
AE / SAEs Observed in Association with Disease Progression 
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Progression of the disease / disorder being studied assessed by measurement of lesions on 
radiographs or other methods as well as associated clinical signs or symptoms (including 
laboratory abnormalities) should not be reported as an AE / SAE, unless the subject’s general 
condition is more severe than expected and / or unless the outcome is fatal within the AE reporting 
period (as defined in Section 6.4.1.3). 
6.4.1.1.3 
Pre-defined AEs of Special Interest (AESI) for Safety 
Monitoring 
Any AE that is suspicious to be a potential irAE (see Section 5.5.3.3), including ophthalmologic 
findings, has to be reported in an expeditious manner and will be considered an AE of special 
interest (AESI). 
Infusion-related reactions / hypersensitivity, regardless of grade, must be reported as AESIs. 
In addition, rash with hyperkeratosis / keratoacanthoma / squamous cell cancer of the skin are 
regarded as AESIs. Please note that squamous cell cancer of the skin should be considered as 
medically important condition and thus as a serious AESI, which has to be reported in an expedited 
manner as a SAE. 
Anemia when considered related to M7824 will be reported as AESI regardless of grade. 
 The reporting of AESI is defined in Section 6.4.1.4. 
6.4.1.2 
Methods of Recording and Assessing Adverse Events 
At each trial visit, the subject will be queried on changes in his or her condition. During the 
reporting period, any unfavorable changes in the subject’s condition will be recorded as AEs, 
whether reported by the subject or observed by the Investigator. 
Complete, accurate and consistent data on all AEs experienced for the duration of the reporting 
period (defined below) will be reported on an ongoing basis in the appropriate section of the eCRF 
(Prometheus). All SAEs and all non-serious AEs of special interest must be additionally 
documented and reported using the eSAE database. 
It is important that each AE report include a description of the event, its duration (onset and 
resolution dates and times to be completed when it is important to assess the time of AE onset 
relative to the recorded treatment administration time), its severity, its causal relationship with the 
trial treatment, any other potential causal factors, any treatment given or other action taken, 
including dose modification or discontinuation of the IMP, and its outcome. In addition, serious 
cases should be identified and the appropriate seriousness criteria documented.  
6.4.1.2.1 
Investigator Communications with Merck/EMD Serono 
• In addition to the regular reporting obligations, the following reportable events must be 
submitted to EMD Serono within 48 hours for fatal/life-threatening SAEs and 5 business days 
for all other SAEs. 
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• Exposure during pregnancy or breastfeeding (even if not associated with an adverse event) and 
occupational exposure (even if not associated with an adverse event) shall also be reported.  
 
Contact information for submission of reportable events and monthly extracts to EMD Serono: 
E-mail: GlobalDrugSafety@merckgroup.com or Fax: +49 6151 72 6914 
Specifying: 
• PROTOCOL Number 
• SUBJECT Number 
• SITE Number/PI Name 
• SAE/ONSET DATE 
 
6.4.1.3 
Definition of the Adverse Event Reporting Period 
The AE reporting period for safety surveillance from the first protocol intervention to 90 days after 
last study drug administration and continues through the trial’s 28-Day Safety Follow-up visit, 
defined as 28 days (± 5 days) after last trial drug administration. After the 28-Day Safety Follow-
up visit only AEs that are deemed attributable to trial drug by the Investigator should be 
documented until the Safety Follow-up visit, defined as 28 days (+/- 7 days) after the last trial drug 
administration. 
Any SAE assessed as related to M7824 must be reported whenever it occurs, irrespective of the 
time elapsed since the last administration of M7824. 
6.4.1.4 
Procedure for Reporting Serious Adverse Events, Adverse 
Events of Special Interest 
Serious Adverse Events 
In the event of any new SAE occurring during the reporting period, the Investigator must 
immediately (within a maximum 24 hours after becoming aware of the event) inform the IND 
Office and/or Merck/EMD Serono using the SAE Report Form following specific completion 
instructions. 
In exceptional circumstances, a SAE (or follow-up information) may be reported by telephone; in 
these cases SAE Report Form must be provided immediately thereafter. 
Reporting procedures and timelines are the same for any new information on a previously reported 
SAE (= follow-up). 
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Relevant pages from the eCRF (Prometheus) may be provided in parallel (for example, medical 
history, concomitant drugs). Additional documents may be provided by the Investigator, if 
available (for example, laboratory results, hospital report, and autopsy report). In all cases, the 
information provided on the SAE Report Form must be consistent with the data about the event 
recorded in the eCRF (Prometheus). 
The Investigator must respond to any request for follow-up information (for example, additional 
information, outcome final evaluation, other records where needed) or to any question the IND 
Office and/or Merck/EMD Serono may have on the AE within the same timelines as those noted 
above for initial reports. This is necessary to ensure a prompt assessment of the event by the IND 
Office and/or Merck/EMD Serono and (as applicable) to allow the IND Office to meet strict 
regulatory timelines associated with expedited safety reporting obligations. 
Adverse Events of Special Interest 
In the event of a non-serious Grade ≥ 3 AESI, the Investigator must report the AESI using the 
eSAE database within 5 days, and the logs should be provided to Merck/EMD Serono every 3 
months. Serious AESIs have to be reported in an expedited manner as SAEs within 24 hours as 
outlined above, and reported to EMD Safety. For Grade 1 and Grade 2 non-serious AESIs, results 
from the eSAE database should be forwarded to Merck/EMD Serono every 3 months.  
Safety Report to Health Authorities, Independent Ethics Committees / Institutional Review Boards 
and Investigators 
The IND Office will send appropriate safety notifications to Health Authorities in accordance with 
applicable laws and regulations. 
The Investigator must comply with any applicable site-specific requirements related to the 
reporting of SAEs (particularly deaths) involving trial subjects to the IEC / IRB that approved the 
trial. 
In accordance with ICH GCP guidelines, Merck/EMD Serono will inform the Investigator of 
“findings that could adversely affect the safety of subjects, impact the conduct of the trial, or alter 
the IEC’s / IRB’s approval / favorable opinion to continue the trial.” In particular and in line with 
respective regulations, Merck/EMD Serono will inform the Investigator of AEs that are both 
serious and unexpected and are considered to be related to the administered product (suspected 
unexpected serious adverse reactions [SUSARs]). The Investigator should place copies of Safety 
Reports in the Investigator Site File. National regulations with regard to Safety Report notifications 
to Investigators will be taken into account. 
When specifically required by regulations and guidelines, Merck/EMD Serono will provide 
appropriate Safety Reports directly to the concerned lead IEC / IRB and will maintain records of 
these notifications. When direct reporting is not clearly defined by national or site-specific 
regulations, the Investigator will be responsible for promptly notifying the concerned IEC / IRB 
of any Safety Reports provided by Merck/EMD Serono and of filing copies of all related 
correspondence in the Investigator Site File. 
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6.4.1.5 
Monitoring of Subjects with Adverse Events 
Adverse events are recorded and assessed continuously throughout the trial (see Section 6.4.1.3) 
and are assessed for final outcome at the End of Treatment visit. After the End of Treatment visit 
only AEs that are deemed attributable to trial drug by the Investigator should be documented until 
the Safety Follow-up visit. 
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 must be followed up in the same manner. 
Reasonable attempts to obtain this information must be made and documented. It is also the 
responsibility of the Investigator to ensure that any necessary additional therapeutic measures and 
follow-up procedures are performed. 
6.4.2 
Pregnancy and In Utero Drug Exposure 
Only pregnancies considered by the Investigator to be related to trial treatment (for example, 
resulting from a drug interaction with a contraceptive medication) are considered to be AEs; 
however, all pregnancies with an estimated conception date during the period defined in Section 
6.4.1.3 must be recorded by convention in the AE page / section of the eCRF (Prometheus). The 
same rule applies to pregnancies in female subjects and to pregnancies in female partners of male 
subjects. The Investigator must also notify the IND Office in an expedited manner of any 
pregnancy using the Paper Pregnancy Report Form, which must be transmitted according to the 
same timelines as described for SAE reporting in Section 6.4.1.4. 
Investigators must actively follow up, document and report on the outcome of all these 
pregnancies, even if the subjects are withdrawn from the trial. 
The Investigator must notify the IND Office of these outcomes using the Pregnancy Report Form. 
If an abnormal outcome occurs, the SAE Report Form will be used if the subject sustains an event 
and the Parent-Child / Fetus Adverse Event Report Form if the child / fetus sustains an event. 
Any abnormal outcome must be reported in an expedited manner as described in Section 6.4.1.4, 
while normal outcomes must be reported within 45 days after delivery. 
In the event of a pregnancy in a subject occurring during the course of the trial, the subject must 
be discontinued from trial medication immediately. The IND Office must be notified without delay 
and the subject must be followed as mentioned above. 
6.4.3 
Clinical Laboratory Assessments 
It is essential that the IND Office be provided with a list of laboratory normal ranges before 
shipment of IMP. Any change in laboratory normal ranges during the trial will additionally be 
forwarded to  the IND Office. 
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Blood samples will be taken from non-fasted subjects. All routine laboratory analyses will be 
performed at a laboratory facility local to the investigational site and relevant results must be drawn 
and checked before administration of M7824. The report of the results must be retained as a part 
of the subject’s medical record or source documents. Complete blood count and full serum 
chemistry must be checked within 72 hours prior to each dose administration. 
ANA, RF, T4, TSH, and urinalysis will be assessed at the time points defined in the Schedules of 
Assessments (Tables 1-3). 
If confirmation of a subject’s postmenopausal status is necessary, a FSH level will also be 
performed at Screening, see Section 6.1.1. 
Table 7: Required Laboratory Panel Tests 
Full Chemistry 
Hematology 
Albumin 
Absolute lymphocyte count 
Alkaline phosphatase 
Absolute neutrophil count 
Alanine aminotransferase  
Hematocrit 
Amylase+ 
Hemoglobin 
Aspartate aminotransferase  
Platelet count 
Bicarbonate 
RBC count 
Blood urea nitrogen / total urea 
White blood cell count and differential count 
Calcium 
Red blood cell morphology** 
Chloride 
Reticulocytes 
 
Mean corpuscular hemoglobin 
Creatine kinase 
Mean corpuscular volume 
Creatinine 
Mean corpuscular hemoglobin concentration 
C-reactive protein 
Glucose 
 
Lactate dehydrogenase 
 
Lipase+ 
 
Phosphorus / phosphates 
Magnesium 
Basic Urinalysis (dipstick, including macroscopic appearance, 
bilirubin, blood, color, glucose, ketones, leukocyte esterase, 
nitrite, pH, protein, specific gravity, urobilinogen) 
Full urinalysis (dipstick plus microscopic evaluation) to be 
performed only at the Screening and 28-Day Safety Follow-up 
visits and a basic urinalysis prior to Day 1 of every cycle. 
Potassium 
Sodium 
Total bilirubin / direct bilirubin/ indirect 
bilirubin* 
Total protein 
Uric acid 
 
 
 
ANA***, RF***, TSH, and T4 
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Hepatitis Screeninga 
Hepatitis B surface antigen, hepatitis B core antibody  
Hepatitis C Antibody  
 
ACTH=adrenocorticotropic hormone; ANA=antinuclear antibody; IMP=Investigational Medicinal Product; PCR = 
polymerase chain reaction; RF=rheumatoid factor; TSH=thyroid-stimulating hormone; T4=free thyroxine. 
** Only in case of anemia onset assessed as related to study treatment 
+Only day 1 of every cycle 
***Only at pre-screening evaluation (see schedule of assessments) 
a If hepatitis B surface antigen positive and hepatitis B core antibody positive, then reflex to 
quantitative HBV DNA (PCR); if hepatitis B core antibody positive alone, then reflex to quantitative 
hepatitis B DNA (PCR); if hepatitis C antibody positive, then reflex to quantitative hepatitis C RNA 
(PCR).  
If a subject has a clinically significant abnormal laboratory test value that is not present at Baseline, 
the test will be repeated weekly and the subject will be followed until the test value has returned 
to the normal range or the Investigator has determined that the abnormality is chronic or stable. 
For pharmacokinetic assessment of M7824, a blood sample should be collected prior to infusion 
of M7824 and following completion (within 30 minutes) of infusion of M7824 (doses 1 and 3), 
prior to dose 2, and prior to dose 6/end of treatment visit (whichever of these two comes first).  
Samples should be processed as follows: 
1.  Collect 3.5 mL of blood in an SST tube with silica clot activator and polymer gel. 
2. Gently invert the tube 5 times to mix the clot activator with the blood. 
3. Allow blood to clot for 30 minutes at room temperature in a vertical position. 
4.  After allowing clot to form, centrifuge the tube for 15 minutes at 1100-1300x g at 25°C.   
     If refrigerated centrifuge is available, set the temperature at 25°C in order to prevent  
     heating during centrifugation and to optimize flow of the barrier material.  Flow may  
     be 
impeded 
if 
chilled 
before 
or 
during 
centrifugation. 
5. Carefully collect and aliquot the serum equally into 2 separate Micronics tubes. 
6. Place the tubes immediately into the freezer in an upright position at -80°C. 
7.  Samples will be analyzed as a batch with EMD Serono at a later date. 
6.4.4 
Vital Signs, Physical Examinations, and Other Assessments 
The ECOG PS will be assessed at Screening and at subsequent visits as indicated in the Schedules 
of Assessments (Tables 1-3) and documented in the eCRF (Prometheus). 
Body weight will be measured at Screening and at subsequent visits as indicated in the Schedules 
of Assessments (Tables 1-3) and documented in the eCRF (Prometheus). Body height will be 
measured at screening only. 
A physical examination will be conducted at Screening and at subsequent visits as indicated in the 
Schedules of Assessments (Tables 1-3) and documented in the eCRF (detailed description in 
Section 6.1). Any abnormalities arising or worsening after the signing of the ICF should be 
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documented in the eCRF (Prometheus) Adverse Event section (see Section 6.4.1). Abnormal 
findings are to be reassessed at subsequent visits. 
Physical examination should include a dermatological examination.  If abnormal skin findings are 
observed, the patient should be referred to a dermatologist for biopsy of suspicious lesions. 
An ophthalmology examination including slit lamp evaluation inclusive of the anterior segment 
and with visual acuity should be conducted at Screening. At subsequent visits, eye signs and 
symptoms should be checked. If there are any clinically relevant findings then an appropriate 
ophthalmology examination including slit lamp evaluation inclusive of the anterior segment and 
with visual acuity should be obtained within 2 days. 
Digital 12-lead EKGs will be recorded as a single recording at the screening visit. Subsequent 
EKGs will likewise be obtained as single recordings.  
All newly diagnosed or worsening conditions, signs and symptoms observed since Screening, 
whether related to trial treatment or not, are to be reported as AEs. 
For female subjects of childbearing potential, serum β-HCG pregnancy test will be carried out 
during the Screening phase. A urine β-HCG test may be performed prior to schedule on treatment 
assessments. Results of the most recent pregnancy test should be available prior to the next dosing 
of IMP. Subjects who are postmenopausal (age-related amenorrhea ≥ 12 consecutive months and 
if needed FSH > 40 mIU/mL [in the postmenopausal range] as outlined in Section 6.1.1), or who 
have undergone hysterectomy or bilateral oophorectomy are exempt from pregnancy testing. If 
necessary to confirm postmenopausal status, an FSH will be drawn at Screening. 
6.4.5 
Biomarkers  
Due to limited understanding of the biological activities induced by M7824 in cancer subjects, 
there can be no certainty that the doses examined will be associated with relevant antitumor 
immune activities. Further details regarding translational studies are listed in Appendix 3.  As the 
consequence, the trial will serve to 
1. Evaluate MSI-H status with CMS subtype 
a. MSI will be assessed by MSI-H CRC either by IHC for loss of protein expression 
in one of 4 mismatch repair proteins (MLH1, MSH2, MSH6, PMS2) or by detection 
of microsatellites within the tumor DNA (as per institutional practices) 
b. External MSI testing in a CLIA certified laboratory with a documentation of MSI-
H status performed prior to screening is acceptable for inclusion in cohort A- C.  
2. Evaluate PD-L1 expression as a predictor of response 
a. Primary tumor will be stained for PD-L1 expression by IHC 
b. PD-L1 staining will be semi-quantitatively scored by absence, weak, moderate,  
strong by a pathologist 
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c. The above will be performed on the mandatory fresh on-treatment biopsy. 
3. Evaluate the effect on TGFβ concentrations in plasma. 
4. Evaluate potential predictive / prognostic biomarker candidates related to the drug and / or 
the cancer (such as the CMS, immune infiltrating populations, systemic cytokine profiles) 
a. CMS will be assessed using a 75 gene FFPE based assay using the Nanostring 
technology in a CLIA-certified laboratory at MD Anderson.  
i. Current discovery of 74 samples run in 18 batches with random duplicate 
samples to assess technical validity demonstrate accuracies compared to 
gold standard gene expression by Affymetrix hybridization: 
1. A 75 gene model had 4 group CMS accuracy of 87.1% with very 
high accuracies (>90%) in CMS1 and CMS2 groups which were 
over-represented in this small cohort 
2. The CMS4 versus other subgroups demonstrated accuracy of 90.6% 
3. The Nanostring technology on FFPE has been successfully applied 
to breast cancer67 and lymphoma68 cohorts 
4. The Nanostring codesets utilized for the CMS classification are now 
being assessed for technical validity in MDA’s CLIA molecular 
pathology laboratory 
 
b. Immune infiltrating populations will be analyzed by immunohistochemistry (IHC), 
and Multiplex IF analyses. 
1. IHC markers will include, but are not limited to, PD-L1, CD3, 
Foxp3, CD25, CD8, CD68, CD56, CD20, CD45RO and granzyme 
B. We may also include PD-L2, B7-H3, B7-x/H4, galectin 9, 
HVEM and CD48 to measure in tumors and PD-1, 2B4, LAG-3, 
Tim-3 and BTLA in TILs. These studies will be conducted at TMP-
IL. 
2. Multiplex IF Analysis. Up to 10 immune markers, 2 panels may be 
utilized. Currently, there are 2 Vectra panels optimized: Panel#1, 
CD3, CD8, CD68, PD-L1, PD-1 pan-cytokeratin and DAPI; Panel 
#2, CD20, CD45RO, FOXP3, Granzyme B, CD57, pan-cytokeratin 
and DAPI.  A third myeloid panel will be developed. For multiplex 
IF analysis, we will use the Opal chemistry and multispectral 
microscopy Vectra system (Perkin-Elmer) which includes the 
Nuance software; analysis will be performed using the InForm 
software. Additional markers will be selected according the results 
of the gene expression analysis and may include other 
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immunotherapy targets (e.g., OX-40, Vista, GITR, TIM-3, LAG-3, 
NKp46/CD16, etc.) and proliferation markers (e.g., Ki67).  
3. RNAscope.  TGF-β and other additional markers may be analyzed 
by RNA scope.  
c. Immune infiltrating populations and systemic cytokine profiles 
i. Blood collections and biopsies prior to week 8 treatment will be collected for 
immune studies under the supervision of the Translational Molecular Pathology 
Immunoprofiling Lab (TMP-IL) at MD Anderson. 
ii. In tumor tissue, IHC studies will be performed to evaluate CD3+, CD4+ and 
CD8+ T cells, Treg, NK cells, macrophage [M1/2 profile] infiltrating populations. 
Fresh tissue will be available for flow cytometry analysis on larger tumor 
samples only. We will assess the proportion of MDSC, macrophage, DC and NK 
cell subsets within the Live CD45+ cells in panel 3. The expression of checkpoint 
ligands will be explored using panel 4. Live cells will be sub-gated as CD45-
negative to exclude immune cells. EPCAM will be used as a marker of tumor 
cells and CD90 as a fibroblast marker. The expression of CD80, CD86, GITR-
L, ICOS-L, MIC A/B, B7-H3, B7-H4, CD73, PD-L2, OX40L and other relevant 
immune cells will be assessed. 
iii. In peripheral blood, evaluation by circulating immune populations will 
include, but not be limited to, CD4+, CD8+, NK, Treg, monocytes and neutrophils 
as outlined by the Schedules of Assessments (Tables 1-3). High order flow 
cytometry panels will be designed. The panels will focus on 1) delineation of 
major immune cell types (T cells, B cells, NK cells, DC), 2) determination of T 
cell differentiation status and limited functionality (IFNγ, TNFα, GB) and 3) 
defining the expression level of costimulatory and coinhibitory molecules on T 
cells. The proposed studies will be conducted retrospectively on cryopreserved 
PBMCs. 
iv. Serum Cytokine Analyses.  Cytokines (IFN-γ, IL-1α, IL-2, IL-4, IL-5, IL-8, 
IL-10, IL-12p70, IL-13, and TNF-α) will be measured in the serum using the 
Meso Scale Discovery Platform (Rockville, MD). This technology allows for the 
detection of up to 40 analytes per well and uses a very low sample volume. This 
method has a sensitivity up to 1000 fold higher than traditional ELISA assays 
with a large linear range of 3-4 logs. The instrument performs immunoassays 
utilizing electrochemiluminescense to detect the signal in a 96 well plate format. 
This technology can be utilized for either single agent detection or in multiplex 
format. A wide menu of validated single or multiplex kits for the detection of 1 
to 40 analytes are available from the manufacturer and can be customized. 
d. Mutational profiling 
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i. KRAS, NRAS and BRAF will be assessed via next generation sequencing 
in a panel of 409 genes that sequences known hotspots to a coverage of at 
least x250 coverage depth performed in the Molecular Diagnostic 
Laboratory (MDL) at MD Anderson. The lab is CAP accredited and CLIA 
certified to perform high complexity molecular testing for clinical purposes. 
ii. Tumor DNA analysis for KRAS, NRAS and BRAF performed in another 
CLIA certified molecular diagnostics laboratory do not need to be tested 
again 
iii. TGFβ signaling pathway mutations will also be assessed via this panel 
which will include, but not limited to, TGFβR2, ACVR2A, SMAD2 and 
SMAD4. 
iv. RNA-seq and WES. This analysis will be performed using fresh frozen 
tissue specimens from CNB at MD Anderson Sequencing Facilities. 
v. Optionally, using plasma specimens, genotyping analysis of circulating free 
DNA (cfDNA), circulating tumor cells (CTCs), and exosome (exo)-DNA 
may be performed to monitor tumor response and progression.  
5.   Microbiome analyses of buccal and fecal biospecimens 
i. Buccal and fecal specimens may be collected at defined time points for 
microbiome studies. Buccal swab (buccal smear or cheek swab) will be 
collected firmly rubbing the entire inner surface of both cheeks for 10 sec 
each side using a sterile polyester swab using standard SOPs.  Stools for 
enteric microbiome analysis will be collected using the OMNIgene kit 
(DNA Genotek, Ottawa, Ontario, Canada). The collection will allow 
obtaining high quality DNA suitable for microbiome profiling and 
sequencing. 
ii. Analysis: Bacterial identification and classification is achieved by profiling 
the 16S rRNA gene, which is present in all bacteria but has sufficient 
sequence level diversity for classification purposes. 16S deep sequencing is 
cost-effective and technically and computationally robust, and can be 
utilized as a primary assay to initially characterize fecal samples. Briefly, 
the bacterial 16S rRNA V3-V4 region from each sample will be amplified 
and amplicons sequenced using a MiSeq 2x250 bps protocol. An internal 
pipeline will be utilized for read processing and analysis. Operational 
taxonomic unit (OTU) classification will be achieved by mapping the 
UPARSE OTU table to an optimized version of the SILVA database. 
Abundances will be recovered by mapping the de-multiplexed reads to the 
UPARSE OTUs and a custom script will construct an OTU table from the 
output files generated in the previous two steps. This OTU table will be used 
to calculate diversity, 2-dimensional visualization, and taxonomic 
summaries. 
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Details of time points and sampling are provided in the Schedules of Assessments (Tables 1-3).  
All proposed biomarker analyses are exploratory and dependent on the quality and availability of 
sufficient materials. The panel of biomarkers might be adjusted based on results from ongoing 
research related to anti-PD-1 / PD-L1 therapies and / or safety, therefore, each subject will also be 
asked whether any remaining tumor tissue and blood-derived samples can be stored at a central 
repository (until such time as these samples cannot support any further analysis) and can be used 
for future exploratory research on the drug and / or disease-related aspects. A subject’s consent to 
the use of any remaining samples for such future exploratory research shall be optional and shall 
not affect the subject’s participation in the current trial. 
6.4.5.1 
Target-related Biomarkers 
Blood will be collected to analyze PD-L1 target occupancy, TGFβ 1, 2, 3 concentrations, and 
circulating cytokine levels according to the Schedule of Assessments (Tables 1-3).  
6.4.5.2 
Immunomonitoring 
As biomarker research is constantly evolving, the selection of markers with the highest specificity 
and relevance to treatment effect may change. 
Leukocyte subpopulations and immune activation status will be assessed by flow cytometry 
(fluorescence-activated cell sorter [FACS]) on PBMC from heparinized blood samples (10 mL, 
tubes) drawn at the time points outlined in the Schedule of Assessments (Tables 1-3). 
Soluble factors (for example, cytokines profile, soluble PD-1, and soluble PD-L1) will be assessed 
on blood (plasma / serum) samples collected as outlined in the Schedule of Assessments (Tables 
1-3). 
Plasma will be stored at -80 degrees and sent for immunoprofiling for interleukin (IL) IL-1α, IL-
1β, IL-2, IL-5, IL-6, IL-8, IL-13, TNF-α, MCP, MIP-1β, G-CSF, GM-CSF, IFN-γ via a cytokine 
assay.  
6.4.5.3 
Predictive and Prognostic Biomarkers 
It is important to identify biomarkers that help to predict and / or evaluate the efficacy of the 
therapy, in order to achieve the optimal benefit from targeted therapies. No thoroughly validated 
biomarkers are available to date for anti-PD-1 / PD-L1 and anti-TGFβ therapies; therefore, this 
trial plans to evaluate biomarkers from pre-treatment and post-treatment tumor biopsies of primary 
tissue and blood samples that might be predictive of therapy outcome for all indications. Of note, 
availability of a tumor sample will be a prerequisite for all subjects. 
The following requirements apply to the tissue samples collected during the trial: 
Tissue collection: Endoscopic biopsies, core needle biopsies, excisional biopsies and surgical 
specimens are acceptable. Fine needle aspiration biopsies are not acceptable.  
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Additionally, a mandatory on-treatment biopsy will be performed in cohort A-C prior to cycle 2, 
day 1 of M7824 administration. A mandatory on-treatment biopsy prior to cycle 1, day 11 and 
cycle 2, day 1 for cohort B will also be performed.  Resected tissue from metastatic resection will 
serve as the baseline, pretreatment specimen for Cohort D.  
Microbiome sample collection: Collection of stool samples for microbiome analyses can be done 
using OMNIgene-Gut kits. OMNIgene-Gut is an all-in-one system for easy self-collections and 
stabilization of microbial DNA from feces. It allows easily self-collection at home. Samples are 
rapidly homogenized and stabilized at the point-of-collection and shipped to the laboratory for 
aliquoting and freezing at -80C prior DNA extraction. This kit allows the collection of high-quality 
DNA suitable for 16 rRNA microbiome profiling, sequencing and other assays. Buccal swab 
(buccal smear or cheek swab) will be collected firmly rubbing the entire inner surface of both 
cheeks for 10 sec each cheek side using a sterile polyester swab and storing in Eppendorf tube at -
80°C until DNA extraction and analyses.  Tissue processing: The cancer tissues should be fixed 
in 10% neutral buffered formalin (NBF), paraffin-embedded and routinely processed for 
histological evaluation. Formalin substitutes are not suited as fixative. 
Tissue storage: Fresh tumor tissue obtained from subjects for the evaluation of efficacy should be 
stored in defined cryopreservation medium containing 10% dimethyl sulfoxide [CryoStor® CS10]. 
Provision of samples: 1. priority: tumor-containing formalin fixed, paraffin embedded (FFPE) 
tissue block; 2. Priority: if the tumor containing FFPE tissue block cannot be provided in total, 
sections from this block should be provided which are freshly cut, 4 μm thick and mounted on 
positively-charged microscope slides. SuperFrost Plus glass slides are recommended. Preferably, 
25 slides should be provided; if not possible a minimum of 10 slides is required. Tumor tissues 
suitable for biomarker analysis are required. Suitable means that the central laboratory can confirm 
that the tissue is evaluable (enough viable tumor cells are present).  
Sample storage: At the central laboratory the FFPE tissue blocks shall be stored at room 
temperature and the fresh-frozen tumor slides shall be frozen in sealed containers at -20°C. 
A panel of putative markers including molecular, soluble and cellular markers will be analyzed at 
baseline from archived tumor tissue (or fresh tumor biopsy, preferred when available), and from 
serum / plasma samples/microbiome to investigate a possible correlation between clinical efficacy 
and analyzed markers. 
The following assessment will be considered: 
• CMS classification based on FFPE based RNA expression.  
• Level of PD-L1 expression in fresh biopsy by IHC staining. Of note, further techniques to 
evaluate the expression of PD-L1 and / or marker candidates impacting the targeting or 
contributing to improve its expression may be also investigated if needed. 
• Level of circulating TGFβ. 
• Frequency and localization of tumor-infiltrated leukocytes (for example, CD3, CD8, CD4 
T-cells, Treg, NK cells, macrophage [M1/2 profile]) by IHC. 
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• If quantity of tissue permits, genomic characterization of TGFβ signaling components (for 
example, SMAD4) 
• Further exploratory markers related to the MoA) of the drug such as soluble PD-L1 sera 
level, intratumoral cytokine profile, and auto-antigen proteomic arrays may be explored. 
• Further cellular and / or molecular markers specific to the cancer may be also investigated 
according to the indication. 
• Microbiome sequencing analyses of buccal and fecal samples will be conducted. 
7 
Statistics 
7.1 
Sample Size Calculations 
7.1.1 
Cohort A-C 
7.1.2 
The total sample size of this cohort is 15 patients. With this 
sample size, the half-width of the 95% confidence interval for 
the estimated response rate will be at most 0.253. Cohort B 
For this cohort, the Simon’s Optimum two-stage design will be implemented. A historical response 
rate of 5% and a target response rate of 25% are assumed under the null and the alternative 
hypotheses, respectively. In the first stage, we will enroll 15 patients; if 1 or fewer achieves a best 
response of CR/PR, we will stop enrolling patients. Otherwise, we will continue to enroll all 29 
patients and the treatment is deemed as promising if there are 4 or more responders out of these 29 
patients. The design has a type I error rate of 0.042, a 90% power and a probability of early 
termination of 82.9% under the null hypothesis. Patient enrollment will be temporarily suspended 
when the enrollment for the first stage patients has been completed yet not enough responders have 
been observed to trigger the start of second stage. 
7.1.3 
Cohort D 
The total sample size of this cohort is 15 patients. With this sample size, the half-width of the 95% 
confidence interval for the estimated response rate will be at most 0.253. 
 
7.2 
Randomization 
Not applicable. 
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7.3 
Endpoints 
7.3.1 
Primary Endpoints 
The primary endpoints are objective response (i.e. CR+PR) according to iRECIST 1.1 criteria for 
cohorts A-C and B, and clearance of ctDNA for cohort D.  
 
7.3.2 
Secondary Endpoints 
The secondary endpoints to this study are: 
• PFS according to iRECIST 1.1 criteria. 
• DFS (cohort D) 
• OS  
• Number, severity, and duration of treatment related AEs according to NCI-CTCAE v4.03 
7.3.3 
Exploratory Endpoints 
The exploratory endpoints for this study are: 
• Changes in intratumoral immune populations, gene expression and proteomic profiles pre 
and post-treatment with M7824 where paired biopsies are available 
• Changes in circulating immune cell populations and cytokine profiles pre and post-
treatment with M7824 
• Circulating levels of TGF-β collected from serial plasma samples. 
7.4 
Analysis sets 
The following analysis sets will be defined: 
Safety Analysis Set: All subjects who receive at least 1 dose of trial treatment. 
7.5 
Description of Statistical Analyses 
7.5.1 
General Considerations 
All data recorded during the study will be presented in individual data listings performed on the 
Safety Analysis Set. All data will be evaluated as observed, and no imputation method for missing 
values will be used. All data will be presented in a descriptive manner. Each cohort will be 
analyzed separately, and no multiplicity adjustment across cohorts will be performed. 
Descriptive statistics will be used to summarize the trial results, that is, statistics for continuous 
variables may include means, medians, ranges, and appropriate measures of variability. 
Categorical variables will be summarized by counts and percentages. The uncertainty of estimates 
will be assessed by confidence intervals. Unless otherwise specified, the calculation of proportions 
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will be based on the sample size of the analysis set of interest. Counts of missing observations will 
be included in the denominator and presented as a separate category. 
All other statistical analyses will be performed using SAS® Version 9.1.3 or higher, or R, Version 
2.10.1 or higher. 
7.5.2 
Analysis of Primary Endpoint 
7.5.2.1 
Response Rate 
7.5.2.1.1 
Cohorts A-C and B 
Patient response will be determined using iRECIST 1.1. Unconfirmed responses will not be used 
in the final analysis. ORR is defined by the number of (PR + CR)/ (total number of treated 
patients) in the safety analysis set. For all cohorts, we will estimate the response rate along with 
the two-sided exact 95% confidence interval. Also for Cohort B, if the trial continues to the full 
enrollment of 29 patients, we will declare M7824 with radiation promising and worthy of further 
investigation if there are at least 4 responders out of these 29 patients. 
7.5.2.1.2 
Cohort D 
Identification of somatic mutations in the blood will be confirmed by sequencing of the resected 
tumor using a CLIA-certified next-generation sequencing panel at MD Anderson.  Clearance of 
ctDNA will be characterized by the disappearance of all somatic mutations identified in the blood, 
as well as no appearance of any additional new somatic mutations following 6 doses of M7824.  
For this cohort, we will estimate the response rate as the percentage of patients whose ctDNA 
status converts from “positive” to “negative” after twelve weeks of therapy with M7824 relative 
to the total number of patients treated. 
7.5.3 
Analysis of Endpoints 
7.5.3.1 
Secondary Endpoints 
The secondary endpoints of PFS (cohorts A-C and B) and DFS (cohort D) according to iRECIST 
1.1 and OS time will be presented using the Kaplan-Meier method.  PFS will be measured in 
months from the date of first administration of M7824 to the date of documented progression by 
RECIST 1.1 or death by any cause, whichever is earlier. For Cohort D, DFS will be measured in 
months from the date of documented recurrence or development of distant metastasis by iRECIST 
1.1 criteria.  Median PFS and DFS and 95% confidence intervals will be estimated using the 
Kaplan-Meier method. 
OS will be measured in months from the date of first administration of M7824 to the date of death 
by any cause. Median OS with 95% confidence interval will be estimated using the Kaplan-Meier 
method. Severity of AEs will be graded using the NCI-CTCAE v4.03 toxicity grading scale. 
Safety will be assessed by descriptive statistics and summarized in tabular format. This data will 
be separated based on organ class, immune-relation, severity and relation to M7824.  
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Adverse events (serious and non-serious) will be considered treatment emergent adverse events 
when emerging during the on-treatment period defined as the time from first trial drug  
administration  to  the  last  drug  administration date + 30 days or the earliest date of subsequent 
anticancer drug therapy minus 1 day, whichever occurs first, unless otherwise stated. All 
premature terminations will be summarized by primary reason for treatment withdrawal.  
7.5.3.2 
Exploratory Endpoints 
Summary statistics will be tabulated for microsatellite instability, CMS1, CIMP, KRAS and BRAF 
status. Paired t-test or Wilcoxon signed rank test will be used to assess the changes in biomarkers 
pre- and post-treatment. The differences in biomarker levels between responders and non-
responders will be assessed using X2 or Fisher’s exact test as appropriate. Similar analysis will be 
used to assess the correlation between biomarker mutation statuses.  
Statistical analyses will be conducted by MDACC statisticians. Tabulations will be produced for 
appropriate demographic, baseline, efficacy and safety parameters.  For categorical variables, 
summary tabulations of the number and percentage of subjects within each category (with a 
category for missing data) of the parameter will be presented, as well as two-sided 95% confidence 
intervals, unless otherwise stated. For continuous variables, the number of subjects, mean, median, 
standard deviation (SD), minimum, and maximum values will be presented.  Time-to-event data 
will be summarized using Kaplan-Meier methodology using 25th, 50th (median), and 75th 
percentiles with associated 2-sided 95% confidence intervals, as well as percentage of censored 
observations. 
7.5.3.3 
Adverse Events 
Severity of AEs will be graded using the NCI-CTCAE v4.03 toxicity grading scale. Safety will 
be assessed by descriptive statistics and summarized in tabular format. This data will be separated 
based on organ class, immune-relation, severity and relation to M7824.  
Adverse events (serious and non-serious) will be considered treatment emergent adverse events 
when emerging in the on-treatment period defined as the time from the first  trial  drug  
administration  to  the  last  drug  administration date + 30 days or the earliest date of subsequent 
anticancer drug therapy minus 1 day, whichever occurs first, unless otherwise stated. All 
premature terminations will be summarized by primary reason for treatment withdrawal. 
7.5.3.4 
Laboratory Variables 
Laboratory results will be classified by grade according to NCI-CTCAE v4.03. The worst on-trial 
grades after the first trial treatment will be summarized. Shifts in toxicity grading from first 
treatment to highest grade will be displayed. Results for variables that are not part of NCI-CTCAE 
will be presented as within or above normal limits. Only subjects with post-Baseline laboratory 
values will be included in these analyses. 
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7.5.3.5 
Physical Examination, Including Vital Signs and 12-Lead 
Electrocardiogram 
Vital signs (body temperature, respiratory rate, heart rate, and blood pressure), eye signs and 
symptoms based on System Organ Class of “eye disorders”, and 12-lead EKG recorded according 
to the Schedules of Assessments (refer to Tables 1-3) will be presented. 
7.6 
 Interim safety monitoring 
For each cohort, we will implement Bayesian toxicity monitoring69 such that we will all stop 
patient enrollment into a cohort if there is a high probability that the AE rate of M7824 is greater 
than 20%. For each cohort separately, we will apply the toxicity monitoring rule in cohort size of 
5, starting from the 5th patient. For cohort A-C, the toxicity stopping rule to be applied is as 
follows: Stop patient enrollment in a cohort if Prob(p>0.20 |data ) > .75, where p denotes the 
probability of toxicity.  
 
Assuming a beta(.4, 1.6) priori for p, the above decision criterion implies that we will stop cohort 
A or cohort C according to table 8 below.  
Table 8: Toxicity stopping boundaries for Cohort A-C and D 
Number 
of 
evaluable 
patients 
Number 
of 
patients 
with 
toxicities is at least 
5 
2 
10 
4 
15 
5 
The operating characteristics for toxicity monitoring in cohort A-C are illustrated in Table 9.  
Table 9: Operating Characteristics for Toxicity Monitoring in Cohort A-C and D 
True toxicity rate 
Prob (stop early) 
Average Sample Size 
0.10 
0.086 
14.2 
0.20 
0.284 
12.3 
0.30 
0.532 
10.0 
0.40 
0.750 
8.0 
0.50 
0.894 
6.5 
 
Similarly for cohort B, the toxicity stopping rule to be applied is as follows: Stop patient enrollment 
if Prob(p>0.20 |data ) > .85, where p denotes the probability of toxicity. Assuming a beta(.4, 1,6) 
priori for p, the above decision criterion implies that we will stop cohort B according to table 10 
below.  
 
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Table 10: Toxicity stopping boundaries for Cohort B 
Number 
of 
evaluable 
patients 
Number 
of 
patients 
with 
toxicities is at least 
5 
3 
10 
4 
15 
5 
20 
7 
25 
8 
29 
9 
The operating characteristics for toxicity monitoring in cohort B are illustrated in Table 11.  
Table 11: Operating Characteristics for Toxicity Monitoring in Cohort B 
True toxicity rate 
Prob (stop early) 
Average Sample Size 
0.10 
0.25 
28.5 
0.20 
0.238 
24.9 
0.30 
0.623 
18.4 
0.40 
0.900 
12.3 
0.50 
0.989 
8.7 
The stopping boundaries and the operating characteristics for cohorts A-C and B were generated 
using Shiny application for Bayesian toxicity monitoring (http://qctrlshiny/postprobtoxicity). 
AEs of 3 or greater and deemed related to M7824 (section 6.4.1.1.1) will count towards toxicity 
calculations with respect to interim safety monitoring. AEs of 3 or greater deemed unrelated to 
M7824 are not included towards safety decision making. These include AEs attributable to disease 
progression (section 6.4.1.1.2) and abnormal laboratory or investigational values that are 
asymptomatic or do not result in treatment discontinuation (section 6.4.1.1.1). 
The time period that grade 3 AEs attributable to M7824 are counted towards interim safety 
monitoring decisions is defined from their onset to 90 days after the last dose of study drug (section 
6.4.1.1.3).  
Any grade 5 event on-study will require suspension of the study pending review of the safety 
data regarding the death. 
The Investigator is responsible for completing an efficacy/safety summary report, and submitting 
it to the IND Office Medical Affairs and Safety Group, for review and approval.  This should be 
submitted after the first 5 evaluable patients per cohort, complete 1 cycle of study treatment, and 
every 5 evaluable patients per cohort, thereafter. On every report submission, the information 
from previous reported patients will need to be updated. 
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A copy of the cohort summary should be placed in the Investigator’s Regulatory Binder under 
“IND Office correspondence”. 
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