Conditions: Carcinoma, Small Cell Lung Cancer Small Cell Lung Cancer
Keywords: Chemosensitivity DNA Damage and Replication PD-1/PD-L1 Solid Tumors Checkpoint Inhibitors
Allocation: NON_RANDOMIZED | Intervention model: SEQUENTIAL
Enrollment: 37
Healthy volunteers: no

Brief summary:
BACKGROUND:

* Small cell lung cancer (SCLC) is an aggressive cancer with a poor prognosis. Although highly responsive to chemotherapy initially, SCLC relapses quickly and becomes refractory to treatment within a few months.
* The inability to destroy residual SCLC cells despite initial chemosensitivity suggests the existence of a highly effective deoxyribonucleic acid (DNA) damage response network. SCLC is also characterized by high DNA replication stress (retinoblastoma (RB1) inactivation, MYC and CCNE1 activation).
* There is only one Food and Drug Administration (FDA) approved treatment for patients with relapsed SCLC after first-line chemotherapy: topotecan, which inhibits religation of topoisomerase I-mediated single-strand DNA breaks leading to lethal double-strand DNA breaks. Temozolomide, an oral alkylating agent, which causes DNA damage by alkylating guanine at position O6 also has activity in relapsed SCLC, particularly for brain metastases.
* Preliminary evidence indicates that disruption of the immune checkpoint programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) pathway can yield responses in a subset of SCLC patients, but response rates (approximately equal to 10%) are lower than non-small cell lung cancer (NSCLC) and other tumors with comparable tumor mutational burden indicating additional immunosuppressive mechanisms at play in the SCLC tumor microenvironment.
* M7824 (MSB0011359C) is a bifunctional fusion protein consisting of an anti-programmed death ligand 1 (PDL1) antibody and the extracellular domain of transforming growth factor beta (TGF-beta) receptor type 2, a TGF-beta trap.
* Safety data from the dose-escalation study in solid tumors as well as preliminary data from expansion cohorts show that M7824 has a safety profile similar to other checkpoint inhibiting compounds.
* Combining immunotherapy, and chemotherapy could synergistically improve the anticancer activity of immunotherapy. Combination of chemotherapy with immunotherapy have improved outcomes in NSCLC and melanoma leading to Food and Drug Administration (FDA) approvals of such combinations.
* We hypothesize that increased DNA damage induced by topotecan and temozolomide will complement the anti-tumor activity of M7824, in recurrent SCLC.

OBJECTIVE:

\- The primary objective of the trial is to determine the efficacy (using objective response rate) of M7824 plus topotecan or temozolomide in relapsed SCLC.

ELIGIBILITY:

* Subjects with histological or cytological confirmation of SCLC.
* Subjects must be greater than or equal to 18 years of age and have a performance status (Eastern Cooperative Oncology Group (ECOG) less than or equal to 2.
* Subjects must not have received chemotherapy or undergone major surgery within 2 weeks and radiotherapy within 24 hours prior to enrollment.
* Subjects must have adequate organ function and measurable disease.

DESIGN:

* Arm A (M7824 monotherapy): Up to 10 patients may be treated with M7824 monotherapy to obtain safety and pharmacokinetic (PK) data, and a preliminary estimate of clinical responses to M7824 in SCLC. Patients with progressive disease on Arm A may then receive M7824 plus temozolomide as per description of treatment for Arm C.
* Arm B (M7824 plus topotecan) and Arm C (M7824 plus temozolomide) will be administered in 3 and 4-week cycles respectively; these arms will have a safety run-in followed by efficacy analysis. Up to 10 patients with extrapulmonary small cell cancer will be enrolled in arm C to receive the combination of M7824 and temozolomide.
* Optional tumor biopsies will be obtained at pre-treatment on cycle 1 day 1 (C1D1) and C1D15 for Arm C; pre-treatment on C1D1 and cycle 2 day 1 (C2D1) for arms A and B.
* Every subject of each arm of the safety run-in will be observed for at least 7 days after first dose of M7824 before the subsequent subject can be treated. Subjects who are not evaluable for dose-limiting toxicity (DLT) will be replaced and not included into evaluation.

ARMS:

* Arm A (3-week cycles): M7824 monotherapy 2400 mg every 3 weeks until disease progression or a criterion in Protocol is met. Patients with progressive disease on Arm A may then receive 1200 mg M7824 every 2 weeks plus temozolomide 200 mg/m\^2/day on days 1-5 every 4 weeks.
* Arm B (3-week cycles): M7824 2400 mg plus topotecan 1 mg/m(2) on days 1-5 every 3 weeks until disease progression or a criterion in Protocol is met.
* Arm C (4-week cycles): M7824 1200 mg every 2 weeks plus temozolomide 200 mg/m(2)/day on days 1-5 every 4 weeks until disease progression or a criterion in Protocol is met.

Detailed description:
Background

Small cell lung cancer (SCLC) is an aggressive cancer with a poor prognosis. Although highly responsive to chemotherapy initially, SCLC relapses quickly and becomes refractory to treatment within a few months.

Extrapulmonary small cell cancers are extremely rare and management of systemic disease with chemotherapy is patterned after the approach used in SCLC.

The inability to destroy residual SCLC cells despite initial chemosensitivity suggests the existence of a highly effective deoxyribonucleic acid (DNA) damage response network. SCLC is also characterized by high DNA replication stress (retinoblastoma (RB1) inactivation, MYC and CCNE1 activation). Similarly, extrapulmonary small cell cancers have no standard treatments and it appears that although these cancers can arise by different mechanisms, they have in common high replication stress, that may be susceptible to DNA damage and immune checkpoint blockade.

There is only one Food and Drug Administration (FDA) approved treatment for patients with relapsed SCLC after first-line chemotherapy: topotecan, which inhibits religation of topoisomerase I-mediated single-strand DNA breaks leading to lethal double-strand DNA breaks. Temozolomide, an oral alkylating agent, which causes DNA damage by alkylating guanine at position O6 also has activity in relapsed SCLC, particularly for brain metastases.

Preliminary evidence indicates that disruption of the immune checkpoint programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) pathway can yield responses in a subset of SCLC patients, but response rates (approximately 10%) are lower than NSCLC and other tumors with comparable tumor mutational burden indicating additional immunosuppressive mechanisms at play in the SCLC tumor microenvironment.

M7824 (MSB0011359C) is a bifunctional fusion protein consisting of an anti-programmed death ligand 1 (PD-L1) antibody and the extracellular domain of transforming growth factor beta (TGF- beta) receptor type 2, a TGF- beta trap.

Safety data from the dose-escalation study in solid tumors as well as preliminary data from expansion cohorts show that M7824 has a safety profile similar to other checkpoint inhibiting compounds.

Combining immunotherapy, and chemotherapy could synergistically improve the anticancer activity of immunotherapy. Combination of chemotherapy with immunotherapy have improved outcomes in non-small cell lung cancer (NSCLC) and melanoma leading to FDA approvals of such combinations.

We hypothesize that increased DNA damage induced by topotecan and temozolomide will complement the anti-tumor activity of M7824, in recurrent SCLC.

Objective

The primary objective of the trial is to determine the efficacy (using objective response rate) of M7824 plus topotecan or temozolomide in relapsed SCLC.

Eligibility

Subjects with histological or cytological confirmation of SCLC or extrapulmonary small cell cancers.

Subjects must be greater than or equal to 18 years of age and have a performance status Eastern Cooperative Oncology Group (ECOG) less than or equal to 2.

Subjects must not have received chemotherapy or undergone major surgery within 2 weeks and radiotherapy within 24 hours prior to enrollment.

Subjects must have adequate organ function and measurable disease.

Design

Arm A (M7824 monotherapy): Up to 10 patients may be treated with M7824 monotherapy to obtain safety and PK data, and a preliminary estimate of clinical responses to M7824 in SCLC. Patients with progressive disease on Arm A may then receive M7824 plus temozolomide as per description of treatment for Arm C.

Arm B (M7824 plus topotecan) and Arm C (M7824 plus temozolomide) will be administered in 3 and 4-week cycles respectively; these arms will have a safety run-in followed by efficacy analysis. Up to 10 patients with extrapulmonary small cell cancer will be enrolled in arm C to receive the combination of M7824 and temozolomide.

Optional tumor biopsies will be obtained at pre-treatment on cycle 1 day 1 (C1D1) and C1D15 for Arm C; pre-treatment on C1D1 and cycle 2 day 1 (C2D1) for arms A and B.

Every subject of each arm of the safety run-in will be observed for at least 7 days after first dose of M7824 before the subsequent subject can be treated. Subjects who are not evaluable for dose-limiting toxicity (DLT) will be replaced and not included into evaluation.

Arms:
arm 1: M7824 (MSB0011359C) intravenous (IV) monotherapy once every 21 days on a 21-day cycle. If patients have progressive disease on arm A, they may receive combination therapy of M7824 and Temozolomide. arm 2: M7824 (MSB0011359C) intravenous (IV) on day 1 plus topotecan (IV) on days 1-5 of a 21-day cycle. At least 6 subjects to receive M7824 plus topotecan to determine safety. 4 more patients enrolled at initial or lower dose for efficacy. If efficacious, an additional 12 subjects enrolled. arm 3: M7824 (MSB0011359C) intravenous (IV) days 1 and 15 plus temozolomide (oral) on days 1-5 of a 28-day cycle. At least 6 subjects with small cell lung cancer (SCLC) to receive M7824 plus temozolomide to determine safety. 4 more SCLC patients enrolled at initial or lower dose for efficacy. If efficacious, an additional 12 SCLC subjects enrolled. After the 6 safety SCLC cohort, subjects with extrapulmonary small cell cancers will be enrolled.

Interventions: intervention 1: M7824 intervention 2: Topotecan intervention 3: Temozolomide intervention 4: EKG intervention 5: CT scan intervention 6: PET scan intervention 7: Acetaminophen intervention 8: Antihistamines intervention 9: Diphenhydramine intervention 10: Dexamethasone intervention 11: Epinephrine
Intervention descriptions: intervention 1: Arm A \& B: 2400mg intravenous (IV) over up to 120 minutes every 3 weeks on a 3-week cycle. Arm C: 1200 mg IV over 1 hour every 2 weeks on a 4-week cycle. intervention 2: Arm B: 1 mg/m(2) intravenous (IV) over 30 minutes days 1-5 on a 3-week cycle. intervention 3: Arm C and progressive disease patients on Arm A: 200 mg/m(2) by mouth (PO) days 1-5 on a 4-week cycle. intervention 4: Screening and baseline. intervention 5: Computed tomography (CT) scan performed at Screening and after every 2 cycles (6 weeks) per Study Calendar for Arm B 3.5.2, Arm B 3.5.2, and/or Arm C 3.5.3 as applicable. intervention 6: Positron emission tomography (PET) not mandatory - If a computed tomography (CT) scan is not sufficient to assess response, a PET scan may be added per Study Calendar for Arm A 3.5.1, Arm B 3.5.2, and/or Arm C 3.5.3 as applicable. intervention 7: For infusion related reaction, 500-1000 mg by mouth (PO) prior to infusion. intervention 8: As medically indicated. intervention 9: For infusion related reaction, 50 mg by mouth (PO) prior to infusion. intervention 10: As medically indicated. intervention 11: As medically indicated.

Protocol document:
Prot_SAP_000.pdf: 
Abbreviated Title: M7824 in Small Cell Cancers
Version Date: 01/11/2024
1
Abbreviated Title: M7824 in Small Cell Cancers
NIH Protocol #: 18-C-0110 
Version Date: 01/11/2024
NCT Number: NCT03554473
Title: Safety Run-In and Phase II Trial of M7824 and Topotecan or Temozolomide in Relapsed 
Small Cell Cancers
NCI Principal Investigator:
Anish Thomas, MBBS, M.D.
Developmental Therapeutics Branch (DTB)
Center for Cancer Research
National Cancer Institute
10 Center Drive, Room 4-5330
Bethesda, MD 20892
Phone: 240-760-7343
E-mail: anish.thomas@nih.gov
Drug Name:
M7824
Topotecan
Temozolomide
IND Number:
136852
Sponsor:
Center for Cancer Research, National Cancer Institute
Manufacturer:
EMD Serono
Generic
Generic
Supplier:
EMD Serono
NIH CC Pharmacy
NIH CC Pharmacy


Abbreviated Title: M7824 in Small Cell Cancers
Version Date: 01/11/2024
2
PRÉCIS 
Background

Small cell lung cancer (SCLC) is an aggressive cancer with a poor prognosis. Although 
highly responsive to chemotherapy initially, SCLC relapses quickly and becomes 
refractory to treatment within a few months. 

Extrapulmonary small cell cancers are extremely rare and management of systemic 
disease with chemotherapy is patterned after the approach used in SCLC.

The inability to destroy residual SCLC cells despite initial chemosensitivity suggests the 
existence of a highly effective DNA damage response network. SCLC is also 
characterized by high DNA replication stress (RB1 inactivation, MYC and CCNE1 
activation). Similarly, extrapulmonary small cell cancers have no standard treatments and 
it appears that although these cancers can arise by different mechanisms, they have in 
common high replication stress, that may be susceptible to DNA damage and immune 
checkpoint blockade.

There is only one FDA approved treatment for patients with relapsed SCLC after first-line 
chemotherapy: topotecan, which inhibits religation of topoisomerase I-mediated single-
strand DNA breaks leading to lethal double-strand DNA breaks. Temozolomide, an oral 
alkylating agent, which causes DNA damage by alkylating guanine at position O6 also has 
activity in relapsed SCLC, particularly for brain metastases. 

Preliminary evidence indicates that disruption of the immune checkpoint PD-1/PD-L1 
pathway can yield responses in a subset of SCLC patients, but response rates (~10%) are 
lower than NSCLC and other tumors with comparable tumor mutational burden indicating 
additional immunosuppressive mechanisms at play in the SCLC tumor microenvironment. 

M7824 is a bifunctional fusion protein consisting of an anti-programmed death ligand 1 
(PD-L1) antibody and the extracellular domain of transforming growth factor beta (TGF-
β) receptor type 2, a TGF-β trap. 

Safety data from the dose-escalation study in solid tumors as well as preliminary data 
from expansion cohorts show that M7824 has a safety profile similar to other checkpoint 
inhibiting compounds. 

Combining immunotherapy, and chemotherapy could synergistically improve the 
anticancer activity of immunotherapy. Combination of chemotherapy with immunotherapy 
have improved outcomes in NSCLC and melanoma leading to FDA approvals of such 
combinations. 

We hypothesize that increased DNA damage induced by topotecan and temozolomide will 
complement the anti-tumor activity of M7824, in recurrent SCLC.
Objective

The primary objective of the trial is to determine the efficacy (using objective response 
rate) of M7824 plus topotecan or temozolomide in relapsed SCLC.


Abbreviated Title: M7824 in Small Cell Cancers
Version Date: 01/11/2024
3
Eligibility

Subjects with histological or cytological confirmation of SCLC or extrapulmonary small 
cell cancers. 

Subjects must be ≥ 18 years of age and have a performance status (ECOG) ≤ 2.

Subjects must not have received chemotherapy, or undergone major surgery within 2 
weeks and radiotherapy within 24 hours prior to enrollment.

Subjects must have adequate organ function and measurable disease.
Design

Arm A (M7824 monotherapy): Up to 10 patients may be treated with M7824 monotherapy 
to obtain safety and PK data, and a preliminary estimate of clinical responses to M7824 in 
SCLC. Patients with progressive disease on Arm A may then receive M7824 plus 
temozolomide as per description of treatment for Arm C.

Arm B (M7824 plus topotecan) and Arm C (M7824 plus temozolomide) will be 
administered in 3 and 4-week cycles respectively; these arms will have a safety run-in 
followed by efficacy analysis. Up to 10 patients with extrapulmonary small cell cancer 
will be enrolled in arm C to receive the combination of M7824 and temozolomide.

Optional tumor biopsies will be obtained at pre-treatment on C1D1 and C1D15 for Arm 
C; pre-treatment on C1D1 and C2D1 for arms A and B.

Every subject of each arm of the safety run-in will be observed for at least 7 days after 
first dose of M7824 before the subsequent subject can be treated. Subjects who are not 
evaluable for DLT will be replaced and not included into evaluation


Abbreviated Title: M7824 in Small Cell Cancers
Version Date: 01/11/2024
4
ARMS 

Arm A (3-week cycles): M7824 monotherapy 2400 mg every 3 weeks until disease 
progression or a criterion in section 3.8.1 is met. Patients with progressive disease on 
Arm A may then receive 1200 mg M7824 every 2 weeks plus temozolomide 
200 mg/m2/day on days 1-5 every 4 weeks.

Arm B (3-week cycles): M7824 2400 mg plus topotecan 1 mg/m2 on days 1-5 every 3 
weeks until disease progression or a criterion in section 3.8.1 is met. 

Arm C (4-week cycles): M7824 1200 mg every 2 weeks plus temozolomide 
200 mg/m2/day on days 1-5 every 4 weeks until disease progression or a criterion in 
section 3.8.1 is met. 
Dose de-escalation Schedule Arm B 
Dose Level
M7824 
Topotecan 
Level 1
2400 mg every 3 weeks
1 mg/m2 on days 1-5 every 3 weeks
Level -1
2400 mg every 3 weeks
0.75 mg/m2 on days 1-5 every 3 
weeks
Dose de-escalation Schedule Arm C 
Dose Level
M7824 
Temozolomide
Level 1
1200 mg every 2 weeks 200 mg/m2/day on days 1-5 every 4 weeks
Level -1
1200 mg every 2 weeks 150 mg/m2/day on days 1-5 every 4 weeks


Abbreviated Title: M7824 in Small Cell Cancers
Version Date: 01/11/2024
5
SCHEMA
Relapsed SCLC
22 patients
M7824 plus topotecan
(2400mg d1 + 1mg/m2 d1-5; q3weeks)
n=10
M7824 
(2400mg q3weeks)
n=10
M7824 plus 
temozolomide
(1200mg d1; q2weeks + 
200mg/m2 d1-5; q4weeks) 
22 patients
Extrapulmonary 
small cell cancer
M7824 plus temozolomide
(1200mg d1; q2weeks + 200mg/m2 d1-5; q4weeks)
n=10
Arm C
Disease Progression


Abbreviated Title: M7824 in Small Cell Cancers
Version Date: 01/11/2024
6
TABLE OF CONTENTS 
PRÉCIS............................................................................................................................................2
ARMS..............................................................................................................................................4
SCHEMA.........................................................................................................................................5
TABLE OF CONTENTS ................................................................................................................6
STATEMENT OF COMPLIANCE ..............................................................................................12
1
INTRODUCTION .................................................................................................................13
1.1
Study Objectives..........................................................................................................13
1.1.1
Primary Objective....................................................................................................13
1.1.2
Secondary Objectives ..............................................................................................13
1.1.3
Exploratory Objectives ............................................................................................13
1.2
Background and Rationale ..........................................................................................13
1.2.1
Immune checkpoint inhibitors in SCLC..................................................................16
1.2.2
Topotecan ................................................................................................................17
1.2.3
Temozolomide .........................................................................................................18
1.2.4
M7824......................................................................................................................19
1.2.5
Study Rationale........................................................................................................23
1.2.6
EMD Serono Investigator Letter Dated 9/23/2021, Discontinuation of 3 
Randomized Clinical Trials Using M7824 (REF 564699)....................................................25
1.2.7
18-C-0110 Trial Summary (as of 10/15/2021) ........................................................27
1.2.8
Rationale for Continuing the Trial...........................................................................31
1.2.9
Arm B Accrual Closure (as of 12/20/2023).............................................................32
2
ELIGIBILITY ASSESSMENT AND ENROLLMENT .......................................................32
2.1
Eligibility Criteria........................................................................................................32
2.1.1
Inclusion Criteria .....................................................................................................32
2.1.2
Exclusion Criteria ....................................................................................................33
2.2
Recruitment Strategies ................................................................................................34
2.3
Screening Evaluation...................................................................................................34
2.3.1
Screening activities performed prior to obtaining informed consent ......................34
2.3.2
Screening activities performed after a consent for screening has been signed........35
2.4
Participant Registration and Status Update Procedures ..............................................35
2.4.1
Treatment Assignment Procedures..........................................................................36


Abbreviated Title: M7824 in Small Cell Cancers
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2.4.2
Screen Failures.........................................................................................................37
2.5
Baseline Evaluation.....................................................................................................37
3
STUDY IMPLEMENTATION .............................................................................................38
3.1
Study Design ...............................................................................................................38
3.1.1
Dose Limiting Toxicity............................................................................................40
3.1.2
Dose De-Escalation .................................................................................................40
3.2
Study Accrual Stopping Rule......................................................................................41
3.3
Drug Administration....................................................................................................41
3.3.1
Topotecan Administration .......................................................................................41
3.3.2
Temozolomide Administration................................................................................41
3.3.3
M7824 Administration.............................................................................................42
3.4
Dose Modifications .....................................................................................................43
3.4.1
Topotecan Dose Modification .................................................................................43
3.4.2
Temozolomide Dose Modification..........................................................................44
3.4.3
Management of M7824 AEs....................................................................................44
3.5
Study Calendars...........................................................................................................57
3.5.1
Arm A (M7824 Monotherapy) ................................................................................58
3.5.2
Arm B (M7824 Plus Topotecan) .............................................................................60
3.5.3
Arm C (M7824 Plus Temozolomide)......................................................................63
3.7
Cost and Compensation...............................................................................................66
3.7.1
Costs ........................................................................................................................66
3.7.2
Compensation ..........................................................................................................66
3.7.3
Reimbursement........................................................................................................66
3.8
Criteria for Removal from Protocol Therapy and Off Study Criteria .........................66
3.8.1
Criteria for removal from protocol therapy .............................................................66
3.8.2
Post therapy follow-up period .................................................................................66
3.8.3
Off-Study Criteria....................................................................................................66
4
CONCOMITANT MEDICATIONS/MEASURES...............................................................67
4.1
Permitted Medicines/Interventions..............................................................................67
4.1.1
Palliative Radiation..................................................................................................67
4.2
Prohibited Medicines...................................................................................................67
4.3
Supportive Care...........................................................................................................67
4.3.1
Pneumocystis Pneumonia Prophylaxis....................................................................67


Abbreviated Title: M7824 in Small Cell Cancers
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5
CORRELATIVE STUDIES FOR RESEARCH ...................................................................67
5.1
Biospecimen Collection ..............................................................................................67
5.1.1
Pharmacokinetics Samples ......................................................................................70
5.1.2
Hair Follicle Studies ................................................................................................71
5.2
Sample Storage, Tracking and Disposition .................................................................72
5.2.1
Developmental Therapeutics Branch Lab ...............................................................73
5.2.2
Clinical Pharmacology Program (Figg Lab)............................................................73
5.2.3
Laboratory of Pathology NCI COMPASS Program................................................74
5.3
Samples for Genetic/Genomic Analysis......................................................................74
5.3.1
Description of the Scope of Genetic/Genomic Analysis .........................................74
5.3.2
Certificate of Confidentiality...................................................................................74
5.3.3
Management of Results ...........................................................................................74
6
DATA COLLECTION AND EVALUATION .....................................................................75
6.1
Data Collection............................................................................................................75
6.2
Data Sharing Plans ......................................................................................................76
6.2.1
Human Data Sharing Plan .......................................................................................76
6.2.2
Genomic Data Sharing Plan.....................................................................................76
6.3
Response Criteria ........................................................................................................76
6.3.1
Disease Parameters ..................................................................................................76
6.3.2
Methods for Evaluation of Measurable Disease......................................................77
6.3.3
Response Criteria.....................................................................................................79
6.3.4
Duration of Response ..............................................................................................82
6.3.5
Progression-Free Survival .......................................................................................82
6.3.6
Response Review.....................................................................................................82
6.4
Toxicity Criteria ..........................................................................................................82
7
NIH REPORTING REQUIREMENTS / DATA AND SAFETY MONITORING PLAN...83
7.1
Definitions...................................................................................................................83
7.2
OHSRP Office of Compliance and Training / IRB Reporting....................................83
7.2.1
Expedited Reporting ................................................................................................83
7.2.2
IRB Requirements for PI Reporting at Continuing Review ....................................83
7.3
NCI Clinical Director Reporting .................................................................................83
7.4
NIH Required Data and Safety Monitoring Plan ........................................................83
7.4.1
Principal Investigator/Research Team.....................................................................83


Abbreviated Title: M7824 in Small Cell Cancers
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8
SPONSOR SAFETY REPORTING......................................................................................84
8.1
Definitions...................................................................................................................84
8.1.1
Adverse Event..........................................................................................................84
8.1.2
Serious Adverse Event (SAE) .................................................................................84
8.1.3
Life-threatening .......................................................................................................84
8.1.4
Severity....................................................................................................................85
8.1.5
Relationship to Study Product .................................................................................85
8.1.6
Adverse Events of Special Interest (AESI) .............................................................85
8.2
Assessment of Safety Events.......................................................................................85
8.3
Reporting of Serious Adverse Events .........................................................................86
8.4
Waiver of expedited reporting to CCR........................................................................86
8.5
Safety Reporting Criteria to the Pharmaceutical Collaborators ..................................86
8.5.1
EMD-Serono............................................................................................................86
8.6
Reporting Pregnancy ...................................................................................................87
8.6.1
Maternal Exposure .................................................................................................87
8.6.2
Paternal Exposure ....................................................................................................87
8.7
Regulatory Reporting for Studies Conducted Under CCR-Sponsored IND ...............88
8.8
Data Safety Monitoring Board (DSMB) .....................................................................88
8.9
Sponsor Protocol Deviation Reporting........................................................................89
9
CLINICAL MONITORING PLAN ......................................................................................89
10
STATISTICAL CONSIDERATIONS ..................................................................................90
10.1
Statistical Hypothesis ..................................................................................................90
10.2
Sample Size Determination.........................................................................................90
10.3
Populations for Analyses.............................................................................................91
10.4
Statistical Analyses......................................................................................................92
10.4.1
General Approach....................................................................................................92
10.4.2
Analysis of the Primary Efficacy Endpoints ...........................................................92
10.4.3
Analysis of the Secondary Efficacy Endpoints .......................................................92
10.4.4
Safety Analyses .......................................................................................................92
10.4.5
Baseline Descriptive Statistics.................................................................................92
10.4.6
Planned Interim Analyses........................................................................................92
10.4.7
Sub-Group Analyses................................................................................................93
10.4.8
Tabulation of Individual Participant Data ...............................................................93


Abbreviated Title: M7824 in Small Cell Cancers
Version Date: 01/11/2024
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10.4.9
Exploratory Analyses...............................................................................................93
11
COLLABORATIVE AGREEMENTS..................................................................................94
11.1
Cooperative Research and Development Agreement (CRADA)................................94
12
HUMAN SUBJECTS PROTECTIONS................................................................................94
12.1
Rationale For Subject Selection ..................................................................................94
12.2
Participation of Children .............................................................................................94
12.3
Participation of Subjects Unable to Give Consent ......................................................94
12.4
Evaluation of Benefits and Risks/Discomforts ...........................................................94
12.4.1
Risks/Benefits Analysis...........................................................................................94
12.4.2
Risks ........................................................................................................................95
12.4.3
Benefits....................................................................................................................96
12.5
Consent Process and Documentation ..........................................................................96
12.5.1
Request for Waiver of Consent for Screening Activities ........................................97
13
REGULATORY AND OPERATIONAL CONSIDERATIONS..........................................97
13.1
Study Discontinuation and Closure.............................................................................97
13.2
Quality Assurance and Quality Control ......................................................................98
13.3
Conflict of Interest Policy ...........................................................................................98
13.4
Confidentiality and Privacy.........................................................................................98
14
PHARMACEUTICAL INFORMATION .............................................................................99
14.1
M7824 (IND # 136852)...............................................................................................99
14.1.1
Source ......................................................................................................................99
14.1.2
Packaging and Labeling Information.......................................................................99
14.1.3
Toxicity..................................................................................................................100
14.1.4
Administration procedures.....................................................................................104
14.1.5
Stability, Storage, and Handling of Drug Product.................................................104
14.1.6
Clinical Supplies Disclosure..................................................................................105
14.2
Topotecan ..................................................................................................................106
14.2.1
Source ....................................................................................................................106
14.2.2
Administration Procedures ....................................................................................106
14.3
Temozolomide...........................................................................................................106
14.3.1
Source ....................................................................................................................106
14.3.2
Administration Procedures ....................................................................................106
15
REFERENCES ....................................................................................................................107


Abbreviated Title: M7824 in Small Cell Cancers
Version Date: 01/11/2024
11
16
APPENDICES .....................................................................................................................112
16.1
Appendix A - Performance Status Criteria................................................................112
16.2
Appendix B - Temozolomide Drug Administration Diary .......................................113


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STATEMENT OF COMPLIANCE
The trial will be carried out in accordance with International Council on Harmonisation Good 
Clinical Practice (ICH GCP) and the following: 
United States (US) Code of Federal Regulations (CFR) applicable to clinical studies (45 
CFR Part 46, 21 CFR Part 50, 21 CFR Part 56, 21 CFR Part 312, and/or 21 CFR Part 812) 
National Institutes of Health (NIH)-funded investigators and clinical trial site staff who are 
responsible for the conduct, management, or oversight of NIH-funded clinical trials have 
completed Human Subjects Protection and ICH GCP Training.
The protocol, informed consent form(s), recruitment materials, and all participant materials will 
be submitted to the Institutional Review Board (IRB) for review and approval. Approval of both 
the protocol and the consent form must be obtained before any participant is enrolled. Any 
amendment to the protocol will require review and approval by the IRB before the changes are 
implemented to the study. In addition, all changes to the consent form will be IRB-approved; an 
IRB determination will be made regarding whether a new consent needs to be obtained from 
participants who provided consent, using a previously approved consent form.


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1
INTRODUCTION
1.1
STUDY OBJECTIVES
1.1.1
Primary Objective

To determine the efficacy (using objective response rate) of M7824 plus topotecan or 
temozolomide in relapsed SCLC.
1.1.2
Secondary Objectives

To assess the safety and tolerability of M7824 plus topotecan or temozolomide relapsed 
SCLC.

To determine the progression-free survival (PFS), duration of response (DOR) and 
overall survival (OS) of a combination of M7824 plus topotecan or temozolomide in 
relapsed SCLC.
1.1.3
Exploratory Objectives

To characterize the immunomodulatory effects of DNA damage-inducing cytotoxic 
therapy.

To characterize gene expression and mutations which predict response and changes 
associated with response and resistance.

To evaluate the pharmacokinetic profile of M7824 in serum, and of Topotecan and 
Temozolomide in plasma.

To evaluate ORR, PFS and OS of patients with extrapulmonary small cell cancer 
receiving M7824 and Temozolomide.

To evaluate the ORR and PFS for patients who are on Arm A but receive combination 
treatment after progression, beginning with the date the second treatment commences.
1.2
BACKGROUND AND RATIONALE
Small cell lung cancer (SCLC) is an aggressive cancer with a poor prognosis. Annually there are 
approximately 34,000 new cases of SCLC in the United States. SCLC is characterized by rapid 
doubling time, high growth fraction and early and widespread metastatic involvement. 
Approximately two thirds of patients present with extensive-stage disease with tumor 
involvement of contralateral lung, liver, adrenal glands, brain, bones and/or bone marrow. 
The primary treatment modality for patients with extensive-stage SCLC (ES-SCLC) is systemic 
chemotherapy consisting of platinum and etoposide followed by prophylactic cranial irradiation 
in patients with a response [1]. Although initial response rates to chemotherapy are very high, the 
tumor usually relapses within months, and nearly all cases relapse within one year, becoming 
generally unresponsive to additional chemotherapy, with fewer than 5% of patients surviving 
two years. The only approved drug for relapsed disease is topotecan, which inhibits religation of 
topoisomerase I-mediated single-strand DNA breaks leading to lethal double-strand DNA 
breaks. Other drugs with more modest activity include amrubicin, doxorubicin, paclitaxel, and 


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temozolomide. The median survival for patients with ES-SCLC ranges from 8 to 13 months. 
Less than 5% of patients survive two years and less than 2% are alive five years after diagnosis.
In patients with disease that is refractory to 
or relapsed after first-line chemotherapy, 
the median survival ranges from 2 to 6 
months.
Active chemotherapeutic agents in SCLC 
have one thing in common: almost all of 
them interfere with DNA replication, 
except paclitaxel which disrupts 
microtubule function. Cisplatin and 
carboplatin form crosslinks between DNA 
bases creating DNA replication barriers. 
Temozolomide is a nonclassic oral 
alkylating agent, which causes DNA 
damage by alkylating guanine at position 
O6. Topotecan, irinotecan, etoposide, 
doxorubicin, and amrubicin trap 
topoisomerases, stalling replication forks 
and causing toxic double-stranded DNA 
breaks. 
The standard treatment of ES-SCLC today 
reflects the prevailing state-of-the-art from 
the early 1980s. Among the many 
strategies that have been evaluated 
unsuccessfully over the last three decades 
are dose-dense chemotherapy regimens, 
addition of a third drug to standard two 
drug chemotherapies, alternating non-cross 
resistant chemotherapy regimens, 
maintenance therapy and more recently 
targeted therapies. Not unexpectedly, the 
outcomes for these patients have also 
largely remained poor. Clearly there is a 
critical need for newer therapeutic 
approaches for patients with SCLC and 
patients with extrapulmonary small cell 
carcinomas.
We recently postulated that replicative 
stress is a SCLC hallmark (Figure 1) [2]. 
DNA damaging agents are the cornerstone of SCLC treatment, yet they provide only transient 
benefit. The inability to destroy residual SCLC cells despite initial chemosensitivity suggests the 
existence of a highly effective DNA damage response (DDR) network. Cellular responses to 
replicative stress-referred to as the DDR-is critical for repair of the damage and normal cell cycle 
progression and may have a role in chemotherapy resistance in SCLC. 
Figure 1. Replicative Stress in SCLC: Causes, 
Consequences and Therapeutic Opportunities 
(adapted from: Thomas & Pommier, Sci Trans 
Med 2016).


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The DNA damage response pathway is depicted in Figure 2[3]. Apical kinases ataxia-
telangiectasia mutated (ATM) and ataxia telangiectasia and Rad3-related (ATR) are recruited via 
DNA damage sensors. In addition to single-stranded DNA breaks, ATR responds to genotoxic 
stress that is caused by DNA replication stress, caused by oncogenes. Eventually via 
phosphorylation of a number of mediators, DNA damage response signaling converges on 
downstream effectors such as p53 and the cell division cycle 25 (CDC25) phosphatases.
Despite the importance of the DNA damage response for cell survival following DNA damage, 
defects in this pathway are common in cancer. For example, loss of ATM signaling capacity is 
frequently observed, either through loss of expression of ATM itself, or through defects in 
upstream regulators and downstream effectors such as p53. Although they appear to confer a 
growth advantage, defects in ATM signaling cause an excessive reliance on remaining DNA 
damage response components, such as ATR, and thus provide an ‘Achilles’ heel’ that could be 
targeted by drugs. 
Figure 2. DNA damage response pathway.
 
The most frequently mutated genes in SCLC are shown in Figure 3 [4]. SCLC is characterized 
by high frequency of alterations in p53, a key downstream effector of the ATM pathway. 
Furthermore, SCLC is also characterized by the widespread expression of oncogenes that drive 
replication stress. This combination of high replication stress and a defective ATM-p53 signaling 
pathway may provide a strong reliance on ATR for survival following DNA damage in SCLC. 


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Figure 3. Most frequently mutated genes in SCLC.
1.2.1
Immune checkpoint inhibitors in SCLC
Emerging data from PD-1 and PD-L1 indicate a clinical benefit in terms of response rates in 
patients with SCLC. The safety and efficacy of pembrolizumab, was assessed in patients with 
PD-L1-expressing relapsed extensive-stage SCLC in the multicohort, phase Ib open-label 
KEYNOTE-028 study[5]. PD-L1 expression was assessed by immunohistochemistry. PD-L1-
positive patients had membranous PD-L1 expression in ≥ 1% of tumor and associated 
inflammatory cells or positive staining in stroma. 163 patients were screened to identify 24 
patients who eventually received treatment. One of 24 patients had a complete response, and 
seven patients had partial responses, resulting in an ORR of 33%. Nivolumab with or without 
ipilimumab was assessed in unselected SCLC patients with disease progression after at least one 
prior platinum containing regimen in the multi-cohort, phase 1/2 CheckMate 032 study[6]. An 
objective response was achieved in ten (10%) of 98 patients receiving nivolumab 3 mg/kg, 14 
(23%) of 61 receiving nivolumab 1 mg/kg plus ipilimumab 3 mg/kg, and ten (19%) of 54 
receiving nivolumab 3 mg/kg plus ipilimumab 1 mg/kg.
Although promising, there are quite a few challenges with immunotherapy in relapsed SCLC, in 
particular, in platinum resistant and or refractory relapsed SCLC. First, due to the high burden of 
disease and the rapidity of progression, the time that it takes to mount an effective anti-tumor 
response may exceed the overall survival of the patient. Second, contrary to what one would 
expect for a smoking-related tumor with a high mutational load, response rates to monotherapy 
with immune checkpoint inhibitors in SCLC is low in comparison to other immune checkpoint 
inhibitor-responsive tumors such as NSCLC and melanoma. Third, the frequency of adverse 
events with combination immunotherapy is high: 16% of patients in the CheckMate 032 study 
discontinued due to treatment-related adverse events and 3 immune-related deaths occurred 
(from pneumonitis, myasthenia gravis, and renal failure). Any grade treatment-related adverse 
events occurred in 82% of the combination vs. 60% for nivolumab alone; Grade 3/4 serious 
adverse events occurred in 33% for the combination vs. 14% for nivolumab alone. Finally, there 
are no known predictive biomarkers of response to immunotherapy in SCLC. PD-L1 expression, 


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unlike in non-small cell lung cancer, is absent in SCLC tumor cells and presented in about 20% 
of stroma and immune infiltrates[7].
The limited activity of immune checkpoint inhibitors in SCLC patients suggests that 
immunosuppressive mechanisms beyond PD-1/L1 and CTLA4 checkpoints may be involved in 
SCLC tumor microenvironemt and targeting these alternate pathways could be of clinical 
relevance. Constitutive expression and secretion of biologically active TGF β1 has been 
described in SCLC[8, 9]. In SCLC cell lines, IL-2-dependent T-cell growth was severely 
suppressed by TGF β1. A specific anti-TGF beta 1 antibody blocked the immunosuppressive 
activity induced by TGF β1. High levels of TGF-β are also detected in the serum of patients with 
lung cancer compared with normal individuals[10]. 
1.2.2
Topotecan
Topotecan has been approved by the FDA for the treatment of metastatic carcinoma of the ovary 
after failure of initial or subsequent chemotherapy, small cell lung cancer sensitive disease after 
failure of first-line chemotherapy, and as a combination therapy with cisplatin for Stage IV-B, 
recurrent, or persistent carcinoma of the cervix which is not amenable to curative treatment with 
surgery and/or radiation therapy. Topotecan is a semi-synthetic derivative of camptothecin and is 
an anti-tumor drug with topoisomerase I-inhibitory activity. Topotecan binds to the 
topoisomerase I-DNA complex and prevents religation of these single-strand breaks. The 
cytotoxicity of topotecan is thought to be due to double-strand DNA damage produced during 
DNA synthesis, when replication enzymes interact with the ternary complex formed by 
topotecan, topoisomerase I, and DNA. Mammalian cells cannot efficiently repair these double 
strand breaks. Bone marrow suppression (primarily neutropenia) is the dose-limiting toxicity of 
topotecan at the approved doses (refer topotecan FDA package insert). 
The NCI SCLC program recently completed a phase I trial of VX-970 (referred to now as 
M6620), a selective inhibitor of ATR, a key DDR mediator, in combination with topotecan. This 
trial showed preliminary pharmacodynamic evidence of ATR inhibition and enhanced DNA 
DSBs to the combination. Immunophenotyping of PBMCs in this trial showed preliminary 
evidence of a favorable immunomodulatory effect after topotecan (manuscript in print JCO). 
A significant decrease was observed in the frequency of myeloid-derived suppressor cells 
(MDSC) after the combination relative to baseline. Total CD14+ monocytes increased 
significantly after topotecan, but markedly decreased after the combination. There was a marked 
redistribution among the monocyte subsets. The more immunosuppressive classical monocytes 
were the major population at baseline, whereas intermediate and nonclassical monocytes, which 
tend to promote antitumor activity were the minor populations. Following the combination, 
classical monocytes significantly decreased whereas intermediate and nonclassical monocytes 
significantly increased. Both monocytes and MDSCs returned to near-baseline-levels in most 
patients 3 weeks after treatment. No significant changes in T cell subsets including Tregs, 
conventional CD4+ T-cells and CD8+ T-cells were observed. The study also demonstrated 
interesting clinical activity signals in refractory SCLC patients, who tend not to respond to 
topotecan alone, and several patients achieving prolonged SD (manuscript under review). 
TOP1-induced DNA damage at ribonucleotide sites leads to replication stress and genome 
instability[11]. Such damage has been known to cause an unchecked inflammatory response and 
has been described in syndromes associated with mutations in genes that encode for proteins that 
are involved in various aspects of nucleic acid repair. Aicardi–Goutieres syndrome (AGS) is a 


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rare, genetic neurological disorder characterized by unchecked inflammatory response in the 
absence of exogenous stimuli[12]. Mutations in the TREX1, RNASEH2A, RNASEH2B, 
RNASEH2C, and SAMHD1 genes have been identified in people with Aicardi-Goutieres 
syndrome. It is thought that in patients with these mutations, there is a high level of aberrant 
nucleic acid because proper DNA and/or RNA processing is compromised. This leads to an 
interferon alpha (INF-α)-mediated, constitutive inflammatory response that has a potent effect on 
neurological development and function. 
1.2.3
Temozolomide 
Temozolomide is a nonclassic oral alkylating agent, which causes DNA damage by alkylating 
guanine at position O6. Temozolomide is rapidly and completely absorbed after oral 
administration and binds minimally to plasma proteins, resulting in limited interactions with 
concurrently administered drugs[13]. Being a small lipophilic molecule, temozolomide 
penetrates the blood–brain barrier and is therefore one of the few drugs with central nervous 
system (CNS) activity. Dose modifications are not needed for liver and renal dysfunction as 
cytochrome P450 enzymes and kidney are not involved in temozolomide metabolism. Adverse 
events are predictable and toxicities are usually reversible and not severe. Despite its antitumor 
activity, favorable pharmacokinetic profile, and tolerability, current use of temozolomide is 
limited to a subset of CNS cancers [14].
Temozolomide is converted to the active metabolite 5-(3-methyltriazen-1-yl) imidazole-4-
carboxamide (MTIC) by nonenzymatic chemical conversion. Among the DNA lesions produced 
by MTIC, the most common is methylation at the N7 position of guanine, followed by 
methylation at the N3 position of adenine and the O6 position of guanine. Although the least 
frequent, methylation of guanine at O6 (O6-MeG) is critical for temozolomide cytotoxicity 
(Figure 4). In normal cells, direct repair of O6-MeG by the enzyme O6-methylguanine–DNA 
methyltransferase (MGMT) effectively removes the methyl adduct, restoring guanine. O6-MeG 
that persists in MGMT-deficient cells mispairs with thymine instead of cytosine during DNA 
replication. This alerts the DNA mismatch repair (MMR) pathway, which exclusively recognizes 
the mispaired thymine on the daughter strand and excises it, while the O6-MeG persists in the 
template strand. The futile cycles of thymine reinsertion and excision result in extensive DNA 
resection and ultimately apoptosis. MMR-deficient cells do not detect alkylation adducts and 
hence are resistant to temozolomide even when they lack MGMT[15]. Temozolomide is 
therefore most cytotoxic in cells with low levels of MGMT and intact MMR. 


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Figure 4. Temozolomide is most cytotoxic in cells with low levels of MGMT and intact MMR 
(adapted from: Thomas, Pommier, et al. Cancer Res 2017).
Temozolomide has single-agent activity for SCLC [16]. In fact the clinical activity of 
monotherapy with alkylating agents for SCLC has been known since the 1960s [17]. Aberrant 
methylation of MGMT has been demonstrated in SCLCs, which leads to loss of MGMT activity 
and improved sensitivity to alkylating agents [18]. 
Temozolomide was evaluated in a phase II trial in patients with relapsed SCLC [19]. Patients 
with disease progression after one or two prior chemotherapy regimens received temozolomide 
at 75 mg/m2/d for 21 days of a 28-day cycle. The primary endpoint was the overall response rate 
(ORR), which was evaluated separately in platinum sensitive and refractory cohorts. Sixty-four 
patients were accrued including 48 patients in the sensitive cohort and 16 in the refractory group. 
One complete response (CR) and 10 partial responses (PRs) were noted in sensitive patients 
(ORR, 23%), 2 PRs were seen in the refractory cohort (ORR, 13%). As second- and third-line 
treatment, the ORR was 22% and 19% respectively. Among the entire cohort of 64 patients, 
there were one CR and 12 PRs for a 20% ORR. The trial however did not meet the prespecified 
primary end points of 25% and 30% ORRs respectively for refractory and sensitive patients. 
In the phase II trial of temozolomide (21-day regimen) had to be discontinued in 7 (11%) 
patients because of prolonged thrombocytopenia and neutropenia. A follow up study (n=25) 
assessed the toxicity of a 5-day dosing regimen of temozolomide in sensitive or refractory 
SCLCs. Patients received temozolomide 200 mg/m2/day orally on days 1–5 of each 28-day 
cycle. This dose was tolerable and active in patients with relapsed SCLCs (ORR 12%). No 
treatment-limiting prolonged cytopenias were observed, making this the preferred schedule for 
further studies[20].
1.2.4
M7824
1.2.4.1
Nonclinical Data 
M7824 is a bifunctional fusion protein consisting of an anti-programmed death ligand 1 (PD-L1) 
antibody and the extracellular domain of transforming growth factor beta (TGF-β) receptor type 
2, a TGF-β trap. The in vitro and in vivo pharmacology data clearly demonstrate the biological 


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activity and therapeutic potential of M7824 for the treatment of cancer. All of the data are 
consistent with a primary MOA that involves the reversal of T cell suppression via PD-L1 
inhibition in the tumor microenvironment combined with the additional benefit of sequestering 
TGFβ, providing enhanced antitumor activity. Importantly, M7824 therapy exhibits hallmarks 
of a successful immunotherapy: continued tumor regression after treatment discontinuation, 
long-lasting tumor growth inhibition, and protective immunity against tumor re-challenge in 
cured mice. 
In the pivotal 4- and 13-week repeat-dose primate toxicology studies, heart rate, ECG, arterial 
blood pressure, respiratory rate, CNS parameters, and body temperature were not affected by the 
treatment with M7824 at all dose levels tested, with an overall NOAEL at the highest and 
maximum feasible dose of 140 mg/kg. Aside from moderate effects on red cell parameters which 
are monitorable, manageable, and demonstrated reversibility in the pivotal 13-week primate 
toxicology study, the overall nonclinical safety profile established for M7824 iv formulation is 
favorable. An optimized cytokine release assay demonstrated evidence of cytokine release in 
PHA prestimulated PBMCs from healthy human volunteers, indicating the potential for immune-
mediated infusion reactions. Although pivotal nonclinical safety assessments from primate 
studies did not suggest infusion-related reactions or hypersensitivity events, such reactions are a 
risk with any biologic. 
Though no effects on the male and female reproductive organs were noted in repeat-dose toxicity 
studies, strict contraception is mandatory. There is no information on M7824 being excreted in 
human breast milk, subjects with pregnancy or in lactation period will be prohibited from being 
enrolled in clinical studies with M7824.
1.2.4.2
Potential Risks 
The potential risks of M7824 include infusion-related reactions including hypersensitivity, 
irAEs/autoimmune disorders, anemia, rash with hyperkeratosis/ keratoacanthomas/ SCC of the 
skin, embryo-fetal toxicity, and alterations in wound healing or repair of tissue damage. All of 
these are considered potential risks. 
1. Infusion-related reactions including hypersensitivity: A known class effect of monoclonal 
antibodies and an identified risk for M7824. 
2. irAEs/autoimmune disorders: Respective warnings and precautions (e.g., for immune-
mediated pneumonitis, immune-mediated colitis, and immune-mediated hepatitis) are 
included in the prescribing information of Keytruda and Opdivo. These 
irAEs/autoimmune disorders are known risks for M7824. 
3. Anemia: Anemia is a potential risk based on toxicological findings with M7824 in 
cynomolgus monkey indicating a decrease in Hgb, RBC, and hematocrit which was fully 
reversible or showed a substantial trend toward recovery. 
4. Rash with hyperkeratosis, keratoacanthoma, and squamous cell carcinoma of the skin 
lesions such as rash with hyperkeratosis, keratoacanthoma, and SCC of the skin (reported 
once) have been observed in Phase I studies with the anti-TGFβ1, 2, and 3 antibody 
fresolimumab. Considering that a syndrome known as Ferguson-Smith disease which is 
caused by mutations in TGFβ is associated with similar findings as described for 
fresolimumab, it is plausible that skin tumors may be related to TGFβ inhibition.


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5. Alterations in wound healing or repair of tissue damage: Due to the involvement of TGF
β in repair of skin and other tissue injuries, alterations in wound healing or repair of 
tissue damage is considered a potential risk. 
6. Embryo-fetal toxicities: Embryo-fetal 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. Embryo-
fetal and reproductive toxicities have also been investigated in animal models for a 
humanized monoclonal antibody targeting TGFβ1. At doses as high as 30 mg/kg, no 
maternal reproductive toxicity or embryo-fetal lethality were observed. Based on above 
pharmacological class effects, the clinical study protocol provides respective safety 
measures which comprise inclusion/exclusion criteria, guidance for prevention, 
monitoring, and medical management of potential risks as well as guidance on study 
treatment interruption, modification, or discontinuation of the study drug.
In addition, after discussion among NCI investigators on multiple protocols using M7824, 
multiple bleeding events ranging from low grade gingival bleeding and epistaxis to more serious 
hemoptysis, GI bleeding and hematuria have been observed. Some of these events can be 
attributed to bleeding events related to cancer directly and others bleeding events can be 
attributed to colitis or cystitis which is a known toxicity of anti-PD-L1 agents including M7824. 
However, there remains the possibility that M7824 may increase the overall risk of bleeding in 
ways that may not be directly related to direct tumor bleeding or inflammatory bleeding events 
described with checkpoint inhibitors like M7824. It is hypothesized that this possible increased 
bleeding risk may be due to TGF beta inhibition which has an effect on angiogenesis; bleeding 
has also been observed in patients receiving M7824 and may be drug-related (e.g., gum bleeding, 
nose bleeds, coughing up blood, blood in their urine, or blood in the stool). Accordingly, patients 
will be notified of the same possible risk in the informed consent document for this study. 
For updated safety information, refer to Investigator Brochure.
1.2.4.3
Clinical data
NCT02517398 (EMR200647-001) is an ongoing phase 1, open label, 3+3 dose-escalation study 
and this preliminary data was presented at ASCO in June 2017 and final results published in 
[21]. Eligible patients received M7824 at 0.3, 1, 3, 10, or 20 mg/kg Q2W until confirmed 
progressive disease, unacceptable toxicity, or trial withdrawal; treatment beyond progression is 
generally allowable. The primary objective was to determine the safety and maximum tolerated 
dose of M7824; secondary objectives included pharmacokinetics (PK), immunogenicity, and best 
overall response per RECIST v1.1. As of Oct 3, 2016, 16 heavily pretreated pts with ECOG 
performance status 0-1 have received M7824. PK data demonstrated a dose-linear increase in 
exposure; furthermore, at dose levels of 3mg/kg and higher, M7824 saturates peripheral PD-L1 
and sequesters any released plasma TGF-β1, -β2, and -β3 throughout the dosing period. Grade 3 
drug-related treatment-emergent adverse events (TEAEs) occurred in 3 patients (skin infection 
secondary to grade 2 bullous pemphigoid [BP], lipase increased, anemia, and colitis); there were 
no grade 4-5 drug-related TEAEs (Table 1). BP and colitis responded well to steroids. Colitis 
and its secondary events of anemia and rectal hemorrhage (in a previously radiated area) were 
considered dose-limiting in 1 patient. (See full Table 1 of AEs below). There was preliminary 
evidence of efficacy across all dose levels, including 1 ongoing confirmed complete response 
(cervical cancer), 1 durable partial response (pancreatic cancer), a 25% reduction in the sum of 
diameters of target lesions after only 2 doses of M7824 (cervical cancer), and 2 cases of 


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prolonged stable disease (pancreatic cancer; carcinoid). Preliminary data from this phase 1 dose-
escalation study suggest that M7824 has a manageable safety profile in patients with heavily 
pretreated advanced solid tumors. Early evidence of clinical efficacy warrants further study. The 
recommended dose for the expansion phase is a flat dose of 1200 mg every 2 weeks (~17 mg/kg 
for a 70 kg patient). The entire dose escalation study was completed at the NCI. M7824 
monotherapy is now in multiple expansion cohorts in 120 centers internationally, given at a flat 
dose of 1200 mg per infusion once every two weeks. 
Table 1. Treatment Related Adverse Events M7824
 
n = 16 cohort
n = 3 backfill data
Any 
Grade
Grade 3
Any 
Grade
Grade 3
Patients with any event, n (%)
7 (43.8)
3 (18.8)
2 (66.7)
Anemia
1 (6.3)
1 (6.3)
Bullous pemphigoid 
1 (6.3)
 
Colitis
1 (6.3)
1 (6.3)
Dermatitis acneiform
1 (6.3)
 
Dyspnea exertional
1 (6.3)
 
Hyperthyroidism
1 (6.3)
 
1 (33.3)
Hypophosphatemia
1 (6.3)
 
Hypothyroidism
2 (12.5)
 
1 (33.3)
Infusion-related reaction
1 (6.3)
 
Keratoacanthoma
1 (6.3)
 
1 (33.3)
Lipase increase
1 (6.3)
1 (6.3)
Nausea
1 (6.3)
 
Peripheral motor neuropathy
1 (33.3)


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Pruritus
1 (6.3)
 
Rash maculopapular
2 (12.5)
 
1 (33.3)
Skin infection
1 (6.3)
1 (6.3)
Vomiting
1 (6.3)
 
For updated information, refer to Investigator Brochure.
1.2.5
Study Rationale 
Small cell lung cancer (SCLC) is an aggressive cancer with a poor prognosis. Although highly 
responsive to chemotherapy initially, SCLC relapses quickly and becomes refractory to treatment 
within a few months. In patients with disease relapsed after first-line chemotherapy, the median 
survival ranges from 2 to 6 months. The median survival of newly diagnosed extensive stage 
SCLC is 8-10 months, two-year survival about 10% and 5-year survival less than 2%. Topotecan 
is the only FDA-approved treatment for patients with relapsed SCLC and among the agents that 
are active in relapsed SCLC are temozolomide. Immune checkpoint inhibitors have shown 
limited activity in SCLC (ORR ~10%), although responses tend to be durable. There is a critical 
need for effective therapeutic approaches for patients with SCLC. 
The dual inhibition mode of PD-L1 and sequestration of TGF-beta through M7824 has the 
potential to improve efficacy of single PD-1 or PD-L1 inhibition. TGF beta-receptors are 
expressed on a large proportion of a broad panel of SCLC cell lines which also produce TGF 
beta mRNAs[8]. In SCLC cell lines, IL-2-dependent T-cell growth was severely suppressed by 
TGF β1 [10]. A specific anti-TGF beta 1 antibody blocked the immunosuppressive activity 
induced by TGF β1. The plasma level of TGF-β1 in lung cancer patients is elevated compared 
with that in normal volunteers, and contributes to the impaired NK function via down-
modulation of activating receptors, such as NKG2D[22]. TGF-β1 levels are elevated in 
bronchoalveolar lavage fluid from patients with lung cancer[23]. In this study, the highest levels 
of TGF-β1 were seen in SCLC patients relative to other types of lung cancer. High levels of 
TGF-β are also detected in the serum of patients with lung cancer compared with normal 
individuals [10]. 
Given the expanding role of immune checkpoint blockade as a therapeutic strategy, the 
interaction of tumor DNA damage with the immune system has recently come into focus, and it 
is now clear that the tumor DNA damage has an important role in driving response to immune 
checkpoint blockade [24]. Increasing evidence suggests that the effects of chemotherapy are 
mediated not only though cytotoxic effects, but also through immunological effects, including 
reducing T-regulatory cell activity and enhancing cross-presentation of tumor antigen[25-28]. 
Combining immunotherapy, and chemotherapy could thus synergistically improve the anticancer 
activity of anti-PD-L1 monotherapy. Combination of chemotherapy with immunotherapy 
improved outcomes in NSCLC and melanoma. The U.S. FDA granted accelerated approval to 
pembrolizumab in combination with pemetrexed and carboplatin for the treatment of patients 
with previously untreated metastatic non-squamous non-small cell lung cancer[29]. The trial 


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demonstrated an improvement in ORR and in PFS for patients randomized to pembrolizumab 
plus chemotherapy. The ORR was 55% for the pembrolizumab plus chemotherapy arm and 29% 
for the chemotherapy alone arm.
We hypothesize that increased DNA damage induced by topotecan and temozolomide will 
complement the anti-tumor activity of M7824, in recurrent SCLC. Results of this pilot trial will 
inform design of larger more definitive studies of the combinations. A range of PD biomarkers 
and potential predictors of response will be assessed in tumor and peripheral blood in the context 
of this study including MMR status, cytokines, STING activation, TOP1 and TOP1 cc 
antibodies, tumor gene expression and mutation, and peripheral blood immune subsets. The 
planned correlative studies will inform our understanding of the intersection of DNA damage 
response and immune response and could provide important insights into design of trials 
combining immune checkpoint inhibitors and chemotherapy.
Extrapulmonary small cell carcinoma is a distinct clinicopathologic entity that can arise in a wide 
range of extrapulmonary sites. These tumors have been described most frequently in the urinary 
bladder, prostate, esophagus, stomach, colon and rectum, gallbladder, larynx, salivary glands, 
cervix, and skin. They are extremely rare and management of systemic disease with 
chemotherapy is patterned after the approach used in SCLC [30]. Extrapulmonary small cell 
cancers of various tissues of origin may arise by different mechanisms. In case of prostate small 
cell, it arises in the setting of therapeutic resistance to highly potent AR-targeting therapy 
whereas in EGFR mutated cancers it arises in the setting of potent EGFR-targeting. But in 
general, extrapulmonary small cell cancers have in common signatures of RB1 loss [31-33] 
which in turn drives replication stress. A recent paper has shown that AR transcriptional activity 
was lower in small cell prostate cancers compared to adenocarcinoma [32]. Accordingly, in 
clinical practice small cell prostate cancer patients are continued on androgen suppression while 
they are on small cell-directed therapy. In a small retrospective study of 34 extrapulmonary small 
cell cancers, PD-1 positivity in the tumor, lymphocytes, or macrophages was observed in 35% of 
cases [34]. Anecdotal reports of the evidence of immune checkpoint blockade has also been 
reported [35, 36]. Taken together, extrapulmonary small cell cancers are orphan diseases with no 
standard treatments and it appears that although these cancers can arise by different mechanisms, 
they have in common high replication stress, that may be susceptible to DNA damage and 
immune checkpoint blockade.
1.2.5.1
Rationale for M7824 Dose Increase of Arm A and B (Amendment B)
For M7824 monotherapy , 1200 mg q2w was selected as a recommended phase 2 dose. 
Therefore, for Arms A and B, a dose of M7824 1800 mg q3w dose was initially selected based 
on the following assumptions: 1) Cave (average concentration throughout dosing interval) 
observed at 1200 mg q2w is an estimate of Ceff (efficacious concentration) that needs to be 
maintained throughout the dosing interval. 2) Exposures are approximately dose-proportional at 
the pharmacologically active dose range (supported by preliminary PK analysis of Study 001 and 
0008) and 3) Projected Cmax margin of >1, relative to that observed at 30 mg/kg (the highest dose 
tested, corresponding to ~2100 mg for a 70 kg subject). However, in combination studies in 
which concomitant therapies are administered q3w, the same dosing interval for M7824 is 
preferred for convenience and compliance. The steady-state Ctrough (Ctrough,ss) at 1200 mg q2w is 
considered the target efficacious Ctrough,ss for q3w dosing of M7824 in combination studies with 
q3w dosing. Based on population PK modeling, median Ctrough,ss achieved with 2400 mg q3w 
dosing is similar to that projected with 1200 mg q2w dosing. In addition, for >90% of the 


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25
participants to be dosed with 2400 mg q3w, Ctrough,ss is estimated to be above the lower bound of 
95% CI for Ctrough,ss projected with 1200 mg q2w. Since Ctrough,ss is 2400 mg q3w is expected to 
achieve target Ctrough,ss and full PD-L1 target occupancy and TGFβ trapping in blood in > 90% of 
the participants. While 1800 mg q3w is projected to maintain similar average steady-state 
concentration compared to monotherapy RP2D, Ctrough,ss at 1800 mg q3w is lower compared to 
that at monotherapy at RP2D. Therefore, as of amendment B, the M7824 q3w dose is 2400 mg 
q3w. For additional information regarding avelumab (parent antibody for M7824) Ctrough data, 
please see data presented at ASCO: 
http://ascopubs.org/doi/abs/10.1200/JCO.2017.35.15_suppl.9086. 
M7824 1200 mg q2weeks dose will be used for Arm C of the current study (and for patients with 
progressive disease in arm A).
1.2.6
EMD Serono Investigator Letter Dated 9/23/2021, Discontinuation of 3 Randomized 
Clinical Trials Using M7824 (REF 564699)
The investigator letter addresses the discontinuation of 3 randomized studies (described below) 
due to the low likelihood of achieving primary objective and superiority in the efficacy 
objectives vs standard of care. Additionally, cases of early progression and death (due to 
progressive disease, signs and symptoms of progressive disease, or known treatment toxicities) 
were seen more frequently in the M7824 arms than in the standard of care arms.
1.2.6.1
MS200647_0037 study (Bintrafusp alfa versus Pembrolizumab as a 1st line Treatment 
in Participants with PD-L1 Expressing Advanced Non-Small Cell Lung Cancer 
[NCT03631706]). 
This study randomized patients with metastatic lung cancer who had PDL1 hi disease (≥80% 
based on Dako 73-10 PD-L1 assay ) to pembrolizumab vs. M7824. There were similar response 
rates seen in both arms however there was a higher discontinuation rate in the M7824 arm in this 
open label study, and this discontinuation imbalance could not be entirely explained by adverse 
events. There was a concomitant trend of decreased PFS leading the independent data monitoring 
committee (IDMC) to recommend discontinuation of the study because it was unlikely to meet 
its co-primary endpoint of PFS [37].
1.2.6.2
MS200647_0055 study (Gemcitabine Plus Cisplatin with or Without Bintrafusp alfa in 
Participants with 1st line Biliary Tract Cancer [NCT04066491]).
This was another first line study in patients with biliary tract cancer that randomized patients to 
receive standard of care chemotherapy with or without M7824. This study showed a statistically 
better response rate for the combination however the PFS data was similar between the two arms 
and the IDMC recommended closing the study as it was not likely to meet the endpoint of 
improvement in OS.
1.2.6.3
MS200647_0005 study (Bintrafusp alfa with concomitant chemoradiation in 
Unresectable Stage III Non-Small Cell Lung Cancer [NCT03840902]). 
This is a study based off the PACIFIC study comparing standard of care (chemoradiation 
followed by durvalumab) vs. chemoradiation with M7824. This study was very immature with 
an estimated primary completion date in mid-2024. However, EMD Serono, following IDMC 
recommendation, decided to discontinue the study due to a low likelihood that the experimental 
arm would achieve superiority in efficacy vs. standard of care.


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26
1.2.6.4
Additional Data Regarding Deaths and Disease Progression
Deaths within 60 days after start of treatment in M7824 arm vs comparator:

16 patients (10.6%) versus 9 patients (5.9%) (p=ns) in MS200647_0037 NSCLC Stage 
IV 1st line (M7824 versus pembrolizumab)

11 patients (7.5%) versus 2 patients (1.3%) (p<0.05) in MS200647_0055 biliary tract 
cancer (BTC) 1st line (M7824 in combination with chemotherapy versus placebo plus 
chemotherapy)

3 patients (4.1%) versus 2 patients (2.6%) (p=ns) in MS200647_0005 NSCLC Stage III 
(M7824 plus concurrent chemoradiation followed by M7824 maintenance versus 
chemoradiation followed by durvalumab)
One explanation for the early PD is due to inferior treatment effect, at least on a subpopulation of 
patients. It should be noted that in the metastatic lung cancer data and in the BTC cancer data the 
response rates were either similar or better with M7824 (and the stage III lung cancer is in the 
adjuvant setting), so if this is the case it would only be a subpopulation that do not fare as well.
Another explanation is that M7824, potentially due to TGF-β sequestration and/or PDL1 
inhibition, caused hyperprogression in some patients. Hyperprogression has been well 
documented in the immunotherapy literature, largely in retrospective studies, and with PD1 
inhibition appears to happen in about 15% of patients (range in reported studies of 5-40% in 
recent Meta-analysis[38]). 
1.2.6.5
NIH Data on Early Deaths (Within 60 Days) Due to Toxicity Or PD
In CCR sponsored studies, 320 patients have been treated with M7824 across 18 trials (two 
additional trials have no accrual yet). There have been 94 patients who have progressed within 
60 days (226 not having progressive disease). Of these 94 patients, 72 were alive at 60 days and 
22 died (16 from progressive disease and 6 from toxicity). Of those 6 who died from toxicity, 2 
were attributable to M7824 (1 bleeding and 1 immune checkpoint inhibitor induced hepatitis). 
The proportion of deaths within 60 days (6.9%) in these studies is similar to what is seen with 
other immune checkpoint inhibitors in refractory patient populations. Furthermore, less than 1% 
grade 5 toxicity were attributable to IND in the first 60 days, similar to other FDA approved 
agents including immunotherapy.
Correlative data from patients enrolled on CCR/NIH studies points to factors that form a 
biologically relevant explanation that may help explain early PD. Patients with HPV cancers 
(n=58, enrolled on 15c1079 and 18c0056) were analyzed for immune parameters and divided by 
patients who died at <60 days or >60 days from the initiation of treatment with M7824. As seen 
in Figure 5, at baseline there were significantly higher plasma levels of IL-8, TGFβ, IL-6, 
NOS3, and VEGFA in patients with early death, all of which are associated with 
immunosuppression and/or more advanced disease. A greater neutrophil to lymphocyte ratio 
(NLR) and higher absolute monocyte counts (AMC) were also seen at baseline in patients 
surviving <60 days compared to those with >60 days survival. 


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27
Figure 5. Baseline plasma levels of IL-8, TGFβ, IL-6, NOS3, and VEGFA in patients with early 
death.
1.2.6.6
Clinical activity data in CCR/NIH studies utilizing M7824
There are data from 3 non-randomized phase 2 studies in patients with HPV associated 
malignances or prostate cancer conducted at the NIH Clinical Center that support the clinical 
activity of M7824 in monotherapy or combination approaches. In the three studies mentioned 
below, the level of activity is unprecedented. 
1. 18C0056 HPV associated malignancies
Preliminary data from this study was published in JITC last year[39]. This showed an 
ORR by RECIST of 30.5% (n=59) with similar response rates across a wide range of 
HPV associated malignancies. About 50% of the patients had cervical cancer. In an 
update presented at ESMO this month with a total of 75 patients, the ORR was holding 
steady at 28% and if you added in the patients with a delayed response, the total clinical 
response was 32%[40]. The median duration of response was 17.3 months, and the 
medial overall survival is 21.3 months. To put this in context, the ORR for PDL1+ 
patients (n=82) in the cervical cancer study that led to the approval for this indication was 
14.6%[41] and in multiple studies of HPV associated malignancies in the second line 
setting, the median overall survival is ≤12 months.
2. 20C0045 HPV associated malignancies triple therapy
In an ongoing trial of M7824, NHS-IL12 (tumor targeted IL12) and an HPV16 targeted 
vaccine the ORR is 50% (88% in HPV 16+ patients) in patients that are immune 
checkpoint inhibitor naïve and 30% (38% in HPV 16+ patients) in immune checkpoint 
inhibitor refractory patients (data updated since oral presentation at ASCO 2021[42]). 
The expected response rate in immune checkpoint inhibitor refractory patients is <10%. 
While this data is still early (34 patients total), these response rates observed, especially 
in immune checkpoint inhibitor refractory, is unprecedented.
3. 18C0078 QuEST (prostate cancer)
Subjects in arm 2.2 (M7824, brachyury vaccine and N-803) had a sustained PSA 
response rate of 46% (6/13 evaluable patients) with 2/3 patients evaluable by RECIST 
having a PR (data updated since EMSO 2020[43]). The expected response rate in 
unselected patients with prostate cancer is about 2%[44].
1.2.7
18-C-0110 Trial Summary (as of 10/15/2021)

Arm A: completed enrollment with 13 patients. Four patients crossed over from Arm A 
to C at the time of disease progression.
< 60
> 60
0
2
4
6
8
10
IL6
NPX
0.0061
< 60
> 60
0
5
10
15
IL8
NPX
0.0066
< 60
> 60
0
1
2
3
4
5
NOS3
NPX
0.0010
< 60
> 60
6
7
8
9
10
11
VEGFA
NPX
0.0104
< 60
> 60
7
8
9
10
11
12
LAP TGFb
NPX
0.0253
< 60
> 60
0
2
4
6
8
10
12
30
40
NLR
NLR
0.0079
< 60
> 60
0.0
0.5
1.0
1.5
AMC
monocyte count K/ul
0.0067
TGFb


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28

Arm C: terminated for futility after enrolling 10 patients. Response was not observed in 
two or more of the first ten patients to allow continued accrual to a total of 22 patients. 

Arm B: enrolled 4 patients. 

Extrapulmonary cohort: enrolled 6 patients
Please refer to Table 2 for characteristics of the 33 patients enrolled. Patients enrolled so far 
have several indicators of poor prognosis including extensive stage at diagnosis (76%), platinum 
resistance (73%), and history of brain metastases (42%). 
Table 2. Clinical characteristic of patients enrolled in 18-C-0110
In terms of efficacy, out of 33 evaluable patients, 4 patients have had partial responses, including 
a patient who is currently in remission 26 months after starting treatment and another patient in 
ongoing complete metabolic response 10 months after starting treatment. 

Arm A (M7824 only): Of 10 evaluable patients, 1 patient had a partial response before 
coming off treatment for brain only progressive disease. Patient was alive for 13 months 
from start of therapy. Of four patients who crossed over two arm C, two patients had 
partial responses. 


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Figure 6. Partial response in a patient treated with M7824 monotherapy on arm A.

Arm C (M7824 + Temozolomide): Of 10 evaluable patients, 1 patient had a PR and was 
taken off trial after 10 months of treatment for pandemic-related travel restrictions/risks. 
Patient remains in follow up 26 months after starting treatment with no evidence of 
recurrent disease.
Figure 7. RECIST partial response (complete metabolic response) in a patient with recurrent 
SCLC Treated in arm C with a combination of M7824 and temozolomide. 

Arm B (M7824 + topotecan): Of 4 evaluable patients, all are off treatment for PD.

Extrapulmonary small cell cancer cohort (M7824 + Temozolomide): Of 3 evaluable 
patients, two patients had partial responses including a patient with small cell cervix 
cancer who had PR and remained on treatment for almost 7 months, and a second patient 


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30
with small cell cancer of the vocal cord who remains on treatment at 10 months with PR 
by RECIST and a metabolic complete response. 
Figure 8. RECIST partial response (complete metabolic response) in a patient with recurrent 
Small cell cancer of the vocal cord treated on arm C with a combination of M7824 and 
temozolomide. 
Toxicities observed on this trial can broadly be classified into three categories, summarized in 
Figure 9: 
1.
M7824 related immune related AEs: one patient had to be taken off treatment for 
grade 3 immune related pruritus and rash, one patient reported a flare of grade 1 
rheumatoid arthritis, one patient who needed hospitalizations for grade 2 ileus, and 
one patient developed grade 3 immune related diabetes mellitus, and grade 2 
hypophysitis and adrenal insufficiency. Other notable immune AEs were grade 2 
adrenal insufficiency and grade 3 pneumonitis. 
2.
M7824 related bleeding: one patient had grade 1 epistaxis and hemoptysis. 2 patients 
with gum bleeding, one patient with grade 4 hepatic/intrabdominal hemorrhage, one 
with grade 3 hematuria and grade 3 anemia. 
3.
Toxicities related to chemotherapy agents including myelosuppression, nausea, 
vomiting etc. There was a DLT of one patient treated with topotecan and M7824. 
Topotecan is known to be associated with high frequency of myelosuppression. 


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Figure 9. Toxicities observed in 18-C-0110 arms A-C through 10/15/2021. 
1.2.8
Rationale for Continuing the Trial
Arm B: The study aims to continue the recruitment of participants with SCLC relapse who have 
progressed on at least one prior chemotherapy and immunotherapy. Standard treatment options 
for this patient population include topotecan (approved in 1996) [45-49] or lurbinectedin 
(approved in 2020)[50]. These therapies provide palliation, but yield only short-term responses, 
A.
B.
C.


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and most patients die within a few months of their relapse (NCCN SCLC guidelines). Response 
rates are <10% in patients with platinum-refractory or resistant disease (relapse within 3 months 
of initial therapy) and approximately 25% in patients with platinum-sensitive relapse (relapse 
after 3 months of initial therapy). Long term responses are exceedingly infrequent to standard 
therapies. M7824 monotherapy or in combination with chemotherapy (topotecan or 
temozolomide) produced durable responses in a small but important proportion of SCLC 
patients, including patients with platinum resistant/refractory relapse. Further studies and 
understanding the determinants of response could advance SCLC therapeutics. 
Assessment of dose limiting toxicity is planned after enrollment of two more patients on Arm B 
(for a total of 6 patients). One patient in this cohort has had grade 4 thrombocytopenia requiring 
platelet transfusion. If a total of 2 or more patients within the first 6 patients experience a DLT, 
then the remaining patients will be treated at dose level -1, with a lower dose of topotecan. If 
there is adequate safety in these initial patients in Arm B, a total of 10 patients (including the 6 
patients evaluated for toxicity and future dose setting) will be enrolled onto the first stage of Arm 
B. If 0 to 1 of the 10 patients demonstrate a partial response, then no further patients will be 
accrued onto this arm. If 2 or more of the first 10 patients have a response, then accrual would 
continue until a total of 22 evaluable patients have been treated in Arm B.
Extrapulmonary small cell cancer cohort: Extrapulmonary small cell cancers are exceedingly 
rare cancers with small cell morphology arising from non-lung primary sites. They are uniformly 
fatal and have no standard therapies at relapse following chemotherapy. Given their rarity and 
heterogeneity, advancing care through clinical trials is challenging. The striking responses in 
patients who had under-gone extensive previous therapies provide compelling rationale to 
rigorously investigate the effect of this combination in extrapulmonary small cell cancer patients. 
Seven additional patients are required to complete enrollment of this cohort. 
1.2.9
Arm B Accrual Closure (as of 12/20/2023)
Five patients were enrolled in Arm B as of March 2022. All five patients were evaluable and all 
had progressive disease as the best response. The toxicities observed include anemia in all 
patients (2 grade 3, and 3 grade 2) and thrombocytopenia in 4 patients (1 grade 4 requiring a 
platelet transfusion (DLT), 1 grade 4, 1 grade 3 and 1 grade 1). Four patients experienced the 
following AESIs: 1 with grade 3 pneumonitis, 1 with grade 2 increased lipase, 1 with grade 2 
hypothyroidism and 1 with grade 1 increased thyroid stimulating hormone. 
Given the low accrual and competing treatment alternatives, Arm B is being closed.
2
ELIGIBILITY ASSESSMENT AND ENROLLMENT 
2.1
ELIGIBILITY CRITERIA
2.1.1
Inclusion Criteria
2.1.1.1
Patients must have histologically or cytologically confirmed SCLC or extrapulmonary 
small cell cancers.
2.1.1.2
Subjects with relapsed SCLC (diagnosed with limited or extensive stage disease) with 
tumor progression on or after at least one prior chemotherapy. Patients with SCLC 


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33
should in addition have received and have disease progression on or after prior 
immunotherapy. 
2.1.1.3
Male and female subjects ≥ 18 years of age. Because no dosing adverse event data are 
currently available on the use of topotecan, temozolomide and M7824 in subjects <18 
years of age, children are excluded from this study.
2.1.1.4
ECOG performance status ≤2. See Appendix A. 
2.1.1.5
Subjects must have measurable disease, per RECIST 1.1. See Section 6.3 for the 
evaluation of measurable disease.
2.1.1.6
Subjects must not have received chemotherapy, or undergone major surgery within 2 
weeks and radiotherapy within 24 hours prior to enrollment. 
2.1.1.7
Patients must have adequate organ and marrow function as defined below: 
a.
hemoglobin
≥ 9.0 g/dL
b. absolute neutrophil count
≥ 1.5x109/L
c.
platelets
>100x109/L
d. total bilirubin
≤ 2.0 mg/dL
e.
AST(SGOT)/ALT(SGPT)
≤ 2.5 x ULN or if liver metastases were 
present, ≤ 5 x ULN
f.
creatinine
≤ 1.5 mg/dL OR creatinine clearance ≥ 40 
mL/min 
2.1.1.8
Ability of subject to understand and the willingness to sign a written informed consent 
document.
2.1.1.9
The effects of the trial treatment on the developing human fetus are unknown; thus, 
women of childbearing potential and men must agree to use highly-effective 
contraception prior to study entry, for the duration of study participation and up to 6 
months for women and 3 months for men after the last dose of study drug. Men should 
not donate sperm during participation in the study and for up to 3 months after the last 
dose of study drug. Should a woman become pregnant or suspect she is pregnant while 
she or her partner is participating in this study, she should inform her treating physician 
immediately.
2.1.2
Exclusion Criteria
2.1.2.1
Subjects with tumor amenable to potentially curative therapy per PI.
2.1.2.2
Subjects who are receiving any other investigational agents. Prior immunotherapy, 
topotecan and temozolomide are allowed.
2.1.2.3
History of allergic reactions attributed to compounds of similar chemical or biologic 
composition to (study agent) or other agents used in study.
2.1.2.4
Subjects with symptomatic brain metastases will be excluded from trial secondary to 
poor prognosis. However, subjects who have asymptomatic brain metastases, and those 
had treatment for their brain metastasis and whose brain disease is stable without steroid 


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34
therapy for 2 weeks may be enrolled (replacement doses ≤ 10 mg of prednisone or 
equivalent per day are allowed). 
2.1.2.5
Subjects with evidence of severe or uncontrolled systemic disease, or any concurrent 
condition, which could compromise participation in the study, including, but not limited 
to, active or uncontrolled infection, immune deficiencies (HIV-positive subjects on 
combination antiretroviral therapy are eligible), Hepatitis B, Hepatitis C, uncontrolled 
diabetes, uncontrolled hypertension, symptomatic congestive heart failure, unstable 
angina pectoris, myocardial infarction within the past 3 months, uncontrolled cardiac 
arrhythmia, stroke/cerebrovascular accident within the past 3 months, bleeding diathesis 
or recent (within 3 months) clinically significant bleeding events or psychiatric 
illness/social situations which would jeopardize compliance with the protocol.
2.1.2.6
Pregnant women are excluded from this study because topotecan and temozolomide are 
Class D agents with the potential for teratogenic or abortifacient effects and because the 
effects of M7824 on the developing human fetus are currently unknown. In addition, 
because there is an unknown but potential risk for adverse events in nursing infants 
secondary to treatment of the mother with topotecan, temozolomide or M7824, 
breastfeeding should be discontinued if the mother is treated with these agents
2.1.2.7
Active autoimmune disease that might deteriorate when receiving an 
immunostimulatory agent with the exceptions:
a.
diabetes type I, 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 ≤ 10 mg 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.
2.1.2.8
Systemic therapy with immunosuppressive agents within 7 days before enrollment.
2.1.2.9
Administration of live vaccines within 30 days prior to the first administration of study 
intervention. Seasonal flu vaccines that do not contain a live virus are permitted. 
Locally approved COVID vaccines are permitted.
2.1.2.10 Subjects unwilling to accept blood products as medically indicated.
2.1.2.11 Known contraindication for topotecan or temozolomide.
2.2
RECRUITMENT STRATEGIES
Trial details will be available on clinicaltrials.gov and personal communications via email will be 
sent to referring physicians in the area. The study will also be publicized on NIH websites and on 
NIH social media platforms. Additionally, patients may be recruited from the ResearchMatch 
online national clinical research registry. 


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2.3
SCREENING EVALUATION
2.3.1
Screening activities performed prior to obtaining informed consent
Minimal risk activities that may be performed before the subject has signed a consent include the 
following: 

Email, written, in person or telephone communications with prospective subjects 

Review of existing medical records to include H&P, laboratory studies, etc. 

Review of existing MRI, x-ray, or CT images

Review of existing photographs or videos

Review of existing pathology specimens/reports from a specimen obtained for diagnostic 
purposes
A waiver of consent for these activities has been requested in section 12.5.1.
2.3.2
Screening activities performed after a consent for screening has been signed
The following activities will be performed only after the subject has signed the study consent OR 
the consent for study 01-C-0129 (provided the procedure is permitted on that study) on which 
screening activities may also be performed. Assessments performed at outside facilities or on 
another NIH protocol within the timeframes below may also be used to determine eligibility once 
a participant has signed the consent.
Screening must be completed within 2 weeks prior to enrolling subjects onto the protocol unless 
otherwise indicated. 

History and physical exam (including height, weight, ECOG performance status and vital 
signs) 

Blood tests (for organ function): 
a.
Complete blood count (CBC/Diff) 
b. Acute care panel
c.
Hepatic panel 
d. Mineral panel 
e.
Prothrombin time (PT) 
f.
Partial thromboplastin time (PTT) 

Viral Markers Protocol Screen (HBsAg, anti-HCV, anti-HIV) (within 3 months of 
screening) 

Confirmation of pathological or cytological diagnosis (may be done prior to the two-
week screening window) 

CT ± PET scan of disease sites. PET scans may be omitted if CT alone can be used to 
assess disease. 

Electrocardiogram (12 lead) 

Urine or serum HCG for women of child-bearing potential 


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2.4
PARTICIPANT REGISTRATION AND STATUS UPDATE PROCEDURES
Registration and status updates (e.g. when a participant is taken off protocol therapy and when a 
participant is taken off-study) will take place per CCR SOP ADCR-2, CCR Participant 
Registration & Status Updates found at: 
https://ccrod.cancer.gov/confluence/pages/viewpage.action?pageId=73203825.
2.4.1
Treatment Assignment Procedures
Cohorts
Number
Name
Description
1
Small cell lung cancer
Subjects with relapsed SCLC 
2
Extrapulmonary small 
cell cancer
Subjects with extrapulmonary small cell cancers 
Arms
Letter
Name
Description
A
M7824 monotherapy
M7824 (IV) monotherapy once every 21 days on a 21-day 
cycle. Patients who progress on monotherapy may be 
treated with M7824 and temozolomide as per description 
of treatment in Arm C. 
B
M7824 plus topotecan 
M7824 (IV) on day 1 plus topotecan (IV) on days 1-5 of a 
21-day cycle.
At least 6 subjects to receive M7824 plus topotecan to 
determine safety. 4 more patients enrolled at initial or 
lower dose for efficacy. If efficacious, an additional 12 
subjects enrolled.
C
M7824 plus 
temozolomide 
M7824 (IV) days 1 and 15 plus temozolomide (oral) on 
days 1-5 of a 28-day cycle. 
At least 6 subjects with SCLC to receive M7824 plus 
temozolomide to determine safety. 
4 more SCLC patients enrolled at initial or lower 
dose for efficacy. If efficacious, an additional 12 
SCLC subjects enrolled.
After the 6 safety SCLC cohort, subjects with 
extrapulmonary small cell cancers will be enrolled. 
Arm Assignment
1. The first 10 evaluable subjects in cohort 1 will be directly assigned to Arm A. After disease 
progression, these subjects are eligible to receive M7824 plus temozolomide as per 
description of treatment in Arm C, but will still remain enrolled on Arm A.


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2. After arm A is completed, for logistical reasons, the remaining subjects in cohort 1 will be 
assigned to Arm C. Accrual will be paused after at least 6 subjects are enrolled, then resume 
at the same or lower doses of the chemotherapy agents depending on the assessment. A 
second pause will be implemented after 10 patients are enrolled to assess for efficacy. 
Enrollment will continue after assessment if efficacy thresholds are met. 
3. After arm C is completed, subjects will be assigned to arm B. Accrual will be paused after at 
least 6 subjects are enrolled, then resume at the same or lower doses of the chemotherapy 
agents depending on the assessment. A second pause will be implemented after 10 patients 
are enrolled to assess for efficacy. Enrollment will continue after assessment if efficacy 
thresholds are met. 
4. After the enrollment of the 6 SCLC safety subjects in arm C, 10 subjects with 
extrapulmonary small cell cancer (cohort 2) will be enrolled in arm C. 
2.4.2
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical trial but are 
not subsequently assigned to the study intervention or entered in the study. A minimal set of 
screen failure information is required to ensure transparent reporting of screen failure 
participants, to meet the Consolidated Standards of Reporting Trials (CONSORT) publishing 
requirements and to respond to queries from regulatory authorities. Minimal information 
includes demography, screen failure details and eligibility criteria.
2.5
BASELINE EVALUATION
All studies must be completed within 7 days of first dose of drug. If tests needed at baseline were 
performed at screening within the 7-day timeframe, they do not need to be repeated.

History and physical exam (including height, weight, performance status and vital signs) 

Blood tests (for organ function): 
o
Complete blood count (CBC/Diff) 
o
Acute care panel
o
Hepatic panel 
o
Mineral panel 
o
Prothrombin time (PT) 
o
Partial thromboplastin time (PTT) 
o
Thyroid screen: TSH and free T4
o
Pancreatic enzymes: amylase and lipase
o
Creatine kinase, serum aldolase, and anti-acetylcholine receptor antibody titers
o
Serum troponin

Electrocardiogram (12 lead)

Complete neurological examination including assessment of cranial nerve function and 
muscle strength will be performed at screening and subsequent visits on all eligible patients 
before starting treatment. 


Abbreviated Title: M7824 in Small Cell Cancers
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3
STUDY IMPLEMENTATION
3.1
STUDY DESIGN
This is a safety run-in and phase II trial of M7824 and topotecan or temozolomide in relapsed 
small cell lung cancer and extrapulmonary small cell cancer. The primary objective of the trial is 
to determine the efficacy of M7824 plus topotecan or temozolomide relapsed SCLC.

Arm A (M7824 monotherapy): 10 patients may be treated with M7824 monotherapy to 
confirm safety of M7824 in SCLC and to obtain PK data and a preliminary estimate of 
clinical responses to M7824 in SCLC. Based on the adverse event profile of M7824 
available so far (>600 pts treated on this dose of M7824 monotherapy across 13 solid 
tumor cohorts), as well as the adverse event profiles of PD-1/PD-L1 targeted agents in 
SCLC, we do not anticipate any unique safety signals in this patient population. Patient 
with progressive disease on Arm A may receive M7824 and temozolomide as per 
description of treatment in Arm C, but will remain on Arm A. Their initial response and 
progression will be part of the primary evaluation for Arm A. 

Following completion of the 10-patient Arm A, for logistical reasons, patients will be 
assigned to Arm C (M7824 plus temozolomide) then to Arm B (M7824 plus topotecan). 

The trial will be conducted as follows:
o
Arm A: 
o
Initially, 10 patients will enroll on Arm A. 
o
Arm C: 
o
Following completion of the 10-patient Arm A, patients will be assigned to 
Arm C initially until there are 6 evaluable patients, and then a pause to the 
accrual of Arm C will take place. These first patients enrolled in C before the 
pause in accrual will be treated at dose level 1 and evaluated for toxicity. If 0 
or 1 of the first 6 patients experiences a dose-limiting toxicity (DLT), then the 
remainder of the patients in C will be treated at that dose. If 2 or more patients 
within the first 6 experience a DLT, then the remaining patients will be treated 
at dose level -1. If 2 or more patients at dose level -1 experience a DLT, then 
no further accrual will take place in the arm unless a treatment modification is 
provided via an amendment. The Sponsor’s DSMB will review the data. The 
accrual halt will be lifted if permitted by the DSMB and IRB.
o
If there is adequate safety in these initial patients in Arm C, a total of 10 
patients (including the 6 patients evaluated for toxicity and future dose 
setting) will be enrolled onto the first stage of Arm C. If 0 to 1 of the 10 
patients demonstrate a partial response, then no further patients will be 
accrued. If 2 or more of the first 10 patients have a response, then accrual 
would continue until a total of 22 evaluable patients have been treated in 
Arms C.
o
A separate cohort of patients with extrapulmonary small cell cancer (n=10) 
will be accrued after the enrollment of the first 6 SCLC evaluable patients and 
will only receive the combination therapy of M7824 and Temozolomide. 


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o
Arm B: 
o
After completion of enrollment of SCLC patients in Arm C, patients will be 
assigned to arm B initially until there are a minimum of 6 evaluable patients in 
that arm, and then a pause to the accrual of Arm B will take place. These first 
patients enrolled in Arm B before the pause in accrual will be treated at dose 
level 1 and evaluated for toxicity. If 0 or 1 of the first 6 patients experiences a 
dose-limiting toxicity (DLT), then the remainder of the patients in arms B will 
be treated at that dose. If 2 or more patients within the first 6 experience a 
DLT, then the remaining patients will be treated at dose level -1. If 2 or more 
patients at dose level -1 experience a DLT, then no further accrual will take 
place unless a treatment modification is provided via an amendment. The 
Sponsor’s DSMB will review the data. The accrual halt will be lifted if 
permitted by the DSMB and IRB.
o
If there is adequate safety in these initial patients in Arm B, a total of 10 
patients (including the 6 patients evaluated for toxicity and future dose 
setting) will be enrolled onto the first stage of Arm B. If 0 to 1 of the 10 
patients demonstrate a partial response, then no further patients will be 
accrued onto this arm. If 2 or more of the first 10 patients have a response, 
then accrual would continue until a total of 22 evaluable patients have been 
treated in Arm B.
An interim analysis will be conducted prior to phase 2 expansion as described in section 10.4.6.1.
It is anticipated that up to 2 patients per month may enroll onto this trial; thus, approximately 2 
to 3 years may be required to complete accrual of up to 10+22+22+10=64 evaluable patients. 
The accrual ceiling will be set at 80 to allow for a small number of inevaluable patients and 
screen failures.
Optional tumor biopsies will be obtained pre-treatment and C1D15 for arm C; pre-treatment and 
C2D1 for arms A and B. Attempts will be made to obtain up to five cores if safe and feasible, 
which will be used for research studies. The use of imaging to facilitate biopsies will be decided 
upon by members of the interventional radiology team. Biopsy will be obtained percutaneously. 
Research biopsies will not be obtained bronchoscopically. 
Every subject of each arm of the safety run-in will be observed for at least 7 days after first dose 
of M7824 before the subsequent subject can be treated. Subjects who are not evaluable for DLT 
will be replaced and not included into evaluation. Patients on Arm A will continue on treatment 
until criteria in section 3.8.1 are met. Patients on arms B and C will receive M7824 plus 
chemotherapy until criteria in section 3.8.1 are met. In cases where patients are unable to tolerate 
the chemotherapy, they will be dose modified and discontinued according to sections 3.1.2 and 
3.4. Patients who discontinue the chemotherapy in Arms B and C for reasons other than 
progressive disease, may continue on M7824 alone until criteria in section 3.8.1 are met. Patients 
who discontinue M7824 for reasons other than progressive disease may continue on 
chemotherapy.
GM-CSF may be administered in Arms B and C as clinically indicated. Although rare, there is a 
possibility of immune-related progression in some patients. Given this, dosing beyond initial 


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progression may be considered in selected patients who per PI are clinically stable and are 
thought to benefit from the treatment. 
3.1.1
Dose Limiting Toxicity
Subjects will be monitored for DLTs during the first cycle (Arm B- 3 weeks and Arm C- 4 
weeks). DLTs will be defined using the National Cancer Institute (NCI) CTCAE (Version 5).
The occurrence of any of the following toxicities will be considered a DLT, if judged by the 
Investigator to be possibly, probably or definitely related to study drug administration:

Grade 4 non-hematologic toxicity (not laboratory).

Grade 4 hematologic toxicity lasting ≥7 days.

Grade 3 non-hematologic toxicity (not laboratory, specifically nausea, vomiting and 
diarrhea) lasting >5 days despite optimal supportive care.

Febrile neutropenia Grade 3 or Grade 4:
A. Grade 3 is defined as ANC <1000/mm3 with a single temperature of >38.3 degrees C (101 
degrees F) or a sustained temperature of ≥38 degrees C (100.4 degrees F) for more than one 
hour
B. Grade 4 is defined as ANC <1000/mm3 with a single temperature of >38.3 degrees C (101 
degrees F) or a sustained temperature of ≥38 degrees C (100.4 degrees F) for more than one 
hour, with life-threatening consequences and urgent intervention indicated.

Thrombocytopenia <25,000/mm3 if associated with:
C. A bleeding event which does not result in hemodynamic instability but requires an elective 
platelet transfusion, or a life-threatening bleeding event which results in urgent intervention 
and 
D. Admission to an Intensive Care Unit

Prolonged delay (>3 weeks) in initiating Cycle 2 due to treatment-related toxicity Grade 
5 toxicity.
3.1.2
Dose De-Escalation
Dose de-escalation Schedule Arm B 
Dose Level
M7824 
Topotecan 
Level 1
2400 mg every 3 weeks
1 mg/m2 on days 1-5 every 3 weeks
Level -1
2400 mg every 3 weeks
0.75 mg/m2 on days 1-5 every 3 weeks


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Dose de-escalation Schedule Arm C 
Dose Level
M7824 
Temozolomide
Level 1
1200 mg every 2 weeks
200 mg/m2/day on days 1-5 every 4 weeks
Level -1
1200 mg every 2 weeks
150 mg/m2/day on days 1-5 every 4 weeks
3.2
STUDY ACCRUAL STOPPING RULE
Once the 6th participant had reached the 6 months follow up period (or potentially would have 
reached the 6 months follow-up if the participant died prior to the 6 months follow-up), the study 
will be halted for a DSMB review of the available data if more than 5 participants have PD ≤ 6 
months following the first dosage.
If two participants experience serious bleeding events within 30 days following the last 
administration of investigational product, the study will be halted from further enrollment and 
the data will be presented in an ad-hoc DSMB meeting. Once the study will be put off hold, only 
bleeding events occurring after the resumption of enrollment will be counted toward the halting 
rule. 
3.3
DRUG ADMINISTRATION
Study drug may be dispensed only under the supervision of the investigator or an authorized 
designee and only for administration to the study subjects. In Arms B and C, M7824 will be 
administered first followed within 15-30 minutes after the end of infusion by topotecan or 
temozolomide. The timing of subsequent administrations is then adjusted to maintain cycle 
length.
For non-medical logistical reasons or for unrelated acute illnesses, dosing can be delayed up to 2 
months. Where at all possible, dosing should be restarted to keep in line with the original 
treatment schedule.
3.3.1
Topotecan Administration
Topotecan is a cytotoxic anticancer drug. Prepare topotecan under a vertical laminar flow hood 
while wearing gloves and protective clothing. If topotecan solution contacts the skin, wash the 
skin immediately and thoroughly with soap and water. If topotecan contacts mucous membranes, 
flush thoroughly with water. Use procedures for proper handling and disposal of anticancer 
drugs. 
Each 4-mg vial of topotecan is reconstituted with 4 mL Sterile Water for Injection. Then the 
appropriate volume of the reconstituted solution is diluted in 50 mL of either 0.9% Sodium 
Chloride Intravenous Infusion or 5% Dextrose Intravenous Infusion prior to administration. 
Topotecan will be administered as an intravenous infusion over 30 minutes.
3.3.2
Temozolomide Administration
Temozolomide will be dispensed at the start of each cycle. Patients will be provided with a pill 
diary (Appendix B), instructed in its use, and asked to bring it with them to each appointment. 
The dose will be determined using the body surface area (BSA) calculated at the beginning of 
each cycle unless significant (> 3 kg) weight loss or gain is observed. The BSA will be 


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calculated from the height obtained at the pretreatment visit and from the weight obtained at the 
visit before each odd cycle. Capsules of temozolomide will be available in 5, 20, and 100 mg for 
this study. The daily dose will be rounded to the nearest 5 mg. The exact dose administered 
should be recorded in the CRF. Each daily dose should be given with the least number of 
capsules. Temozolomide will be administered and maintained in accordance with SOP #: PM-8 
that is available via 
https://ccrod.cancer.gov/confluence/display/CCRCRO/Documenting+Drug+Accountability+for+
Oral+Investigational+Agents. Prior to each treatment cycle with temozolomide a complete blood 
count (CBC) will be obtained.
3.3.3
M7824 Administration
M7824 will be administered as a 1-hour (-10 minutes / +20 minutes) IV infusion on days 1 and 
15 of each cycle in arm C and progressive disease patients in arm A.
For subjects receiving 2400 mg (monotherapy arm A [amendment B onward] and arm B), total 
infusion time may be up to 120 minutes. 
Current experience revealed that infusion related reactions (IRRs) to M7824 seldom occur and 
are generally mild to moderate in severity. Therefore, administration of a premedication is 
generally not required.
If an Investigator deems it necessary to administer a premedication to a particular participant, an 
antihistamine (for example, 25-50 mg diphenhydramine and 500-650 mg acetaminophen 
intravenously or equivalent oral dose is recommended) approximately 30 to 60 minutes prior to 
each dose of M7824. If Grade ≥ 2 infusion reactions are seen during the first two infusions, 
premedication should not be stopped. Steroids as premedication are not permitted.
M7824 should be administered through a peripheral IV or titanium port. A 0.2 micron 
polyethersulfone (PES) in-line filter is mandatory for [M7824] administration. Please refer to 
pharmacy manual for details. 
 Hypersensitivity reactions may require immediate intensive care. M7824 should be administered 
in a setting that allows for immediate access to an intensive care unit or equivalent environment 
and administration of therapy for anaphylaxis, such as the ability to implement immediate 
resuscitation measures. Steroids (dexamethasone 10 mg), epinephrine (1:1,000 dilution), allergy 
medications (IV antihistamines), bronchodilators, or equivalents, and oxygen should be available 
for immediate access. 
A complete guideline for the emergency treatment of anaphylactic reactions according to the 
Working Group of the Resuscitation Council United Kingdom and can be found at 
https://www.resus.org.uk/pages/reaction.pdf.
For prophylaxis of flu like symptoms, a nonsteroidal anti-inflammatory drug (NSAID), e.g., 
ibuprofen 400 mg or comparable NSAID dose, may be administered 2 hours before and 8 hours 
after the start of each IV infusion.
Vital signs will be measured before, at least one time during the infusion of M7824 and at the 
end of infusion. Following M7824 infusions, subjects must be observed for a minimum of 1 hour 
post end of infusion for potential infusion-related reactions with vital signs taken every 30 
minutes ±15 minutes. If an allergic reaction occurs, the subject must be treated according to the 
best available medical practice. Please see the guidelines for handling of infusion-related 


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reaction in the section on dose modifications. After 3 cycles, if the patient never develops any 
infusion related reaction, vital signs are only required pre and post infusion.
Investigators should also monitor subjects closely for potential irAEs, which may become 
manifest after several weeks of treatment. Such events may consist of persistent rash, diarrhea 
and colitis, autoimmune hepatitis, arthritis, glomerulonephritis, cardiomyopathy, or uveitis and 
other inflammatory eye conditions.
3.4
DOSE MODIFICATIONS
3.4.1
Topotecan Dose Modification
No dose modifications of topotecan may be made during cycle 1. 
The dose of topotecan may be reduced other than in Cycle 1 for toxicity using the following 
guidelines depending on the toxicities (and drug deemed to be responsible for toxicity) observed, 
see Table 3. Topotecan dose reductions will be accomplished by decreasing the dose of 
topotecan for each of the 5 days.
To initiate subsequent cycles of topotecan the day 1 ANC should be >1500/mm3 and platelets 
>100,000/mm3. Treatment interruptions may occur for a maximum of 21 days.
Based on the below criteria, a maximum of 2 dose reductions will be permitted. 
Table 3. Dose Adjustments
Table 3a. Dose adjustments for renal functions
Creatinine clearance 
Dose adjustment (% decrease in topotecan dose)
>60
no adjustment
40-59
-20%
20-39
-25%
<20
Discontinue
Table 3b. Dose adjustments for non-hematologic toxicities
Non-hematologic toxicity
Dose adjustment (% decrease in topotecan 
dose)
Grades 1 and 2
no adjustment
Grades 3 and 4 (except grade 3 nausea)
-20%
Table 3c. Dose adjustments for hematologic toxicities
Hematologic toxicity
Dose adjustment (topotecan mg/m2)


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Grades 1 and 2
no adjustment
Grade 3 neutropenia persisting after day 21
-20%
Grade 4 thrombocytopenia or Grade 4 
neutropenia with fever or infection or of 
duration ≥ 7 days
-20%
In addition, in case of Grade 3 or higher toxicity during any cycle beyond Cycle 1, treatment 
may be interrupted and may be resumed when all toxicities have returned to Grade 2 or less, at 
the discretion of the investigator. 
Subjects who develop intolerance to topotecan, but who may be benefiting from therapy, may 
continue on single agent M7824 until disease progression.
3.4.2
Temozolomide Dose Modification
Temozolomide dose is modified only if toxicity is specifically attributed to temozolomide. If 
during a TMZ dosing period, there is a drop in ANC to < 1000 or platelets < 50 000 a dose 
reduction should occur in the subsequent cycle. See tables. Sequence cycles of temozolomide 
will not be started unless ANC is above 1500 and the platelet count exceeds 100,000/μL. A 
maximum of 2 dose reductions will be permitted. 
Dose adjustments for Temozolomide 
Grade
Dose adjustments
Grades 1 and 2
None 
Grades 3 and 4
-25% 
Subjects who develop intolerance to temozolomide, but who may be benefiting from therapy, 
may continue on single agent M7824 until disease progression.
3.4.3
Management of M7824 AEs
M7824 should be withheld for any Grade 2 or 3 adverse drug reactions (ADR) until resolution 
to Grade ≤ 1 unless the ADR in the opinion of the investigator is not clinically relevant or can 
be medically managed with minimal risk to the patient. 
Grade 4 isolated laboratory values out of normal range that do not have any clinical correlation 
may not require treatment discontinuation. Work-up, management, and treatment continuation 
versus hold versus discontinuation for isolated Grade 4 laboratory abnormalities should be 
carefully evaluated.
Should a clinically relevant grade 2 or 3 ADR persist for more than 4 weeks, consideration 
should be given to discontinuing treatment with M7824 at the discretion of the investigator. 
If a Grade 2 ADR resolves to Grade ≤ 1 by the last day of the current cycle, treatment may 
continue.


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Infusion-related reactions and hypersensitivity reactions (Grades 1 to 4) should be handled 
according to the Guidelines provided below.
3.4.3.1
Infusion-related Reactions
Signs and symptoms usually develop during or shortly after drug infusion and generally resolve 
completely within 24 hours of completion of infusion.
Symptoms:

Fever

Chills

Rigors

Diaphoresis

Headache
Table 4. Treatment Modification Guidance for Symptoms of Infusion-Related Reactions 
including Immediate Hypersensitivity
NCI-CTCAE Grade 
Infusion of M7824
Treatment
Premedication 
at subsequent 
dosing
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.
The total infusion time 
for M7824 should not 
exceed 120 minutes
Increase monitoring 
of vital signs as 
medically indicated 
until the subject is 
deemed medically 
stable in the opinion 
of the investigator.
Hold infusion if 
deemed necessary by 
the investigator.
None
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.
If symptoms resolve 
within one hour of 
stopping drug infusion, 
the infusion may be 
restarted at 50% of the 
original infusion rate 
(e.g., from 100 mL/hr to 
50 mL/hr).
Otherwise dosing will 
be held until symptoms 
resolve and the subject 
should be pre-medicated 
Monitor symptoms.
Therapy include but 
is not limited to:
IV fluids
Antihistamines
NSAIDS
Acetaminophen
Narcotics
Increase monitoring 
of vital signs as 
medically indicated 
until the subject is 
deemed medically 
Subject to be pre-
medicated 1.5h 
(± 30 minutes) 
prior to infusion 
of M7824 with:
Diphenhydramine 
50 mg po (or 
equivalent dose 
of antihistamine).
Acetaminophen 
500-1,000 mg PO 
(or equivalent 
dose of 
antipyretic).


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NCI-CTCAE Grade 
Infusion of M7824
Treatment
Premedication 
at subsequent 
dosing
for the next scheduled 
dose.
If not improving, 
consider administration 
of glucocorticoids and 
stop the infusion for that 
day.
Subjects who develop 
Grade 2 toxicity 
despite adequate 
premedication should 
be permanently 
discontinued from 
further trial treatment 
administration.
stable in the opinion 
of the investigator.
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.
Stop the M7824 infusion 
immediately and 
disconnect infusion 
tubing from the subject.
If resolved within 6 
hours, infusion may be 
restarted by discretion of 
PI
Subject to be pre-
medicated 1.5h 
(± 30 minutes) 
prior to infusion 
of M7824 with:
Diphenhydramine 
50 mg po (or 
equivalent dose 
of antihistamine).
Acetaminophen 
500-1,000 mg PO 
(or equivalent 
dose of 
antipyretic).
Grade 4 
Life-threatening 
consequences; urgent 
intervention indicated.
Subjects have to be 
withdrawn immediately 
from M7824 treatment 
and must not receive any 
further M7824 treatment
Therapy includes but 
is not limited to:
-
IV fluids
-
Antihistamines
-
NSAIDS
-
Acetaminophen
-
Narcotics
-
Oxygen
-
Pressors
-
Corticosteroids
-
Epinephrine
Increase monitoring 
of vital signs as 
medically indicated 
until the subject is 
deemed medically 
stable in the opinion 
of the investigator.
Hospitalization may 
be indicated.
Administration of 
glucocorticoids may 
be required.
No subsequent 
dosing.


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NCI-CTCAE Grade 
Infusion of M7824
Treatment
Premedication 
at subsequent 
dosing
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 4 including reducing the infusion rate by 
50%), the Investigator may consider treatment with corticosteroids and the infusion of M7824 
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.
3.4.3.2
Severe Hypersensitivity Reactions and Flu-like Symptoms
If a hypersensitivity reaction occurs, the subject must be treated according to the best available 
medical practice including ACLS guidelines. Hypersensitivity reactions may require immediate 
intensive care. M7824 should be administered in a setting that allows 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. Potent steroids (e.g. 
dexamethasone), catecholamines (e.g. epinephrine), allergy medications (IV antihistamines), 
bronchodilators, or equivalents and oxygen should be available for immediate access.
Subjects should be instructed to report any delayed reactions to the Investigator immediately.

Symptoms

Impaired airway

Decreased oxygen saturation (< 92%)

Confusion

Lethargy

Hypotension

Pale / clammy skin

Cyanosis

Management

Epinephrine injection and IV dexamethasone

Patient should be placed on cardiac, blood pressure, heart rate, and oxygen saturation 
monitor immediately

Alert intensive care unit for possible transfer if required


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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. The risk of bleeding will be discussed with participants prescribed/using 
NSAIDs.
3.4.3.3
Management of Immune-Related Adverse Events
Since inhibition of PD-L1 and TGFβ signaling stimulates the immune system, irAEs may occur. 
Immune-related AEs are specific to immunotherapies and vary by organ system. The following 
immune-related AEs are important identified risks for M7824:
Immune-related pneumonitis
Immune-related hepatitis
Immune-related colitis
Immune-related nephritis and renal dysfunction
Immune-related endocrinopathies (thyroid disorders, adrenal insufficiency, type 1 diabetes 
mellitus, pituitary disorders)
Immune related rash
Other immune-related events (myositis, myocarditis, encephalitis)
The following immune-related AEs are important potential risks for M7824:
Guillain-Barré syndrome
Uveitis
Pancreatitis
Myasthenia gravis/myasthenic syndrome
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 Table 5. 
Table 5. Management of Immune-Related Adverse Events
Gastrointestinal irAEs
Severity of Diarrhea/Colitis
(NCI-CTCAE v5)
Initial Management
Follow-up Management
Grade 1
Diarrhea: < 4 stools/day over 
Baseline
Colitis: asymptomatic 
Continue M7824 therapy
Symptomatic treatment (e.g. 
loperamide)
Close monitoring for worsening 
symptoms
Educate subject to report worsening 
immediately
If worsens:


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Treat as Grade 2, 3 or 4. 
Grade 2 
Diarrhea: Increase of 4 – 6 stools per 
day over baseline; moderate increase 
in ostomy output compared to 
baseline; limiting instrumental ADL 
Colitis: abdominal pain; blood in 
stool 
Withhold M7824 therapy
Symptomatic treatment
If improves to Grade ≤ 1: 
Resume M7824 therapy
If persists > 5-7 days or recurs:
Treat as Grade 3 or 4.
Grade 3 to 4
Diarrhea (Grade 3): Increase of >=7 
stools per day over baseline; 
hospitalization indicated; severe 
increase in ostomy output compared 
to baseline; limiting self-care ADL 
Colitis (Grade 3): severe abdominal 
pain, , peritoneal signs
Grade 4: Life-threatening 
consequences; urgent intervention 
indicated
Withhold M7824 for 
Grade 3.
Permanently discontinue 
M7824 for Grade 4 or 
recurrent Grade 3.
1.0 to 2.0 mg/kg/day 
prednisone IV or equivalent
Add prophylactic antibiotics 
for opportunistic infections 
Consider lower endoscopy 
If improves: 
Continue steroids until Grade ≤ 1, then 
taper over at least 1 month; resume 
M7824 therapy following steroids taper 
(for initial Grade 3). 
If worsens, persists > 3 to 5 days, or 
recurs after improvement:
Add infliximab 5mg/kg (if no 
contraindication). Note: infliximab 
should not be used in cases of 
perforation or sepsis. 
Dermatological irAEs
Grade of Rash
(NCI-CTCAE v5)
Initial Management
Follow-up Management
Grade 1 to 2 
Covering ≤ 30% body surface area 
Continue M7824 therapy 
Symptomatic therapy (for 
example, antihistamines, 
topical steroids) 
If persists > 1 to 2 weeks or recurs: 
Withhold M7824 therapy 
Consider skin biopsy 
Consider 0.5-1.0 mg/kg/day prednisone 
or equivalent. Once improving, taper 
steroids over at least 1 month, consider 
prophylactic antibiotics for 
opportunistic infections, and resume 
M7824 therapy following steroids taper.
If worsens: 
Treat as Grade 3 to 4. 
Grade 3 to 4
Grade 3: Covering > 30% body 
surface area; 
Grade 4: Life threatening 
consequences 
Withhold M7824 for 
Grade 3.
Permanently discontinue for 
Grade 4 or recurrent Grade 
3. 
If improves to Grade ≤ 1: 
Taper steroids over at least 1 month; 
resume M7824 therapy following 
steroids taper (for initial Grade 3).


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Consider skin biopsy 
Dermatology consult 
1.0 to 2.0 mg/kg/day 
prednisone or equivalent
Add prophylactic antibiotics 
for opportunistic infections 
Pulmonary irAEs
Grade of Pneumonitis
(NCI-CTCAE v5)
Initial Management
Follow-up Management
Grade 1
Asymptomatic; clinical or diagnostic 
observations only; intervention not 
indicated
Consider withholding 
M7824 therapy 
Monitor for symptoms every 
2 to 3 days 
Consider Pulmonary and 
Infectious Disease consults 
Re-assess at least every 3 weeks
If worsens: 
Treat as Grade 2 or Grade 3 to 4. 
Grade 2
Symptomatic; medical intervention 
indicated; limiting instrumental 
ADL
Withhold M7824 therapy
Pulmonary and Infectious 
Disease consults
Monitor symptoms daily; 
consider hospitalization 
1.0 to 2.0 mg/kg/day 
prednisone or equivalent
Add prophylactic antibiotics 
for opportunistic infections 
Consider bronchoscopy, lung 
biopsy 
Re-assess every 1 to 3 days 
If improves: 
When symptoms return to Grade ≤ 1, 
taper steroids over at least 1 month, and 
then resume M7824 therapy following 
steroids taper 
If not improving after 2 weeks or 
worsening: 
Treat as Grade 3 to 4. 
Grade 3 to 4
Grade 3: Severe symptoms; limiting 
self-care ADL; oxygen indicated
Grade 4: Life-threatening respiratory 
compromise; urgent intervention 
indicated (e.g., tracheotomy or 
intubation)
Permanently discontinue 
M7824 therapy.
Hospitalize.
Pulmonary and Infectious 
Disease consults.
1.0 to 2.0 mg/kg/day 
prednisone or equivalent 
Add prophylactic antibiotics 
for opportunistic infections 
Consider bronchoscopy, lung 
biopsy 
If improves to Grade ≤ 1: 
Taper steroids over at least 1 month 
If not improving after 48 hours or 
worsening: 
Add additional immunosuppression (for 
example, infliximab, 
cyclophosphamide, IV immunoglobulin, 
or mycophenolate mofetil) 
Hepatic irAEs
Grade of Liver Test Elevation
(NCI-CTCAE v5)
Initial Management
Follow-up Management
Grade 1
Continue M7824 therapy
Continue liver function monitoring 
If worsens: 
 Treat as Grade 2 or 3 to 4. 


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Grade 1 AST or >ULN – 3.0 x ULN 
if baseline was normal; 1.5 – 3.0 x 
baseline if baseline was abnormal 
and/or Total bilirubin 
>ULN – 1.5 x ULN if baseline was 
normal; > 1.0 – 1.5 x baseline if 
baseline was abnormal
Grade 2
AST or ALT >3.0 – 5.0 x ULN if 
baseline was normal; >3.0 – 5.0 x 
baseline if baseline was abnormal 
and/or total bilirubin > 1.5 to ≤ 3 x 
ULN if baseline was normal; >3.0 – 
10.0 x baseline if baseline was 
abnormal
Withhold M7824 therapy
Increase frequency of 
monitoring to every 3 days.
If returns to Grade ≤ 1:
Resume routine monitoring; resume 
M7824 therapy.
If elevation persists > 5 to 7 days or 
worsens: 
Treat as Grade 3 to 4.
Grade 3 to 4
Grade 3: AST or ALT >5.0 – 20.0 x 
ULN if baseline was normal; >5.0 – 
20.0 x baseline if baseline was 
abnormal and/or total bilirubin >3.0 
– 10.0 x ULN if baseline was 
normal; >3.0 – 10.0 x baseline if 
baseline was abnormal
Grade 4: AST or ALT >20.0 x ULN 
if baseline was normal; >20.0 x 
baseline if baseline was abnormal 
and/or total bilirubin >10.0 x ULN if 
baseline was normal; >10.0 x 
baseline if baseline was abnormal
Permanently discontinue 
M7824 therapy 
Increase frequency of 
monitoring to every 1 to 
2 days 
1.0 to 2.0 mg/kg/day 
prednisone or equivalent
Add prophylactic antibiotics 
for opportunistic infections 
Consult gastroenterologist/ 
hepatologist
Consider obtaining MRI/CT 
scan of liver and liver biopsy 
if clinically warranted 
If returns to Grade ≤ 1: 
Taper steroids over at least 1 month 
If does not improve in > 3 to 5 days, 
worsens or rebounds: 
Add mycophenolate mofetil 1 gram (g) 
twice daily 
If no response within an additional 3 to 
5 days, consider other 
immunosuppressants per local 
guidelines.
Renal irAEs
Grade of Creatinine Increased 
(NCI-CTCAE v5)
Initial Management
Follow-up Management
Grade 1
Creatinine increased > ULN to 1.5 x 
ULN
Continue M7824 therapy
Continue renal function 
monitoring
If worsens:
Treat as Grade 2 to 3 or 4.
Grade 2 to 3
Creatinine increased > 1.5 and ≤ 6 x 
ULN
Withhold M7824 therapy
Increase frequency of monitoring to 
every 3 days
1.0 to 2.0 mg/kg/day prednisone or 
equivalent.
Add prophylactic antibiotics for 
opportunistic infections
Consider renal biopsy
If returns to Grade ≤1:
Taper steroids over at least 1 
month, and resume M7824 
therapy following steroids taper.
If worsens: 
Treat as Grade 4.


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Grade 4
Creatinine increased > 6 x ULN
Permanently discontinue M7824 
therapy
Monitor creatinine daily
1.0 to 2.0 mg/kg/day prednisone or 
equivalent.
Add prophylactic antibiotics for 
opportunistic infections
Consider renal biopsy
Nephrology consult
If returns to Grade ≤1:
Taper steroids over at least 1 
month.
Cardiac irAEs
Myocarditis
Initial Management
Follow-up Management
New onset of cardiac signs or 
symptoms and / or new laboratory 
cardiac biomarker elevations (e.g. 
troponin, CK-MB, BNP) or 
cardiac imaging abnormalities 
suggestive of myocarditis. 
Withhold M7824 therapy.
Hospitalize.
In the presence of life threatening 
cardiac decompensation, consider 
transfer to a facility experienced in 
advanced heart failure and arrhythmia 
management.
Cardiology consult to establish etiology 
and rule-out immune-mediated 
myocarditis. 
Guideline based supportive treatment as 
per cardiology consult. *
Consider myocardial biopsy if 
recommended per cardiology consult.
If symptoms improve and 
immune-mediated etiology is 
ruled out, re-start M7824 
therapy.
If symptoms do not 
improve/worsen, viral 
myocarditis is excluded, and 
immune-mediated etiology is 
suspected or confirmed 
following cardiology consult, 
manage as immune-mediated 
myocarditis.
Immune-mediated myocarditis
Permanently discontinue M7824.
Guideline based supportive treatment as 
appropriate as per cardiology consult. *
1.0 to 2.0 mg/kg/day prednisone or 
equivalent
Add prophylactic antibiotics for 
opportunistic infections.
Once improving, taper 
steroids over at least 1 month.
If no improvement or 
worsening, consider additional 
immunosuppressants (e.g. 
azathioprine, cyclosporine A).


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*Local guidelines, or e.g. ESC or AHA guidelines 
ESC guidelines website: https://www.escardio.org/Guidelines/Clinical-Practice-Guidelines
AHA guidelines website: 
http://professional.heart.org/professional/GuidelinesStatements/searchresults.jsp?q=&y=&t=1001
Endocrine irAEs
Endocrine Disorder
Initial Management
Follow-up Management
Grade 1 or Grade 2 
endocrinopathies 
(hypothyroidism, 
hyperthyroidism, adrenal 
insufficiency, type I diabetes 
mellitus)
Continue M7824 therapy
Endocrinology consult if needed
Start thyroid hormone replacement 
therapy (for hypothyroidism), 
anti-thyroid treatment (for 
hyperthyroidism), corticosteroids (for 
adrenal insufficiency) or insulin (for 
Type I diabetes mellitus) as 
appropriate. 
Rule-out secondary endocrinopathies 
(i.e. hypopituitarism / hypophysitis)
Continue hormone 
replacement/suppression and 
monitoring of endocrine 
function as appropriate.
Grade 3 or Grade 4 
endocrinopathies 
(hypothyroidism, 
hyperthyroidism, adrenal 
insufficiency, type I diabetes 
mellitus)
Withhold M7824 therapy (for type I 
diabetes until glucose level improves 
to grade 2 or less per CTCAE version 
4)
Consider hospitalization
Endocrinology consult
Start thyroid hormone replacement 
therapy (for hypothyroidism), 
anti-thyroid treatment (for 
hyperthyroidism), corticosteroids (for 
adrenal insufficiency) or insulin (for 
type I diabetes mellitus) as 
appropriate. 
Rule-out secondary endocrinopathies 
(i.e. hypopituitarism / hypophysitis)
Resume M7824 once 
symptoms and/or laboratory 
tests improve to Grade ≤ 1 
(with or without hormone 
replacement/suppression).
Continue hormone 
replacement/suppression and 
monitoring of endocrine 
function as appropriate. 
Hypopituitarism/Hypophysitis 
(secondary endocrinopathies)
If secondary thyroid and/or adrenal 
insufficiency is confirmed (i.e. 
subnormal serum FT4 with 
inappropriately low TSH and/or low 
serum cortisol with inappropriately 
low ACTH) :
1.0 Refer to endocrinologist for 
dynamic testing as indicated and 
measurement of other hormones 
(FSH, LH, GH/IGF-1, PRL, 
testosterone in men, estrogens in 
women) 
Resume M7824 once 
symptoms and hormone tests 
improve to Grade ≤ 1 (with or 
without hormone 
replacement).
In addition, for hypophysitis 
with abnormal MRI, resume 
M7824 only once shrinkage 
of the pituitary gland on 
MRI/CT scan is documented. 


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2.0 Hormone 
replacement/suppressive therapy 
as appropriate 
3.0 Perform pituitary MRI and visual 
field examination as indicated
If hypophysitis confirmed:

Continue M7824 if mild 
symptoms with normal MRI. 
Repeat the MRI in 1 month

Withhold M7824 if moderate, 
severe or life-threatening 
symptoms of hypophysitis and/or 
abnormal MRI. Consider 
hospitalization. Initiate 
corticosteroids (1 to 2 mg/kg/day 
prednisone or equivalent) 
followed by corticosteroids taper 
during at least 1 month.

Add prophylactic antibiotics for 
opportunistic infections.
Continue hormone 
replacement/suppression 
therapy as appropriate.
Other irAEs (not described above)
Grade of other irAEs 
(NCI-CTCAE v5)
Initial Management
Follow-up Management
Grade 2 or Grade 3 clinical signs 
or symptoms suggestive of a 
potential irAE
Withhold M7824 therapy pending 
clinical investigation
If irAE is ruled out, manage 
as appropriate according to 
the diagnosis and consider re-
starting M7824 therapy
If irAE is confirmed, treat as 
Grade 2 or 3 irAE.
Grade 2 irAE or first occurrence 
of Grade 3 irAE
Withhold M7824 therapy
1.0 to 2.0 mg/kg/day prednisone or 
equivalent 
Add prophylactic antibiotics for 
opportunistic infections 
Specialty consult as appropriate
If improves to Grade ≤ 1: 
Taper steroids over at least 1 
month and resume M7824 
therapy following steroids 
taper.
Recurrence of same Grade 3 
irAEs
Permanently discontinue M7824 
therapy

to 2.0 mg/kg/day
prednisone or equivalent
Add prophylactic antibiotics for 
opportunistic infections 
Specialty consult as appropriate
If improves to Grade ≤ 1: 
Taper steroids over at least 1 
month.
Grade 4 
Permanently discontinue M7824 
therapy (single laboratory values out 
of normal range that do not have any 
clinical correlate may not require 
permanent discontinuation – see 
section 3.4.3)

to 2.0 mg/kg/day
If improves to Grade ≤ 1: 
Taper steroids over at least 1 
month


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prednisone or equivalent and/or other 
immunosuppressant as needed
Add prophylactic antibiotics for 
opportunistic infections 
Specialty consult.
Requirement for 10 mg per day 
or greater prednisone or 
equivalent for more than 12 
weeks for reasons other than 
hormonal replacement for 
adrenal insufficiency
Persistent Grade 2 or 3 irAE 
lasting 12 weeks or longer
Permanently discontinue M7824 
therapy
Specialty consult
3.4.3.4
Management of M7824 Mediated Skin Reactions 
Monitoring will include skin assessments every cycle with biopsy of suspicious lesions. 
Dermatological consults should be requested as needed.
TGF-β inhibition mediated skin reactions are considered important identified risk for M7824. Skin assessment 
must be performed at baseline and at least every 6 weeks during treatment and at the end of treatment or 28 
(±5 days) days post-treatment safety follow-up (if not performed in the previous 6 weeks).

Hyperkeratosis

Keratoacanthoma

Cutaneous squamous cell carcinoma (cSCC)

Basal cell carcinoma

Actinic keratosis
Management

Baseline skin assessment with detailed medical history

Discontinuation or termination not required in most cases. Continuation of treatment should be evaluated 
by the Investigator.

Emollients may be used

Develop diagnostic and treatment plan in collaboration with Investigator and dermatologist

Treatment follow-up will depend on number and localization of lesions.
o
Single lesion: full excision may be recommended
o
Multiple lesion or location not suitable for full excision: Mohrs surgery, cryotherapy or other 
standard treatment options depending on pathology. Retinoids may be used after discussion with 
Investigator.

Close clinical follow-up for re-evaluation, resolution and potential recurrence should be implemented

In general, treatment of TGF-β mediated skin lesions should be based on local guidelines/standard of 
care.
Additional consideration: Keratoacanthoma lesions may resolve spontaneously without surgical intervention 
within weeks after discontinuing M7824.
Consult with Medical Monitor as needed for management of TGF-β mediated skin lesions.
3.4.3.5
Management of Impaired Wound Healing 
Management should be discussed on a case-by-case basis. Dermatological consults should be 
requested as needed. 


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
Impaired wound healing is considered important potential risk for M7824

Management should be discussed with Medical Monitor for participants requiring surgery on study.

It is recommended to hold study intervention for approximately 4 weeks post major surgery for 
observation.

Post-operative wound healing should be closely monitored
3.4.3.6
Management of Treatment related Anemia 

Anemia is considered an important identified risk for M7824.

Hematology assessment must be performed at baseline, prior to each M7824 dose, at the end of treatment 
visit and at 28 (±5 days) days post-treatment safety follow-up.

Participants must enter the study with Hgb values at least 9g/dl

All relevant hematological testing for treatment-related anemias should be done prior to a blood 
transfusion, if clinically feasible
Basic Anemia Evaluation

CBC with emphasis on red cell indices

If indicated and at clinical discretion, the following should be considered:
o
Iron studies
o
Serum Folate and Vit B12 values
o
Coagulation factors
o
Fecal occult blood
o
Urinalysis
o
Hormone panel: TSH, Erythropoietin
o
Peripheral blood smear
Further Recommendation Based on Suspected Etiology (in Addition to Basic Anemia Testing)

Suspected Hemolysis
o
bilirubin, LDH, Coombs test, haptoglobin

Suspected bleeding: 
o
Consider imaging/interventional radiology consultation as indicated
o
Consider imaging and/or endoscopy as clinically indicated

Suspected aplastic anemia:
o
Hematology consultation
o
Consider bone marrow aspiration/morphologic evaluation
Additional consideration: 
In general, blood transfusions and erythroid growth factors are permitted as clinically indicated.
Abbreviation: CBC: complete blood count, TSH: thyroid stimulating hormone, LDH: lactate dehydrogenase
3.4.3.7
Management of Bleeding Adverse Events
Bleeding Adverse Events

Bleeding adverse events are considered important identified risk for M7824.

In general, mild and moderate mucosal bleedings resolve without discontinuation of treatment.

These events may include, but are not limited to the following:
o
Epistaxis
o
Hemoptysis 
o
Gingival bleeding
o
Hematuria
Non-tumor Bleeding
Grading
Management


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Grade 2

If resolves to Grade ≤ 1 by the day before the 
next infusion, study intervention may be 
continued

If not resolved to Grade ≤ 1 by the day before the 
next infusion, but is manageable and /or not 
clinically relevant, consult Medical Monitor to 
assess if clinically reasonable to administer the 
following infusion.
Grade 3

Permanently discontinue treatment unless an 
alternative explanation can be identified (such as 
concomitant use of antithrombotic agents, 
traumatic events, etc.) 

In case of alternative explanations, hold study 
treatment until the event recovers to Grade ≤ 1
Grade 4

Treatment must be permanently discontinued if 
no alternative explanation is identified.
Tumor Bleeding
Grade ≥ 2

Study treatment must be held till the event 
recovers to Grade ≤ 1

Permanently discontinue treatment if the 
Investigator considers the participant to be at risk 
for additional severe bleeding.
3.4.3.8
Dose Interruptions for Adverse Events not Related to Study Drug
In case of Grade 3 and Grade 4 AEs which are not study drug related, the study treatment may be 
interrupted for up to 2 months based on the Investigator assessment. 
3.5
STUDY CALENDARS
Evaluation and drug administration and can be performed +/- 3 days due to holidays, inclement 
weather, conflicts, or similar reasons. All baseline studies must be completed within 7 days of 
first dose of drug. If tests needed at baseline were performed at screening within the 7 day 
timeframe, they do not need to be repeated.


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3.5.1
Arm A (M7824 Monotherapy)
Cycle (3 weeks)
1
2
3 
(forward)
Procedure
Screening 2
Baseline 3
Day 
1 3
Day 
2
Day 
1
Day 
1
End of 
treatment 
and 
follow up 
visits 1
History and physical exam
X
X
X
X
X
Vital signs 4
X
X
X
X20
X
ECOG Performance Score
X
X
X
X
X
Labs (CBC+diff, acute care panel, 
hepatic panel, mineral panel, PT/PTT) 
5, 13
X
X
X
X
X
X
TSH, Free T4, Amylase and Lipase 13
X
X
X
X
Viral Markers6
X
Creatine kinase, serum aldolase, and 
anti-acetylcholine receptor antibody 
titers 13
X
X
X
X
Pregnancy test 7
X
X
X
X
Complete neurological examination 8, 
16
X
X
X
X
X
Optional biopsies 10
X
X
Confirmation of diagnosis
X
Blood/Plasma for Correlative 
Research Studies 11, 14, 17:
Germline exome sequencing
X
Immune subsets
X
X
Immune studies
X
X
X
X
X
CtDNA
X
X
X
X
X
Paraneoplastic autoantibodies
X9
PK 12, 14, 15, 17
X
X
X
X
X
Radiological Assessments 19
X
Every 2 cycles (6 weeks)
Response Evaluation
Every 2 cycles (6 weeks)
EKG
X
X
Blood Troponin 14, 17
X
Adverse Events and Bleeding Events 18
X
Concomitant Medications
X
M7824 17, 21
X
X
X
Hair Follicle Collection (5.1.2)
X
X
X
1.
End of treatment visit will occur approximately 30 days after the last dose of study drug. If the patient 
cannot return to the Clinical Center for this visit, a request will be made to collect required clinical 
labs from a local physician or laboratory. If this is not possible, patients may be assessed by telephone 
for symptoms. Patients will be monitored for survival via phone call every 4 months after the last 
dose until death. 
2.
Screening must be completed within 2 weeks prior to enrolling subjects onto the protocol. 


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3.
Baseline studies must be completed within 7 days of first dose of drug. Assessments do not need to be 
repeated on day 1 if performed within 7 days of drug administration. See footnote 14 below for 
exceptions.
4.
Include height (only required at screening/baseline), weight, heart rate, temperature, blood pressure 
and respiration rate. 
5.
CBC with differential: Neutrophils, Lymphs, Monos, Eos, Basos, WBC, RBC, Hemoglobin, 
Hematocrit, RBC Indices, MCV, RDW, Platelet; Acute Care Panel: Sodium (NA), Potassium (K), 
Chloride (CL) Total CO2 (Bicarbonate), Creatinine, Glucose, Urea nitrogen, eGFR; Hepatic Panel: 
Alkaline Phosphatase, ALT/GPT, AST/GOT, Total Bilirubin, Direct Bilirubin; Mineral Panel: 
Albumin, Calcium, Magnesium (Mg), Phosphorus. 
6.
HbsAg, anti-HCV, anti-HIV within 3 months prior to screening.
7.
Only for women of child-bearing potential. 
8.
Assessment of cranial nerve function and muscle strength will be performed at screening and 
subsequent visits on all eligible patients before starting treatment. 
9.
One additional red top tube (10 mL) will be collected for future evaluation of paraneoplastic 
autoantibodies. 
10. Please refer to section 5.1. for details on tumor samples analyses. 
11. Collected at pre-treatment. Please refer to section 5.1 for details on blood and plasma correlative 
samples analyses.
12. 3.5 mL of serum (for M7824) is collected for pharmacokinetics prior to infusion and at the end of 
infusion (EOI), on day 2 (24 hours after infusion) during dose 1 (C1D1) and prior to infusion and at 
the end of infusion of dose 3 (C3D1), prior to infusion during doses 2 (C2D1) and 6 (C6D1 – not 
shown on the calendar) and at the end of treatment (EOT). Please refer to section 5.1 for collection 
and processing details.
13. Do not need to repeat PT, PTT, TSH, FT4, amylase, lipase, CK, aldolase, or AchRAb on Day 1 of a 
cycle if they have been done within the last 21 days. These tests are exempt from the 7 day reporting 
window for baseline/C1D1 labs covered in footnote 4 above.
14. Pre-treatment correlative studies may be drawn any time prior to drug administration.
15. PK sampling: Any change in the actual drawing time will be documented as a deviation and reported 
per requirements in section 7.2.
16. A complete neurological exam is to be performed at baseline and at each visit.
17. Patients may be hospitalized for convenience and logistical reasons for drug administration and/or 
research blood draws. 
18. In addition to adverse events, participants will also be asked specific questions relating to bleeding so 
that participants with hematochezia, hematuria, gum bleeding, hemoptysis or epistaxis can be 
identified.
19. If a CT scan is not sufficient to assess response, a PET scan may be added.
20. After 3 cycles, if the patient never develops any infusion related reaction, vital signs are only required 
pre and post infusion. Before cycle 3 and/or if patient develops an infusion related reaction, vital 
signs will be collected per section 3.3.3.
21. Patients with progressive disease on Arm A may then receive 1200mg M7824 every 2 weeks plus 
temozolomide 200 mg/m2/day on days 1-5 every 4 weeks. The study procedures will follow that of 
arm C but patients will remain in arm A.


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3.5.2
Arm B (M7824 Plus Topotecan)
Cycle (3 weeks)
1
2
3 
(forward)
Procedure
Screening 3
Baseline 4
Day 
1
Day 
2-5
Day 7 
& 
weekly 
Day 
1
Day
1
End of 
treatment 
and 
follow up 
visits1
History and physical exam 2
X
X
X
X
X
Vital signs 5
X
X
X
X23
X
ECOG Performance Score
X
X
X
X
X
Labs (CBC+diff, acute care 
panel, hepatic panel, mineral 
panel, PT/PTT) 6, 
X
X
X
X7
X
X
X
TSH, Free T4, Amylase and 
Lipase 
X
X
X
X
Viral Markers 8
X
Creatine kinase, serum 
aldolase, and anti-
acetylcholine receptor 
antibody titers
X
X
X
X
Pregnancy test 9
X
X
X
X
Complete neurological 
examination 10
X
X
X
X
X
Optional biopsies 12
X
X
Confirmation of diagnosis
X
Blood/Plasma for Correlative 
Research Studies13, 17, 19:
Germline exome 
sequencing
X
Immune subsets 14
X
X
X
Immune studies 14
X
X
X
X
X
CtDNA 14
X
X
X
X
X
Paraneoplastic 
autoantibodies
X11
PK 15, 17, 18, 19
X
X
X
X
X
Radiological Assessments 22
X
Every 2 cycles (6 weeks)
Response Evaluation
Every 2 cycles (6 weeks)
EKG
X
X
Blood Troponin 17, 19
X
Adverse Events and Bleeding 
Events 21
X
Concomitant Medications
X
M7824 19
X
X
X
Topotecan 16
X
X
X


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Cycle (3 weeks)
1
2
3 
(forward)
Procedure
Screening 3
Baseline 4
Day 
1
Day 
2-5
Day 7 
& 
weekly 
Day 
1
Day
1
End of 
treatment 
and 
follow up 
visits1
Hair Follicle Collection 
(5.1.2)
X
X20
X
1.
End of treatment visit will occur approximately 30 days after the last dose of study drug. If the patient 
cannot return to the Clinical Center for this visit, a request will be made to collect required clinical 
labs from a local physician or laboratory. If this is not possible, patients may be assessed by telephone 
for symptoms. Patients will be monitored for survival via phone call every 4 months after the last 
dose until death. Same procedures will be performed if patients have progressive disease that does not 
meet criteria in section 6.3.3.
2.
Physical exam will include skin assessment. 
3.
Screening must be completed within 2 weeks prior to enrolling subjects onto the protocol. 
4.
Baseline studies must be completed within 7 days of first dose of drug. Assessments do not need to be 
repeated on day 1 if performed within 7 days of drug administration. PT, PTT, TSH, FT4, amylase, 
lipase, CK, aldolase, or AchRAb do not need to be repeated at baseline if done within the last 21 
days.
5.
Include height (only required at screening/baseline), weight, heart rate, temperature, blood pressure 
and respiration rate. 
6.
CBC with differential: Neutrophils, Lymphs, Monos, Eos, Basos, WBC, RBC, Hemoglobin, 
Hematocrit, RBC Indices, MCV, RDW, Platelet; Acute Care Panel: Sodium (NA), Potassium (K), 
Chloride (CL) Total CO2 (Bicarbonate), Creatinine, Glucose, Urea nitrogen, eGFR; Hepatic Panel: 
Alkaline Phosphatase, ALT/GPT, AST/GOT, Total Bilirubin, Direct Bilirubin; Mineral Panel: 
Albumin, Calcium, Magnesium (Mg), Phosphorus. 
7.
Patients on this cohort will need weekly CBC diff during cycle 1.
8.
HbsAg, anti-HCV, anti-HIV within 3 months of screening.
9.
Only for women of child-bearing potential. 
10. A complete neurological exam including assessment of cranial nerve function and muscle strength 
will be performed at baseline and at day 1 of each cycle. 
11. One additional red top tube (10 mL) will be collected for future evaluation of paraneoplastic 
autoantibodies. 
12. Please refer to section 5.1 for details on tumor samples analyses. 
13. Collected at pre-treatment. Please refer to section 5.1 for details on blood and plasma correlative 
samples analyses.
14. Collected on days 1-5. 
15. 3.5 mL of plasma and 3.5 mL of serum are collected for pharmacokinetics. For M7824, blood 
collection for serum is to be performed prior to infusion and at the end of infusion (EOI) during doses 
1 (C1D1) and 3 (C3D1), prior to infusion during doses 2 (C2D1) and 6 (C6D1 – not shown on the 
calendar) and at the end of treatment (EOT). For topotecan, blood collection for plasma is to be 
performed at the following timepoints during C1D1: Pre, EOI, 0.5, 1, 2, 4 (optional), 8 (optional), 
24hr (day 2), 48hr (day 3), 96hr (day 5) post EOI of topotecan. Please refer to section 5.1 for 
collection and processing details.
16. Topotecan is administered on days 1-5 every 3 weeks. 
17. Pre-treatment correlative studies may be drawn at any time prior to drug administration.
18. PK sampling: any change in the actual drawing time will be documented a deviation and reported per 
requirements in section 7.2.


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19. Patients may be hospitalized for convenience and logistical reasons for drug administration and/or 
research blood draws.
20. Hair follicles are to be collected Day 2 only, not Days 2-5.
21. In addition to adverse events, participants will also be asked specific questions relating to bleeding so 
that participants with hematochezia, hematuria, gum bleeding, hemoptysis or epistaxis can be 
identified. 
22. Performed after every 2 cycles. If a CT scan is not sufficient to assess response, a PET scan may be 
added.
23. After 3 cycles, if the patient never develops any infusion related reaction, vital signs are only required 
pre and post infusion. Before cycle 3 and/or if patient develops an infusion related reaction, vital 
signs will be collected per section 3.3.3.


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3.5.3
Arm C (M7824 Plus Temozolomide)
Cycle (4 weeks)
1
2
3 (forward)
Procedure
Screening 2
Baseline 3
Day 
1 3
Day 
2
Day 
7
Day 
15
Day 
21
Day 
1
Day 
15
Day
1
Day
15
End of 
treatment 
and 
follow up 
visits 1
History and 
physical exam 4
X
X
X
X
X
X
X
X
Vital signs 5
X
X
X
X
X
X21
X21
X
ECOG 
Performance 
Score
X
X
X
X
X
X
X
X
Labs (CBC+diff, 
acute care panel, 
hepatic panel, 
mineral panel, 
PT/PTT) 6
X
X
X
X15
X22
X15
X
X22
X
X22
X
TSH, Free T4, 
Amylase and 
Lipase
X
X
X
X
Viral Markers 7
X
Creatine kinase, 
serum aldolase, 
and anti-
acetylcholine 
receptor 
antibody titers
X
X
X
X
Pregnancy test 8
X
X
X
X
X
X
X
Complete 
neurological 
examination 9
X
X
X
X
X
Optional biopsies 
11
X
X
Confirmation of 
diagnosis
X
Blood/Plasma 
for Correlative 
Research Studies 
12, 16, 18:
Germline 
exome 
sequencing
X
Immune 
subsets
X
X
X
X
Immune 
studies
X
X
X
X
X
X
CtDNA
X
X
X
X
X
X
Paraneoplastic 
autoantibodies
X10


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Cycle (4 weeks)
1
2
3 (forward)
Procedure
Screening 2
Baseline 3
Day 
1 3
Day 
2
Day 
7
Day 
15
Day 
21
Day 
1
Day 
15
Day
1
Day
15
End of 
treatment 
and 
follow up 
visits 1
PK 13, 16, 17, 18
X
X
X
X
Radiological 
Assessments 20
X
Every 2 cycles (8 weeks)
Response 
Evaluation
Every 2 cycles (8 weeks)
EKG
X
X
Blood Troponin 
16, 18
X
Adverse Events 
and Bleeding 
Events 19
X
Concomitant 
Medications
X
M7824 18
X
X
X
X
X
X
Temozolomide 14
X
X
X
X
Hair Follicle 
Collection (5.1.2)
X
X
X
1.
End of treatment visit will occur approximately 30 days after the last dose of study drug. If the patient 
cannot return to the Clinical Center for this visit, a request will be made to collect required clinical 
labs from a local physician or laboratory. If this is not possible, patients may be assessed by telephone 
for symptoms. Patients will be monitored for survival via phone call every 4 months after the last 
dose until death. Same procedures will be performed if patients have progressive disease that does not 
meet criteria in section 6.3.3.
2.
Screening must be completed within 2 weeks prior to enrolling subjects onto the protocol. 
3.
Baseline studies must be completed within 7 days of first dose of drug. Assessments do not need to be 
repeated on day 1 if performed within 7 days of drug administration. PT, PTT, TSH, FT4, amylase, 
lipase, CK, aldolase, or AchRAb do not need to be repeated at baseline if done within the last 21 
days. 
4.
Physical exam will include skin assessment.
5.
Include height (only required at screening/baseline), weight, heart rate, temperature, blood pressure 
and respiration rate. 
6.
CBC with differential: Neutrophils, Lymphs, Monos, Eos, Basos, WBC, RBC, Hemoglobin, 
Hematocrit, RBC Indices, MCV, RDW, Platelet; Acute Care Panel: Sodium (NA), Potassium (K), 
Chloride (CL) Total CO2 (Bicarbonate), Creatinine, Glucose, Urea nitrogen, eGFR; Hepatic Panel: 
Alkaline Phosphatase, ALT/GPT, AST/GOT, Total Bilirubin, Direct Bilirubin; Mineral Panel: 
Albumin, Calcium, Magnesium (Mg), Phosphorus. 
7.
HbsAg, anti-HCV, anti-HIV within 3 months of screening.
8.
Only for women of child-bearing potential. 
9.
A complete neurological exam including assessment of cranial nerve function and muscle strength 
will be performed at baseline and at day 1 of each cycle.
10. One additional red top tube (10 mL) will be collected for future evaluation of paraneoplastic 
autoantibodies. 
11. Please refer to section 5.1 for details on tumor samples analyses. 
12. Collected at pre-treatment. Please refer to section 5.1 for details on blood and plasma correlative 
samples analyses.


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13. 3.5 mL of plasma and 3.5 mL of serum are collected for pharmacokinetics. For M7824, blood 
collection for serum must be performed prior to infusion of M7824 and at the end of infusion (EOI) 
during doses 1 (C1D1) and 3 (C2D1), prior to infusion during doses 2 (C1D15) and 6 (C3D15 – not 
shown on the calendar) and at the end of treatment (EOT). For temezolomide, blood collection for 
plasma must be performed at the following timepoints during C1D1: pre temozolomide and 1, 2, 4, 8 
(optional), 12 (optional), and 24 hours post treatment temozolomide. Please refer to section 5.1 for 
collection and processing details.
14. Temozolomide is administered on days 1-5 every 4 weeks.
15. Only CBC with differentials is required on C1D7 and C1D21. These may be performed at a local 
physician and results faxed to research team.
16. Pre-treatment correlative studies may be drawn at any time prior to drug administration.
17. PK sampling: any change in the actual drawing time will be documented as a deviation and reported 
per requirements in section 7.2.
18. Patients may be hospitalized for convenience and logistical reasons for drug administration and/or 
research blood draws.
19. In addition to adverse events, participants will also be asked specific questions relating to bleeding so 
that participants with hematochezia, hematuria, gum bleeding, hemoptysis or epistaxis can be 
identified.
20. Performed after every 2 cycles. If a CT scan is not sufficient to assess response, a PET scan may be 
added.
21. After 3 cycles, if the patient never develops any infusion related reaction, vital signs are only required 
pre and post infusion. Before cycle 3 and/or if patient develops an infusion related reaction, vital 
signs will be collected per section 3.3.3.
22. Do not need to repeat PT/PTT on day 15 of each cycle.


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3.7
COST AND COMPENSATION 
3.7.1
Costs
NIH does not bill health insurance companies or participants for any research or related clinical 
care that participants receive at the NIH Clinical Center. If some tests and procedures are 
performed outside the NIH Clinical Center, participants may have to pay for these costs if they 
are not covered by an insurance company. Medicines that are not part of the study treatment will 
not be provided or paid for by the NIH Clinical Center. 
3.7.2
Compensation
Participants will not be compensated on this study.
3.7.3
Reimbursement 
The NCI will cover the costs of some expenses associated with protocol participation. Some of 
these costs may be paid directly by the NIH and some may be reimbursed to the 
participant/guardian as appropriate. The amount and form of these payments are determined by 
the NCI Travel and Lodging Reimbursement Policy. 
3.8
CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF STUDY CRITERIA
Prior to removal from study, effort must be made to have all subjects complete a safety visit 
approximately 30 days following the last dose of study therapy.
3.8.1
Criteria for removal from protocol therapy

Progressive disease in Arm A after combination therapy of M7824 and Temozolomide

Progressive disease in Arms A (after combination therapy), B or C which does not meet 
criteria in 6.3.3

Progressive disease in Arm C documented in two consecutive imaging scans

Participant requests to be withdrawn from active therapy

Unacceptable Toxicity as defined in section 3.4

Investigator discretion

Positive pregnancy test
3.8.2
Post therapy follow-up period
Patients will be monitored for survival via phone call every 4 months after the last dose until 
death.
3.8.3
Off-Study Criteria

Participant requests to be withdrawn from study

Investigator decision to end the study

Death

Permanent loss of capacity to consent

Screen failure


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4
CONCOMITANT MEDICATIONS/MEASURES
4.1
PERMITTED MEDICINES/INTERVENTIONS
Any medications (other than those excluded by the clinical trial protocol) that are considered 
necessary to protect subject welfare and will not interfere with the trial medication may be given 
at the Investigator’s discretion.
4.1.1
Palliative Radiation
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.
4.2
PROHIBITED MEDICINES 
The following treatments must not be administered during the trial:

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. 

Prophylactic use of corticosteroids for infusion related reactions is prohibited.

Herbal remedies with immunostimulating properties (for example, mistletoe extract) or 
known to potentially interfere with major organ function (for example, hypericin).

Any live vaccine therapies for the prevention of infectious disease. Administration of 
inactivated vaccines is allowed (for example, inactivated influenza vaccines).
Subsequent doses of M7824 should be delayed for 14-28 days for patients undergoing major 
surgeries, and wound healing should be closely evaluated prior to re-dosing with M7824.
4.3
SUPPORTIVE CARE 
4.3.1
Pneumocystis Pneumonia Prophylaxis
Prophylaxis may be provided for pneumocystis pneumonia concomitantly with temozolomide 
administration and may be continued in participants who develop lymphopenia until resolution to 
grade 1 or less.
5
CORRELATIVE STUDIES FOR RESEARCH
5.1
BIOSPECIMEN COLLECTION 
Please note that tubes and media referenced in this protocol maybe be substituted based on 
availability with the permission of the PI or laboratory investigator.


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Test/assay
Volume 
(approx.)
Type of 
tube
Collection time-points
Location of 
specimen 
storage/ analysis
Exome sequencing
All arms (pre-treatment)

C1D1 
RNA sequencing
Tumor 
sample, 
up to 5 
cores 
N/A
Arms A/B (pre-treatment)

C1D1

C2D1
Arm C (pre-treatment)

C1D1

C1D15
Doug Figg, 
NCI/NCI 
COMPASS
Evaluation of paraneoplastic 
autoantibodies *
1 x 10 mL
Red Top
Baseline
DTB, NCI
Germline exome sequencing
Blood, 
1x 5 mL
Purple top
EDTA 
All arms (pre-treatment)

C1D1
Doug Figg, 
NCI/NCI 
COMPASS
Peripheral blood immune subsets
Blood, 
2x 8mL 
CPT citrate
blue/black
Arm A (pre-treatment)

C1D1

C2D1 
Arm B (pre-treatment)

C1D1-5

C2D1
Arm C (pre-treatment)

C1D1

C1D2

C1D15 

C2D1 
DTB, NCI
Immune studies (cytokines, TCR 
sequencing, Antibodies to TOP1 and 
TOP1cc, STAT1 phosphorylation
IFN V score, others) 
Blood,
2x 3.5 mL
Blood,
1x 8 mL 
EDTA 
(purple 
top)
CPT citrate
blue/black
Arm A (pre-treatment) 

C1D1

C1D2

C2D1 (and D1 of 
each subsequent 
cycle)

EOT
Arm B (pre-treatment) 

C1D1-5

C2D1 (and D1 of 
each subsequent 
cycle)

EOT 
Arm C (pre-treatment) 

C1D1

C1D2

C1D15

C2D1 (and D1 of 
each subsequent 
cycle)

EOT
Doug Figg, NCI


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Test/assay
Volume 
(approx.)
Type of 
tube
Collection time-points
Location of 
specimen 
storage/ analysis
M7824 Pharmacokinetics
Serum
1x 3.5 mL
Serum 
Separator 
Tubes 
(SST®) 
(gold 
capped)
See section 
5.1.1 for 
handling 
instructions

Dose 1: Prior to 
infusion, End of 
infusion, 24 hr post 
infusion +/- 1 hr 

Dose 2: Prior to 
infusion – 1 hr

Dose 3: Prior to 
infusion, End of 
infusion + 15 min

Dose 6: Prior to 
infusion

End-of-treatment visit 
Serono EMD
Processed by 
Doug Figg, NCI
Temozolomide Pharmacokinetics
Plasma, 
1x 3.5 mL
Na Heparin 
(green top) 
tube
See section 
5.1.1 for 
handling 
instructions
C1D1: Pre, 1, 2, 4, 8 
(optional), 12 (optional), 
24hr post treatment +/- 
1hr
Doug Figg, NCI
Topotecan Pharmacokinetics
Plasma, 
1x 3.5 mL
Na Heparin 
(green top) 
tube
See section 
5.1.1 for 
handling 
instructions
C1D1: Pre, EOI, 0.5 hr, 
1hr +/- 15 min, 2 hr +/- 15 
min, 4 hr (optional) +/- 30 
min, 8 hr +/- 30 min 
(optional), 24 +/- 1hr, 48 
+/- 2hrs, 96hr +/- 4hrs 
post EOI
Doug Figg, NCI 
CtDNA 
Plasma, 
1x 10 mL
EDTA 
(purple 
top)
Arm A (pre-treatment)

C1D1

C1D2

C2D1 (and D1 of 
each subsequent 
cycle)

EOT 
Arm B (pre-treatment)

C1D1-5

C2D1 (and D1 of 
each subsequent 
cycle)

EOT 
Arm C (pre-treatment)

C1D1

C1D2

C1D15

C2D1 (and D1 of 
each subsequent 
cycle)

EOT
Doug Figg, NCI
Micronuclei, extrachromosomal 
elements, apoptotic bodies, gamma 
Hair: 
Microfuge 
tubes 
Arm A

C1D1 before M7824
Mirit Aladjem, 
NCI


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Test/assay
Volume 
(approx.)
Type of 
tube
Collection time-points
Location of 
specimen 
storage/ analysis
H2AX, phosphoRPA, phosphoIRF3 
and or other inflammatory proteins in 
the CGAS pathway (5.1.2)
15-30 
hairs 
containing 
a full 
intact 
follicle 
and sheath
containing 
cold PBS 
and stored 
on ice

C1D2 24 ± 1 hours 
after M7824

C2D1 before M7824
Arm B

C1D1 before M7824 
plus topotecan

C1D2 24 ± 1 hours 
after M7824 plus 
topotecan; prior to 
day 2 topotecan 

C2D1 before M7824 
plus topotecan
Arm C

C1D1 before M7824 
plus TMZ

C1D2 24 ± 1 hours 
after M7824 plus 
TMZ; prior to day 2 
TMZ

C2D15 before M7824
Contact: 
Christophe Redon, 
NCI
Additional assays may be performed to address the exploratory objectives of characterizing the 
immunomodulatory effects of DNA damage-inducing cytotoxic therapy and predictors of 
response including but not limited to tumor PD-L1 expression and mutational burden.
* One additional red top tube (10 mL) will be collected and frozen at baseline for future 
evaluation of paraneoplastic autoantibodies. The antibodies of interest include Anti-Hu, Anti-Ri, 
Anti-amphiphysin, antineuronal antibodies Ma1 and Ma2 and anti-Yo or anti-Purkinje cell 
antibody. Since these antibodies are not truly paraneoplastic antibodies, as they can also occur in 
the non-paraneoplastic setting, but their baseline levels will be of use in the work-up of patients 
who develop paraneoplastic syndromes on the trial.
5.1.1
Pharmacokinetics Samples
5.1.1.1
M7824 
Serum M7824 PK measurements will be done at EMD Serono. 
M7824 PK blood draws must be kept in fridge or on wet ice immediately, but they must be 
processed into serum within 1 hour of collection. A non-additive or coagulation discard tube 
needs to be drawn first. Once the SST blood is drawn, gently invert the tube 5 times to mix the 
clot activator with blood. Allow blood to clot for 30 minutes at room temperature in a vertical 
position. After allowing clot to form, centrifuge the tube for 15 minutes at 1100-1300 x g at 
room temperature (if refrigerated centrifuge is available, set the temperature at 25 degrees 
Celsius 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). Carefully collect and 
aliquot the serum equally in 2 separate micronics tubes. Put the tubes immediately in the freezer 


Abbreviated Title: M7824 in Small Cell Cancers
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71
in an upright position at -80 degrees Celsius. If not available, store at –20 degrees Celsius (for a 
maximum of one month). In case of temperature deviations, the affected samples, the length of 
deviation and maximum temperature reached should be tracked and promptly communicated to 
the EMD Serono.
Samples will be processed by the Clinical Pharmacology Program per the guidelines in section 
5.2.2 and shipped to EMD Serono. 
5.1.1.2
Temozolomide
Temozolomide PK measurements will be performed by Clinical Pharmacology Program. 
At each sample time point a discard blood volume appropriate for the IV access device must be 
drawn prior to the sample. Blood (3 mL) will be drawn from a peripheral vein in the patient’s 
arm and collected in green top tubes containing sodium heparin anticoagulant. Promptly mix the 
plasma collection tube by gently inverting 6-times, then place it on wet ice, until centrifuged at 
1,300 x g for 10 min at 4°C. Samples will be centrifuged for harvesting plasma as soon as 
possible after collection (within 1 hour). Upon centrifugation, the plasma will be separated from 
the blood cells using a pipette and transferred into an appropriately labeled polypropylene freezer 
vial. The samples should be processed to plasma within 30 minutes from centrifugation and the 
pH adjusted to <4 with the use of 8.5% phosphoric acid (15μL of 8.5% phosphoric acid per 
0.5mL of plasma). Plasma will then be stored frozen at -70°C until subsequent batch analysis.
5.1.1.3
Topotecan
Topotecan PK measurements will be performed by Clinical Pharmacology Program. 
Topotecan PK samples will be processed per section 5.2.2. Bioanalytical measurements will be 
conducted on an ultra HPLC-MSMS system using an assay developed and validated by the 
Clinical Pharmacology Program.
5.1.2
Hair Follicle Studies
The goal of the hair follicle studies is to assess replicative stress (γH2AX, pRPA), evidence of 
the kind of DNA damage that might trigger an immune response (micronuclei, 
extrachromosomal elements) and activation of the CGAS pathway (phosphoIRF3) in hair 
follicles with an immune checkpoint inhibitor alone or with chemotherapy. 
Timepoints for hair follicle collection: 
Arm A: 

Cycle 1 day 1: before M7824

Cycle 1 day 2: 24 ± 1 hours after M7824 

Cycle 2 day 1: before M7824 
Arm B: 

Cycle 1 day 1: before M7824 plus topotecan 

Cycle 1 day 2: 24 ± 1 hours after M7824 plus topotecan; prior to day 2 topotecan 

Cycle 2 day 1: before M7824 plus topotecan
Arm C: 


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
Cycle 1 day 1: before M7824 plus TMZ 

Cycle 1 day 2: 24 ± 1 hours after M7824 plus TMZ; prior to day 2 TMZ 

Cycle 2 day 15: before M7824Assays: Micronuclei, extrachromosomal elements, 
apoptotic bodies, gamma H2AX, phosphoRPA, phosphoIRF3 and or other 
inflammatory proteins in the CGAS pathway
Hair follicles will be collected at multiple time points as indicated. At least 24 hours prior to the 
start of the study, the research nurse will contact Dr. Redon in Dr. Aladjem’s lab 
(LMP/CCR/NCI, Bldg 37/ Rm 5056) to inform him when samples will be taken (Tel: 240-760-
7338 (L); 301-760-6275 (Cell); redonc@mail.nih.gov). Dr. Redon will provide tubes for 
collecting the plucked hairs. The tubes contain ice cold PBS labeled with the date/time of 
sampling, the protocol, and the unique 900 identifier. Dr. Redon will also provide forceps for 
plucking. Dr. Redon should be notified of when the samples should be picked up. 
Single hairs are plucked from the scalp with forceps. Plucked hairs from eyebrows will be 
collected only if scalp hairs cannot be provided. The aim is to acquire 15-30 hairs that contain a 
full intact follicle and sheath (Figure 3, image in the middle). If it is determined by Dr. Redon 
that the hairs collected at baseline do not contain a full intact follicle and sheath, hair collection 
at the next time-point may be omitted. All the hairs from a patient are placed in microfuge tubes 
containing cold PBS and stored on ice. Upon delivery in Dr. Aladjem’s lab, hairs will be fixed 
with paraformaldehyde and analyzed under a dissection microscope to select those containing a 
full intact follicle and sheath. Plucked hairs will be fluorescentlystainedforγ-H2AX and images 
will be recorded by using a confocal microscope.
5.2
SAMPLE STORAGE, TRACKING AND DISPOSITION
All blood samples (except PBMC immune subsets and germline exome sequencing which will 
go to DTB lab) will initially be sent to the laboratory of Dr. Douglas Figg, where they will be 
stored until ready for transfer to the recipient labs for the correlative studies. Please e-mail 
NCIBloodcore@mail.nih.gov at least 24 hours before transporting samples (the Friday before is 
preferred). For sample pickup, page 102-11964. For immediate help, call 240-760-6180 (main 
blood processing core number) or, if no answer, 240-760-6190 (main clinical pharmacology lab 
number).
Tumor samples will be sent to and stored in DTB Lab. Tumor biopsy may be obtained by 
interventional radiology or surgical resection. The site of biopsy will be determined in discussion 
with interventional radiologist/ surgeon. If it can be safely obtained, 5 cores of tumor tissue will 
be collected. Two cores will be sent to pathology- one for confirmation of diagnosis and another 
will be used for making an FFPE block. The other 3 cores will be flash frozen at the time of 
biopsy. When the patient is scheduled, the DTB lab will be contacted (by email to Sunmin Lee 
leesun@mail.nih.gov). Interventional Radiology will call the lab at 240-760-6330 when the 
patient arrives in IR and a lab member will be present at Interventional Radiology for the 
procedure. The cores will be flash frozen, 2D barcoded, and stored in liquid nitrogen.
Samples will be ordered in CRIS and tracked through a Clinical Trial Data Management system. 
Should a CRIS screen not be available, the CRIS downtime procedures will be followed. 
Samples will not be sent outside NIH without appropriate approvals and/or agreements, if 
required. Any transfer of materials to other NIH or non-NIH investigators will occur following 
NIH Intramural Research Program guidelines. 


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All specimens obtained in the protocol are used as defined in the protocol. Any specimens that 
are remaining at the completion of the protocol will be stored in the conditions described below. 
The study will remain open so long as sample or data analysis continues. Samples from 
consenting subjects will be stored until they are no longer of scientific value or if a subject 
withdraws consent for their continued use, at which time they will be destroyed. The PI will 
report any loss or unanticipated destruction of samples as a deviation. Reporting will be per the 
requirements of section 7.2. 
If the subject withdraws consent the participant’s data will be excluded from future distributions, 
but data that have already been distributed for approved research use will not be able to be 
retrieved.
5.2.1
Developmental Therapeutics Branch Lab
Samples will be processed immediately by the DTB laboratory. Biospecimens will be collected 
and processed using validated SOPs that will ensure both specimen quality and patient 
confidentiality. Using a computerized inventory system and a backup hardcopy process, all 
specimen collection and processing steps will be documented and the specific location of each 
specimen will be tracked. Each new specimen collected will be assigned a unique barcode 
identifier that can be linked to the original specimen collected and other relevant information 
within the inventory system. Specimen labels will indicate: protocol number, order in which the 
patient enrolled on the trial, type of sample, collection time, and total volume collected, as 
appropriate. The inventory process contains other security provisions sufficient to safeguard 
patient privacy and confidentiality. Access to the inventory system and associated documents 
will be restricted to appropriate individuals. Requests to use specimens stored in the repository 
must be approved. SOPs ensure that any changes in informed consent made by a patient and 
relayed to the PI will be reflected in the inventory system to ensure that specimens are destroyed 
as appropriate. All laboratory personnel will be trained to adhere to SOPs and will be monitored 
for high-quality performance.
5.2.2
Clinical Pharmacology Program (Figg Lab)
Upon arrival in the Clinical Pharmacology Program, samples will be centrifuged and transferred 
into cryovials for storage at -80°C until the time of analysis. In addition, samples will be 
barcoded.
All PK samples will be bar-coded, with data entered and stored in Labmatrix, utilized by the 
CPP. This is a secure program, with access to PSDM System limited to defined CPP personnel, 
who are issued individual user accounts. The program creates a unique barcode ID for every 
sample and sample box, which cannot be traced back to patients with Labmatrix access. The data 
recorded for each sample includes the patient ID, name, trial name/protocol number, time drawn, 
cycle time point, dose, material type, as well as box and freezer locations. Patient demographics 
associated with the clinical center patient number are provided in the system. For each sample, 
there are notes associated with the processing method (e.g. delay in sample processing, storage 
conditions on the ward, etc.).
Barcoded samples are stored in bar-coded boxes in locked freezers at either -20°C or -80°C 
according to stability requirements. These freezers are located onsite in the CPP and offsite at 
NCI Frederick Central Repository Services in Frederick, MD. Samples will be stored until 
requested by a researcher named on the protocol. All requests are monitored and tracked in 


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Labmatrix. All researchers are required to sign a form stating that the samples are only to be used 
for research purposes associated with this trial (as per IRB approved protocol) and that any 
unused samples must be returned to the CPP.
Following completion of this study, samples will remain in storage as detailed above. Access to 
these samples will only be granted following IRB approval of an additional protocol, granting 
the rights to use the material.
If, at any time, a patient withdraws from the study and does not wish for their existing samples to 
be utilized, the individual must provide a written request. Following receipt of this request, the 
samples will be destroyed (or returned to the patient, if so requested)
Sample bar-codes are linked to patient demographics and limited clinical information. This 
information will only be provided to investigators listed on this protocol, via registered use of 
Labmatrix. It is critical that the sample remains linked to patient information such as race, age, 
dates of diagnosis and death, and histological information about the tumor, in order to correlate 
genotype with these variables.
5.2.3
Laboratory of Pathology NCI COMPASS Program
Participants may undergo genetic analysis through the NCI COMPASS program for tumor-
normal exome and transcriptome. For additional information on consenting, ordering and results, 
refer to CCR SOP ADGC-5, Tumor/Normal Whole Exome Sequencing: Consenting, Ordering, 
and Obtaining Results found at 
https://ccrod.cancer.gov/confluence/pages/viewpage.action?pageId=73203825. 
5.3
SAMPLES FOR GENETIC/GENOMIC ANALYSIS
5.3.1
Description of the Scope of Genetic/Genomic Analysis
One of the exploratory endpoints of this protocol is to characterize mutations which predict 
response and changes associated with the development of chemoresistance. To this end, whole 
and targeted exome sequencing, RNA sequencing and protein analysis will be performed on 
tumor samples collected pre-treatment and during treatment. Since analysis of germline variants 
is essential to fully characterize the somatic mutations identified in exome sequencing, these 
assays will involve both somatic and germline DNA.
5.3.2
Certificate of Confidentiality
Please see section 13.4.
5.3.3
Management of Results
Subjects will be contacted if a clinically actionable gene variant is discovered. Clinically 
actionable findings for the purpose of this study are defined as disorders appearing in the 
American College of Medical Genetics and Genomics recommendations for the return of 
incidental findings that is current at the time of primary analysis. (A list of current guidelines is 
maintained on the CCR intranet: 
https://ccrod.cancer.gov/confluence/display/CCRCRO/Incidental+Findings+Lists). Subjects 
will be contacted at this time with a request to provide a sample to be sent to a CLIA certified 
laboratory. If the research findings are verified in the CLIA certified lab, the subject will be 
offered the opportunity to come to NIH (at our expense) to have genetic education and 


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counseling to explain this result. If the subject does not want to come to NIH, a referral to a 
local genetic healthcare provider will be provided (at their expense).
This is the only time during the course of the study that incidental findings will be returned. No 
interrogations regarding clinically actionable findings will be made after the primary analysis.
For samples undergoing analysis through the NCI COMPASS, results will be reported per CCR 
SOP ADGC-5, Tumor/Normal Whole Exome Sequencing: Consenting, Ordering, and Obtaining 
Results found at https://ccrod.cancer.gov/confluence/pages/viewpage.action?pageId=73203825. 
6
DATA COLLECTION AND EVALUATION 
6.1
DATA COLLECTION
The PI will be responsible for overseeing entry of data into a 21 CFR Part 11-compliant data 
capture system provided by the NCI CCR and ensuring data accuracy, consistency and 
timeliness. The principal investigator, associate investigators/research nurses and/or a contracted 
data manager will assist with the data management efforts. Primary and final analyzed data will 
have identifiers so that research data can be attributed to an individual human subject participant.
Document AEs from the first study intervention through 30 days after the subject received the 
last study treatment administration. Adverse events that are serious need to be recorded through 
30 days after the subject received the last treatment administration. Beyond 30 days after the last 
study intervention, only adverse events which are serious and related to the study intervention 
need to be recorded.
All adverse events, including clinically significant abnormal findings on laboratory evaluations, 
regardless of severity, will be followed until return to baseline or stabilization of event.
An abnormal laboratory value will be recorded in the database as an AE only if the laboratory 
abnormality is characterized by any of the following:

Results in discontinuation from the study

Is associated with clinical signs or symptoms 

Requires treatment or any other therapeutic intervention

Is associated with death or another serious adverse event, including hospitalization. 

Is judged by the Investigator to be of significant clinical impact
If any abnormal laboratory result is considered clinically significant, the investigator will provide 
details about the action taken with respect to the test drug and about the patient’s outcome.
End of study procedures: Data will be stored according to HHS, FDA regulations, and NIH 
Intramural Records Retention Schedule as applicable. 
Loss or destruction of data: Should we become aware that a major breach in our plan to protect 
subject confidentiality and trial data has occurred, this will be reported expeditiously per 
requirements in section 7.2.1. 


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6.2
DATA SHARING PLANS
6.2.1
Human Data Sharing Plan
What data will be shared?
I will share human data generated in this research for future research as follows:

Coded, linked data in an NIH-funded or approved public repository. 

Coded, linked data in BTRIS (automatic for activities in the Clinical Center)

Coded, linked or identified data with approved outside collaborators under appropriate 
agreements.
How and where will the data be shared? 
Data will be shared through:

An NIH-funded or approved public repository: clinicaltrials.gov; dbGaP.

BTRIS (automatic for activities in the Clinical Center)

Approved outside collaborators under appropriate individual agreements.

Publication and/or public presentations.
When will the data be shared?

Before publication.

At the time of publication or shortly thereafter.
6.2.2
Genomic Data Sharing Plan
Unlinked genomic data will be deposited in public genomic databases such as dbGaP in 
compliance with the NIH Genomic Data Sharing Policy.
6.3
RESPONSE CRITERIA
For the purposes of this study, patients should be re-evaluated for response every 6 weeks (8 
weeks for Arm C and patients in arm A that receive treatment with M7824 + temozolomide after 
progression on M7824 monotherapy). In addition to a baseline scan, confirmatory scans should 
also be obtained at least 4 weeks following initial documentation of objective response.
Response and progression will be evaluated in this study using the new international criteria 
proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline 
(version 1.1) [51]. Changes in the largest diameter (unidimensional measurement) of the tumor 
lesions and the shortest diameter in the case of malignant lymph nodes are used in the RECIST 
criteria.
6.3.1
Disease Parameters
Measurable disease: Measurable lesions are defined as those that can be accurately measured in at 
least one dimension (longest diameter to be recorded) as: 
1. By chest x-ray: >20 mm; 
2. By CT scan: 


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a.
Scan slice thickness 5 mm or under as >10 mm with CT scan
b.
Scan slice thickness >5 mm: double the slice thickness 
3. With calipers on clinical exam: >10 mm. 
All tumor measurements must be recorded in millimeters (or decimal fractions of centimeters). 
Malignant lymph nodes. To be considered pathologically enlarged and measurable, a lymph node 
must be >15 mm in short axis when assessed by CT scan (CT scan slice thickness recommended 
to be no greater than 5 mm). At baseline and in follow-up, only the short axis will be measured 
and followed.
Non-measurable disease. All other lesions (or sites of disease), including small lesions (longest 
diameter <10 mm or pathological lymph nodes with ≥10 to <15 mm short axis), are considered 
non-measurable disease. Bone lesions, leptomeningeal disease, ascites, pleural/pericardial 
effusions, lymphangitis cutis/pulmonitis, inflammatory breast disease, and abdominal masses 
(not followed by CT or MRI), are considered as non-measurable.
Note: Cystic lesions that meet the criteria for radiographically defined simple cysts should not be 
considered as malignant lesions (neither measurable nor non-measurable) since they are, by 
definition, simple cysts.
‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable lesions, 
if they meet the definition of measurability described above. However, if non-cystic lesions are 
present in the same patient, these are preferred for selection as target lesions.
Target lesions. All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in 
total, representative of all involved organs, should be identified as target lesions and recorded 
and measured at baseline. Target lesions should be selected on the basis of their size (lesions 
with the longest diameter), be representative of all involved organs, but in addition should be 
those that lend themselves to reproducible repeated measurements. It may be the case that, on 
occasion, the largest lesion does not lend itself to reproducible measurement in which 
circumstance the next largest lesion which can be measured reproducibly should be selected. A 
sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target 
lesions will be calculated and reported as the baseline sum diameters. If lymph nodes are to be 
included in the sum, then only the short axis is added into the sum. The baseline sum diameters 
will be used as reference to further characterize any objective tumor regression in the measurable 
dimension of the disease.
Non-target lesions. All other lesions (or sites of disease) including any measurable lesions over 
and above the 5 target lesions should be identified as non-target lesions and should also be 
recorded at baseline. Measurements of these lesions are not required, but the presence, absence, 
or in rare cases unequivocal progression of each should be noted throughout follow-up. 
6.3.2
Methods for Evaluation of Measurable Disease
All measurements should be taken and recorded in metric notation using a ruler or calipers. All 
baseline evaluations should be performed as closely as possible to the beginning of treatment and 
never more than 4 weeks before the beginning of the treatment.
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. Imaging-based evaluation is 


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preferred to evaluation by clinical examination unless the lesion(s) being followed cannot be 
imaged but are assessable by clinical exam.
Clinical lesions: Clinical lesions will only be considered measurable when they are superficial 
(e.g., skin nodules and palpable lymph nodes) and 10 mm diameter as assessed using calipers 
(e.g., skin nodules). In the case of skin lesions, documentation by color photography, including a 
ruler to estimate the size of the lesion, is recommended. 
Chest x-ray: Lesions on chest x-ray are acceptable as measurable lesions when they are clearly 
defined and surrounded by aerated lung. However, CT is preferable. 
Conventional CT and MRI: This guideline has defined measurability of lesions on CT scan based 
on the assumption that CT slice thickness is 5 mm or less. If CT scans have slice thickness 
greater than 5 mm, the minimum size for a measurable lesion should be twice the slice thickness. 
MRI is also acceptable in certain situations (e.g. for body scans). 
Use of MRI remains a complex issue. MRI has excellent contrast, spatial, and temporal 
resolution; however, there are many image acquisition variables involved in MRI, which greatly 
impact image quality, lesion conspicuity, and measurement. Furthermore, the availability of MRI 
is variable globally. As with CT, if an MRI is performed, the technical specifications of the 
scanning sequences used should be optimized for the evaluation of the type and site of disease. 
Furthermore, as with CT, the modality used at follow-up should be the same as was used at 
baseline and the lesions should be measured/assessed on the same pulse sequence. It is beyond 
the scope of the RECIST guidelines to prescribe specific MRI pulse sequence parameters for all 
scanners, body parts, and diseases. Ideally, the same type of scanner should be used and the 
image acquisition protocol should be followed as closely as possible to prior scans. Body scans 
should be performed with breath-hold scanning techniques, if possible.
PET-CT: At present, the low dose or attenuation correction CT portion of a combined PET-CT is 
not always of optimal diagnostic CT quality for use with RECIST measurements. However, if 
the site can document that the CT performed as part of a PET-CT is of identical diagnostic 
quality to a diagnostic CT (with IV and oral contrast), then the CT portion of the PET-CT can be 
used for RECIST measurements and can be used interchangeably with conventional CT in 
accurately measuring cancer lesions over time. Note, however, that the PET portion of the CT 
introduces additional data which may bias an investigator if it is not routinely or serially 
performed. 
Ultrasound: Ultrasound is not useful in assessment of lesion size and should not be used as a 
method of measurement. Ultrasound examinations cannot be reproduced in their entirety for 
independent review at a later date and, because they are operator dependent, it cannot be 
guaranteed that the same technique and measurements will be taken from one assessment to the 
next. If new lesions are identified by ultrasound in the course of the study, confirmation by CT or 
MRI is advised. If there is concern about radiation exposure at CT, MRI may be used instead of 
CT in selected instances.
Endoscopy, Laparoscopy: The utilization of these techniques for objective tumor evaluation is 
not advised. However, such techniques may be useful to confirm complete pathological response 
when biopsies are obtained or to determine relapse in trials where recurrence following complete 
response (CR) or surgical resection is an endpoint.


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Tumor markers: Tumor markers alone cannot be used to assess response. If markers are initially 
above the upper normal limit, they must normalize for a patient to be considered in complete 
clinical response. Specific guidelines for both CA-125 response (in recurrent ovarian cancer) and 
PSA response (in recurrent prostate cancer) have been published [52-54]. In addition, the 
Gynecologic Cancer Intergroup has developed CA-125 progression criteria which are to be 
integrated with objective tumor assessment for use in first-line trials in ovarian cancer [55] .
Cytology, Histology: These techniques can be used to differentiate between partial responses 
(PR) and complete responses (CR) in rare cases (e.g., residual lesions in tumor types, such as 
germ cell tumors, where known residual benign tumors can remain).
The cytological confirmation of the neoplastic origin of any effusion that appears or worsens 
during treatment when the measurable tumor has met criteria for response or stable disease is 
mandatory to differentiate between response or stable disease (an effusion may be a side effect of 
the treatment) and progressive disease.
FDG-PET: While FDG-PET response assessments need additional study, it is sometimes 
reasonable to incorporate the use of FDG-PET scanning to complement CT scanning in 
assessment of progression (particularly possible 'new' disease). New lesions on the basis of FDG-
PET imaging can be identified according to the following algorithm: 
1. Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of PD 
based on a new lesion.
2. No FDG-PET at baseline and a positive FDG-PET at follow-up: If the positive FDG-PET 
at follow-up corresponds to a new site of disease confirmed by CT, this is PD. If the 
positive FDG-PET at follow-up is not confirmed as a new site of disease on CT, 
additional follow-up CT scans are needed to determine if there is truly progression 
occurring at that site (if so, the date of PD will be the date of the initial abnormal FDG-
PET scan). If the positive FDG-PET at follow-up corresponds to a pre-existing site of 
disease on CT that is not progressing on the basis of the anatomic images, this is not PD.
3. FDG-PET may be used to upgrade a response to a CR in a manner similar to a biopsy in 
cases where a residual radiographic abnormality is thought to represent fibrosis or 
scarring. The use of FDG-PET in this circumstance should be prospectively described in 
the protocol and supported by disease-specific medical literature for the indication. 
However, it must be acknowledged that both approaches may lead to false positive CR 
due to limitations of FDG-PET and biopsy resolution/sensitivity.
Note: A ‘positive’ FDG-PET scan lesion means one which is FDG avid with an uptake greater 
than twice that of the surrounding tissue on the attenuation corrected image.
6.3.3
Response Criteria
6.3.3.1
Evaluation of Target Lesions
Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes 
(whether target or non-target) must have reduction in short axis to <10 mm.
Partial Response (PR): At least a 30% decrease in the sum of the diameters of target lesions, 
taking as reference the baseline sum of diameters.


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Progressive Disease (PD): At least a 20% increase in the sum of the diameters of target lesions, 
taking as reference the smallest sum on study (this includes the baseline sum if that is the 
smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an 
absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also 
considered progressions). Treatment may be continued despite progression in arm C according to 
RECIST 1.1 at any time if:
•
There are no new or concerning symptoms.
•
There is no decrease in ECOG PS.
•
The Investigator does not consider it necessary to administer a salvage therapy.
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum of diameters while on study.
6.3.3.2
Evaluation of Non-Target Lesions
Complete Response (CR): Disappearance of all non-target lesions and normalization of tumor 
marker level. All lymph nodes must be non-pathological in size (<10 mm short axis).
Note: If tumor markers are initially above the upper normal limit, they must normalize for a 
patient to be considered in complete clinical response.
Non-CR/Non-PD: Persistence of one or more non-target lesion(s) and/or maintenance of tumor 
marker level above the normal limits.
Progressive Disease (PD): Appearance of one or more new lesions and/or unequivocal 
progression of existing non-target lesions. Unequivocal progression should not normally trump 
target lesion status. It must be representative of overall disease status change, not a single lesion 
increase. Treatment may be continued despite progression in arm C according to RECIST 1.1 at 
any time if:
• There are no new or concerning symptoms.
• There is no decrease in ECOG PS.
• The Investigator does not consider it necessary to administer a salvage therapy.
Although a clear progression of “non-target” lesions only is exceptional, the opinion of the 
treating physician should prevail in such circumstances, and the progression status should be 
confirmed at a later time by the review panel (or Principal Investigator).
The Investigator may perform scans in addition to a scheduled trial scan for medical reasons or if 
the Investigator suspects PD. 
6.3.3.3
Evaluation of Best Overall Response
The best overall response is the best response recorded from the start of the treatment until 
disease progression/recurrence (taking as reference for progressive disease the smallest 
measurements recorded since the treatment started). The patient's best response assignment will 
depend on the achievement of both measurement and confirmation criteria.


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


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For Patients with Non-Measurable Disease (i.e., Non-Target Disease)
6.3.4
Duration of Response
Duration of overall response: The duration of overall response is measured from the time 
measurement criteria are met for CR or PR (whichever is first recorded) until the first date that 
recurrent or progressive disease is objectively documented (taking as reference for progressive 
disease the smallest measurements recorded since the treatment started).
The duration of overall CR is measured from the time measurement criteria are first met for CR 
until the first date that progressive disease is objectively documented.
Duration of stable disease: Stable disease is measured from the start of the treatment until the 
criteria for progression are met, taking as reference the smallest measurements recorded since the 
treatment started, including the baseline measurements. 
6.3.5
Progression-Free Survival
PFS is defined as the duration of time from start of treatment to time of progression or death, 
whichever occurs first.
6.3.6
Response Review
Tumor measurements will be performed by the Center for Cancer Research Radiology and 
Imaging Sciences image processing service.
6.4
TOXICITY CRITERIA
The following adverse event management guidelines are intended to ensure the safety of each 
patient while on the study. The descriptions and grading scales found in the revised NCI 
Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 will be utilized for AE 
reporting. All appropriate treatment areas should have access to a copy of the CTCAE version 
5.0. A copy of the CTCAE version 5.0 can be downloaded from the CTEP web site 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm# ). 
Non-Target Lesions
New Lesions
Overall Response
CR
No
CR
Non-CR/non-PD
No
Non-CR/non-PD*
Not all evaluated
No
not evaluated
Unequivocal PD
Yes or No
PD
Any
Yes
PD
* ‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since 
SD is increasingly used as an endpoint for assessment of efficacy in some trials 
so to assign this category when no lesions can be measured is not advised


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7
NIH REPORTING REQUIREMENTS / DATA AND SAFETY MONITORING PLAN
7.1
DEFINITIONS
Please refer to definitions provided in Policy 801: Reporting Research Events found  at: 
https://irbo.nih.gov/confluence/pages/viewpage.action?pageId=36241835#Policies&Guidance-
800Series-ComplianceandResearchEventReportingRequirements.
7.2
OHSRP OFFICE OF COMPLIANCE AND TRAINING / IRB REPORTING
7.2.1
Expedited Reporting 
Please refer to the reporting requirements in Policy 801: Reporting Research Events and Policy 
802 Non-Compliance Human Subjects Research found at: 
https://irbo.nih.gov/confluence/pages/viewpage.action?pageId=36241835#Policies&Guidance-
800Series-ComplianceandResearchEventReportingRequirements.
 Note: Only IND Safety Reports that meet the definition of an unanticipated problem will need to 
be reported per these policies.
7.2.2
IRB Requirements for PI Reporting at Continuing Review
Please refer to the reporting requirements in Policy 801: Reporting Research Events found at: 
https://irbo.nih.gov/confluence/pages/viewpage.action?pageId=36241835#Policies&Guidance-
800Series-ComplianceandResearchEventReportingRequirements. 
7.3
NCI CLINICAL DIRECTOR REPORTING 
Problems expeditiously reviewed by the OHSRP in the NIH eIRB system will also be reported to 
the NCI Clinical Director/designee; therefore, a separate submission for these reports is not 
necessary.
In addition to those reports, all deaths that occur within 30 days after receiving a research 
intervention should be reported via email unless they are due to progressive disease. 
To report these deaths, please send an email describing the circumstances of the death at 
NCICCRQA@mail.nih.gov within one business day of learning of the death.
7.4
NIH REQUIRED DATA AND SAFETY MONITORING PLAN
7.4.1
Principal Investigator/Research Team 
The clinical research team will meet on a weekly basis when patients are being actively treated 
on the trial to discuss each patient. Decisions about dose level enrollment and dose escalation if 
applicable will be made based on the toxicity data from prior patients. 
All data will be collected in a timely manner and reviewed by the principal investigator or a lead 
associate investigator. Events meeting requirements for expedited reporting as described in 
section 7.2.1 will be submitted within the appropriate timelines. 
The principal investigator will review adverse event and response data on each patient to ensure 
safety and data accuracy. The principal investigator will personally conduct or supervise the 
investigation and provide appropriate delegation of responsibilities to other members of the 
research staff. 


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8
SPONSOR SAFETY REPORTING
8.1
DEFINITIONS
8.1.1
Adverse Event 
Any untoward medical occurrence in a patient or clinical investigation subject administered a 
pharmaceutical product and which does not necessarily have a causal relationship with this 
treatment. An adverse event (AE) can therefore be any unfavorable and unintended sign 
(including an abnormal laboratory finding), symptom, or disease temporally associated with the 
use of a medicinal (investigational) product, whether or not related to the medicinal 
(investigational) product (ICH E6 (R2)).
8.1.2
Serious Adverse Event (SAE)
An adverse event or suspected adverse reaction is considered serious if in the view of the 
investigator or the sponsor, it results in any of the following:

Death,

A life-threatening adverse event (see 8.1.3)

Inpatient hospitalization or prolongation of existing hospitalization
o
A hospitalization/admission that is pre-planned (i.e., elective or scheduled surgery 
arranged prior to the start of the study), a planned hospitalization for pre-existing 
condition, or a procedure required by the protocol, without a serious deterioration in 
health, is not considered a serious adverse event.
o
A hospitalization/admission that is solely driven by non-medical reasons (e.g., 
hospitalization for patient or subject convenience) is not considered a serious adverse 
event. 
o
Emergency room visits or stays in observation units that do not result in admission to 
the hospital would not be considered a serious adverse event. The reason for seeking 
medical care should be evaluated for meeting one of the other serious criteria.

Persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions

A congenital anomaly/birth defect.

Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered a serious adverse drug experience when, based upon 
appropriate medical judgment, they may jeopardize the patient or subject and may require 
medical or surgical intervention to prevent one of the outcomes listed in this definition.
8.1.3
Life-threatening 
An adverse event or suspected adverse reaction is considered "life-threatening" if, in the view of 
either the investigator or sponsor, its occurrence places the patient or subject at immediate risk of 
death. It does not include an adverse event or suspected adverse reaction that, had it occurred in a 
more severe form, might have caused death. (21CFR312.32).


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8.1.4
Severity
The severity of each Adverse Event will be assessed utilizing the CTCAE version 5.
8.1.5
Relationship to Study Product
All AEs will have their relationship to study product assessed using the terms: related or not 
related. 

Related – There is a reasonable possibility that the study product caused the adverse 
event. Reasonable possibility means that there is evidence to suggest a causal relationship 
between the study product and the adverse event.

Not Related – There is not a reasonable possibility that the administration of the study 
product caused the event.
8.1.6
Adverse Events of Special Interest (AESI)
Adverse events of special interest (AESIs) are serious or nonserious AEs that are of clinical 
interest and should be closely followed. 
AESIs include following:

Infusion-related reactions including immediate hypersensitivity

Immune-related adverse events

TGFβ inhibition mediated skin reactions

Anemia

Bleeding AEs
8.2
ASSESSMENT OF SAFETY EVENTS
AE information collected will include event description, date of onset, assessment of severity 
and relationship to study product and alternate etiology (if not related to study product), date of 
resolution of the event, seriousness and outcome. The assessment of severity and relationship to 
the study product will be done only by those with the training and authority to make a diagnosis 
and listed on the Form FDA 1572 as the site principal investigator or sub-investigator. AEs 
occurring during the collection and reporting period will be documented appropriately regardless 
of relationship. AEs will be followed through resolution.
SAEs will be:

Assessed for severity and relationship to study product and alternate etiology (if not 
related to study product) by a licensed study physician listed on the Form FDA 1572 as 
the site principal investigator or sub-investigator.

Recorded on the appropriate SAE report form, the medical record and captured in the 
clinical database.

Followed through resolution by a licensed study physician listed on the Form FDA 1572 
as the site principal investigator or sub-investigator.


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For timeframe of recording adverse events, please refer to section 6.1. All serious adverse events 
recorded from the time of first investigational product administration must be reported to the 
sponsor with the exception of any listed in section 8.4.
8.3
REPORTING OF SERIOUS ADVERSE EVENTS
Any AE that meets a protocol-defined serious criteria or meets the definition of Adverse Event 
of Special Interest that require expedited reporting must be submitted immediately (within 24 
hours of awareness) to OSRO Safety using the CCR SAE report form. Any exceptions to the 
expedited reporting requirements are found in section 8.4.
All SAE reporting must include the elements described in section 8.2.
SAE reports will be submitted to the Center for Cancer Research (CCR) at: 
OSROSafety@mail.nih.gov and to the CCR PI and study coordinator. CCR SAE report form and 
instructions can be found at: 
https://ccrod.cancer.gov/confluence/display/CCRCRO/Forms+and+Instructions
Following the assessment of the SAE by OSRO, other supporting documentation of the event 
may be requested by the OSRO Safety and should be provided as soon as possible.
8.4
WAIVER OF EXPEDITED REPORTING TO CCR 
As death/hospitalization due to disease progression are part of the study objectives (ORR, PFS, 
DOR), and captured as an endpoint in this study, they will not be reported in expedited manner 
to the sponsor. However, if there is evidence suggesting a causal relationship between the study 
drug and the event, report the event in an expedited manner according to section 8.3.
8.5
SAFETY REPORTING CRITERIA TO THE PHARMACEUTICAL COLLABORATORS
8.5.1
EMD-Serono
8.5.1.1
The following reportable events must be submitted to EMD Serono by the Sponsor
The following reportable events must be submitted to EMD Serono within 2 business days or 3 
calendar days (whichever comes first) using the mandatory MedWatch form 3500a or equivalent. 
The Sponsor will assume responsibility for submitting the reportable event(s) below to EMD 
Serono as well as ensuring that any local reporting requirements are completed in parallel.

Serious Adverse Events (refer to section 8.1.2):

Exposure during Pregnancy or Breastfeeding (even if not associated with an adverse 
event)
8.5.1.2
The following reportable events must be submitted to EMD Serono by the PI or 
designee

Occupational exposure (even if not associated with an adverse event)

Potential drug-induced liver injury (Hy’s Law cases): These events are considered 
important medical events and should be reported as SAEs. 

In addition, all AEs will be collected in tabulated form and reported to EMD Serono as 
outlined in the Collaborative Agreement. 


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
Reporting of Overdose of M7824: An overdose is defined as any dose 5% greater than 
the highest dose included in the clinical trial protocol. Any overdose must be recorded in 
the trial medication section of the eCRF. For monitoring purposes, any case of overdose, 
whether or not associated with an AE (serious or non-serious), must be reported. There 
are no known symptoms of M7824 overdose to date. The Investigator should monitor 
closely for AEs should an overdose occur and use his or her clinical judgment in 
providing symptomatic / supportive care as medically indicated. There is no known 
antidote for M7824.
Contact information for submission of reportable events to EMD Serono:
Fax: +49 6151 72 6914
OR
E-mail: ICSR_CT_GPS@merckgroup.com
Specifying:
PROTOCOL Number and/or Title
EMD Serono assigned Study Number: MS200647-0045
SUBJECT Number
SITE Number/PI Name
SAE/ONSET DATE
8.6
REPORTING PREGNANCY 
All required pregnancy reports/follow-up to OSRO will be submitted to: 
OSROSafety@mail.nih.gov and to the CCR PI and study coordinator. 
Forms and instructions can be found here: 
https://ccrod.cancer.gov/confluence/display/CCRCRO/Forms+and+Instructions
8.6.1
Maternal Exposure
If a patient becomes pregnant during the course of the study, the study treatment should be 
discontinued immediately, and the pregnancy reported to the Sponsor no later than 24 hours of 
when the Investigator becomes aware of it. The Investigator should notify the Sponsor no later 
than 24 hours of when the outcome of the Pregnancy become known,
Pregnancy itself is not regarded as an SAE. However, congenital abnormalities or birth defects 
and spontaneous miscarriages that meet serious criteria (8.1.2) should be reported as SAEs. 
The outcome of all pregnancies should be followed up and documented.
8.6.2
Paternal Exposure
Male patients should refrain from fathering a child or donating sperm during the study and for 3 
months after the last dose of study drug.
Pregnancy of the patient’s partner is not considered to be an AE. However, the outcome of all 
pregnancies occurring from the date of the first dose until (120 days) after the last dose should, if 
possible, be followed up and documented. Pregnant partners may be offered the opportunity to 


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participate in an institutional pregnancy registry protocol (e.g., the NIH IRP pregnancy registry 
study) to provide data about the outcome of the pregnancy for safety reporting purposes.
8.7
REGULATORY REPORTING FOR STUDIES CONDUCTED UNDER CCR-SPONSORED IND
Following notification from the investigator, CCR, the IND sponsor, will report any suspected 
adverse reaction that is both serious and unexpected. CCR will report an AE as a suspected 
adverse reaction only if there is evidence to suggest a causal relationship between the study 
product and the adverse event. CCR will notify FDA and all participating investigators (i.e., all 
investigators to whom the sponsor is providing drug under its INDs or under any investigator’s 
IND) in an IND safety report of potential serious risks from clinical trials or any other source, as 
soon as possible, in accordance to 21 CFR Part 312.32. 
All serious events will be reported to the FDA at least annually in a summary format.
8.8
DATA SAFETY MONITORING BOARD (DSMB)
The safety oversight for this protocol will be under the direction of a DSMB composed of 
individuals with the appropriate expertise, including a biostatistician experienced in statistical 
methods for clinical trials and a clinician with relevant expertise. Members of the DSMB should 
be independent from the study conduct and free of conflict of interest, or measures should be in 
place to minimize perceived conflict of interest. The DSMB will operate according to the charter 
which is reviewed and approved as part of the initial DSMB meeting. The charter will define the 
DSMB reviews for this protocol including the frequency of cumulative data reviews. 
Types of DSMB reviews include:

Initial review for a new protocol:
Review of the Protocol, ICF, presentation from the PI/designee, study-related documents, halting 
rules, statistical methods, set triggers for data review or analyses, establish guidelines for 
monitoring, and finalize Report formats.

Cumulative data review, at least once a year but may be more frequent.

Ad hoc review as described in the protocol when:
o
Clinical trial halting criteria are met.
o
Occurrence of a specific time point, or event described in the protocol (e.g., interim 
analysis (see section 10.4.6.1), dose escalation criteria are not met resulting in a halt 
in enrollment) 
o
At the request of the Sponsor due to a safety concern or clinical trial conduct issue 

Final review meeting at the end of the clinical trial. Additional meetings are not required 
unless the Sponsor requests consultation by the committee, or a potential safety concern or 
study-related issue arises.
Following each DSMB review, the DSMB will provide its recommendations to the Sponsor. The 
recommendations signed by the Committee Chair and the Sponsor determination on the 
recommendations signed by the OSRO Director, will be distributed to the PI for the protocol under 
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8.9
SPONSOR PROTOCOL DEVIATION REPORTING
A Protocol Deviation is defined as any non-compliance with the clinical trial Protocol, Manual 
of Operational Procedures (MOP) and other Sponsor approved study related documents, GCP, or 
protocol-specific procedural requirements on the part of the participant, the Investigator, or the 
study site staff inclusive of site personnel performing procedures or providing services in support 
of the clinical trial.
It is the responsibility of the study Staff to document any protocol deviation identified by the 
Staff or the site Monitor in the CCR Protocol Deviation Tracking System (PDTS) online 
application. The entries into the PDTS online application should be timely, complete, and 
maintained per CCR PDTS user requirements. 
In addition, any deviation to the protocol should be documented in the participant’s source 
records and reported to the reviewing IRB per their guidelines. OSRO required protocol 
deviation reporting is consistent with E6(R2) GCP: Integrated Addendum to ICH E6(R1): 4.5 
Compliance with Protocol; 5.18.3 (a), and 5.20 Noncompliance; and ICH E3 16.2.2 Protocol 
deviations.
9
CLINICAL MONITORING PLAN
Clinical site monitoring is conducted to ensure:

that the rights of the participants are protected; 

that the study is implemented per the approved protocol, Good Clinical Practice and 
standard operating procedures; and, 

the quality and integrity of study data and data collection methods are maintained. 
Monitoring for this study will be performed by NCI CCR Office of Sponsor and Regulatory 
Oversight (OSRO) Sponsor and Regulatory Oversight Support (SROS) Services contractor. 
Clinical site monitoring activities will be based on OSRO standards, FDA Guidance E6(R2) 
Good Clinical Practice: Integrated Addendum to ICH E6(R1) March 2018, and applicable 
regulatory requirements.
Details of clinical site monitoring will be documented in a Clinical Monitoring Plan (CMP) 
developed by OSRO. CMPs will be protocol-specific, risk-based and tailored to address human 
subject protections and integrity of the study data. OSRO will determine the intensity and 
frequency of monitoring based on several factors, including study type, phase, risk, complexity, 
expected enrollment rate, and any unique attributes of the study and the site. The Sponsor will 
conduct a periodic review of the CMP to confirm the plan's continued appropriateness. A change 
to the protocol, significant or pervasive non-compliance with GCP, or the protocol may trigger 
CMP updates.
OSRO SROS Monitoring visits and related activities will be conducted throughout the life cycle 
of each protocol. The first activity is before the study starts to conduct a Site Assessment Visit 
(SAV) (as warranted), followed by a Site Initiation Visit (SIV), Interim Monitoring Visit(s) 
(IMVs), and a study Close-Out Visit (COV).
Some monitoring activities may be performed remotely, while others will occur at the study site(s). 
Monitoring visit reports will describe visit activities, observations, and associated action items or 
follow-up required for resolution of any issues, discrepancies, or deviations. Monitoring reports 


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will be distributed to the study PI, NCI CCR QA, CCR Protocol Support Office, coordinating 
center (if applicable), and the Sponsor regulatory file.
The site Monitor will inform the study team of any deviations observed during monitoring visits. 
If unresolved, the Monitor will request that the site Staff enter the deviations in the CCR 
Protocol Deviation Tracking System (PDTS) for deviation reporting to the Sponsor and as 
applicable per institutional and IRB guidance. 
10 STATISTICAL CONSIDERATIONS 
10.1 STATISTICAL HYPOTHESIS
Targeting additional immunosuppressive mechanisms beyond PD-1/PD-L1 and amplifying the 
immune response by causing DNA damage may drive further improve responses to PD-L1 
blockade. Increased DNA damage induced by topotecan and temozolomide will complement the 
anti-tumor activity of M7824, in recurrent SCLC. The primary objective of the trial is to 
determine an estimate of efficacy of M7824 plus topotecan or temozolomide relapsed SCLC. 
10.2 SAMPLE SIZE DETERMINATION
Arm A (M7824 monotherapy): Initially, 10 patients will be treated with M7824 monotherapy to 
obtain limited safety and PK data on the monotherapy in this population and to obtain a 
preliminary estimate of clinical responses to M7824 in SCLC. Based on prior publications using 
other PD-L1 inhibitors, the estimated response rate for M7824 monotherapy may be 10% or 
slightly higher. In addition to reporting safety data, the responses noted in arm A will be reported 
along with two-tailed 80% and 95% confidence intervals to aid in interpretation of the findings 
in the context of the prior data on this treatment. 

Following completion of the 10-patient Arm A, patients will be assigned to Arm C 
(M7824 plus temozolomide) and then to Arm B. The combination therapy portion of the 
trial will use a Simon two stage minimax design in each arm to rule out a 15% objective 
response rate (p0=0.15) and target a modest response rate of 35% (p1=0.35), with alpha 
=0.10 (10% probability of accepting a poor combination) and beta=0.20 (20% probability 
of rejecting a good combination). 

The trial will be conducted as follows:
o
Arm A: Initially, 10 patients will enroll on Arm A. 
o
Arm C: Following completion of the 10-patient Arm A, then from that point onward, 
patients will be assigned to C initially until there are a minimum of 6 evaluable in 
that arm, and then a pause to the accrual of Arm C will take place. These first 
patients enrolled in Arm C before the pause in accrual will be treated at dose level 1 
and evaluated for toxicity. If 0 or 1 of the first 6 patients experiences a dose-limiting 
toxicity (DLT), then the remainder of the patients in C will be treated at that dose. If 
2 or more patients within the first 6 experience a DLT, then the remaining patients 
will be treated at dose level -1. If 2 or more patients at dose level -1 experience a 
DLT, then no further accrual will take place unless a treatment modification is 
provided via an amendment. 
If there is adequate safety in these initial patients in Arm C, a total of 10 patients 
(including the 6 patients evaluated for toxicity and future dose setting) will be 


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enrolled onto the first stage of Arm C. If 0 to 1 of the 10 patients demonstrate a 
partial response then no further patients will be accrued into arm C. If 2 or more of 
the first 10 patients have a response, then accrual would continue until a total of 22 
evaluable patients have been treated in Arm C. If there are 1 to 5 patients with a 
response in the total of 22 evaluable patients, then this would be an uninterestingly 
low rate, while if there were 6 or more patients of the 22 who have a response 
(27.3%), this would be sufficiently interesting to warrant further study of the 
combination of these agents in later trials. Under the null hypothesis (15% response 
rate), the probability of early termination in this Arm is 54.4%. 
A separate cohort of patients with extrapulmonary small cell cancer (n=10) will be 
accrued after the enrollment of the first 6 evaluable SCLC Arm C patients and will 
only receive the combination therapy of M7824 and Temozolomide.
o
Arm B: Once enrollment of SCLC patients in arm C is complete, SCLC patients will 
be assigned to arm B until there are a minimum of 6 evaluable patients in that arm, 
and then a pause to the accrual of Arm B will take place. These first patients enrolled 
in Arm B before the pause in accrual will be treated at dose level 1 and evaluated for 
toxicity. If 0 or 1 of the first 6 patients experiences a dose-limiting toxicity (DLT), 
then the remainder of the patients in arms B will be treated at that dose. If 2 or more 
patients within the first 6 experience a DLT, then the remaining patients will be 
treated at dose level -1. If 2 or more patients at dose level -1 experience a DLT, then 
no further accrual will take place unless a treatment modification is provided via an 
amendment. 
If there is adequate safety in these initial patients in Arm B, a total of 10 patients 
(including the 6 patients evaluated for toxicity and future dose setting) will be 
enrolled onto the first stage of Arm B. If 0 to 1 of the 10 patients demonstrate a 
partial response, then no further patients will be accrued onto this arm. If 2 or more 
of the first 10 patients have a response, then accrual would continue until a total of 
22 evaluable patients have been treated in Arm B. If there are 1 to 5 patients with a 
response in the total of 22 evaluable patients, then this would be an uninterestingly 
low rate, while if there were 6 or more patients of the 22 who have a response 
(27.3%), this would be sufficiently interesting to warrant further study of the 
combination of these agents in later trials. Under the null hypothesis (15% response 
rate), the probability of early termination in this Arm is 54.4%. 
It is anticipated that up to 2 patients per month may enroll onto this trial; thus, approximately 3 
to 4 years may be required to complete accrual of up to 10+22+22+10=64 evaluable patients. 
The accrual ceiling will be set at 80 to allow for a small number of inevaluable patients and 
screen failures.
10.3 POPULATIONS FOR ANALYSES
Modified intention to treat: all patients who receive at least one dose of the intended agent(s) will 
be included in the statistical analyses performed. Subjects with progressive disease on Arm A 
who are subsequently treated with M7824 and temozolomide will be included in the analysis for 
both the monotherapy and combination therapy arm per section 10.4.2 and 10.4.9.


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10.4 STATISTICAL ANALYSES
10.4.1 General Approach
Separately by arm, the proportion of evaluable patients who experience a PR or CR will be 
reported along with a confidence interval. Safety will be evaluated by tabulating and describing 
the toxicities noted in Arm A and any toxicity as well as DLTs in the first 6 patients of the 
combination therapy arms.
10.4.2 Analysis of the Primary Efficacy Endpoints
In each of the three arms, the fraction of evaluable patients who experience a PR or CR will be 
determined and this fraction will be reported along with an 80% and 95% confidence interval. 
The fraction of patients experiencing a DLT will be reported, by arm, along with descriptions of 
the type and grade of toxicities identified. Patients treated on Arm A who progress and then 
receive M7824 plus temozolomide will have their initial response to M7824 counted as the 
response for the Arm A primary evaluation. 
10.4.3 Analysis of the Secondary Efficacy Endpoints
Progression-free survival (PFS), duration of response (DOR) and overall survival (OS) of a 
combination of M7824 plus topotecan or temozolomide in relapsed SCLC will be considered the 
secondary endpoints. Each of these estimates will be made using the Kaplan-Meier method, and 
will be reported along with a 95% confidence interval at 6 months. PFS will begin at the on-
study date, and will consider progressions as well as death without progression as an event; OS 
will also begin at the on-study date and will consider any death as an event. DOR will begin at 
the date that a PR or CR has been identified and will be shown as continuing until the patient is 
no longer considered to be responding.
10.4.4 Safety Analyses
Safety of the agent will be assessed by determining the grade of adverse events noted in each 
patient, and reporting the fraction with grade 3 and grade 4 adverse events. The primary safety 
analyses will be made based on the patients in Arm A as well as first 6 patients enrolled into 
each of the two combination therapy arms. Safety data will be presented in summaries, overall 
and by arm. The safety data will consist of the reporting of all adverse events, and may also 
include reporting vital signs, physical examination data, and laboratory safety data.
10.4.5 Baseline Descriptive Statistics
Limited demographic and clinical characteristics of all patients will be reported.
10.4.6 Planned Interim Analyses
10.4.6.1 Prior to Phase 2 Expansion
Prior to expanding Arm B, if one or fewer of 3 or 6 participants in the safety run in portion of the 
study experiences a DLT, a report including the supporting safety data and delineation of each 
criterion met for phase 2 expansion will be provided to the Sponsor by email 
(OSROSafety@nih.gov). Sponsor approval is required before additional participants will be 
enrolled onto the study. The Dose Escalation Determination form on the sponsor website: 
https://ccrod.cancer.gov/confluence/display/CCRCRO/Forms+and+Instructions may be used for 
this purpose. This report will also be provided to the DSMB for review. 


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10.4.6.2 Efficacy Analysis for Simon 2 stage design
As described in section 10.2, the two-stage Simon minimax design will include interim evaluations 
of response after 10 evaluable patients have been enrolled in arms B. After the first restaging scan 
of the last evaluable patient required for the interim analysis, enrollment to the cohort will be halted 
to allow for an analysis by the study team. An interim analysis report will be created by the study 
team to document the number of responses in the first stage, and will be reviewed by the PI and 
study team. The memo will be provided to and approved by the study sponsor prior to continuation 
of accrual. Alternatively, if the required number of responses is observed before that time, the 
memo may be generated, reviewed and provided to the study sponsor at that point without a pause 
in accrual. 
For Arm B, an interim evaluation for futility will take place after 6 patients have enrolled on the 
arm. If any unusual patterns are detected at this time including trends for early and rapid disease 
progression, this may warrant an early study closure.
The interim analysis report will also be provided to the DSMB.
10.4.7 Sub-Group Analyses
Results will be reported according to the arm in which the patient was treated, but no other 
subgroup analyses are planned.
10.4.8 Tabulation of Individual Participant Data
No individual participant data is intended to be reported.
10.4.9 Exploratory Analyses
Exploratory analyses may include the following: evaluating the intratumoral immunogenicity of 
M7824 plus topotecan or temozolomide; evaluating the pharmacokinetic profile of M7824 alone 
or in combination with topotecan or temozolomide; characterizing the immunomodulatory 
effects of DNA damage-inducing cytotoxic therapy; and characterizing gene expression and 
mutations which predict response and changes associated with response and resistance. Each of 
these analyses will be done with descriptive statistical methods and with exploratory intent. If 
any statistical tests are performed, such as comparisons of responders vs. non-responders with 
respect to mutational status using non-parametric tests, they will be presented without any formal 
adjustment for multiple comparisons but in the context of the number of tests performed.
A small cohort of patients with extrapulmonary small cell cancer patients will be included. Up to 
10 patients with extrapulmonary small cell cancer will receive the combination of M7824 and 
temozolomide. ORR, PFS and OS of patients with extrapulmonary small cell cancer will be 
evaluated in an exploratory manner. These results will be considered hypothesis generating and 
an ORR of 30% or greater will be interesting and may lead to consideration of more definitive 
future trials in this population.
Patients who are enrolled on Arm A and progress, who subsequently receive M7824 plus 
temozolomide will have their response and PFS based on the combination evaluated separately 
from the primary results associated with Arm A; response and PFS evaluations based on the data 
starting with the commencement of the combination therapy will be considered as an exploratory 
evaluation. 


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11 COLLABORATIVE AGREEMENTS
11.1 COOPERATIVE RESEARCH AND DEVELOPMENT AGREEMENT (CRADA)
A CRADA has been executed with EMD Serono for the supply of M7824 (02999).
12 HUMAN SUBJECTS PROTECTIONS 
12.1 RATIONALE FOR SUBJECT SELECTION
As previously described, the subjects for this study will include all subjects who meet the 
eligibility criteria outlined in section 2.1. No gender, racial, or ethnic groups will be excluded 
from participation in this trial.
Participants who do not accept blood transfusions will be excluded. As there is a risk of severe 
bleeding with M7824, participants must be willing to receive blood transfusions if medically 
necessary for their own safety. Participants must be able to receive blood transfusions in order to 
minimize the risks of receiving M7824. Another reason for this is that including these patients 
could compromise the scientific validity of the study. For example, death from blood loss could 
make it difficult to assess other aspects of the investigational immunotherapy’s safety—a 
primary scientific goal in this early-phase immunotherapy trial, which are carried out in small 
numbers of participants.
12.2 PARTICIPATION OF CHILDREN
Because no dosing adverse event data are currently available on the use of topotecan or 
temozolomide in combination with M7824 in subjects <18 years of age, children are excluded 
from this study, but will be eligible for future pediatrics trials. 
12.3 PARTICIPATION OF SUBJECTS UNABLE TO GIVE CONSENT
Adults unable to give consent are excluded from enrolling in the protocol. However, re-consent 
may be necessary and there is a possibility, though unlikely, that subjects could become 
decisionally impaired. For this reason and because there is a prospect of direct benefit from 
research participation (section 12.4.3), all subjects ≥ age 18 will be offered the opportunity to fill 
in their wishes for research and care, and assign a substitute decision maker on the “NIH 
Advance Directive for Health Care and Medical Research Participation” form so that another 
person can make decisions about their medical care in the event that they become incapacitated 
or cognitively impaired during the course of the study. Note: The PI or AI will contact the NIH 
Ability to Consent Assessment Team (ACAT) for evaluation as needed for the following: an 
independent assessment of whether an individual has the capacity to provide consent; assistance 
in identifying and assessing an appropriate surrogate when indicated; and/or an assessment of the 
capacity to appoint a surrogate. For those subjects that become incapacitated and do not have 
pre-determined substitute decision maker, the procedures described in policy 403 for appointing 
a surrogate decision maker for adult subjects who are (a) decisionally impaired, and (b) who do 
not have a legal guardian or durable power of attorney, will be followed.
12.4 EVALUATION OF BENEFITS AND RISKS/DISCOMFORTS
12.4.1 Risks/Benefits Analysis
The primary objective of the trial is to determine a preliminary estimate of efficacy of M7824 
plus topotecan or temozolomide in relapsed SCLC. 


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From a safety standpoint, overlapping toxicities are not expected with topotecan or 
temozolomide (largely consisting of myelosuppression) plus M7824 (immune-related adverse 
events) since the toxicity profile of individual agents are distinct. Safety data from the dose-
escalation study of M7824 in solid tumors as well as preliminary data from expansion cohorts 
demonstrate a similar safety profile to other checkpoint inhibiting compounds. Presumed TGF-β-
mediated cutaneous lesions (e.g. keratoacanthomas and cutaneous squamous cell cancers) are 
unique to this agent compared to other checkpoint inhibitors, but have been reported with prior 
TGF-β targeting agents[56]. These lesions have so far developed in ~5% of patients on study, are 
well managed by surgical excision and spontaneously regress following M7824 withdrawal; the 
lesions themselves are not an indication for discontinuing this agent. The first 10 patients on 
study will be treated with M7824 monotherapy prior to enrolling patients on combination arms. 
Chemotherapy will be administered on the same day as M7824 (similar to the FDA approved 
chemo-immunotherapy combination for NSCLC). Additional safety data were shared in an EMD 
investigator letter dated 9/23/2021 which include cases of early progression and death (due to 
progressive disease, signs and symptoms of progressive disease, or known treatment toxicities) 
seen more frequently in the M7824 arms than in the standard of care arms (refer to section 1.2.6 
for more information). Recent evidence suggests that nuclear DNA can be leaked into the 
cytoplasm upon DNA damage, thereby promoting activation of cGAS-STING signaling[57-60]. 
Such cytoplasmic DNA leakage can result from the genotoxic agents and can activate an innate 
immune response. We recently completed a phase I clinical trial of ATR inhibitor M6620 
(previously VX-970) combined with topotecan. Interestingly, PBMC immune phenotyping data 
from this study showed evidence of a favorable immunomodulatory effect on the innate immune 
system. Mutations in certain genes involved in DNA repair have also been associated with 
syndromes characterized by unchecked inflammatory response in the absence of exogenous 
stimuli. 
A combination of MGMT activity and mismatch repair (MMR) status of the tumor are important 
parameters that determine sensitivity to temozolomide[61]. Temozolomide is most cytotoxic in 
cells with low levels of MGMT and intact MMR. MMR-deficient cells do not detect alkylation 
adducts and hence are resistant to temozolomide even when they lack MGMT. Treatment with 
temozolomide would select for the MMR-deficient cancer cells, which are immune to 
temozolomide, but hypersensitive to the immune checkpoint inhibitors[62]. A combination of 
temozolomide and immune checkpoint inhibition could therefore target both mismatch repair 
proficient and deficient cancer cells. A safe dose of the M7824 plus temozolomide established in 
this trial and the biomarker results of this trial would inform the design of a planned biomarker 
trial of the combination in solid tumors. 
12.4.2 Risks
12.4.2.1 Study drug risks
The risks associated with the specific study agents are described in Section 14. Subjects will be 
adequately monitored for the occurrence of any possible side effects. 
12.4.2.2 Biopsy risks
The risks associated with biopsies are pain and bleeding at the biopsy site. In order to minimize 
pain, local anesthesia will be used. Rarely, there is a risk of infection at the sampling site. CT 
guidance may be used in obtaining biopsies (see 12.4.2.3 for radiation risk). 


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There is a possibility that conscious sedation may be used for the procedure. The common side 
effects of conscious sedation include drowsiness, delayed reflexes, hypotension, headache, and 
nausea. These are generally mild and last no more than a few hours.
12.4.2.3 Radiation risks
The risk of radiation exposure is expected from up to 10 CT scans, 10 PET scans and 2 CT 
guided biopsies. The total estimated effective dose for one year is approximately 21.6 rem. The 
risk of getting cancer from the radiation exposure in this study is 2.2 out of 100 (2.2%) and of 
getting a fatal cancer is 1.1 out of 100 (1.1%). 
12.4.2.4 CT contrast risks
Itching, hives or headaches are possible risks associated with contrast agents that may be used 
during CT imaging. Symptoms of a more serious allergic reaction include shortness of breath 
and swelling of the throat or other parts of the body. Very rarely, the contrast agents used in CT 
can cause kidney problems for certain patients, such as those with impaired kidney function.
12.4.2.5 Risks related to blood sampling
Side effects of blood draws include pain and bruising, lightheadedness, and rarely, fainting.
12.4.2.6 Risk related to hair follicle collection
 A side effect of hair follicle collection is pain.
12.4.3 Benefits
The benefits include a possible decrease in the size of the tumor and the scientific knowledge 
that could be acquired through this trial. 
12.5 CONSENT PROCESS AND DOCUMENTATION
The informed consent document will be provided as a physical or electronic document to the 
participant or consent designee(s) as applicable for review prior to consenting. A designated 
study investigator will carefully explain the procedures and tests involved in this study, and the 
associated risks, discomforts and benefits. In order to minimize potential coercion, as much time 
as is needed to review the document will be given, including an opportunity to discuss it with 
friends, family members and/or other advisors, and to ask questions of any designated study 
investigator. A signed informed consent document will be obtained prior to entry onto the study.
The initial consent process as well as re-consent, when required, may take place in person or 
remotely (e.g., via telephone or other NIH approved remote platforms used in compliance with 
local policy, including HRPP Policy 303) per discretion of the designated study investigator and 
with the agreement of the participant/consent designee(s). Whether in person or remote, the 
privacy of the subject will be maintained. Consenting investigators (and participant/consent 
designee, when in person) will be located in a private area (e.g., clinic consult room). When 
consent is conducted remotely, the participant/consent designee will be informed of the private 
nature of the discussion and will be encouraged to relocate to a more private setting if needed. 
Consent will be documented with required signatures on the physical document (which includes 
the printout of an electronic document sent to participant) or as described below, with a manual 
(non-electronic) signature on the electronic document. When required, witness signature will be 
obtained similarly as described for the investigator and participant.


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Manual (non-electronic) signature on electronic document:
When a manual signature on an electronic document is used for the documentation of consent at 
the NIH Clinical Center, this study will use the following to obtain the required signatures:

Adobe platform (which is not 21 CFR Part 11 compliant); or, 

iMedConsent platform (which is 21 CFR Part 11 compliant)
During the consent process, participants and investigators will view individual copies of the 
approved consent document on screens at their respective locations (if remote consent); the same 
screen may be used when in the same location, but is not required. 
Both the investigator and the participant will sign the document using a finger, stylus or mouse. 
Note: Refer to the CCR SOP PM-2, Obtaining and Documenting the Informed Consent Process 
for additional information (e.g., verification of participant identity when obtaining consent 
remotely) found at: 
https://ccrod.cancer.gov/confluence/pages/viewpage.action?pageId=73203825.
12.5.1 Request for Waiver of Consent for Screening Activities
Prior to the subject signing the consent for this study pre-screening activities listed in section 
2.3.1 may be performed. 
We request a waiver of consent for these activities as they involve only minimal risk to the 
subjects. A waiver will not adversely affect the rights and welfare of the subjects given that the 
activities are only intended to determine suitability for screening for participation in research 
protocols. These activities could not practicably be carried out without the wavier as central 
recruiting services, utilized in the NIH Clinical Center, perform pre-screening activities for 
multiple studies and obtaining consent for each one is beyond their resources. The subjects will 
be provided with additional pertinent information after participation as they will be informed 
whether or not they are eligible to sign a consent for additional screening.
13 REGULATORY AND OPERATIONAL CONSIDERATIONS 
13.1 STUDY DISCONTINUATION AND CLOSURE
This study may be temporarily suspended or prematurely terminated if there is sufficient 
reasonable cause. Written notification, documenting the reason for study suspension or 
termination, will be provided by the suspending or terminating party to study participants, 
investigator, funding agency, the Investigational New Drug (IND) or Investigational Device 
Exemption (IDE) sponsor and regulatory authorities. If the study is prematurely terminated or 
suspended, the Principal Investigator (PI) will promptly inform study participants, the 
Institutional Review Board (IRB), and sponsor and will provide the reason(s) for the termination 
or suspension. Study participants will be contacted, as applicable, and be informed of changes to 
study visit schedule.
 Circumstances that may warrant termination or suspension include, but are not limited to:

Determination of unexpected, significant, or unacceptable risk to participants

Demonstration of efficacy that would warrant stopping 

Insufficient compliance to protocol requirements

Data that are not sufficiently complete and/or evaluable


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
Determination that the primary endpoint has been met

Determination of futility
Study may resume once concerns about safety, protocol compliance, and data quality are 
addressed, and satisfy the sponsor, IRB and as applicable, Food and Drug Administration (FDA).
13.2 QUALITY ASSURANCE AND QUALITY CONTROL
The clinical site will perform internal quality management of study conduct, data and biological 
specimen collection, documentation and completion. An individualized quality management plan 
will be developed to describe a site’s quality management.
Quality control (QC) procedures will be implemented beginning with the data entry system and 
data QC checks that will be run on the database will be generated. Any missing data or data 
anomalies will be communicated to the site(s) for clarification/resolution.
Following written Standard Operating Procedures (SOPs), the monitors will verify that the 
clinical trial is conducted and data are generated and biological specimens are collected, 
documented (recorded), and reported in compliance with the protocol, International Council on 
Harmonisation Good Clinical Practice (ICH GCP), and applicable regulatory requirements (e.g., 
Good Laboratory Practices (GLP), Good Manufacturing Practices (GMP)). 
The investigational site will provide direct access to all trial related sites, source data/documents, 
and reports for the purpose of monitoring and auditing by the sponsor, and inspection by local 
and regulatory authorities.
13.3 CONFLICT OF INTEREST POLICY
The independence of this study from any actual or perceived influence, such as by the 
pharmaceutical industry, is critical. Therefore, any actual conflict of interest of persons who have 
a role in the design, conduct, analysis, publication, or any aspect of this trial will be disclosed 
and managed. Furthermore, persons who have a perceived conflict of interest will be required to 
have such conflicts managed in a way that is appropriate to their participation in the design and 
conduct of this trial. The study leadership in conjunction with the National Cancer Institute has 
established policies and procedures for all study group members to disclose all conflicts of 
interest and will establish a mechanism for the management of all reported dualities of interest.
13.4 CONFIDENTIALITY AND PRIVACY
Participant confidentiality and privacy is strictly held in trust by the participating investigators, 
their staff, and the sponsor(s). This confidentiality is extended to cover testing of biological 
samples and genetic tests in addition to the clinical information relating to participants. 
Therefore, the study protocol, documentation, data, and all other information generated will be 
held in strict confidence. No information concerning the study or the data will be released to any 
unauthorized third party without prior written approval of the sponsor. 
All research activities will be conducted in as private a setting as possible.
The study monitor, other authorized representatives of the sponsor, representatives of the 
Institutional Review Board (IRB), and/or regulatory agencies may inspect all documents and 
records required to be maintained by the investigator, including but not limited to, medical 
records (office, clinic, or hospital) and pharmacy records for the participants in this study. The 
clinical study site will permit access to such records.


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The study participant’s contact information will be securely stored at the/each clinical site for 
internal use during the study. At the end of the study, all records will continue to be kept in a 
secure location for as long a period as dictated by the reviewing IRB, Institutional policies, or 
sponsor requirements.
Study participant research data, which is for purposes of statistical analysis and scientific 
reporting, will be stored at the NCI CCR. This will not include the participant’s contact or 
identifying information. Rather, individual participants and their research data will be identified 
by a unique study identification number. The study data entry and study management systems 
used by the clinical site(s) and by NCI CCR research staff will be secured and password 
protected. At the end of the study, all study databases will be archived at the NIH.
To further protect the privacy of study participants, a Certificate of Confidentiality has been 
issued by the National Institutes of Health (NIH). This certificate protects identifiable research 
information from forced disclosure. It allows the investigator and others who have access to 
research records to refuse to disclose identifying information on research participation in any 
civil, criminal, administrative, legislative, or other proceeding, whether at the federal, state, or 
local level. By protecting researchers and institutions from being compelled to disclose 
information that would identify research participants, Certificates of Confidentiality help achieve 
the research objectives and promote participation in studies by helping assure confidentiality and 
privacy to participants.
14 PHARMACEUTICAL INFORMATION 
14.1 M7824 (IND # 136852) 
14.1.1 Source 
M7824 will be provided by EMD Serono.
14.1.2 Packaging and Labeling Information 
Packaging and labelling 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.
M7824 drug product is supplied by EMD Serono as a sterile liquid formulation. The liquid 
formulation, compared with the prior freeze-dried formulation, has the same composition in 
terms of excipients, qualitatively and quantitatively, except for the addition of water. Of note, 
there is no change to the drug substance process. The Concentrate for Solution for Infusion 
(liquid formulation) is packaged at a 10mg/mL concentration in USP / Ph Eur type I 50R vials 
that are filled with drug product solution to allow an extractable volume of 60 mL (600mg/60 
mL). The vials are closed with rubber stoppers with the same composition as used for freeze-
dried formulation, but in serum format complying with USP and Ph Eur with an aluminium 
crimp seal closure. 


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For applications in clinical studies, the liquid formulation is diluted directly with 0.9% NaCl 
solution. The estimated volumes of delivery are anticipated to be no more than 250 mL, which 
are clinically acceptable.
14.1.3 Toxicity
Refer to section 1.2 on nonclinical and clinical data that outlines toxicities associated with 
M7824. Updated clinical data has been presented in Table 6 and Table 7. In addition, at least 2 
instances of nodular regenerative hyperplasia have been observed with the use of this agent. 
Furthermore, a participant on the study experienced enteric dysmotility which may have resulted 
in anorexia, weight loss and constipation (related to both M7824 and temozolomide).
Table 6. Adverse Drug Reactions by Preferred Term in the Pooled Safety Analysis Set
Pooled Safety Analysis Set
(N=765)
System Organ Class 
Preferred Term
All Grades
n (%)
Grade ≥ 3
n (%)
Blood and lymphatic system disorders
Anemia
222 (29.0)
132 (17.3)
Blood loss anemia
2 (0.3)
1 (0.1)
Disseminated intravascular coagulation
2 (0.3)
2 (0.3)
Hemolytic anemia
1 (0.1)
1 (0.1)
Increased tendency to bruise
1 (0.1)
0
Microcytic anemia
1 (0.1)
0
Normocytic anemia
1 (0.1)
1 (0.1)
Cardiac disorders
Myocarditis *
1 (0.1)
1 (0.1)
Ear and labyrinth disorders 
Ear hemorrhage
2 (0.3)
0
Endocrine disorders
Adrenal insufficiency *
14 (1.8)
6 (0.8)
Autoimmune thyroiditis *
1 (0.1)
0
Basedow's disease *
1 (0.1)
0
Hyperthyroidism *
4 (0.5)
0
Hypophysitis *
3 (0.4)
2 (0.3)
Hypopituitarism *
2 (0.3)
1 (0.1)
Hypothyroidism *
33 (4.3)
2 (0.3)
Lymphocytic hypophysitis *
1 (0.1)
0
Secondary adrenocortical insufficiency *
1 (0.1)
0
Thyroiditis *
Eye disorders
3 (0.4)
0
Conjunctival hemorrhage
6 (0.8)
0
Retinal hemorrhage
2 (0.3)
0
Vitreous hemorrhage
1 (0.1)
1 (0.1)
Gastrointestinal disorders
Abdominal pain
111 (14.5)
15 (2.0)


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Pooled Safety Analysis Set
(N=765)
System Organ Class 
Preferred Term
All Grades
n (%)
Grade ≥ 3
n (%)
Anal hemorrhage
1 (0.1)
0
Autoimmune colitis *
2 (0.3)
2 (0.3)
Colitis *
5 (0.7)
3 (0.4)
Constipation
137 (17.9)
3 (0.4)
Diarrhea
105 (13.7)
5 (0.7)
Diarrhea *
8 (1.0)
5 (0.7)
Diverticulum intestinal hemorrhagic
1 (0.1)
1 (0.1)
Duodenal ulcer hemorrhage
1 (0.1)
1 (0.1)
Enterocolitis *
1 (0.1)
0
Gastric hemorrhage
2 (0.3)
1 (0.1)
Gastritis hemorrhagic
1 (0.1)
1 (0.1)
Gastroduodenal hemorrhage
1 (0.1)
1 (0.1)
Gastrointestinal hemorrhage
14 (1.8)
8 (1.0)
Gastrointestinal vascular malformation hemorrhagic
1 (0.1)
1 (0.1)
Gingival bleeding
38 (5.0)
0
Hematemesis
6 (0.8)
1 (0.1)
Hematochezia
5 (0.7)
0
Hemorrhagic ascites
1 (0.1)
0
Hemorrhoidal hemorrhage
8 (1.0)
2 (0.3)
Intra-abdominal hematoma
1 (0.1)
1 (0.1)
Intra-abdominal hemorrhage
3 (0.4)
3 (0.4)
Lower gastrointestinal hemorrhage
4 (0.5)
1 (0.1)
Melaena
12 (1.6)
2 (0.3)
Mouth hemorrhage
9 (1.2)
0
Nausea
137 (17.9)
12 (1.6)
Esophageal hemorrhage
1 (0.1)
1 (0.1)
Esophageal varices hemorrhage
2 (0.3)
2 (0.3)
Rectal hemorrhage
5 (0.7)
0
Small intestinal hemorrhage
1 (0.1)
0
Upper gastrointestinal hemorrhage
14 (1.8)
8 (1.0)
Vomiting
100 (13.1)
11 (1.4)
General disorders and administration site conditions
Asthenia
126 (16.5)
15 (2.0)
Chills
3 (0.4)
0
Fatigue
160 (20.9)
24 (3.1)
Mucosal hemorrhage
2 (0.3)
0
Oedema peripheral
79 (10.3)
2 (0.3)
Pyrexia
141 (18.4)
7 (0.9)
Hepatobiliary disorders
Hepatic function abnormal *
1 (0.1)
1 (0.1)
Hepatic hemorrhage
1 (0.1)
1 (0.1)
Hepatitis *
2 (0.3)
1 (0.1)
Immune system disorders
Drug hypersensitivity
1 (0.1)
0
Injury, poisoning and procedural complications
1 (0.1)
0
Contusion
9 (1.2)
1 (0.1)
Extradural hematoma
1 (0.1)
1 (0.1)
Infusion related reaction
26 (3.4)
1 (0.1)


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Pooled Safety Analysis Set
(N=765)
System Organ Class 
Preferred Term
All Grades
n (%)
Grade ≥ 3
n (%)
Subcutaneous hematoma
1 (0.1)
0
Subdural hematoma
1 (0.1)
1 (0.1)
Investigations
Alanine aminotransferase increased *
6 (0.8)
4 (0.5)
Aspartate aminotransferase increased
87 (11.4)
19 (2.5)
Aspartate aminotransferase increased *
6 (0.8)
5 (0.7)
Blood creatine phosphokinase increased *
2 (0.3)
1 (0.1)
Blood thyroid stimulating hormone increased *
2 (0.3)
0
Hemoglobin decreased
4 (0.5)
3 (0.4)
Transaminases increased *
1 (0.1)
0
Metabolism and nutrition disorders
Decreased appetite
189 (24.7)
18 (2.4)
Latent autoimmune diabetes in adults *
1 (0.1)
1 (0.1)
Type 1 diabetes mellitus *
1 (0.1)
0
Musculoskeletal and connective tissue disorders
Back pain
1 (0.1)
0
Myositis *
2 (0.3)
2 (0.3)
Neoplasms benign, malignant and unspecified (incl cysts and 
polyps)
Basal cell carcinoma
6 (0.8)
1 (0.1)
Bowen's disease
2 (0.3)
2 (0.3)
Intracranial tumor hemorrhage
1 (0.1)
1 (0.1)
Keratoacanthoma
57 (7.5)
5 (0.7)
Lip squamous cell carcinoma
4 (0.5)
2 (0.3)
Skin neoplasm bleeding
1 (0.1)
0
Squamous cell carcinoma of skin
27 (3.5)
11 (1.4)
Tumor hemorrhage
13 (1.7)
10 (1.3)
Nervous system disorders
Cerebellar hemorrhage
1 (0.1)
1 (0.1)
Cerebral hemorrhage
1 (0.1)
1 (0.1)
Hemorrhage intracranial
3 (0.4)
3 (0.4)
Hemorrhagic transformation stroke
1 (0.1)
0
Headache
86 (11.2)
5 (0.7)
Immune-mediated encephalitis *
1 (0.1)
1 (0.1)
Renal and urinary disorders
Acute kidney injury *
3 (0.4)
3 (0.4)
Haematuria
22 (2.9)
3 (0.4)
Nephritis *
1 (0.1)
1 (0.1)
Tubulointerstitial nephritis *
1 (0.1)
1 (0.1)
Reproductive system and breast disorders
Breast hemorrhage
1 (0.1)
0
Vaginal hemorrhage
4 (0.5)
0
Respiratory, thoracic and mediastinal disorders
Bronchial hemorrhage
1 (0.1)
0
Cough
87 (11.4)
0
Dyspnea
134 (17.5)
31 (4.1)


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Pooled Safety Analysis Set
(N=765)
System Organ Class 
Preferred Term
All Grades
n (%)
Grade ≥ 3
n (%)
Epistaxis
81 (10.6)
3 (0.4)
Hemoptysis
41 (5.4)
4 (0.5)
Hemothorax
1 (0.1)
1 (0.1)
Interstitial lung disease *
4 (0.5)
2 (0.3)
Laryngeal hemorrhage
1 (0.1)
0
Pharyngeal hemorrhage
1 (0.1)
0
Pneumonitis *
8 (1.0)
3 (0.4)
Pulmonary hemorrhage
4 (0.5)
2 (0.3)
Respiratory tract hemorrhage
1 (0.1)
0
Skin and subcutaneous tissue disorders 
Actinic keratosis
12 (1.6)
0
Blood blister
3 (0.4)
0
Dermatitis acneiform *
14 (1.8)
2 (0.3)
Drug eruption *
1 (0.1)
0
Ecchymosis
1 (0.1)
0
Erythema *
3 (0.4)
0
Hyperkeratosis
12 (1.6)
2 (0.3)
Lichen planus *
1 (0.1)
0
Pemphigoid *
3 (0.4)
3 (0.4)
Petechiae
2 (0.3)
0
Pruritus
143 (18.7)
2 (0.3)
Pruritus *
38 (5.0)
3 (0.4)
Purpura
5 (0.7)
0
Rash *
42 (5.5)
11 (1.4)
Rash erythematous *
4 (0.5)
0
Rash macular *
8 (1.0)
2 (0.3)
Rash maculo-papular *
44 (5.8)
16 (2.1)
Rash papular *
2 (0.3)
1 (0.1)
Rash pruritic *
9 (1.2)
1 (0.1)
Skin hemorrhage
1 (0.1)
0
Toxic skin eruption *
1 (0.1)
1 (0.1)
Vascular disorders 
Flushing
2 (0.3)
0
Hematoma
6 (0.8)
0
Hypotension
5 (0.7)
0
Shock hemorrhagic
1 (0.1)
1 (0.1)
Source: ADSL 23DEC2020 8:38, ADAE 23DEC2020 9:27,OutputID:T-38-aefrq.
* Immune-related adverse reaction as identified via customized MedDRA PT query and assessed based on a detailed 
medical review using predefined criteria.


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Table 7. Serious Adverse Drug Reactions by Preferred Term (reported for ≥ 2 
Participants per PT) Considered Expected for the Purpose of Safety Reporting to 
Regulatory Authorities in the European Union
Pooled Safety Analysis Set 
(N=765)
System Organ Class 
Preferred Term
Treatment-related SARs
n (%)
Blood and lymphatic system disorders
Anaemia
6 (0.8)
Endocrine disorders
Adrenal insufficiency 
Hypophysitis
7 (0.9)
2 (0.3)
Gastrointestinal disorders
Colitis
Autoimmune colitis
Diarrhea
4 (0.5)
2 (0.3)
2 (0.3)
Musculoskeletal and connective tissue disorders
Myositis
2 (0.3)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Squamous cell carcinoma of skin
Keratoacanthoma
Lip squamous cell carcinoma
Basal cell carcinoma
Bowen's disease
19 (2.5)
10 (1.3)
3 (0.4)
2 (0.3)
2 (0.3)
Renal and urinary disorders
Acute kidney injury
2 (0.3)
Respiratory, thoracic and mediastinal disorders
Pneumonitis
Interstitial lung disease
5 (0.7)
4 (0.5)
Skin and subcutaneous tissue disorders
Rash maculo-papular
Rash
3 (0.4)
2 (0.3)
Source: ADSL 23DEC2020 8:38, ADAE 23DEC2020 9:27,OutputID:T-39-aefrq.
SAR = serious adverse reactions.
14.1.4 Administration procedures
Refer to section 3.3.3 for details on preparation and administration. 
14.1.5 Stability, Storage, and Handling of Drug 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. 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, the freeze-dried M7824 drug product must be reconstituted with 
4.5 mL of Water for Injection and diluted with 0.9% NaCl solution (sodium chloride injection) 
while the liquid formulation must be diluted with 0.9% NaCl solution. The chemical and 
physical in-use stability for the infusion solution of M7824 in 0.9% NaCl 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 


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dilution has taken place in controlled and validated aseptic conditions. Prepared solution for 
dosing should be kept at room temperature and used immediately after preparation. Prepared 
solution for dosing is not intended to be stored; however, if dilution has taken place under all of 
the controlled aseptic conditions in place at the local site, it may be stored for no more than 72 
hours after dilution at room temperature, including infusion time. No other drugs should be 
added to the infusion containers containing M7824. The drug may be administered using a 
central or peripheral line.
Calculation of Volume of M7824 and Normal Saline Required: based on flat dosing and a total 
infusion volume of 250 mL. 
Dosage: 1200 mg 
The volume of M7824 required to prepare the infusion bag is 120 mL (10 mg/mL vial) 
The volume of normal saline required to prepare the infusion bag = 250 mL – 120 mL = 130 mL
Dosage: 2400 mg
The volume of M7824 required to prepare the infusion bag is 240 mL (10 mg/mL vial) 
The volume of normal saline required to prepare the infusion bag = 250 mL – 240 mL = 10 mL
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.
14.1.6 Clinical Supplies Disclosure 
The Investigator is responsible for ensuring drug product accountability, including reconciliation 
of drugs and maintenance of records.
Upon receipt of M7824, the responsible person will check for accurate delivery and 
acknowledge receipt by signing or initialing and dating the appropriate documentation and 
returning it to EMD Serono. A copy will be archived for the Investigator Site File.
M7824 dispensing will be recorded on the appropriate drug accountability forms.
Trial site M7824 accountability records will include the following:
Confirmation of M7824 receipt, in good condition and in the defined temperature range.
The inventory of M7824 provided for the clinical trial and prepared at the site.
The use of each dose by each subject.
The disposition (including return, if applicable) of any unused M7824.
Dates, quantities, batch numbers, vial numbers, expiry dates, formulation (for M7824 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 M7824 provided were fully reconciled.


Abbreviated Title: M7824 in Small Cell Cancers
Version Date: 01/11/2024
106
Unused M7824 must not be used for any purpose other than the present trial. No M7824 that is 
dispensed to a subject may be redispensed to a different subject.
At the conclusion or termination of this trial, trial site personnel 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. 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 that the M7824 is not used
after the expiry date, and 
after the retest date unless the M7824 is reanalyzed and its retest date extended.
14.2 TOPOTECAN
Refer to the package insert for toxicities, formulation and preparation, stability and storage and 
incompatibility information.
14.2.1 Source 
Topotecan will be purchased from commercial sources by the NIH CC Pharmacy.
14.2.2 Administration Procedures
Please refer to section 3.3.1.
14.3 TEMOZOLOMIDE
Refer to the package insert for toxicities, formulation and preparation, stability and storage and 
incompatibility information.
14.3.1 Source 
Temozolomide will be purchased from commercial sources by the NIH CC Pharmacy.
14.3.2 Administration Procedures
Refer to section 3.3.2.


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107
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Abbreviated Title: M7824 in Small Cell Cancers
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16 APPENDICES
16.1 APPENDIX A - PERFORMANCE STATUS CRITERIA
ECOG Performance Status Scale
Karnofsky Performance Scale
Grade
Descriptions
Percent
Description
100
Normal, no complaints, no 
evidence of disease.
0
Normal activity. Fully active, able 
to carry on all pre-disease 
performance without restriction.
90
Able to carry on normal activity; 
minor signs or symptoms of 
disease.
80
Normal activity with effort; 
some signs or symptoms of 
disease.
1
Symptoms, but ambulatory. 
Restricted in physically strenuous 
activity, but ambulatory and able 
to carry out work of a light or 
sedentary nature (e.g., light 
housework, office work).
70
Cares for self, unable to carry on 
normal activity or to do active 
work.
60
Requires occasional assistance, 
but is able to care for most of 
his/her needs.
2
In bed <50% of the time. 
Ambulatory and capable of all 
self-care, but unable to carry out 
any work activities. Up and about 
more than 50% of waking hours.
50
Requires considerable assistance 
and frequent medical care.
40
Disabled, requires special care 
and assistance.
3
In bed >50% of the time. Capable 
of only limited self-care, confined 
to bed or chair more than 50% of 
waking hours.
30
Severely disabled, 
hospitalization indicated. Death 
not imminent.
20
Very sick, hospitalization 
indicated. Death not imminent.
4
100% bedridden. Completely 
disabled. Cannot carry on any 
self-care. Totally confined to bed 
or chair.
10
Moribund, fatal processes 
progressing rapidly.
5
Dead.
0
Dead.


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Version Date: 01/11/2024
113
16.2 APPENDIX B - TEMOZOLOMIDE DRUG ADMINISTRATION DIARY
Today’s Date ________________________________ Cycle #__________ 
Patient Name_______________________________ Patient Study ID ___________________ 
(initials acceptable for patient’s name) 
Please bring your pill bottle and this form to your physician when you go for your next appointment. 
This is required for study compliance.
1. Complete one form for each cycle (28 days). 
2. You will take ___ (number) ____ mg (dosage) capsules(s) once daily. 
3. Taking on an empty stomach will minimize nausea. 
4. Capsules should not be opened or chewed. They should be swallowed whole with a glass of 
water.
If capsules are accidentally opened or damaged, precautions should be taken to avoid inhalation or 
contact with the skin or mucous membranes. 
4. Record the date, the number of pills you took, and when you took them. 
5. If you have any comments or notice any side effects, please record them in the Comments 
column 
Date 
Day 
# pills and when taken: 
Comments
1
2
3
4
5
Patient’s signature and date: 
Study Team will complete this section: 
1. Date patient started protocol treatment_____________________ 
2. Date patient was removed from study _____________________ 
3. Patient’s planned daily dose______________________________ 
4. Total number of pills taken this month ______________________ 
Physician/Nurse’s Signature ___________________________________________________________

ICF_001.pdf: 
PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 01/11/2024
Page 1 of 21
CC ICF template v. 09.27.19
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
PRINCIPAL INVESTIGATOR: Anish Thomas, M.D
STUDY TITLE:
Safety Run-In and Phase II Trial of M7824 and Topotecan or 
Temozolomide in Relapsed Small Cell Cancers
STUDY SITE: 
NIH Clinical Center (CC)
Cohort: 
Affected Patient
Consent Version: 
01/11/2024
WHO DO YOU CONTACT ABOUT THIS STUDY? 
Principal Investigator:
Anish Thomas, MD
Phone: 240-760-7343
Email: anish.thomas@nih.gov
This consent form describes a research study and is designed to help you decide if you would like 
to be a part of the research study. 
You are being asked to take part in a research study at the National Institutes of Health (NIH). 
Members of the study team will talk with you about the information described in this document. 
Some people have personal, religious, or ethical beliefs that may limit the kinds of medical or 
research treatments they would want to receive (such as blood transfusions). Take the time needed 
to ask any questions and discuss this study with NIH staff, and with your family, friends, and 
personal health care providers. Taking part in research at the NIH is your choice.
If the individual being asked to participate in this research study is not able to give consent to be 
in this study, you are being asked to give permission for this person as their decision-maker. The 
term “you” refers to you as the decision-maker and/or the individual being asked to participate in 
this research, throughout the remainder of this document. 
IT IS YOUR CHOICE TO TAKE PART IN THE STUDY
You may choose not to take part in this study for any reason. If you join this study, you may change 
your mind and stop participating in the study at any time and for any reason. In either case, you 
will not lose any benefits to which you are otherwise entitled. However, to be seen at the NIH, you 
must be taking part in a study or are being considered for a study. If you do choose to leave the 
study, please inform your study team to ensure a safe withdrawal from the research. 
WHY IS THIS STUDY BEING DONE?
Small cell lung cancer (SCLC) is an aggressive cancer with poor outcomes. Patients with SCLC 
tend to be very responsive to chemotherapy in the beginning but then become resistant to treatment 
after a few months. There have been different strategies used over the years to treat SCLC without 
successful breakthroughs; therefore, there is a need for new treatment approaches. 
IRB NUMBER: 18C0110
IRB EFFECTIVE DATE: 1/29/2024


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 01/11/2024
Page 2 of 21
CC ICF template v. 09.27.19
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
Extrapulmonary small cell cancers are not common cancers and there are no standard treatment 
for this disease. It has been discovered that patients with extrapulmonary small cell cancers may 
respond to similar treatment to that of patients with SCLC.
Chemotherapy drugs currently used to treat SCLC work by altering DNA of cancer cells; however, 
they do not destroy all cancers cells due to the ability of cancer cells to repair their damaged DNA. 
In this study we would like to test topotecan and temozolomide in combination with a drug called 
M7824. Topotecan is approved by the FDA for use in small cell lung cancer, ovarian cancer and 
in cancers of the cervix. Temozolomide is approved by the FDA to treat brain cancers, but has 
shown activity in SCLC in small studies. M7824 is an investigational immunotherapy agent 
designed to block the ability of cancer cells to avoid being destroyed by immune system. 
Investigational means that it has not been approved by the US Food and Drug Administration. The 
aim of this investigational drug is to control tumor growth by helping the immune system to fight 
the tumor. We think that increased DNA damage to cancer cells caused by topotecan and 
temozolomide will complement the anti-tumor activity of M7824, in recurrent SCLC.
M7824 is a new immunotherapy drug and although it may cause similar side effects of other 
immunotherapy agents, it has also been found to cause additional skin problems, different 
problems with the immune system, low red blood cell count (anemia) and bleeding. It is possible 
that the anemia and/or bleeding may be so severe that you require a blood transfusion. You cannot 
join this study if you are not willing to have a blood transfusion.
M7824 has been tried in other types cancers. Recently, the manufacturer of the drug closed 3 large 
studies because the drug was not shown to help those patients more than standard therapies. In 
addition, in some cases it seemed like the drug might make the cancer grow faster. However, the 
type of cancer treated in those studies was not the same as your cancer.
Approximately the first 6 participants enrolled in the study will receive M7824 alone to test for 
safety in the first part of the study. We will then test how effective the combinations of M7824 and 
topotecan or M7824 and temozolomide are in treating SCLC. For a group of 10 participants with 
extrapulmonary small cell cancer, we will also test how effective the combination of M7824 and 
temozolomide is in treating this type of cancer. 
We will start with one dose of M7824 in this group of participants, but the dose may be lowered 
in later participants if we find it causes too many side effects. The dose that does not cause too 
many side effects will be considered a safe dose. We will test the safe dose in the next group of 
participants to see if it’s effective.
WHY ARE YOU BEING ASKED TO TAKE PART IN THIS STUDY?
You have been asked to take part in this study because you have been diagnosed with Small Cell 
Lung Cancer (SCLC) or extrapulmonary small cell cancer, and your disease has not responded to 
prior treatment. 
HOW MANY PEOPLE WILL TAKE PART IN THIS STUDY? 
Up to 80 people will take part in this study. 
IRB NUMBER: 18C0110
IRB EFFECTIVE DATE: 1/29/2024


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 01/11/2024
Page 3 of 21
CC ICF template v. 09.27.19
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
DESCRIPTION OF RESEARCH STUDY
WHAT WILL HAPPEN IF YOU TAKE PART IN THIS RESEARCH STUDY? 
Before you begin the study
Before you begin this study, you will have several exams and tests to make sure you are eligible 
for this study. The following tests may be performed on this study, another NIH protocol or records 
may be collected from your outside provider:

Medical history and physical examination to determine your current health status.

Blood tests to assess how your organs are functioning (about a tablespoon of blood will be 
collected).

As part of this study, we will test you for infection with the human immunodeficiency virus 
(HIV), the virus that causes AIDS, and hepatitis B and C (about a tablespoon of blood will 
be collected for these tests). If you are infected with HIV and you are receiving treatment, 
you will be able to be in this study. If you have hepatitis B, hepatitis C, or you are not 
receiving treatment for HIV, you will not be part of the study. We will tell you what the 
results mean, how to find care, how to avoid infecting others, how we report these 
infections, and the importance of informing your partners who are at possible risk because 
of your viral infection.

Electrocardiogram (EKG) – An electrocardiogram (ECG) is a test that looks at electrical 
activity of your heart. You will need to lie still for about 5 minutes. We will place electrodes 
on your chest, arms, and legs. Electrodes are small stickers that are attached to wires that 
go to the machine. The signals are recorded by the machine. If you have a lot of hair on 
your chest, it may hurt a little bit to remove the stickers.

CT scan – The CT scanner is a donut-shaped machine that uses x-rays to make computer 
pictures of the inside of your body. During the procedure, you will need to lie still on a 
table inside the CT machine. The table will move you in and out of the machine during the 
scan, and you will be told to hold your breath.

PET scan (may not need to be performed if your study doctor determines the CT to be 
sufficient) – The PET scanner is a donut-shaped machine that uses x-rays combined with 
a dose of a radioactive material (tracer) to make computer pictures showing the inside of 
your body. 

We will confirm your diagnosis by reviewing records from past biopsies. 

Pregnancy Test - If you are a woman who can become pregnant, you will have a pregnancy 
test done through a urine or blood test (about a teaspoon of blood may be drawn).
During the study
The first group (Arm A) will consist of about 10 participants who will enroll and receive M7824 
alone. Two doses of M7824 will be evaluated. You will receive M7824 through a tube inserted in 
your vein for approximately 1 or 2 hours on day 1 of a 21-day cycle depending on the dose 
received. You will continue this therapy as long as the disease is responding to treatment. If your 
disease worsens, you may be assigned to receive M7824 in combination with temozolomide. Any 
time you take temozolomide, you may be given drugs to help with infections that have been 
associated with temozolomide. If there are no slots available in the combination arms, we will 
discuss other potential clinical trials with you.
IRB NUMBER: 18C0110
IRB EFFECTIVE DATE: 1/29/2024


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 01/11/2024
Page 4 of 21
CC ICF template v. 09.27.19
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
After Arm A has completed, the next participants will be assigned to receive M7824 in 
combination with temozolomide (Arm C). If enrollment of SCLC participants in Arm C is 
complete, then participants will be assigned to receive M7824 in combination with topotecan (Arm 
B). A small number of participants with extrapulmonary small cell cancer will also be enrolled in 
Arm C.
If you have been assigned to Arm B, you will receive M7824 in your vein for approximately 2 
hours on day 1. You will receive topotecan in your vein for approximately 30 minutes on day 1 
within 15-30 minutes after you finished infusion of M7824. You will continue receiving topotecan 
every day for an additional 4 days and a total of 5 days including day 1. Each cycle of therapy will 
be 21 days. 
If you have been assigned to Arm C, you will receive M7824 in your vein for approximately 1 
hour on days 1 and 15. You will take temozolomide by mouth within 15-30 minutes after you 
finished infusion of M7824 on day 1 and continue taking temozolomide once daily for a total of 5 
days. You will be given a pill diary at the beginning of each cycle to fill out and bring back to the 
study nurse at the end of the cycle. You will take temozolomide on an empty stomach with a glass 
of water. Capsules should be swallowed whole and should not be opened or chewed. Each cycle 
of therapy will be 28 days.
If you are receiving M7824 plus one of the chemotherapy agents (topotecan or temozolomide), 
treatment will be continued until your disease progresses. If you are in arm B or C and cannot 
tolerate the chemotherapy agent, M7824 alone may be continued until your disease progresses if 
your study doctor finds that you are benefiting from therapy. This would not apply for arm A 
participants receiving M7824 and temozolomide who already had their disease worsen on M7824 
alone. 
For the safety run-in portion of the study, participants will be enrolled into each combination group 
and will receive treatment at a pre-planned dose. Once each combination group enrolls at least 6 
participants, enrollment will be paused to assess the safety of the combinations. For each drug 
combination, if the dose given during the safety lead-in is considered safe, the remaining 
participants will receive the same dose. If too many side effects occur, remaining participants will 
receive a lower dose. If there are too many side effects at the reduced dose, then no more 
participants will be enrolled for that combination. 
There will be a second pause in enrollment after 10 participated have received each combination 
to find out whether the combinations are helping to shrink your tumor (an efficacy assessment). 
Enrollment will continue after this point only if the combination in question appears to have some 
effect on tumor size. It is possible that none, one or both of the combinations will move beyond 
the efficacy assessment. 
Research Studies
An important part of the research is to determine how your body and tumor respond to the 
combination of drugs. To understand this, we will collect your blood, tumor, and hair follicles at 
different time points. Biopsies will be optional. If you agree to have the biopsies, these will be 
performed before you start treatment and during cycle one day 15 or cycle two day 1 depending 
on the arm you are assigned to. You will be asked to sign a separate consent for the biopsy at the 
time of the procedure. 
IRB NUMBER: 18C0110
IRB EFFECTIVE DATE: 1/29/2024


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You may receive conscious sedation before undergoing a biopsy. Conscious sedation is usually 
given to help someone relax and minimize discomfort. It can be given as a pill, a shot, an IV 
(intravenous catheter, a small plastic tube that is put into a vein, usually in your arm) or even 
inhaled. You may have to wait up to an hour to start feel the effects depending on how it is given. 
Once it takes effect, you will be mostly awake, though relaxed or drowsy. You will be monitored 
throughout the procedure.
We will be using the biopsies and blood samples to look at the genes (pieces of DNA) that are 
present in tumor cells and in blood cells. We will be using the hair follicles to look for any damage 
in your DNA that might lead to inflammation which might cause cancer. This information may 
help us understand why some patients respond to certain treatments better than the others. In the 
course of examining your DNA, it is possible that we could identify possible changes in genes that 
are not the target of our investigation, but which are associated with diseases. These are called 
incidental or secondary findings. 
Some of your samples may be tested in a laboratory that is certified to perform genetic testing. If 
this happens, we will offer to share the results for these tests. Some of the analyses will be 
performed in our laboratory and are for research purposes only; they are not nearly as sensitive as 
the tests that are performed in a laboratory that is certified to perform genetic testing. Changes that 
we observe unrelated to our research may or may not be valid. Therefore, we do not plan to inform 
you of the results of testing on your specimens that is performed in our research lab. However, in 
the unlikely event that we discover a finding that is believed to be clinically important based on 
medical standards at the time we first analyze your results, we will contact you. This could be 
many years in the future. We will ask you to provide a sample to verify the findings we have seen 
in our lab. If the results are verified, you will be re-contacted and referred to a genetic healthcare 
provider to discuss the results.
Please see the section discussing the risks that you might experience other than the drug side effects 
for the implications of receiving genetic information.
We will also collect your blood in order to see how quickly study medications are processed in 
your blood. These are called pharmacokinetic studies. These studies may require hospitalization. 
The timelines of when we will collect blood for pharmacokinetic studies are shown below and in 
the study chart.
Arm A (M7824 only): We will collect blood samples before and after the infusion when you 
receive dose 1 as well as 24 hours after the infusion; before and after dose 3; and before the infusion 
when you receive doses 2 and 6 of M7824 and at the end of treatment. 
Arm B (M7824 and topotecan): If you are assigned to this arm, we will also sample your blood on 
day 1 of the first cycle to test the levels of topotecan. Blood will be collected before the 
chemotherapy infusion and periodically (6 -7 times) after the chemotherapy infusion for up to 24 
hours. Additional blood collection will be done 3 days and 5 days after the infusion as well. 
Arm C (M7824 and temozolomide): If you are assigned to this arm, we will also sample your 
blood on day 1 of the first cycle to test the levels of temozolomide. Blood will be collected before 
the chemotherapy infusion and periodically (6 - 7 times) after the chemotherapy infusion for up to 
24 hours. 
IRB NUMBER: 18C0110
IRB EFFECTIVE DATE: 1/29/2024


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
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When you are finished taking the drugs (treatment)
In the case that you have to stop receiving treatment, you will have a clinic visit approximately 4 
weeks after you discontinue taking the study drugs, in which the health care provider will perform 
a physical exam and blood will be drawn. 
STUDY CHART
Day
What to do and what will happen to you
Before 
starting
The research team’s health care provider will go over your medical history 
and will perform a physical exam.
Laboratory tests will be performed to measure organ functions (up to 2 
tablespoons).
An electrocardiogram and CT scan will be performed. A PET scan may be 
added if the CT scan is not sufficient.
Blood test to measure troponin (an enzyme produced by a heart when its 
damaged) levels will be performed. About a teaspoon of blood may be 
collected.
Blood test for certain viruses will be performed. About a tablespoon of blood 
may be collected.
We will perform a neurological examination to measure the strength of your 
muscles. 
You will have a pregnancy test if you are a woman who can become 
pregnant. If tested by blood, about a teaspoon may be collected.
Cycle 1
Day 1
The research team’s health care provider will perform a physical exam.
1, 5 Laboratory tests will be performed to measure organ functions (up to 2 
tablespoons).
Blood samples will be collected for research purposes (about 3 and a half 
tablespoons).
2 Blood will be collected to measure levels of drug (pharmacokinetics - about 
a tablespoon of blood at each timepoint).
Hair follicles will be collected for research purposes.
We will perform a neurological examination to measure the strength of your 
muscles. 
You will receive M7824 alone or in combination with topotecan or 
temozolomide.
IRB NUMBER: 18C0110
IRB EFFECTIVE DATE: 1/29/2024


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An optional tumor biopsy will be performed.
Day 2 
(24 hours after 
infusion)
Blood will be collected to measure levels of drug (pharmacokinetics - about 
a tablespoon of blood).
Hair follicles will be collected for research purposes.
Day 3 
(48 hours after 
infusion)
Blood will be collected to measure levels of drug (pharmacokinetics – about 
a tablespoon of blood) if you are receiving M7824 in combination with 
topotecan.
Day 5 
(96 hours after 
infusion)
Blood will be collected to measure levels of drug (pharmacokinetics - about 
half a tablespoon of blood) if you are receiving M7824 in combination with 
topotecan.
Day 15 3
(Arm C only)
The research team’s health care provider will perform a physical exam.
Laboratory tests will be performed to measure organ function (up to 2 
tablespoons).
Blood samples will be collected for research purposes (about 3 tablespoons).
2 Blood will be collected to measure levels of drug (pharmacokinetics – 
about a tablespoon of blood).
You will receive M7824.
An optional tumor biopsy will be performed.
You will have a pregnancy test if you are a woman who can become 
pregnant. If tested by blood, about a teaspoon may be collected.
You will receive M7824.
Cycle 2 
Day 1
The research team’s health care provider will perform a physical exam.
Laboratory tests will be performed to measure organ functions (up to 2 
tablespoons).
Blood samples will be collected for research purposes (about 3 tablespoons).
2, 4 Blood will be collected to measure levels of drug (pharmacokinetics - about 
a tablespoon of blood).
Hair follicles will be collected for research purposes (arms A and B).
We will perform a neurological examination to measure the strength of your 
muscles. 
You will receive M7824 with or without topotecan or temozolomide 
depending on your treatment assignment.
IRB NUMBER: 18C0110
IRB EFFECTIVE DATE: 1/29/2024


PATIENT IDENTIFICATION
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NIH-2977 (4-17)
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CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
An optional tumor biopsy will be performed if you are in the group to receive 
M7824 alone or in combination with topotecan.
You will have a pregnancy test if you are a woman who can become pregnant.
Day 15 3
(Arm C)
The research team’s health care provider will perform a physical exam.
Laboratory tests will be performed to measure organ functions (up to 2 
tablespoons).
Hair follicles will be collected for research purposes.
You will have a pregnancy test if you are a woman who can become 
pregnant. If tested by blood, about a teaspoon may be collected.
You will receive M7824.
Cycle 3 and beyond
Day 1
The research team’s health care provider will perform a physical exam.
Laboratory tests will be performed to measure organ functions (up to 2 
tablespoons).
CT scan will be performed either every 6 weeks or 8 weeks until disease 
progression depending on the arm you are enrolled in. A PET scan may be 
added if the CT scan is not sufficient.
Blood samples will be collected for research purposes (about 3 tablespoons).
We will perform a neurological examination to measure the strength of your 
muscles. 
You will receive M7824 with or without topotecan or temozolomide 
depending on your treatment assignment.
You will have a pregnancy test if you are a woman who can become 
pregnant. If tested by blood, about a teaspoon may be collected.
Day 15 3
(Arm C)
The research team’s health care provider will perform a physical exam.
Laboratory tests will be performed to measure organ functions (up to 2 
tablespoons).
You will have a pregnancy test if you are a woman who can become 
pregnant. If tested by blood, about a teaspoon may be collected.
You will receive M7824.
Off Treatment
The research team’s health care provider will perform a physical exam.
IRB NUMBER: 18C0110
IRB EFFECTIVE DATE: 1/29/2024


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Laboratory tests will be performed to measure organ functions (up to 2 
tablespoons).
CT scan will be performed either every 6 weeks or 8 weeks until disease 
progression depending on the arm you are enrolled in. A PET scan may be 
added if the CT scan is not sufficient.
2 Blood samples will be collected for research purposes (about 3 tablespoons).
We will perform a neurological examination to measure the strength of your 
muscles. 
1 Some of the tests may not need to be repeated again if they were performed close to the start of 
your treatment. 
2 You will have to be admitted to a hospital overnight on this day in order to collect blood for 
pharmacokinetic studies (if performed on that day).
3 This visit will take place only if you are in a group to receive M7824 with temozolomide (Arm 
C).
4 Blood for pharmacokinetic studies will be collected for the last time at the time you will receive 
the sixth dose of M7824 which will fall on cycle 3 day 15, if you are in Arm C, or cycle 6 day 1 if 
you are in Arm A or Arm B. 
5 If you are enrolled on the combination treatment of M7824 and temozolomide, you will have 
additional laboratory tests to measure organ functions on days 7 and 21. Since these are not the 
days you would come in for treatment, these labs can be performed by your local doctor and results 
faxed to us. Note: At each study visit, you will be able to report any side effects that you have 
experienced to the research team. You will also need to bring the completed pill diary.
BIRTH CONTROL
If you are able to become pregnant, we will ask you to have a pregnancy test before starting this 
study. You must use effective birth control methods and try not to become pregnant during study 
treatment, and for 6 months after you finish study treatment. If you become pregnant, there may 
be unknown risks to the fetus or unborn child, or risks that we did not anticipate. There may be 
long-term effects of the treatment being studied that could increase the risk of harm to a fetus. You 
must tell the study doctor if your birth control method fails while you are in the study. If you think 
or know you have become pregnant while participating in this research study, please contact the 
study team as soon as possible. If you plan to become pregnant in the future, please discuss with 
the study team how long you need to wait before becoming pregnant after completing the study.
If you are a sexually active person with a partner able to become pregnant, it is important that your 
partner not become pregnant during study treatment, and for 3 months after you finish study 
treatment. There may be unknown risks to a fetus or risks we did not anticipate. You and your 
partner must agree to use birth control if you want to take part in this study. You should not donate 
sperm for the duration of the study and for 3 months after your last dose of study drug. If you think 
your partner has become pregnant during your participation in this study, please contact the study 
team as soon as possible. If you and your partner plan for your partner to become pregnant after 
your participation in this study, please discuss this with the study team.
IRB NUMBER: 18C0110
IRB EFFECTIVE DATE: 1/29/2024


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RISKS OR DISCOMFORTS OF PARTICIPATION
From M7824 
Common side effects (occurring in more than 5% of patients)

Fatigue (tiredness and lack of energy) 

Nausea 

Diarrhea

Constipation

Vomiting

Swelling of your lower legs or hands

Fever

Decreased appetite

Loss of body fluids (dehydration)

Skin growths called keratoacanthomas that resemble skin cancer. These usually go away 
after treatment and can leave a scar.

Rash, blisters, skin discoloration and other skin abnormalities

Bleeding has been frequently observed in patients receiving M7824. Patients may 
experience bleeding in different organs such as gums, nose, ears, eyes, vagina, breast, blood 
in the urine, stool, or bleeding in the internal organs or skull, coughing up or vomiting 
blood. Occasionally, this bleeding can be serious and potentially life threatening and 
require you to receive a blood transfusion. If you experience any bleeding on this trial, 
please tell the study team immediately. Tell your doctor if you have had a life-long problem 
of frequent or excessive bleeding or bruising, or if you take aspirin or prescription 
medication to thin your blood.

Shortness of breath

Cough

Anemia - low number of red blood cells that can cause tiredness and shortness of breath. 
May require a transfusion.

Abdominal pain

Headache

Itching
Occasional side effects (occurring in less than 5% of patients)

Chills (feeling cold)

Blood clots that form throughout the body, blocking small blood vessels. Symptoms may 
include chest pain, shortness of breath, leg pain, problems speaking, or problems moving 
parts of the body

Easy bruising

Reaction to other drugs such as rash, anaphylaxis, and changes in blood

Infusion-related reaction, including dizziness or fainting (low blood pressure), flushing, 
rash, fever, shortness of breath or sick to your stomach, or pain at the site of infusion. 
Although usually reversible with treatment, it can be severe or life threatening.

Back pain

Cancerous growth on the skin that can be removed
IRB NUMBER: 18C0110
IRB EFFECTIVE DATE: 1/29/2024


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
Stroke

Slow wound healing

Thickening of the skin, nails
In addition to the above, we have seen a few cases of nodular regenerative hyperplasia. This is 
when small growths, or nodules, occur in the liver. These usually do not cause symptoms, but can 
occasionally be associated with high blood pressure in the vein to the liver which could over time 
lead to liver damage.
Allergic reactions or reactions in the context with the infusions might occur during study treatment. 
Although M7824 is a fully human protein the risk cannot be completely excluded. In general, these 
reactions are mild to moderate and can be handled with appropriate drugs, but in very rare cases 
severe to life-threatening and even fatal reactions might occur, which require advanced cardiac life 
support. 
In addition, immune-related side effects are possible. These side effects are caused by overactivity 
of your body’s immune system. The immune system normally works to protect you from things 
that are harmful such as infections, foreign substances, and sometimes from cancer. If the immune 
system is overactive, it can attack normal parts of the body because it mistakenly recognizes them 
as foreign/harmful.
Examples of these side effects are listed below. In rare cases, immune-related side effects can be 
life-threatening or fatal.
Types of immune-related side effects

Inflammation in the lungs (pneumonitis): symptoms may include but are not limited to a 
new or worsening cough, shortness of breath possibly with fever. Preliminary data 
suggested that there may be the tendency of higher frequency and severity in Japanese 
patients compared with non-Japanese patients: tell your study doctor right away if you have 
any of these symptoms as it may need to be treated urgently

Hypothyroidism (decreased function of the thyroid gland)

Hyperthyroidism (increased function of thyroid gland)

Thyroiditis (inflammatory disease of the thyroid gland)

You may develop inflammation of the liver called hepatitis. Signs and symptoms of this 
include yellowing of the skin or whites of the eyes, dark urine, severe nausea and vomiting, 
pain in the upper right side of your abdomen, skin itchiness, not feeling hungry and 
bleeding or bruising more easily than normal

Thrombocytopenia (decrease of the blood platelets)

Uveitis (inflammation in the eyes) 

Diabetes mellitus (high blood sugar levels)

Problems with your adrenal glands (Adrenal Insufficiency): may cause stomach pains, 
vomiting, muscle weakness and fatigue, depression, low blood pressure, weight loss, 
kidney problems, and changes in mood and personality. These complications may be 
permanent and may require hormone replacement

Myositis (inflammation of the muscles characterized by pain and tenderness)
IRB NUMBER: 18C0110
IRB EFFECTIVE DATE: 1/29/2024


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
Inflammation of the intestine (colitis). It may cause abdominal pain and diarrhea with or 
without blood. Fever may be present. It may require you to receive additional fluids. If left 
untreated, in rare occasions this may lead to a tear in the wall of the intestine which can be 
serious and life threatening

Autoimmune encephalitis is a type of brain inflammation where the body's immune system 
attacks healthy cells and tissues in the brain or spinal cord

Myocarditis (inflammation of the heart muscle)

Pemphigoid (fluid-filled blisters that can be itchy)

Kidney problems: you may have an increase of creatinine levels in a blood test (creatinine 
is a protein marker that measures kidney function) but not have any symptoms or feel 
unwell. Uncommonly a patient may experience nephritis which is an inflammation of the 
kidneys that stops the kidneys from working properly

Problems with the pituitary gland (hypopituitarism): Hypopituitarism refers to decreased 
output of hormones from the pituitary gland in the brain and may be caused by 
inflammation of the pituitary gland (hypophysitis). Symptoms may include headaches, 
thirstiness, and trouble seeing or double vision, leakage of breast milk or irregular periods 
in women. These complications may be permanent and may require hormone replacement

Pancreatitis (inflammation of the pancreas)

Liver problems: Increases in the blood level of substances called enzymes found within 
your liver cells. The enzyme changes are unlikely to make you feel unwell, however, if 
these blood enzyme levels become very high, your study doctor may need to stop the study 
medication

Nervous system problems: symptoms can include unusual weakness of legs, arms, or face, 
numbness, or tingling in hands or feet. In rare situations, there is the potential for the 
inflammation of the nervous system to be severe. 

Abnormal contraction of the intestinal muscles which can lead to severe constipation, 
nausea or vomiting. You may also experience loss of appetite and weight loss.
Embryofetal toxicity
Based on how the study drug works, there is also a risk of embryofetal toxicity (risks to your 
unborn baby). Therefore, every effort should be made not to become pregnant or father a child 
while on treatment and for 120 days following the end of treatment.
From Topotecan
Likely, some may be serious (experienced by more than 20% of persons taking the drug)

Anemia which may require a blood transfusion

Low white blood cell counts

Constipation, diarrhea, nausea, vomiting

Fever

Pain

Bruising, bleeding

Infection, especially when white blood cell count is low

Tiredness

Shortness of breath
IRB NUMBER: 18C0110
IRB EFFECTIVE DATE: 1/29/2024


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Less likely, some may be serious (experienced by between 3 and up to 20% of persons taking 
the drug)

Sores in mouth which may cause difficulty swallowing

Headache

Cough

Scarring of the lungs
Rare but Serious (experienced by 3% of fewer of persons taking the drug)

Allergic reaction which may cause rash, low blood pressure, wheezing, shortness of 
breath, swelling of the face or throat

Low white blood cell counts which may result in life-threatening infections
Note: Some of the side effects associated with these drugs could potentially lead to death.
From Temozolomide
Most common (seen in 20 or more out of 100 people taking temozolomide):

Fatigue

Swelling

Fever

Dizziness

Hair loss

Rash

Nausea or vomiting

Constipation or diarrhea

Loss of appetite

Muscle weakness, paralysis, or difficulty walking

Trouble with memory

Difficulty sleeping 
Less Likely (seen in 4-20 out of 100 people taking temozolomide):

Headache

Seizure

Infection, especially when white blood cell count is low

Depression

Anxiety

Mouth sores

Weight gain

Cough

Blurry vision

Shortness of breath

Anemia (low red blood cell count) which may cause tiredness

Thrombocytopenia (low platelet count)

Bruising and/or bleeding
IRB NUMBER: 18C0110
IRB EFFECTIVE DATE: 1/29/2024


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
Damage to the bone marrow (which is not reversible) and may cause infection, bleeding, 
or require blood transfusions
Rare but Serious (seen in 3 or fewer out of 100 people taking temozolomide)

Severe rash, including skin rash with blisters; can involve inside of the mouth and other 
parts of the body

Allergic reaction which may cause rash, low blood pressure, wheezing, shortness of breath, 
and/or swelling of the face or throat

Cancer of bone marrow caused by chemotherapy

Interstitial lung disease (lung injury) which can cause respiratory failure

Numbness or tingling of fingers or toes

Liver damage which may cause yellowing of eyes and skin, swelling, and may result in 
liver failure.

Abnormal contraction of the intestinal muscles which can lead to severe constipation, 
nausea or vomiting. You may also experience loss of appetite and weight loss.

A new cancer including leukemia resulting from treatment. 

Damage to the lungs caused by an infection from fungus.
 Risks you might experience other than the drug side effects 
Radiation
During your participation in this research study, you will be exposed to radiation from up to 10 
CT scans, up to 10 PET scans and 2 CT guided biopsies. The amount of radiation exposure you 
will receive from these procedures is equal to approximately 21.6 rem. A rem is a unit of absorbed 
radiation. 
Every day, people are exposed to low levels of radiation that come from the sun and the 
environment around them. The average person in the United States receives a radiation exposure 
of 0.3 rem per year from these sources. This type of radiation is called “background radiation.” 
This study will expose you to more radiation than you get from everyday background radiation. 
No one knows for sure whether exposure to these low amounts of radiation is harmful to your 
body. 
The CT and PET scans that you get in this study will expose you to roughly the same amount of 
radiation as 72 years’ worth of background radiation. Being exposed to too much radiation can 
cause harmful side effects such as an increase in the risk of cancer. The risk depends on how much 
radiation you are exposed to. Please be aware that about 40 out of 100 people (40%) will get cancer 
during their lifetime, and 20 out of 100 (20%) will die from cancer. The risk of getting cancer from 
the radiation exposure in this study is 2.2 out of 100 (2.2%) and of getting a fatal cancer is 1.1 out 
of 100 (1.1%).
You may not participate in this study if you are pregnant. If you are able to become pregnant, we 
will perform a pregnancy test before exposing you to radiation. You must tell us if you may have 
become pregnant within the previous 14 days because the pregnancy test is unreliable during that 
time.
IRB NUMBER: 18C0110
IRB EFFECTIVE DATE: 1/29/2024


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 01/11/2024
Page 15 of 21
CC ICF template v. 09.27.19
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
CT contrast risks
Itching, hives or headaches are possible risks associated with contrast agents that may be used 
during CT imaging. Symptoms of a more serious allergic reaction include shortness of breath and 
swelling of the throat or other parts of the body. Very rarely, the contrast agents used in CT can 
cause kidney problems for certain participants, such as those with impaired kidney function.
Blood Draws
Risks associated with blood draw, which include pain and bruising, lightheadedness, and rarely, 
fainting
Hair Follicle Collection
The risk associated with hair follicle collection is pain.
Risks from Biopsy 
This procedure usually causes only brief discomfort at the site from which the biopsy is taken. 
Risks of biopsy may include bleeding, injury to internal organs, and infection. Rarely, these 
complications from biopsy could result in hospitalization and require additional medical care. 
Risks of sedation will be described at the time of procedure.
There is a possibility that conscious sedation may be used for the procedure. The common side 
effects of conscious sedation include drowsiness, delayed reflexes, hypotension, headache, and 
nausea. These are generally mild and last no more than a few hours.
Privacy Risks Associated with Genetic Testing
It may be possible that genetic information from you could be used by law enforcement 
agencies or other entities to identify you or your blood relatives
Psychological or Social Risks Associated with Return of Incidental or Secondary Findings
As part of the research study, it is possible that you could learn that you have genetic risks for 
another disease or disability. This may be upsetting and, depending on what you learn, might 
create a need to make challenging decisions about how to respond. 
Although your genomic information is unique to you, you share some genomic similarities with 
your children, parents, brothers, sisters, and other blood relatives. Therefore, learning your 
research results could mean something about your family members and might cause you or your 
family distress. Before joining the study, it may be beneficial to talk with your family members 
about whether and how they want you to share your results with them.
Protections against misuse of genetic information 
This study involves genetic testing on samples. Some genetic information can help predict future 
health problems of you and your family and this information might be of interest to your 
employers or insurers. The Genetic Information Nondiscrimination Act (GINA) is a federal law 
that prohibits plans and health insurers from requesting genetic information or using genetic 
information. It also prohibits employment discrimination based on your health information. 
However, GINA does not address discrimination by companies that sell life insurance, disability 
IRB NUMBER: 18C0110
IRB EFFECTIVE DATE: 1/29/2024


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 01/11/2024
Page 16 of 21
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MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
insurance, or long-term care insurance. GINA also does not protect you against discrimination 
based on an already-diagnosed condition or disease that has a genetic component.
POTENTIAL BENEFITS OF PARTICIPATION
Are there benefits to taking part in this study?
The aim of this study is to see if this experimental treatment will cause your tumors to shrink. We 
do not know if you will receive personal, medical benefit from taking part in this study. These 
potential benefits could include shrinking of your tumor or lessening of your symptoms, such as 
pain, that are caused by the cancer. Because there is not much information about the drug’s effect 
on your cancer, we do not know if you will benefit from taking part in this study, although the 
knowledge gained from this study may help others in the future who have cancer. 
ALTERNATIVE APPROACHES OR TREATMENTS
WHAT OTHER CHOICES DO I HAVE IF I DO NOT TAKE PART IN THIS STUDY? 
Instead of being in this study, you have these options:

Getting treatment or care for your cancer without being in a study

Taking part in another study

Getting comfort care, also called palliative care. This type of care helps reduce pain, tiredness, 
appetite problems and other problems caused by the cancer. It does not treat the cancer directly. 
Instead, it tries to improve how you feel. Comfort care tries to keep you as active and 
comfortable as possible.
Please talk to your doctor about these and other options.
STOPPING THERAPY 
Your doctor may decide to stop your therapy for the following reasons:

if he/she believes that it is in your best interest

if your disease comes back during treatment

if you have side effects from the treatment that your doctor thinks are too severe

if new information shows that another treatment would be better for you
In this case, you will be informed of the reason therapy is being stopped.
You can stop taking part in the study at any time. However, if you decide to stop taking part in the 
study, we would like you to talk to the study doctor and your regular doctor first.
CONFLICT OF INTEREST 
The National Institutes of Health (NIH) reviews NIH staff researchers at least yearly for conflicts 
of interest. This process is detailed in a COI Guide. You may ask your research team for a copy of 
the COI Guide or for more information. Members of the research team who do not work for NIH 
are expected to follow these guidelines but they do not need to report their personal finances to the 
NIH.
IRB NUMBER: 18C0110
IRB EFFECTIVE DATE: 1/29/2024


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 01/11/2024
Page 17 of 21
CC ICF template v. 09.27.19
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
The National Institutes of Health and the research team for this study are using a drug (M7824) 
developed by EMD Serono through a joint study with your researchers and the company. The 
company also provides financial support for this study.
USE OF SPECIMENS AND DATA FOR FUTURE RESEARCH
To advance science, it is helpful for researchers to share information they get from studying human 
samples. They do this by putting it into one or more scientific databases, where it is stored along 
with information from other studies. A researcher who wants to study the information must apply 
to the database and be approved. Researchers use specimens and data stored in scientific databases 
to advance science and learn about health and disease. 
We plan to keep some of your specimens and data that we collect and use them for future research 
and share them with other researchers. We will not contact you to ask about each of these future 
uses. These specimens and data will be stripped of identifiers such as name, address or account 
number, so that they may be used for future research on any topic and shared broadly for research 
purposes. Your specimens and data will be used for research purposes only and will not benefit 
you. It is also possible that the stored specimens and data may never be used. Results of research 
done on your specimens and data will not be available to you or your doctor. It might help people 
who have cancer and other diseases in the future. 
If you do not want your stored specimens and data used for future research, please contact us in 
writing and let us know that you do not want us to use your specimens and/or data. Then any 
specimens that have not already been used or shared will be destroyed and your data will not be 
used for future research. However, it may not be possible to withdraw or delete materials or data 
once they have been shared with other researchers.
Genomic Data Sharing
As part of this research study, we will put your genomic data in a large database for broad sharing 
with the research community. These databases are commonly called data repositories. The 
information in this database will include but is not limited to genetic information, race and 
ethnicity, and sex. If your individual data are placed in one of these repositories, they will be 
labeled with a code and not with your name or other information that could be used to easily 
identify you, and only qualified researchers will be able to access them. These researchers must 
receive prior approval from individuals or committees with authority to determine whether these 
researchers can access the data.
Summary information about all of the participants included in this study (including you) is being 
placed in a database and will be available through open access. That means that researchers and 
non-researchers will be able to access summary information about all the participants included in 
the study, or summary information combined from multiple studies, without applying for 
permission. The risk of anyone identifying you with this information is very low.
NIH policies require that genomic data be placed in a repository for sharing. Therefore, we cannot 
offer you a choice of whether your data will be shared. If you do not wish to have your data placed 
in a repository, you should not enroll in this study.
IRB NUMBER: 18C0110
IRB EFFECTIVE DATE: 1/29/2024


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 01/11/2024
Page 18 of 21
CC ICF template v. 09.27.19
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
COMPENSATION, REIMBURSEMENT, AND PAYMENT
Will you receive compensation for participation in the study?
Some NIH Clinical Center studies offer compensation for participation in research. The amount of 
compensation, if any, is guided by NIH policies and guidelines.
You will not receive compensation for participation in this study. 
Will you receive reimbursement or direct payment by NIH as part of your participation?
Some NIH Clinical Center studies offer reimbursement or payment for travel, lodging or meals 
while participating in the research. The amount, if any, is guided by NIH policies and guidelines.
On this study, the NCI will cover the cost for some of your expenses. Some of these costs may be 
paid directly by the NIH and some may be reimbursed after you have paid. Someone will work 
with you to provide more information.
Will taking part in this research study cost you anything? 
NIH does not bill health insurance companies or participants for any research or related clinical 
care that you receive at the NIH Clinical Center. 

If some tests and procedures are performed outside the NIH Clinical Center, you may have 
to pay for these costs if they are not covered by your insurance company.

Medicines that are not part of the study treatment will not be provided or paid for by the 
NIH Clinical Center.

Once you have completed taking part in the study, medical care will no longer be provided 
by the NIH Clinical Center.
CLINICAL TRIAL REGISTRATION AND RESULTS REPORTING
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required 
by U.S. Law. This Web site will not include information that can identify you. At most, the Web 
site will include a summary of the results. You can search this Web site at any time.
CONFIDENTIALITY PROTECTIONS PROVIDED IN THIS STUDY 
Will your medical information be kept private? 
We will do our best to make sure that the personal information in your medical record will be kept 
private. However, we cannot guarantee total privacy. Organizations that may look at and/or copy 
your medical records for research, quality assurance, and data analysis include:

The NIH and other government agencies, like the Food and Drug Administration (FDA), 
which are involved in keeping research safe for people.

National Institutes of Health Intramural Institutional Review Board

Center for Cancer Research, NCI or their agent(s)

Qualified representatives from EMD Serono, the pharmaceutical company that produces 
M7824.
The researchers conducting this study and the NIH follow applicable laws and policies to keep 
your identifying information private to the extent possible. However, there is always a chance that, 
IRB NUMBER: 18C0110
IRB EFFECTIVE DATE: 1/29/2024


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 01/11/2024
Page 19 of 21
CC ICF template v. 09.27.19
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
despite our best efforts, your identity and/or information about your participation in this research 
may be inadvertently released or improperly accessed by unauthorized persons.
In most cases, the NIH will not release any identifiable information collected about you without 
your written permission. However, your information may be shared as described in the section of 
this document on sharing of specimens and data, and as further outlined in the following sections. 
Further, the information collected for this study is protected by NIH under a Certificate of 
Confidentiality and the Privacy Act. 
Certificate of Confidentiality
To help us protect your privacy, the NIH Intramural Program has received a Certificate of 
Confidentiality (Certificate). With this certificate, researchers may not release or use data or 
information about you except in certain circumstances. 
NIH researchers must not share information that may identify you in any federal, state, or local 
civil, criminal, administrative, legislative, or other proceedings, for example, if requested by a 
court. 
The Certificate does not protect your information when it: 
1. is disclosed to people connected with the research, for example, information may be used 
for auditing or program evaluation internally by the NIH; or 
2. is required to be disclosed by Federal, State, or local laws, for example, when information 
must be disclosed to meet the legal requirements of the federal Food and Drug 
Administration (FDA); 
3. is for other research;
4. is disclosed with your consent. 
The Certificate does not prevent you from voluntarily releasing information about yourself or your 
involvement in this research. 
The Certificate will not be used to prevent disclosure to state or local authorities of harm to self or 
others including, for example, child abuse and neglect, and by signing below you consent to those 
disclosures. Other permissions for release may be made by signing NIH forms, such as the Notice 
and Acknowledgement of Information Practices consent.
Privacy Act
The Federal Privacy Act generally protects the confidentiality of your NIH medical records we 
collect under the authority of the Public Health Service Act. In some cases, the Privacy Act 
protections differ from the Certificate of Confidentiality. For example, sometimes the Privacy Act 
allows release of information from your medical record without your permission, for example, if 
it is requested by Congress. Information may also be released for certain research purposes with 
due consideration and protection, to those engaged by the agency for research purposes, to certain 
federal and state agencies, for HIV partner notification, for infectious disease or abuse or neglect 
reporting, to tumor registries, for quality assessment and medical audits, or when the NIH is 
involved in a lawsuit. However, NIH will only release information from your medical record if it 
is permitted by both the Certificate of Confidentiality and the Privacy Act.
IRB NUMBER: 18C0110
IRB EFFECTIVE DATE: 1/29/2024


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 01/11/2024
Page 20 of 21
CC ICF template v. 09.27.19
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
POLICY REGARDING RESEARCH-RELATED INJURIES 
The NIH Clinical Center will provide short-term medical care for any injury resulting from your 
participation in research here. In general, no long-term medical care or financial compensation for 
research-related injuries will be provided by the NIH, the NIH Clinical Center, or the Federal 
Government. However, you have the right to pursue legal remedy if you believe that your injury 
justifies such action.
PROBLEMS OR QUESTIONS
If you have any problems or questions about this study, or about your rights as a research 
participant, or about any research-related injury, contact the Principal Investigator, Anish Thomas, 
M.D., anish.thomas@nih.gov, Telephone: 240-760-7343. You may also call the NIH Clinical 
Center Patient Representative at 301-496-2626, or the NIH Office of IRB Operations at 301-402-
3713, if you have a research-related complaint or concern.
CONSENT DOCUMENT 
Please keep a copy of this document in case you want to read it again.
IRB NUMBER: 18C0110
IRB EFFECTIVE DATE: 1/29/2024


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 01/11/2024
Page 21 of 21
CC ICF template v. 09.27.19
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
Adult Research Participant: I have read the explanation about this study and have been given the opportunity 
to discuss it and to ask questions. I consent to participate in this study.
Signature of Research Participant
Print Name of Research Participant
Date
Legally Authorized Representative (LAR) for an Adult Unable to Consent: I have read the explanation 
about this study and have been given the opportunity to discuss it and to ask questions. I am legally authorized 
to make research decisions on behalf of the adult participant unable to consent and have the authority to 
provide consent to this study. As applicable, the information in the above consent was described to the adult 
participant unable to consent who agrees to participate in the study.
Signature of LAR
Print Name of LAR
Date
Investigator:
Signature of Investigator
Print Name of Investigator
Date
Witness should sign below if either:
1. A short form consent process has been used to enroll a non-English speaking subject or
2. An oral presentation of the full consent has been used to enroll a blind or illiterate subject
Signature of Witness
Print Name of Witness
Date
NIH ADMINISTRATIVE SECTION TO BE COMPLETED REGARDING THE USE OF AN 
INTERPRETER:
An interpreter, or other individual, who speaks English and the participant’s preferred language facilitated
the administration of informed consent and served as a witness. The investigator obtaining consent may not 
also serve as the witness.
An interpreter, or other individual, who speaks English and the participant’s preferred language facilitated
the administration of informed consent but did not serve as a witness. The name or ID code of the person 
providing interpretive support is:
.
IRB NUMBER: 18C0110
IRB EFFECTIVE DATE: 1/29/2024