Clinical trial NCT04501094
Conditions: Urothelial Cancer
Keywords: TGF-Beta Immune Therapy PD-L1 Immunocytokine
Sponsor: National Cancer Institute (NCI)
Start date: 2020-10-26; Completion date: 2021-10-13
Enrollment: 2 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Background:

Metastatic urothelial carcinoma is lethal and has no cure. Response rates to current treatments are modest. Researchers want to find new strategies to treat the disease. In this study, they will test a drug called Bintrafusp alfa (M7824). The drug is a new immunotherapy that blocks the pathways that cancer cells use to stop the immune system from fighting cancer.

Objective:

To learn if M7824 can help the immune system's ability to fight urothelial cancer.

Eligibility:

People age 18 and older who have urothelial cancer that has spread to other parts of their body and they have been previously treated with chemotherapy or immunotherapy

Design:

Participants will be screened with a medical history and physical exam. They will have blood and urine tests. They will have imaging scans. They will have an electrocardiogram to measure heart function. Their ability to perform their normal activities will be evaluated. They may have a tumor biopsy. They will take a pregnancy test if needed.

Participants will repeat some of the screening tests during the study.

Treatment will be given in a series of 28-day cycles. Participants will get M7824 once every 2 weeks. It is given through an intravenous infusion. For this, a small plastic tube is put into an arm vein. They will get M7824 until their disease gets worse, they have unacceptable side effects, or they decide to stop treatment.

Participants will have a follow-up visit 30 days after treatment ends. Then they will be followed every 12 weeks in the clinic or by telephone/email. Follow-up will last indefinitely.

Detailed description:
Background:

* Metastatic urothelial carcinoma is lethal and incurable with a median overall survival of 14 months from diagnosis.
* Immune checkpoint inhibitors targeting the Programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1) pathway have greatly changed clinical management of metastatic urothelial carcinoma (mUC) improving survival by 3 months in the second-line setting.
* Five PD-1/PD-L1 inhibitors are Food and Drug Administration (FDA)-approved for for second-line metastatic urothelial carcinoma (mUC), two agents for first-line cisplatin-ineligible mUC. However, response rates are modest, ranging from15-20% in the second-line and 24% in the first-line cisplatin-ineligible.
* Therefore, novel strategies are needed to extend benefit of immunotherapy to the remaining approximately 75% of non-responders.
* Higher levels of transforming growth factor-beta (TGF-beta) are associated with immune escape, therapy resistance and poor outcomes in advanced malignancies. Non-responders to anti-PD-1/PD-L1 antibodies have also been found to have increased TGF-beta in the tumor microenvironment.
* Bintrafusp alfa (M7824) is a novel first-in-class bifunctional fusion protein composed of a monoclonal antibody against PD-L1 fused to the extracellular domain of human TGF-beta receptor II (TGFbetaRII), which effectively functions to sequester or "trap" all three TGF-beta isoforms. A phase I study of M7824 (NCT02517398) demonstrated a manageable safety profile and clinical efficacy among patients with heavily pre-treated advanced solid tumors.
* We hypothesize that M7824 is safe and improves outcomes in patients with checkpoint naive or refractory urothelial carcinoma.

Objectives:

-To evaluate the activity of M7824 as determined by objective response rate (ORR) in two metastatic urothelial carcinoma cohorts:

* Cohort 1: Checkpoint inhibitor naive

  * Cohort 1A: cisplatin ineligible
  * Cohort 1B: refractory post-platinum therapy
* Cohort 2: Checkpoint inhibitor previously treated patients

  * Cohort 2A: previously achieved a Complete Response (CR)/Partial Response (PR)
  * Cohort 2B: previously had Stable Disease (SD)/Progressive Disease (PD)

Eligibility:

* Patients must have a histologically confirmed diagnosis of metastatic urothelial cancer.
* Patients may have been previously treated with prior cytotoxic chemotherapy regimen or targeted agent. Patients may have received any number of prior cytotoxic agents.
* 18 years of age or older

Design:

* This is an open label, non-randomized, single arm phase II trial of M7824 in checkpoint inhibitor naive and previously treated patients with urothelial carcinoma of the bladder.
* M7824 (intravenous 1200 mg fixed dose) will be delivered every 2 weeks
* Patients will receive treatment in cycles consisting of 4 weeks.
* A maximum of 75 subjects will be enrolled in this trial.

Arms: arm 1: Treatment with Bintrafusp alfa (M7824)
Interventions: intervention 1: Bintrafusp alfa (M7824)
Intervention descriptions: intervention 1: 1200 mg administered intravenous (IV) every two weeks

Protocol documents:
Prot_SAP_000.pdf: 
1
Abbreviated Title: Phase II M7824 in UC
Version Date: 06/23/2021
Abbreviated Title: Phase II M7824 in UC
NIH Protocol #: 20C0142 
Version Date: 06/23/2021
NCT Number: NCT04501094
Title: A Phase II Study of Bintrafusp alfa (M7824) in Checkpoint Inhibitor Naïve and Refractory 
Subjects with Urothelial Carcinoma
NCI Principal Investigator:
Andrea B. Apolo, M.D.
Genitourinary Malignancies Branch (GMB)
Center for Cancer Research
National Cancer Institute
Building 10, Room 13N240
Bethesda, MD 20892
Ph: 301-480-0536
Email: andrea.apolo@nih.gov
Investigational Agents:    
Drug Name:
Bintrafusp alfa (M7824)
IND Number:
149968
Sponsor:
Center for Cancer Research 
(CCR), NCI, NIH
Manufacturer:
EMD Serono
Supplier
EMD Serono
Commercial Agents: None   
 


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Abbreviated Title: Phase II M7824 in UC
Version Date: 06/23/2021
PRÉCIS 
Background:

Metastatic urothelial carcinoma is lethal and incurable with a median overall survival of 
14 months from diagnosis.

Immune checkpoint inhibitors targeting the PD-1/PD-L1 pathway have greatly changed 
clinical management of metastatic urothelial carcinoma (mUC) improving survival by 3 
months in the second-line setting.

Five PD-1/PD-L1 inhibitors are FDA-approved for for second-line mUC, two agents for 
first-line cisplatin-ineligible mUC. However, response rates are modest, ranging from15–
20% in the second-line and 24% in the first-line cisplatin-ineligible. 

Therefore, novel strategies are needed to extend benefit of immunotherapy to the remaining 
~75% of non-responders. 

Higher levels of transforming growth factor-beta (TGF-β) are associated with immune 
escape, therapy resistance and poor outcomes in advanced malignancies. Non-responders 
to anti-PD-1/PD-L1 antibodies have also been found to have increased TGF-β in the tumor 
microenvironment.

Bintrafusp alfa (M7824) is a novel first-in-class bifunctional fusion protein composed of a 
monoclonal antibody against PD-L1 fused to the extracellular domain of human TGF-β 
receptor II (TGFβRII), which effectively functions to sequester or “trap” all three TGF-β 
isoforms. A phase I study of M7824 (NCT02517398) demonstrated a manageable safety 
profile and clinical efficacy among patients with heavily pre-treated advanced solid tumors.

We hypothesize that M7824 is safe and improves outcomes in patients with checkpoint 
naïve or refractory urothelial carcinoma.
Objectives:

To evaluate the activity of M7824 as determined by objective response rate (ORR) in two 
metastatic urothelial carcinoma cohorts: 
o
Cohort 1: Checkpoint inhibitor naïve

Cohort 1A: cisplatin ineligible

Cohort 1B: refractory post-platinum therapy
o
Cohort 2: Checkpoint inhibitor previously treated patients

Cohort 2A: previously achieved a CR/PR 

Cohort 2B: previously had SD/PD
Eligibility:

Patients must have a histologically confirmed diagnosis of metastatic urothelial cancer.

Patients may have been previously treated with prior cytotoxic chemotherapy regimen or 
targeted agent. Patients may have received any number of prior cytotoxic agents. 

18 years of age or older


3
Abbreviated Title: Phase II M7824 in UC
Version Date: 06/23/2021
Design:

This is an open label, non-randomized, single arm phase II trial of M7824 in checkpoint 
inhibitor naïve and previously treated patients with urothelial carcinoma of the bladder.

M7824 (intravenous 1200 mg fixed dose) will be delivered every 2 weeks 

Patients will receive treatment in cycles consisting of 4 weeks.

A maximum of 75 subjects will be enrolled in this trial.


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Abbreviated Title: Phase II M7824 in UC
Version Date: 06/23/2021
TABLE OF CONTENTS 
PRÉCIS............................................................................................................................................2
TABLE OF CONTENTS ................................................................................................................4
STATEMENT OF COMPLIANCE ................................................................................................7
1
INTRODUCTION ...................................................................................................................7
1.1
Study Objectives ...............................................................................................................7
1.2
Background .......................................................................................................................8
2
ELIGIBILITY ASSESSMENT AND ENROLLMENT .......................................................14
2.1
Eligibility Criteria ...........................................................................................................14
2.2
Screening Evaluation ......................................................................................................18
2.3
Participant Registration and Status Update Procedures..................................................19
2.4
Baseline Evaluation.........................................................................................................20
3
STUDY IMPLEMENTATION .............................................................................................20
3.1
Study Design...................................................................................................................20
3.2
Drug Administration .......................................................................................................22
3.3
Dose Modifications.........................................................................................................22
3.4
Study Calendar................................................................................................................33
3.5
Cost and Compensation ..................................................................................................33
3.6
Criteria for Removal from Protocol Therapy and Off Study Criteria.............................34
4
CONCOMITANT MEDICATIONS/MEASURES...............................................................35
4.1
Permitted Medicines .......................................................................................................35
4.2
Prohibited Medicines ......................................................................................................35
5
Correlative Studies for Research ...........................................................................................35
5.1
Biospecimen Collection ..................................................................................................35
5.2
Sample collection schedule.............................................................................................46
5.3
Sample Storage, Tracking and Disposition.....................................................................48
5.4
Samples for Genetic/Genomic Analysis .........................................................................50
6
DATA COLLECTION AND EVALUATION .....................................................................51
6.1
Data Collection ...............................................................................................................51
6.2
Data Sharing Plans..........................................................................................................53
6.3
Response Criteria ............................................................................................................53
6.4
Toxicity Criteria..............................................................................................................59


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Abbreviated Title: Phase II M7824 in UC
Version Date: 06/23/2021
7
NIH REPORTING REQUIREMENTS/DATA AND SAFETY MONITORING PLAN.....59
7.1
Definitions.......................................................................................................................59
7.2
OHSRP Office of Compliance and Training / IRB Reporting........................................59
7.3
NCI Clinical Director Reporting.....................................................................................59
7.4
NIH Required Data and Safety Monitoring Plan............................................................60
8
SPONSOR PROTOCOL/SAFETY REPORTING................................................................60
8.1
Definitions.......................................................................................................................60
8.2
Assessment of Safety Events ..........................................................................................61
8.3
Reporting of Serious Adverse Events .............................................................................62
8.4
Waiver of expedited reporting to CCR ...........................................................................62
8.5
Safety Reporting Criteria to the Pharmaceutical Collaborators......................................62
8.6
Reporting Pregnancy.......................................................................................................63
8.7
Regulatory Reporting for Studies Conducted Under CCR-Sponsored IND...................63
8.8
Sponsor Protocol Non-Adherence Reporting .................................................................63
9
Clinical Monitoring ...............................................................................................................64
10
STATISTICAL CONSIDERATIONS ..................................................................................64
10.1
Statistical Hypothesis......................................................................................................64
10.2
Sample Size Determination.............................................................................................65
10.3
Populations for Analyses ................................................................................................66
10.4
Statistical Analyses .........................................................................................................67
11
COLLABORATIVE AGREEMENTS..................................................................................68
11.1
CRADA...........................................................................................................................68
12
HUMAN SUBJECTS PROTECTIONS................................................................................68
12.1
Rationale For Subject Selection......................................................................................68
12.2
Participation of Children.................................................................................................68
12.3
Participation of Subjects Unable to Give Consent..........................................................68
12.4
Evaluation of Benefits and Risks/Discomforts ...............................................................69
12.5
Risks/Benefits Assessment .............................................................................................69
12.6
Consent Process and Documentation..............................................................................71
13
REGULATORY AND OPERATIONAL CONSIDERATIONS..........................................72
13.1
Study Discontinuation and Closure.................................................................................72
13.2
Quality Assurance and Quality Control..........................................................................73


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Abbreviated Title: Phase II M7824 in UC
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13.3
Conflict of Interest Policy...............................................................................................73
13.4
Confidentiality and Privacy ............................................................................................73
14
PHARMACEUTICAL AND INVESTIGATIONAL DEVICE INFORMATION...............74
14.1
M7824 (Bintrafusp alfa, MSB0011359C) (IND # 149968)............................................74
15
REFERENCES ......................................................................................................................79
16
Appendices ............................................................................................................................84
16.1
Appendix A: Study Calendar ..........................................................................................84
16.2
Appendix B: Performance Status Criteria.......................................................................86


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Abbreviated Title: Phase II M7824 in UC
Version Date: 06/23/2021
STATEMENT OF COMPLIANCE
The trial will be carried out in accordance with International Conference on Harmonisation Good 
Clinical Practice (ICH GCP) and the following: 
United States (US) Code of Federal Regulations (CFR) applicable to clinical studies (45 
CFR Part 46, 21 CFR Part 50, 21 CFR Part 56, 21 CFR Part 312, and/or 21 CFR Part 812) 
National Institutes of Health (NIH)-funded investigators and clinical trial site staff who are 
responsible for the conduct, management, or oversight of NIH-funded clinical trials have 
completed Human Subjects Protection and ICH GCP Training.
The protocol, informed consent form(s), recruitment materials, and all participant materials will 
be submitted to the Institutional Review Board (IRB) for review and approval.  Approval of both 
the protocol and the consent form must be obtained before any participant is enrolled. Any 
amendment to the protocol will require review and approval by the IRB before the changes are 
implemented to the study. In addition, all changes to the consent form will be IRB-approved; an 
IRB determination will be made regarding whether a new consent needs to be obtained from 
participants who provided consent, using a previously approved consent form.
1
INTRODUCTION
1.1
STUDY OBJECTIVES
1.1.1
Primary Objective
To evaluate the activity of Bintrafusp alfa (M7824) as determined by objective response rate 
(ORR) in two metastatic urothelial carcinoma cohorts: 
o
Cohort 1: Checkpoint inhibitor naïve

Cohort 1A: cisplatin ineligible

Cohort 1B: refractory post-platinum therapy
o
Cohort 2: Checkpoint inhibitor previously treated patients

Cohort 2A: previously achieved a CR/PR 

Cohort 2B: previously had SD/PD
1.1.2
Secondary Objective(s)

To evaluate the activity of Bintrafusp alfa (M7824) in metastatic urothelial carcinoma 
patients as determined by progression free survival (PFS) and overall survival (OS).

To evaluate the safety of bintrafusp alfa (M7824) in metastatic urothelial carcinoma 
patients.
1.1.3
Exploratory Objective(s)
(1) Determine peripheral immune modulation using: 

Multi-parametric flow cytometry – immune subset analysis

Cytokine/chemokine analysis  (i.e TNF, IFN- IL-6, IL-8, etc.)

Blood-based immune parameters (neutrophil-to-lymphocyte ratio)

C-Met analysis

Circulating Tumor Cells (CTCs), and circulating cell-free tumor DNA (cfDNA) 


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Abbreviated Title: Phase II M7824 in UC
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(2) Determine immune status of the tumor microenvironment using:

Multiplex IHC for PD-L1 expression, CD8, CD4, FoxP3 T-cell infiltration

RNA-Seq transcriptome sequencing for tumor/immune gene expression profile 
(and peripheral blood mononuclear cells)

T-cell receptor (TCR) sequencing for T-cell clonality and MET protein levels

Next generation sequencing (TSO-500) for tumor biomarkers in tumor samples
(3) Determine the diagnostic accuracy of diffusion weighted whole body MRI in this 
patient population, compared to standard imaging
1.2
BACKGROUND 
1.2.1
Immunotherapy and Targeting the PD-1/PD-L1 axis in urothelial carcinoma
For decades, the standard-of-care for advanced urothelial carcinoma (UC) has almost exclusively 
revolved around cisplatin-based chemotherapy [1]. However, approximately 50% of patients are 
deemed cisplatin-ineligible and patients with adverse prognostic features derive marginal benefit 
from cisplatin-based chemotherapy [2-4]. Cisplatin-ineligible and platinum-refractory patients 
have limited options with an unclear impact on prolonging survival [5]. As such, less toxic and 
more efficacious therapies are needed. Immunotherapy in the form of Bacillus Calmette-Guérin 
(BCG), an attenuated strain of Mycobacterium bovis has been a long-standing pillar in the 
management of non-muscle invasive bladder cancer (NMIBC) and has provided some insights that 
immune-based approaches may be effective in more advanced and lethal forms of urothelial 
carcinoma [6].
The advent of immune checkpoint blockade has revolutionized cancer immunotherapy leading to 
an explosion of FDA approvals in UC. This class of agents disrupts immune-inhibitory molecular 
pathways, termed immune checkpoints, via blockade of ligand-receptor interactions thereby 
promoting T-cell activation and effector function [7]. At present, monoclonal antibodies targeting 
immune checkpoints, cytotoxic T-lymphocyte antigen-4 (CTLA-4), programmed cell death 
protein-1 (PD-1) or cognate ligand, programmed cell death-ligand 1 (PD-L1), are the only FDA-
approved immune checkpoint blocking agents. There are currently five PD-1/PD-L1 inhibitors 
approved for second-line advanced UC [8-13], two additional indications in the first-line setting 
[14, 15].
Despite altering the prognostic landscape for a subset of patients with limited and toxic treatment 
options, many patients fail to respond to upfront therapy with immune checkpoint blockade and 
additional subsets of patients ultimately develop acquired resistance to this approach. To 
underscore this point, objective response rates in the second-line UC setting range from 15-21% 
with modestly higher response rates in the upfront UC setting (23.5-24%). As shown by Keynote-
45 PD-1/PD-L1 check point blockade can have a durable response in metastatic urothelial patients. 
When compared to chemotherapy in the second line setting patients receiving pembrolizumab had 
an overall survival of 10.3 months (95% confidence interval [CI], 8.0 to 11.8) compared with 7.4 
months (95% CI, 6.1 to 8.3). Novel combination strategies are needed to extend the benefit of 
immunotherapy to the remaining 75-85% of non-responders with metastatic non-prostate 
genitourinary cancer [8]. This population represents a clear unmet clinical need as these patients 
continue to succumb to rapid and lethal progression of disease despite currently approved 
therapies.


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Abbreviated Title: Phase II M7824 in UC
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1.2.2
Rationale to Target Dual Immunosuppressive Pathways: PD-L1 and TGF-β blockade
Given that only a subset of patients (~20%) derive clinical benefit from anti-PD-1/PD-L1 immune 
checkpoint blockade, there is growing interest in combination approaches to improve outcomes. 
The concurrent targeting of additional immune suppressive pathways to enhance responses to anti-
PD-1/PD-L1 blockade is emerging as an attractive therapeutic strategy.
TGF-β is pleotropic cytokine with potent immunosuppressive activity within the tumor 
microenvironment (TME) in advanced cancer. 
Several recent preclinical reports have demonstrated that TGF-β signaling can directly and 
indirectly restrain effector T-cell function which promotes tumor immune evasion and therapeutic 
resistance to immunotherapy [16-18]. Poor response to anti-PDL-1 agent was associated with 
TGF- β signaling in fibroblasts, particularly in patients with CD8+ T cells that were excluded from 
the tumor parenchyma and instead found in the fibroblasts and collagen-rich peritumoral stroma, 
which is common in patients with metastatic UC [19]. Blockade of surface-bound TGF-β on 
regulatory T-cells (Tregs) has been shown to abrogate suppression of effector T-cell function 
within the TME [20]. Recent clinical investigation in metastatic urothelial cancer patients has 
demonstrated that TGF-β attenuates response to PD-L1 blockade (atezolizumab) via T-cell 
exclusion and reduced T-cell tumor infiltration. TGFBR2 gene expression was significantly 
associated with clinical non-response and with reduced overall survival (see Figure 1). 
Figure 1: TGF-β expression adversely correlates with clinical outcomes. TGFBR2 gene expression in 
urothelial carcinoma patients is significantly associated with non-response (P=0.0001) and reduced 


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Abbreviated Title: Phase II M7824 in UC
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overall survival when split by quartiles (P=0.022) [top panel]. EMT6 and MC38 murine models 
demonstrate tumor regression and TME changes following therapeutic anti-TGF-β and anti PD-L1 
treatment [middle and lower panel] [21]. 
Preclinical murine models demonstrated that stromal TGF-β signaling recapitulates an immune-
excluded phenotype common to anti-PD-L1 non-responders. Further, the combination of PD-L1 
blockade and TGF-β blockade facilitated T cell penetration into the center of the tumor, causing 
immune-mediated tumor regression and led to superior survival to either monotherapy in EMT6 
and MC38 tumor models (see Figure 1). Additional, preclinical studies modeling human 
microsatellite-stable colorectal cancers which traditionally are characterized by low mutational 
load and poor response rates to anti-PD-1/PD-L1 checkpoint blockade have demonstrated that 
TGF-β inhibition promotes effector T-cell driven anti-tumor immune response and renders tumors 
susceptible to anti-PD-1/PD-L1 immunotherapy [22]. Other groups have independently confirmed 
the correlation of high mRNA expression of TGF-β1-3 with adverse prognosis and with reduced 
disease-free survival. Taken together, TGF-β (stromal and non-stromal) signaling within the TME 
appears to be a dominant mechanism of immune evasion and therapeutic targeting of this 
immunosuppressive axis may enrich the proportion of patients responding to anti-PD-1/PD-L1 
immunotherapy and/or re-invigorate responses to PD-1/PD-L1 blockade. 
1.2.3
Preclinical Activity with M7284, a bifunctional molecule targeting PD-L1 and TGF-β 
Figure 2: M7824, a bifunctional fusion protein simultaneously targeting PD-L1 and TGF-β. M7824 
Structure (Left panel): Structure of M7824 composed of a fully human PD-L1 (IgG1) monoclonal antibody 
and TGF-β neutralizing trap moiety, fused to the CH3-C terminus of the FCγ1 domain of IgG via a flexible 
(Gl4-Ser)4 Gly linker. Simultaneous binding (Right Panel): 
M7824 (MSB0011359C) is a novel first-in-class bifunctional fusion protein composed of a 
monoclonal antibody against PD-L1 fused to the extracellular domain of human TGF-β receptor 
II (TGFβRII), which effectively functions to sequester or “trap” all three TGF-β isoforms [23]. 


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Abbreviated Title: Phase II M7824 in UC
Version Date: 06/23/2021
Preclinical studies have shown that M7824 can simultaneously bind PD-L1 and TGF-β in vitro 
(Figure 2) and this bifunctional immunomodulatory capacity has translated to enhanced anti-
tumor efficacy in vivo relative to blockade of either immune-inhibitory protein alone. Specifically, 
treatment with M7284 (IV 482µg) suppressed tumor growth, reduced lung metastases and 
prolonged survival in MC38 or EMT-6 tumor-bearing mice in comparison to treatment with 
isotype control, anti-PD-L1, Trap control and anti-PD-L1/Trap control.  Furthermore, treatment 
with M7824 led to the development of long-term anti-tumor immunity in mice initially cured by 
M7284 that were subsequently re-challenged with EMT-6 or MC38 tumors – 100% and 80% of 
mice rejected tumor and survived re-challenge, respectively [23]. Quantitative and 
immunophenotypic analysis has shown that M7824 treatment is associated with robust CD8+ TME 
infiltration and a pro-inflammatory immune signature consistent with active innate and adaptive 
immunity (Figure 3). M7824 has also demonstrated encouraging efficacy across an array of human 
urothelial carcinoma cell lines (UMUC-3, UMUC-5, HTB-4, HTB-1, HTB-2, HTB-9 and HTB-5) 
[24]. Mechanistically, M7284 enhanced immune recognition of human urothelial cells via 
immunogenic modulation, increases in chemokine expression associated with T-cell trafficking, 
upregulation of TRAIL and antigen-specific CD8+ T-cell mediated lysis.
Figure 3: M7824 promotes a distinct pro-immunogenic innate and adaptive immune cell signature in 
tumor-bearing mice. Representative anti-CD8a immunohistochemistry of treated EMT-6 tumors [right 
upper panels] and multi-parameter flow cytometric analysis of intratumoral immune subsets [left upper 
panels]. RNA-seq analysis of gene expression signatures associated with T -cell, NK cell, macrophages and 
dendritic cells tumor infiltrate and IFN-γ responses within intratumoral tissue [left lower panel] [23].
The NCI led the first-in-human phase I trial of M7824 (NCT02517398) which demonstrated a 
manageable safety profile and nascent yet encouraging evidence of clinical activity in cohort of 
patients with heavily pre-treated advanced solid tumors [25]. In this standard 3+3 design phase I 
dose-escalation study, patients with tissue-confirmed metastatic or locally advanced solid tumors 


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Abbreviated Title: Phase II M7824 in UC
Version Date: 06/23/2021
that were refractory to or ineligible for standard therapy (ineligible if previously treated with prior 
immune checkpoint blockade) were treated with infusional M7824 doses of 1mg/kg, 3mg/kg, 
10mg/kg and 20mg/kg once every two weeks (Q2W). A separate cohort of patients was initially 
treated with 0.3mg/kg to establish a pharmacokinetic/pharmacodynamic relationship followed by 
10mg/kg dosing thereafter. A total of 19 patients were enrolled with maximum tolerated dose 
(MTD) not reached at the highest dose level of 20mg/kg Q2W. A total of 9 patients (47.4%) 
experienced any grade adverse event (AE) and four patients (21.1%) experienced > grade 3 AE. 
Ultimately, three patients discontinued therapy due to treatment-related AEs (bullous pemphigoid, 
colitis, gastroparesis) leading the authors to conclude that M7824 had a manageable and acceptable 
toxicity/side effect profile across all evaluated dose levels. The side effect profile of M7824 is 
similar to other anti-PD-1/PD-L1 agents with the exception of increased incidence of 
keratocanthomas presumed to be related to TGF-β axis modulation which resolved following 
discontinuation of M7824 [26]. PK/PD studies demonstrated saturation of PD-L1 target occupancy 
and potent sequestration of all TGF-β isoforms at doses >1mg/kg. 
Clinical activity was observed across all M7824 dose levels (Figure 4). One durable complete 
response (CR), two durable/confirmed partial responses (PR), one near PR, and two patients with 
stabilization of disease were observed. A single patient with progression of disease ultimately 
achieved a 45% decline in tumor burden on day 280 restaging suggestive of a treatment response 
with delayed kinetics [25]. As MTD was not reached, ongoing dose-expansion cohorts are 
evaluating several dose schedules including 1200mg Q2W and 10mg/kg Q2W.


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Version Date: 06/23/2021
Figure 4: Largest change from baseline in the sum of longest diameter per RECIST v1.1 and clinical 
responses with M7824. Dotted line at 30% indicates threshold for PR and at +20% indicates threshold for 
PD [upper panel]. Pre-treatment and post- M7824 (day 183) CT imaging and CEA biomarker trend in a 
49-year-old patient with metastatic cervical cancer achieving a CR (per RECIST vl.l) [lower panels] 
A. This 49-year-old woman with metastatic cervical cancer after cisplatin/taxol followed by 
carboplatin/taxol plus bevacizumab was enrolled with two pathologically enlarging mediastinal lymph 
nodes (arrows in left side of figure). Restaging scan 7.5 months after enrollment showed reduction in lymph 
nodes to <1 cm by short-axis measurement, meeting RECIST v1.1 criteria for a CR. CR was durable as of 
her 13-month restaging scan (right side of figure). B. CEA curve for patient with ongoing durable confirmed 
CR. [25].
1.2.4
M7824 dose levels and toxicity 
In line with early clinical experience of similar anti-TGFβ agents, the toxicity profile of M7824 is 
predominantly manageable and highly comparable to that of checkpoint inhibitors. In the recently 
released results of the phase I study NCT02517398 (M7824) ‘Phase 1 Trial of M7824, a 
Bifunctional Fusion Protein Targeting PD-L1 and TGFβ, in Advanced Solid Tumors’ with dose 
escalation cohorts of 1, 3, 10, and 20mg/kg (exceeding the 1,200mg flat dose in this study), M7824 
was given every two weeks and the MTD was not reached. Data suggested overall good tolerance. 
One out of 16 patients developed a keratoacanthoma which could be related to the TGFβ inhibition 
mechanism of M7824 [25]. There was no grade 4-5 TEAEs. The only dose-limiting toxicity (DLT) 


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observed was colitis. The highest dose for M7824 tested in EMR200647-001 was 30 mg/kg once 
every 2 weeks and the maximum tolerated dose was not reached. Three participants in 
EMR200647-001 dose escalation cohorts received the actual dose of at least 2400 mg q2w: 2 in 
30 mg/kg cohort and 1 in 20 mg/kg. All 3 participants who received ≥ 2400 mg q2w had no DLTs. 
The overall safety profile of M7824 in Phase I was considered well tolerated, can be adequately 
managed and consistent across various tumor types. Refer to Investigator’s Brochure for more 
details.
1.2.5
Hypothesis and Summary
Although PD-1/PD-L1 immune check-point inhibitors can lead to a durable response in advanced 
urothelial cancer patients, only a subset ranging from 15-20% have a clinical “response.” Therefor 
enhancing PD-1/PD-L1 blockage to increase the responder rates is a logical strategy. Higher levels 
of transforming growth factor (TGF-β) are associated with immune escape, therapy resistance, and 
poor outcomes in advanced malignancies[27, 28]. Non-responders to anti-PD-L1 antibodies have 
been found to have increased TGF-β in the tumor microenvironment as well. [23, 29] Thus, TGF-β 
plays an important role in immune resistance to checkpoint inhibitors and other therapies. 
M7824 is a bifunctional fusion protein composed of the extracellular domain of two TGF-β 
sequestering or trap molecule fused to a fully humanized monoclonal antibody against PD-L1 [30]. 
M7824 simultaneous blocks the PD-1 and TGF-β pathways of immune evasion which effects both 
the innate and adaptive immune systems. Preclinical studies show that M7824 enables immune-
cell infiltration and can overcome resistance seen with other antibodies targeting the PD-1/PD-L1 
interaction through phenotypic modifications[23, 31]. Early data from phase 1 trials demonstrated 
that M7824 has an acceptable safety profile and higher responses than expected in heavily 
pretreated patients with immunologically “cold” tumors [25, 31]. M7824-induced combined PD-
L1 inhibition and TGF-β sequestration has the potential to overcome immune escape thereby 
increasing anti-tumor activity. This could potentially increase clinical response rates compared to 
standard PD-1/PD-L1 checkpoint blockage. There is currently no standard therapy for advanced 
urothelial cancer patients who have received prior PD-1/PD-L1 therapy that allows for challenging 
with a subsequent immunotherapy therapy. These patients are left with 2nd/3rd line chemotherapy 
such as taxanes and pemetrexed which have low response rates. Thus, M7824 could represent a 
potential treatment option for these patients. We hypothesize that M7824 is safe and improves 
outcomes in urothelial carcinoma of the bladder patients who are checkpoint naïve or refractory.
2
ELIGIBILITY ASSESSMENT AND ENROLLMENT 
2.1
ELIGIBILITY CRITERIA
2.1.1
Inclusion Criteria
2.1.1.1
Ability to understand the purpose of the study, provide signed and dated informed 
consent, and able to comply with all procedures.
2.1.1.2
Male or female patients aged ≥ 18 years of age at time of consent.
2.1.1.3
Patients with histologically confirmed diagnosis of  urothelial carcinoma of the urinary 
tract, including the renal pelvis, ureter, bladder, or urethra. Differentiation with variant 


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Abbreviated Title: Phase II M7824 in UC
Version Date: 06/23/2021
histologies (e.g. squamous cell differentiated) will be permitted. Mixed histologies are 
required to have a dominant urothelial/transitional cell pattern. 
2.1.1.4
Patients must have metastatic disease defined as new or progressive lesions on cross-
sectional imaging. Radiological evaluation should occur within 21 days prior to 
enrollment.
2.1.1.5
Patient must have evaluable and measurable disease, per RECIST 1.1. See Section 6.3 
for the evaluation of measurable disease.
2.1.1.6
Patients may have been previously treated with prior cytotoxic chemotherapy regimen or 
targeted agent. Patients may have received any number of prior cytotoxic agents. 
2.1.1.7
Patients may have had prior immunomodulating therapy including therapy targeting the 
PD-1/PDL-1 axis (cohort 2A and B) but excluding prior treatment with M7824.
2.1.1.8
Pre-treatment tissue biopsy and/or archival tissue availability for PD-L1 expression 
testing is mandatory for enrollment. 
2.1.1.9
Eastern Cooperative Oncology Group (ECOG) performance status ≤2(see Section 16.2)
2.1.1.10 Required laboratory values reflective of organ function are listed below:

Absolute neutrophil count ≥ 1500/µL

Platelets ≥ 100,000/µL

Hemoglobin ≥ 9 g/dL (erythrocyte tranfusions are allowed to achieve acceptable Hgb)

AST(SGOT)/ALT(SGPT) ≤ 1.5 × institutional upper limit of normal (ULN) with the 
following exception: 
o
Patients with liver involvement who have AST and ALT ≤ 5 × ULN may be 
enrolled.

Total bilirubin within normal limits with the following exceptions:
o
Patients with known Gilbert disease who have serum bilirubin level ≤ 3 ULN may 
be enrolled.
o
Patients with tumor liver involvement bilirubin with ≤ 3.0 × ULN.

INR and aPTT ≤ 1.5 × ULN
o
This applies only to patients who are not receiving therapeutic anticoagulation; 
patients receiving therapeutic anticoagulation (such as low-molecular-weight 
heparin or warfarin) should be on a stable dose.

Creatinine clearance (CrCl) ≥ 30 mL/min/1.73 m2 (GFR may be used in place of CrCl. 
Creatinine clearance or eGFR should be calculated per institutional standard)
2.1.1.11 The effects of M7824 on the developing human fetus are unknown.  For this reason, 
women of child-bearing potential and men must agree to use strict and effective 
contraception (hormonal or barrier method of birth control; abstinence) during treatment 


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Abbreviated Title: Phase II M7824 in UC
Version Date: 06/23/2021
and for at least 65 days for women and 125 days for men, after the last dose of M7824 
administration.  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. 
2.1.1.12 Human immunodeficiency virus (HIV) positive patients are eligible if on stable dose of 
highly active antiretroviral therapy (HAART), CD4 counts are greater than 350 cells/mm3 
and viral load is undetectable.
2.1.1.13 Patients with previously treated brain or central nervous system (CNS) metastases are 
eligible provided that the subjects have recovered from any acute effects of radiotherapy 
and is not requiring steroids, and any whole brain radiation therapy or any stereotactic 
radiosurgery was completed at least 2 weeks prior to M7824 administration.
2.1.1.14 Hepatitis B virus (HBV) positive patients are eligible-they must have been treated and on 
a stable dose of antivirals (eg, entecavir, tenofovir, or lamivudine; adefovir or interferon 
are not allowed) at study entry and with planned monitoring and management according 
to appropriate labeling guidance. 
2.1.1.15 Hepatitis C virus (HCV) positive patients are eligible if participants are on active HCV 
therapy at study entry and on a stable dose without documented clinically significant 
impaired liver function test or hematologic abnormalities and with planned monitoring 
and management according to appropriate labeling guidance. 
2.1.2
Cohort 1A Cisplatin Ineligible Specific Inclusion Criteria (first-line for metastatic 
cisplatin-ineligible)

No prior chemotherapy for inoperable locally advanced or metastatic or recurrent UC
o
For patients who received prior adjuvant/neoadjuvant chemotherapy or 
chemoradiation for UC, a treatment-free interval > 12 months between the last 
treatment administration and the date of recurrence is required in order to be 
considered treatment naive in the metastatic setting. Prior local intravesical 
chemotherapy or immunotherapy is allowed if completed at least 4 weeks prior to 
the initiation of study treatment.

Ineligible (“unfit”) for chemotherapy or cisplatin-based chemotherapy as defined by any 
one of the following criteria [32]:
o
Impaired renal function (CrCl > 30 but < 60 mL/min); GFR should be calculated 
per institutional standard.
o
A hearing loss (measured by audiometry) of 25 dB at two contiguous frequencies
o
Grade ≥ 2 peripheral neuropathy (i.e., sensory alteration or paresthesias including 
tingling)
o
ECOG performance score of 2
o
Patient declines chemotherapy after informed discussion with the study doctor


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Abbreviated Title: Phase II M7824 in UC
Version Date: 06/23/2021
2.1.3
Cohort 1B Refractory Post-platinum Therapy Specific Inclusion Criteria (second-line for 
metastatic disease)

Disease progression during or following treatment with a platinum-containing regimen for 
inoperable locally advanced or metastatic urothelial carcinoma or disease recurrence. 
Examples of regimens include cisplatin + gemcitabine (GC), methotrexate + vinblastine 
sulfate + doxorubicin + cisplatin (MVAC), and carboplatin + gemcitabine (CarboGem).
o
Patients who received prior adjuvant/neoadjuvant chemotherapy and progressed 
within 12 months of treatment with a platinum-containing adjuvant/neoadjuvant 
regimen will be considered as second-line patients.
2.1.4
Cohort 2A Checkpoint Inhibitor Previously Treated Patients that Previously Achieved a 
Complete Response (CR) or Partial Respsonse (PR) Specific Inclusion Criteria

Patients must have been treated with at least one treatment of a PD-1/PD-L1 checkpoint 
inhibitor for advance or metastatic UC and achieved a complete response or partial 
respsonse by RECIST 1.1 criteria.
2.1.5
Cohort 2B Checkpoint inhibitor previously treated patients that previously had stable 
disease (SD) or progressive disease (PD) 
2.1.6
Specific Inclusion Criteria

Patients must have been treated with at least one treatment of a PD-1/PD-L1 checkpoint 
inhibitor for advance or metastatic UC and had stable disease or a progressive disease by 
RECIST 1.1 criteria.
2.1.7
Exclusion Criteria
2.1.7.1
History of allergic reactions attributed to compounds of similar chemical or biologic 
composition to M7824 investigational agents used in the study.
2.1.7.2
Uncontrolled intercurrent illness including, but not limited to, symptomatic congestive 
heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social 
situations that would limit compliance with study requirements.
2.1.7.3
Symptomatic central nervous system metastasis.
2.1.7.4
Subjects unwilling to accept blood products as medically indicated
2.1.7.5
Pregnant women are excluded from this study because M7824 is an agent with the 
potential for teratogenic or abortifacient effects. Because there is an unknown but 
potential risk for adverse events in nursing infants secondary to treatment of the mother 
with M7824, breastfeeding should be discontinued if the mother is treated with these 
agents.  
2.1.7.6
Patients with any active or recent history of a known or suspected autoimmune disease 
(with the exception of diabetes type I, vitiligo, psoriasis, or hypo- or hyperthyroid diseases 
not requiring immunosuppressive treatment) or recent history of a syndrome that required 
treatment with either systemic corticosteroids (>10 mg daily prednisone equivalent) or 


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Abbreviated Title: Phase II M7824 in UC
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immunosuppressive medications. Inhaled steroids and adrenal replacement steroid doses 
up to 10 mg daily prednisone equivalents are permitted in the absence of active 
autoimmune disease.
2.1.7.7
Patients with a “currently active” second malignancy other than non-melanoma skin 
cancers or cervical carcinoma in situ or incidental organ-confined prostate cancer found 
on cystoprostatectomy (provided that the following criteria are met: Stage T2N0M0 or 
lower; Gleason score ≤ 3+4, PSA undetectable). Patients are not considered to have a 
“currently active” malignancy if they have completed therapy and are free of disease for 
≥ 2 years and currently do not require systemic therapy.
2.1.7.8
Patients who have received or will receive a live vaccine 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.
2.1.7.9
Patients having tumor lesion(s) in the liver or chest which are 10 cm or larger.
2.1.7.10 Patients previously treated with M7824.
2.1.7.11 Patients previously treated with PD-1/PD-L1 checkpoint inhibitors (for Cohorts 1A and 
1B only)
2.1.8
Recruitment Strategies
Both men and women and members of all races and ethnic groups are eligible for this trial. This 
protocol may be abstracted into a plain language announcement posted on NIH websites and on 
NIH social media. This study will be listed on www.clinicaltrials.gov and participants will be 
recruited from the current patient population as well as referrals at NIH.
2.2
SCREENING EVALUATION
2.2.1
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.
2.2.2
Screening activities performed after a consent for screening has been signed
Screening evaluation testing/procedures are conducted under the separate screening protocol, 01-
C-0129 (Eligibility Screening and Tissue Procurement for the NIH Intramural Research Program 
Clinical Protocols). Assessments performed at outside facilities or on another NIH protocol within 
the timeframes below may also be used to determine eligibility once a patient has signed the 
consent. 


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Abbreviated Title: Phase II M7824 in UC
Version Date: 06/23/2021
All screening tests and procedures must be performed within 21 days prior to initiation of study 
therapy except physical exam with skin assessment, ECOG, vital signs, blood tests and preganacy 
test (repeated if >7 days):

Complete medical history and physical examination (including height, weight, vital 
signs, and ECOG performance status) and skin assessment.

Electrocardiogram (ECG)

CT scan of chest, abdomen and pelvis with IV and PO (as indicated) contrast, or CT 
chest and MRI abdomen/pelvis may be performed, and [18F]-Sodium Fluoride (NaF) 
PET/CT bone scan (if indicated). 

Laboratory assessments: CBC with differential, acute care panel (sodium, potassium, 
chloride, total CO2 (Bicarbonate), creatinine, glucose, urea nitrogen), mineral panel 
(albumin, calcium total, magnesium total, phosphorus), hepatic panel (alkaline 
phosphatase, ALT/GPT, AST/GOT, total bilirubin, direct bilirubin), ionized calcium, 
amylase, lipase, LDH, total protein, GGT, Hepatitis B and C, PT/INR, PTT, urine 
analysis. 

Hepatitis B and C antibody panel 

Thyroid function tests – TSH, reflex T3 and T4 

Pre-treatment tissue biopsy and/or archival tissue availability for PD-L1 expression 
retrospective testing is mandatory for enrollment. PD-L1 will be performed 
retrospectively by EMD Serono using a test determined by EMD Serono.

Pregnancy test for females of childbearing-potential (within 3 days prior to first dose 
of study drug).

Lymphocyte Phenotyping - CD4/CD8 will be performed on known HIV-positive 
patients. 
2.3
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 here. 
2.3.1
Treatment Assignment Procedures
Cohorts
Patients will be assigned to the appropriate cohort depending on prior checkpoint inhibitor therapy 
and documented or reviewed radiologic responses to prior checkpoint inhibitor therapy. Whenever 
possible prior scans will be loaded to our PACS and reviewed for chort 2A and 2B.
Subjects from all cohorts will be treated with a flat dose of M7824 (1200 mg) every 2 weeks (+/- 
3 days for scheduling issues).


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Abbreviated Title: Phase II M7824 in UC
Version Date: 06/23/2021
Number
Name
Description
1
Cohort 1A
Checkpoint inhibitor naïve patients who are cisplatin-
ineligible
2
Cohort 1B
Checkpoint inhibitor naïve patients who are refractory 
post-platinum therapy
3
Cohort 2A
Checkpoint inhibitor refractory patients with prior 
Complete Response (CR) or Partial Response (PR) as 
per RECIST 1.1 as best response
4
Cohort 2B
Checkpoint inhibitor refractory patients with Stable 
Disease (SD) or Progressive Disease (PD) as per 
RECIST 1.1 as best response
Arms
Number
Name
Description
1
Arm 1
Treatment with fixed dose of M7824 (1200 
mg) every 2 weeks
Arm assignment
Subjects from all cohorts (1A, 1B, 2A and 2B) will be directly assigned to Arm 1.
2.4
BASELINE EVALUATION
Tests done at screening do not need to be repeated on baseline (C1D1) if performed within 21 days 
prior to initiation of study therapy except physical exam, ECOG, vital signs, blood tests (CBC with 
differential, acute care, mineral and hepatic panels, amylase, lipase, LDH, GGT, thyroid function 
tests) and pregnancy test (repeated if >7 days). Please refer to Section 2.2 for details.
Correlative Studies: Please refer to Section 5.2 for information regarding collection of blood, and 
tissue for correlative research studies.
3
STUDY IMPLEMENTATION
3.1
STUDY DESIGN

This is an open label, non-randomized, single arm phase II trial of M7824 in checkpoint 
inhibitor naïve and refractory patients with urothelial carcinoma.

We will plan to use a fixed dose of 1200 mg delivered IV every 2 weeks (Q2W) based on 
the recent NCI-led phase I dose-escalation trial of M7824 in advanced solid tumors 
(NCT02517398) [33]. M7284 appeared to have a manageable safety profile and early 
evidence of clinically efficacy. The MTD was not reached in this study at 20mg/kg and 


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Abbreviated Title: Phase II M7824 in UC
Version Date: 06/23/2021
PD-L1 receptor occupancy and sequestration of TGF-β isoforms 1-3 was achieved at 
M7284 dose levels >1mg/kg.

A maximum of 68 evaluable subjects will be enrolled in checkpoint naïve [Cohort 1] and 
checkpoint inhibitor refractory [Cohort 2] patients with urothelial carcinoma of the bladder. 
o
Cohort 1A: Checkpoint inhibitor naïve patients who are cisplatin-ineligible
o
Cohort 1B: Checkpoint inhibitor naïve patients who are refractory post-
platinum therapy
o
Cohort 2A: Checkpoint inhibitor refractory patients with Complete Response 
(CR) or Partial Response (PR) as per RECIST 1.1 
o
Cohort 2B: Checkpoint inhibitor refractory patients with Stable Disease (SD) 
or Progressive Disease (PD) as per RECIST 1.1 

Enrollment of 2-3 patients per month is expected on this trial; thus, 2 to 3 years is 
anticipated as the accrual period.

Restaging will be performed every 2 cycles (8 weeks). Safety/tolerability analysis and 
secondary clinical efficacy analysis will be ongoing through cycle 4. Patients can continue 
study drug in all arms provided there is no confirmed evidence of progression, 
unacceptable toxicity or withdrawal from the study.
3.1.1
Schema
1L - First line; 2L - Second line; CR - complete response; PR - partial response; SD - stable disease; PD - progressive 
disease
Treatment Schema of M7824: 28-day cycle (D1/D15)
If appropriate screening imaging is done within 21 days of C1D1 repeat screening imaging is not 
required.


22
Abbreviated Title: Phase II M7824 in UC
Version Date: 06/23/2021
Cycles and Day
C1D1
C1D15
C2D1
C2D15
C3D1
C3D15
C4D1
C4D15
M7824 (1200mg IV 
Q2W)
X
X
X
X
X
X
X
X
3.2
DRUG ADMINISTRATION
3.2.1
M7824
See Section 14.1 for drug preparation, administration and infusion times.
3.3
DOSE MODIFICATIONS
3.3.1
M7824
M7824 is planned to be administered at 1200 mg (flat dose) every two weeks. Dosing may be 
delayed up to 12 weeks for toxicity or logistical reasons, including the inability of the patient to 
get to the clinic. Dose reductions are not allowed.
3.3.1.1
Premedications
Current experience revealed that infusion-related reactions (IRRs) to bintrafusp alfa occur 
seldomly and are generally mild to moderate in severity. Therefore, administration of a 
premedication is generally not required.
If an Investigator deems necessary to administer a premedication to a particular participant, an 
antihistamine (e.g. 25 to 50 mg diphenhydramine) and paracetamol (acetaminophen, 500 to 650 
mg intravenously or equivalent oral dose) 30 to 60 minutes prior to bintrafusp alfa infusion is 
recommended. Premedication should be administered for subsequent bintrafusp alfa doses based 
upon clinical judgment and presence/severity of prior infusion reactions. This regimen may be 
modified based on local treatment standards and guidelines as appropriate, provided it does not 
include systemic corticosteroids. If Grade ≥ 2 infusion reactions are seen during the first two 
infusions, premedication should not be stopped. Steroids as premedication are not permitted.
3.3.1.2
Adverse Drug Reactions (ADRs) Requiring Treatment Discontinuation 
Any Grade 4 ADRs require permanent treatment discontinuation except for single laboratory 
values out of normal range that do not have any clinical correlate, and resolve to Grade ≤ 1 or 
baseline grade within 7 days with adequate medical management. Grade 3 or 4 symptomatic 
endocrinopathies (e.g., thyroiditis or hypophysitis), treatment should be delayed and treatment 
started according to NCCN guidelines. If condition improves to Grade 1, treatment may be 
resumed. 
Subjects with grade 4 amylase or lipase abnormalities must permanently discontinue treatment. 
If the participant develops any evidence of pancreatitis, it should be managed accordingly.


23
Abbreviated Title: Phase II M7824 in UC
Version Date: 06/23/2021
Any Grade 3 ADRs require treatment discontinuation except for any of the following: 
Transient (≤ 6 hours) Grade 3 flu-like symptoms or fever, which is controlled with medical 
management.
Transient (≤ 24 hours) Grade 3 fatigue, local reactions, headache, nausea, emesis that resolves 
to ≤ Grade 1 or Baseline grade. 
Tumor flare phenomenon defined as local pain, irritation, or rash localized at sites of known or 
suspected tumor that resolves within 7 days with optimal medical management.
Any single Grade ≥ 3 drug-related transaminase, alkaline phosphatase, or bilirubin abnormality 
with no other associated laboratory (or other) abnormality that is not associated with symptoms 
or clinical manifestations of hepatitis. If the liver function abnormality not associated with 
symptoms or clinical manifestations of hepatitis has not resolved to Grade ≤ 1 within the 
subsequent 2 cycles (28 days), the subject should permanently discontinue treatment with 
M7824. 
Subjects with asymptomatic Grade 3 drug-related amylase or lipase abnormalities may continue 
treatment.
. 
Grade 3 Hgb decrease (< 8.0 g/dL) that is clinically manageable with blood transfusions or 
erythroid growth factor use. 
Increases in Eastern Cooperative Oncology Group performance status (ECOG PS) ≥ 3 that 
resolves to  2 by Day 1 of the next cycle (infusions should not be given if the ECOG PS is ≥ 3 
on the day of M7824 administration and should be delayed until ECOG PS ≤ 2).
Keratoacanthoma and squamous cell carcinoma of the skin. Any suspicious skin lesion should 
be biopsied for confirmation of diagnosis and be surgically removed as indicated by 
dermatologist and a dermatological consult obtained. 
Other immune-related ADRs, see NCCN guidelines for the management of immune related 
adverse events
3.3.1.3
Adverse Drug Reactions Requiring Management
Any Grade 2 ADR should be managed as follows:
If a Grade 2 ADR resolves to Grade ≤ 1 by the last day of the current cycle, treatment may 
continue.
If a Grade 2 ADR does not resolve to Grade ≤ 1 by the last day of the current cycle but it is 
manageable and / or not clinically relevant, it is possible the infusion will be given on the 
following cycle.
3.3.1.4
Infusion-related Reactions (IRR) 
Signs and symptoms usually develop during or shortly after drug infusion and generally resolve 
completely within 24 hours of completion of infusion. These possible IRR are identified based on 
a list of MedDRA PTs and divided into reactions versus signs and symptoms.


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Abbreviated Title: Phase II M7824 in UC
Version Date: 06/23/2021
An IRR should be considered when onset is on the day of infusion (during or after the infusion) 
or the day after the infusion (irrespective of resolution date) for any infusion related reaction, 
drug hypersensitivity, anaphylactic reaction, hypersensitivity and/or Type 1 hypersensitivity.
Signs and symptoms of infusion related reactions and hypersensitivity/allergic reactions should 
be considered when onset is on the day of infusion (during or after the infusion) and resolved 
completely with the end date within 2 days after onset. Signs and symptoms may include but 
not limited to: fever, chills or shaking, rigors, flushing, hypotension, wheezing, pruritus, rash 
and hypoxemia, shortness of breath, back or neck pain, facial swelling, dizziness, feeling of 
passing out.
Infusion-related reactions and hypersensitivity reactions (Grades 1 to 4) should be handled 
according to the Guidelines provided in Table 1.
Management of immune-mediated reactions is described in Table 2.
Table 1: Treatment Modifications for Symptoms of Infusion-related Reactions including Immediate 
Hypersensitivity
NCI-CTCAE Grade 
Treatment Modification
Grade 1 - mild
Mild transient reaction; in general, infusion 
interruption not indicated; intervention not 
indicated

Increase monitoring of vital signs as medically 
indicated as participants are deemed medically 
stable by the attending Investigator.

Hold infusion if deemed necessary by the 
investigator.
Grade 2 – moderate
Therapy or infusion interruption indicated but 
responds promptly to symptomatic treatment 
(for example, antihistamines, nonsteroidal 
anti-inflammatory drugs, narcotics, IV fluids); 
prophylactic medications indicated for  24 h.

Stop the infusion of the study intervention. 

Increase monitoring of vital signs as medically 
indicated as participants are deemed medically 
stable by the attending Investigator.

If symptoms resolve quickly, resume infusion at 
50% of original rate with close monitoring of 
any worsening signs and symptoms, otherwise 
dosing held until resolution of symptoms with 
mandated premedication for the next scheduled 
visit.

If not improving, consider administration of 
glucocorticoids and stop the infusion for that 
day.

If the participant has a second IRR Grade ≥ 2 on 
the slower infusion rate despite premedication, 
the infusion should be stopped, and the 
investigator may consider withdrawal of this 
participant from the study.
Grade 3 or Grade 4 – severe or 
life-threatening
o
Grade 3: Prolonged (for example, not 
rapidly responsive to symptomatic 

Stop the infusion of study intervention 
immediately and disconnect infusion tubing 
from the participant with additional appropriate 
medical measures and closely monitor until 


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Abbreviated Title: Phase II M7824 in UC
Version Date: 06/23/2021
medication and/or brief interruption of 
infusion); recurrence of symptoms 
following initial improvement; 
hospitalization indicated for clinical 
sequelae.
o
Grade 4: Life-threatening consequences; 
urgent intervention indicated.
deemed medically stable by the attending 
Investigator. Hospitalization and/or close 
monitoring is recommended
 Administration of glucocorticoids may be required

For Grade 3 or 4 IRRs, permanent 
discontinuation of study intervention is 
mandated.
Once the infusion is interrupted or rate reduced to 50% of previous infusion rate, it must remain 
decreased for all subsequent infusions. 
For all types and grades of infusion reactions, details about drug physical constitution, method of 
preparation, and infusion must be recorded.
Participants should be instructed to report any delayed reaction immediately.
1
IRR=infusion-related reactions, IV=intravenous, NCI-CTCAE=National Cancer Institute-Common 
Terminology Criteria for Adverse Event, NSAIDs=nonsteroidal anti-inflammatory drugs. 
Table 2: Management of immune- mediated adverse events
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
Recommended guidance and management for specific irAEs are provided in the current 
National Comprehensive Cancer Network (NCCN) guideline available at 
http://www.nccn.org.
Requirements in addition to NCCN guidelines:

Permanent treatment discontinuation is required in case of immune-related Grade 4 
rash/inflammatory dermatitis, nephritis, autoimmune hemolytic anemia, hemolytic uremic 


26
Abbreviated Title: Phase II M7824 in UC
Version Date: 06/23/2021
syndrome, 
aplastic 
anemia, 
immune 
thrombocytopenia, 
acquired 
thrombotic 
thrombocytopenic purpura inflammatory arthritis, myositis and polymyalgia-like syndrome.

For Grade 4 immune-related lymphopenia, permanent treatment discontinuation will be 
required, if lymphopenia is considered immune-related in nature, no clear alternative 
explanation exists for the event, and it does not resolve within 14 days. Permanent treatment 
discontinuation is not required when the AE is manifested by a single laboratory value out 
of normal range without any clinical correlates. In this case, treatment should be held until 
the etiology is determined. If the event is not considered immune-related and resolves to 
Grade ≤ 1, restarting treatment may be considered.

For Grade 1 immune-related pneumonitis: continue treatment. If clinically indicated, 
monitor participants weekly or more frequently as needed with history, physical examination 
and pulse oximetry. If symptoms appear and/or changes in the physical exam are noted, treat 
as Grade 2.

For myositis: in case of management with rituximab, treatment should be discontinued.

For Grade 3 or 4 endocrinopathies: withhold until clinically stable or permanently 
discontinue depending on severity.

For hepatitis with no tumor involvement of the liver: withhold if total bilirubin increases to 
more than 1.5 and up to 3 times ULN, permanently discontinue if more than 3 times ULN

Hepatitis with tumor involvement of the liver: permanently discontinue if total bilirubin 
increases to more than 3 times ULN.
3.3.1.5
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 1.
Management of immune-mediated reactions is described in Table 2.
Table 1: Treatment Modifications for Symptoms of Infusion-related Reactions including Immediate 
Hypersensitivity
NCI-CTCAE Grade 
Treatment Modification
Grade 1 - mild
Mild transient reaction; in general, infusion 
interruption not indicated; intervention not 
indicated

Increase monitoring of vital signs as medically 
indicated as participants are deemed medically 
stable by the attending Investigator.

Hold infusion if deemed necessary by the 
investigator.
Grade 2 – moderate
Therapy or infusion interruption indicated but 
responds promptly to symptomatic treatment 
(for example, antihistamines, nonsteroidal 

Stop the infusion of the study intervention. 

Increase monitoring of vital signs as medically 
indicated as participants are deemed medically 
stable by the attending Investigator.


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anti-inflammatory drugs, narcotics, IV fluids); 
prophylactic medications indicated for  24 h.

If symptoms resolve quickly, resume infusion at 
50% of original rate with close monitoring of 
any worsening signs and symptoms, otherwise 
dosing held until resolution of symptoms with 
mandated premedication for the next scheduled 
visit.

If not improving, consider administration of 
glucocorticoids and stop the infusion for that 
day.

If the participant has a second IRR Grade ≥ 2 on 
the slower infusion rate despite premedication, 
the infusion should be stopped, and the 
investigator may consider withdrawal of this 
participant from the study.
Grade 3 or Grade 4 – severe or 
life-threatening
o
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.
o
Grade 4: Life-threatening consequences; 
urgent intervention indicated.

Stop the infusion of study intervention 
immediately and disconnect infusion tubing 
from the participant with additional appropriate 
medical measures and closely monitor until 
deemed medically stable by the attending 
Investigator. Hospitalization and/or close 
monitoring is recommended
 Administration of glucocorticoids may be required

For Grade 3 or 4 IRRs, permanent 
discontinuation of study intervention is 
mandated.
Once the infusion is interrupted or rate reduced to 50% of previous infusion rate, it must remain 
decreased for all subsequent infusions. 
For all types and grades of infusion reactions, details about drug physical constitution, method of 
preparation, and infusion must be recorded.
Participants should be instructed to report any delayed reaction immediately.
2
IRR=infusion-related reactions, IV=intravenous, NCI-CTCAE=National Cancer Institute-Common 
Terminology Criteria for Adverse Event, NSAIDs=nonsteroidal anti-inflammatory drugs. 
 (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), 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 may be removed from M7824 treatment at the discretion of the investigator.
3.3.1.6
Immediate Hypersensitivity Reaction
Hypersensitivity reactions may require immediate intensive care. Bintrafusp alfa should be 
administered in a setting that allows immediate access to an intensive care unit or equivalent 


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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.
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.
3.3.1.7
Severe Hypersensitivity Reactions and Flu-like Symptoms
If a hypersensitivity reaction occurs, the subject must be treated according to the best available 
medical practice including ACLS guidelines. 
Subjects should be instructed to report any delayed reactions to the investigator immediately.
A. Symptoms

Impaired airway

Decreased oxygen saturation (< 92%)

Confusion

Lethargy

Hypotension

Pale / clammy skin

Cyanosis
B. 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
Treatment is based on clinical assessment and at the discretion of the Investigator. 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.
3.3.1.8
Immune-Related Adverse Events
Immune-related adverse events (irAEs) are specific to immunotherapy. IrAEs are important 
identified risks for M7824. Immune-related adverse events should be documented as an ‘Adverse 
Event of Special Interest (AESI),’ and it is recommended to involve the principal investigator at 
first incidence and subsequently as needed for follow-up. Details of the diagnostic work-up will 
be requested by the study team. An immune related adverse event (irAE) is defined as off target 
side effects associated with exposure of immunogenic drug and is consistent with immune 
mechanism. In the process of identification of irAEs, any possible etiology of neoplastic, 
infectious, metabolic, toxin, or any other factor should be ruled out. Serologic, histologic (biopsy), 


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and/or immunologic results should be obtained to evaluate the differential diagnosis and/or support 
an immune-mediated cause. 
The recommendations for irAE management, in accordance with the joint American Society of 
Clinical Oncology (ASCO) Clinical Practice Guidelines (Brahmer, 2018) and National 
Comprehensive Cancer Network (NCCN Guidelines®). General management by CTCAE v5.0 
grading, as per ASCO, is listed below (ASCO organ/system specific toxicity management takes 
precident over below general guidelines):
Grade 1: study treatment should be continued with close monitoring, with the exception of some 
neurologic, hematologic, and cardiac toxicities. 
Grade 2: study treatment may be suspended for most Grade 2 toxicities, with consideration of 
resuming when symptoms revert to Grade 1 or less. Corticosteroids may be administered (initial 
dose of 0.5 to 1 mg/kg/d of prednisone or equivalent). 
Grade 3: study treatment is generally suspended and the high-dose corticosteroids (prednisone 1 
to 2 mg/kg/d or methylprednisolone 1 to 2 mg/kg/d) treatment should initiated. Corticosteroids 
should be tapered over the course of at least 4 to 6 weeks. Some refractory cases may require 
infliximab or other immunosuppressive therapy. 
Grade 4: in general, permanent discontinuation of study treatment is recommended, with the 
exception of endocrinopathies that have been controlled by hormone replacement.
3.3.1.9
Anemia
For anemia events assessed as treatment-related, items queried may include but are not limited to 
detailed relevant past medical and treatment history, bruising tendency, history of blood 
transfusions and/or dependency, details such as concomitant medications, all laboratory data, 
updated dosing information and recent tumor evaluation scans. 
M7824 treatment-related anemia is an important risk (see Investigators’ Brochure). Notably, there 
are many reasons for anemia in patients with advanced cancer, and Hb level of at least 9 g/dl is 
required for this study. A thorough investigation of new anemia cases of unspecified etiology is 
requested. Safety laboratory testing of relevant blood parameters is conducted per schedule of 
assessment.
General Guidance for anemia management and evaluation:

Participants must enter the study with Hgb values at least 9 g/dL and baseline anemia 
evaluation is conducted per Table 3.

All relevant hematologic testing for treatment related anemias should be done prior to blood 
transfusion, if clinically feasible.
If a participant experiences significant anemia (<8g/dl), then the amount of blood to be drawn 
may be reduced by not taking blood at selected time points for -exploratory biomarkers. The 
decision to reduce the time points for these biomarkers will be taken by the investigator in 
consultation with the medical monitor. This will be documented. 
Transfusion should be performed at the discretion of the investigator, based on clinical 
assessment and considered when participant experiences significant anemia. Attempt should be 
made to initiate work-up (as specified below) for cause of anemia prior to transfusion if 
clinically feasible to not confound this workup.


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Guidance for evaluation of suspected treatment-related anemias is provided in Table 3.
Management of treatment-related anemias is provided in Table 4.
Table 3: Evaluation Guidance of Suspected Treatment-related Anemia AEs
Basic anemia evaluation (prior to transfusion, if feasible)
CBC with differential (e.g. MCV, RDW, ANC, hemoglobin, hematocrit) 
Reticulocytes counts
Peripheral blood smear for cell morphological assessment
Complete metabolic panel including liver panel-LFTs, bilirubin, LDH, renal function, and serum folate, B12 values and 
other chemistries
Coagulation factors (PT, PTT, INR)
Urinalysis including culture
Iron panel (TIBC, ferritin, Fe)
TSH/thyroid panel
Fecal-occult blood testing
Erythropoietin
Haptoglobin
Further recommendation based on suspected etiology (in addition to baseline anemia testing)
Unknown etiology, suspect 
possible hemolysis
Coombs test, fibrinogen, d-dimer
Consider hematology consultation.
Consider blood transfusion at clinical discretion.
Unknown etiology, suspect 
possible bleeding
Consider blood transfusion at clinical discretion.
Consider surgical/interventional radiology consultation.
Consider imaging, as clinically indicated (e.g. FAST scan, CT scan, MRI, angiography).
Consider endoscopy (upper/lower) 
Unknown etiology despite 
above work-up
Hematology consultation
Consider bone marrow aspiration/morphologic evaluation
Table 4: Management of Treatment-Related Anemia

Hematology assessment must be performed at baseline, prior to each bintrafusp alfa 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
Diagnostic Work-up

Baseline Anemia Evaluation

CBC with emphasis on red cell indices

If indicated and at clinical discretion, the following should be considered:

Iron studies

Serum Folate and Vit B12 values

Coagulation factors

Fecal occult blood

Urinalysis

Hormone panel: TSH, Erythropoietin

Peripheral blood smear


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Further recommendation based on suspected etiology (in addition to basic anemia testing)                           

Suspected Hemolysis

bilirubin, LDH, Coombs test, haptoglobin

Suspected bleeding: 

Consider imaging/interventional radiology consultation as indicated

Consider imaging and/or endoscopy as clinically indicated

Suspected aplastic anemia:

Hematology consultation

Consider bone marrow aspiration/morphologic evaluation 
Additional consideration
In general, blood transfusions and erythroid growth factors are permitted as clinically indicated.
3.3.1.10 Rash with Hyperkeratosis / Keratoacanthoma / Squamous Cell Carcinoma of the Skin
Monitoring will include skin assessments every 4 weeks with biopsy of suspicious lesions. 
Dermatological consults should be requested as needed. Treatment modifications for reactions 
caused by M7824 are addressed in Table 5.
Table 5: Management of M7824 mediated Skin Reactions

Hyperkeratosis

Keratoacanthoma

Cutaneous squamous cell carcinoma (cSCC)

Basal cell carcinoma

Actinic keratosis
Management

Discontinuation or termination not required in most cases. Continuation of treatment should 
be evaluated by the Investigator.

Emollients may be used

Develop diagnostic and treatment plan in collaboration with Investigator and dermatologist

Treatment follow-up will depend on number and localization of lesions.
o
Single lesion: full excision may be recommended
o
Multiple lesion or location not suitable for full excision: Mohrs surgery, cryotherapy 
or other standard treatment options depending on pathology. Retinoids may be used 
per Investigator decision.

Close clinical follow-up for re-evaluation, resolution and potential recurrence should be 
implemented

In general, treatment of M7824 mediated skin lesions should be based on local 
guidelines/standard of care.
Additional consideration: Keratoacanthoma lesions may resolve spontaneously without surgical 
intervention within weeks after discontinuing bintrafusp alfa.
Consult with Medical Monitor as needed for management of M7824 mediated skin lesions.


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3.3.1.11 Impaired Wound Healing o
Management should be discussed on a case-by-case basis. Dermatological consults should be 
requested as needed.

Impaired wound healing is considered an important potential risk for bintrafusp alfa

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
3.3.1.12 Dose Interruptions for Adverse Events not Related to Study Drug 
In case of Grade 3 and Grade 4 AEs not study drug related, the study treatment may be interrupted 
based on the investigator assessment and the subject will be medically treated for the event.
If the AE reduces to a lower tolerable grade the study treatment might be resumed in the subsequent 
cycle. If the AE remains the same despite the medical treatment until the next treatment (second 
cycle after the AE occurred) a consideration of a possible extension of the dose interruption for up 
to 1 additional cycle or a permanent withdrawal from the study treatment should be considered.
If upon the resumed study treatment, the subject experiences the same AE, permanent withdrawal 
from the study treatment should be considered.
Grade 3 and 4 laboratory abnormalities that do not have clinical significance and are not related to 
study drugs do not require dose interruption.
3.3.1.13 Embryo-Fetal Toxicities
Embryo-fetal toxicities are a known risk of the PD-1/PD-L1 targeting class and are considered 
important potential risk for M7824. Animal models link the PD-1/PD-L1 signaling pathway with 
maintenance of pregnancy through induction of maternal immune tolerance to fetal tissue [34-37]. 
Embryofetal toxicity is an important potential risk of bintrafusp alfa. Embryo-fetal and 
reproductive toxicities have also been investigated in animal models for a humanized mAb 
targeting TGFβ1. At doses as high as 30 mg/kg, no maternal reproductive toxicity or embryo-fetal 
lethality were observed in rabbits [38]. To mitigate these potential risks, pregnant participants are 
excluded from the study, and all participants of childbearing/conceiving potential must use highly 
effective contraception (See Section 2.1.1.11). 
3.3.1.14 Mild to Moderate Bleeding Events
Bleeding events of mild to moderate severity were observed in participants treated with M7824 in 
ongoing studies and are a potential risk for M7824. Events may include epistaxis, hemoptysis, 
gingival bleeding, or hematuria among others. In general, majority of these events were observed 
to be self-limiting, did not require intervention, and resolved without discontinuation of study 
treatment.
Management of bleeding is provided in Table 6.


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Abbreviated Title: Phase II M7824 in UC
Version Date: 06/23/2021
Table 6: Management of Bleeding Adverse Events
Bleeding Adverse Events

Bleeding adverse events are considered 
important identified risk for bintrafusp 
alfa.

In general, mild and moderate mucosal 
bleedings resolve without 
discontinuation of treatment.

These events may include, but are not 
limited to the following:
o
Epistaxis
o
Hemoptysis 
o
Gingival bleeding
o
Hematuria
Non-tumor Bleeding
Grading
Management
Grade 2

If resolves to Grade ≤ 1 by the day before the next infusion, study 
intervention may be continued

If not resolved to Grade ≤ 1 by the day before the next infusion, but is 
manageable and /or not clinically relevant, consult Medical Monitor to 
assess if clinically reasonable to administer the following infusion.
Grade 3

Permanently discontinue treatment unless an alternative explanation 
can be identified (such as concomitant use of antithrombotic agents, 
traumatic events, etc.) 

In case of alternative explanations, hold study treatment until the 
event recovers to Grade ≤ 1
Grade 4

Treatment must be permanently discontinued if no alternative 
explanation is identified.
Tumor Bleeding
Grade ≥ 2

Study treatment must be held till the event recovers to Grade ≤ 1

Permanently discontinue treatment if the Investigator considers the 
participant to be at risk for additional severe bleeding.
3.4
STUDY CALENDAR
Please refer to Appendix A: Study Calendar.
3.5
COST AND COMPENSATION
3.5.1
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 performed 
outside the NIH Clinical Center, participants may have to pay for these costs if they are not covered 
by insurance company.  Medicines that are not part of the study treatment will not be provided or 
paid for by the NIH Clinical Center.


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Abbreviated Title: Phase II M7824 in UC
Version Date: 06/23/2021
3.5.2
Compensation
No compensation will be provided for study participation.
3.5.3
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..
3.6
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 28-30 days after the last dose of study therapy.
3.6.1
Criteria for removal from protocol therapy

Completion of study therapy

Progressive disease

DLT if clincially indicated.

Intercurrent illness or medical circumstances.

Voluntary withdrawal from the treatment regimen

PI determines further treatment on this study is not in patient’s best interest 

Patients who are off-treatment but still on-study will be followed as per the schedule in 
Appendix A: Study Calendar, until they begin alternative therapy or voluntarily withdrawal 
from follow-up testing.  Thereafter, they may be followed on-study for survival and other 
secondary endpoints.

Positive pregnancy test
3.6.2
Off-Study Criteria

Death

Patient request to be withdrawn from study

Non-compliance with study treatment and/or testing, or lost to follow-up, at discretion of 
PI 
3.6.3
Lost to Follow-up
A participant will be considered lost to follow-up if he or she fails to return for 6 scheduled visits 
and is unable to be contacted by the study site staff. 
The following actions must be taken if a participant fails to return to the clinic for a required study 
visit:

The site will attempt to contact the participant and reschedule the missed visit for 3 months 
and counsel the participant on the importance of maintaining the assigned visit schedule 
and ascertain if the participant wishes to and/or should continue in the study.


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Abbreviated Title: Phase II M7824 in UC
Version Date: 06/23/2021

Before a participant is deemed lost to follow-up, the investigator or designee will make 
every effort to regain contact with the participant (where possible, 3 telephone calls and, if 
necessary, a certified letter to the participant’s last known mailing address or local 
equivalent methods). These contact attempts should be documented in the participant’s 
medical record or study file. 

Should the participant continue to be unreachable, he or she will be considered to have 
withdrawn from the study with a primary reason of lost to follow-up.
4
CONCOMITANT MEDICATIONS/MEASURES
4.1
PERMITTED MEDICINES
Any medications (other than those excluded by the clinical trial protocol) that are considered 
necessary to protect subject welfare and will not interfere with the trial medication may be given 
at the Investigator’s discretion. 
4.2
PROHIBITED MEDICINES
The following treatments must not be administered during the trial:
Immunotherapy including interferon, immunosuppressive drugs (for example, systemic 
corticosteroids except for short term treatment of allergic reactions, endocrine replacement 
therapy at low dose prednisone [>10 mg daily] or equivalent, or for the treatment of irAEs or 
other appropriate short-term steroid use), or other experimental pharmaceutical products. Short 
term administration of systemic steroid or other immunosuppressant such as infliximab or 
mycophenolate (that is, for allergic reactions or the management of irAEs) is allowed. Steroids 
with no or minimal systemic effect (topical, inhalation) are allowed. 
Prophylactic use of corticosteroids for infusion related reactions is prohibited.
Herbal remedies with immunostimulating properties (for example, mistletoe extract) or known 
to potentially interfere with major organ function (for example, hypericin).
Any live vaccine therapies for the prevention of infectious disease. Administration of 
inactivated vaccines is allowed (for example, inactivated influenza or SARS-CoV-2 vaccines, 
and locally approved COVID vaccines).
If the administration of a non-permitted concomitant drug becomes necessary during the trial, the 
subject will be withdrawn from trial treatment.
5
CORRELATIVE STUDIES FOR RESEARCH
5.1
BIOSPECIMEN COLLECTION
Please refer to Section 5.2 for sample collection and timepoints. 
5.1.1
Immune Monitoring and Peripheral Immune Subset Analysis 
Peripheral Blood Mononuclear Cells (PBMCs) will be analyzed for changes in standard immune 
cell types (T-cell receptor clonality, CD4 and CD8 T cells, natural killer [NK] cells, regulatory T 


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Abbreviated Title: Phase II M7824 in UC
Version Date: 06/23/2021
cells [Tregs], myeloid-derived suppressor cells [MDSCs], and dendritic cells) as well as 123 
immune cell subsets, as described elsewhere [39, 40]. 
PBMC analysis may include phenotypic and functional analysis of immune-cell subsets (such as 
CD4 and CD8 T cells, NK cells, Tregs, and MDSCs) including proliferation, cytokine production, 
lysis, and suppression using multicolor flow cytometry based assays.
Collection and handling:
For PBMCs collection, six 10mL sodium heparin (green top) tubes will be used.
Sample Transport/Storage:
Samples will be stored by Clinical Services Program – Leidos Biomedical Research, Inc. (CSP)..
Attn: Theresa Burks/Dr. Inglefield 
1050 Boyles Street
Bldg. 496/Room 121
Frederick, MD 21702
On days samples are drawn, Jen Bangh at CSP (part of NCI Frederick Central Repositories) should 
be notified (phone: [301] 846-5893; fax [301] 846-6222). She will arrange same-day courier 
delivery of the specimens. Samples can be picked up Monday through Friday, three times per day 
(~9, 11, 2).
Samples will be analyzed by the Jeffery Schlom, Laboratory of Tumor Immunology and Biology 
(LTIB)NCI.
5.1.2
Comprehensive Cytokine/Chemokine analysis 
To evaluate for circulating systemic levels of cytokines, chemokines of patients on treatment and 
correlate levels and changes with clinical activity of the study drug, plasma will be collected per 
PI discretion:
1. Plasma may be analyzed pre- and post-therapy for the following soluble factors: sCD27, 
sCD40 ligand using assays adapted to ECL platform.
2. Plasma may be analyzed for changes in cytokines (IFN-γ, IL-6, IL-8, TNF-α , etc.), 
chemokines, antibodies, tumor-associated antigens, and/or other markers using ELISA or 
multiplexed assays (e.g. Mesoscale, Luminex, cytokine bead array).
Collection and handling:
For plasma collection, one 4 ml lavender top EDTA tube will be used.. 
Sample Transport/Storage:
Blood samples will be stored by Dr. Figg’s laboratory and processed and analyzed by Dr. Liang 
Cao’s laboratory. 
For Figg lab, 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).  


37
Abbreviated Title: Phase II M7824 in UC
Version Date: 06/23/2021
For questions regarding sample processing, contact NCIBloodcore@mail.nih.gov by e-mail or at 
240-858-3191.
5.1.3
Circulating cell-free DNA (cfDNA) isolation
The primary purpose of these studies is to evaluate for circulating cell-free DNA (cfDNA) of 
patients on treatment and correlate levels and changes with clinical activity of the study drug 
combination.

Blood draw and storage
o
Draw 2 X 10 mL blood samples to EDTA tubes (lavender tops) follow the 
manufacture’s instruction.    
o
Remove tube from adaptor and immediately mix by gentle inversion 8 to 10 times.  
CRITICAL STEP: Do not shake or vortex tubes as cellular lysis could occur.
o
Tubes should be stored and transport at room temperature for up to four (4) hrs.  
Do not freeze.
Sample Transport/Storage:
Blood/plasma samples will be stored by Dr. Figg’s laboratory and processed and analyzed by Dr. 
Liang Cao’s laboratory. 
For Figg lab, please e-mail NCIBloodcore@mail.nih.gov at least 24 hours before transporting 
samples (the Friday before is preferred). 
For sample pickup, page 102-11964. For immediate help, call 240-760-6180 (main blood 
processing core number) or, if no answer, 240-760-6190 (main clinical pharmacology lab number).  
For questions regarding sample processing, contact NCIBloodcore@mail.nih.gov by e-mail or at 
240-858-3191.
5.1.4
HGF and Met
Plasma will be collected to determine whether plasma HGF and Met levels are biomarkers for 
metastatic non-prostate genitourinary tumors and/or response to treatment.
Collection and handling 
10mL of whole blood collected in one 10mL EDTA tube at room temperature will be collected at 
each time point. Plasma samples will be stored by Dr. Figg’s laboratory and processed and 
analyzed by Dr. Cao’s laboratory.
5.1.5
Circulating Tumor Cells (CTCs)
To evaluate and characterize changes in expression of immune-related markers on CTCs. All 
patients enrolled on study will have CTC’s measured using Epic Science’s “no cell left behind” 
platform [41]. 
Collection and handling
CTC Samples should be collected in the 10 mL Streck Cell-Free DNA BCT. These tubes are 
commercially available through Streck (Omaha, NE). 


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Abbreviated Title: Phase II M7824 in UC
Version Date: 06/23/2021
IMPORTANT: The first 5 mL of blood collected from the fresh venipuncture cannot be used for 
the collection into the Streck tubes due to possibility of contaminating epithelial cells during 
venipuncture. Please ensure that at least one blood tube of 5 mL or more is collected prior to 
collection of the CTC sample to avoid adversely affecting the test results. 
Prevention of Backflow: 
Since Streck Cell-Free DNA BCT tubes contain chemical additives, it is important to avoid 
possible backflow from the tube. To guard against backflow, observe the following precautions: 

Keep patient’s arm in the downward position during the collection procedure. 

Hold the tube with the stopper uppermost. 

Release tourniquet once the blood starts to flow into the tube, or within 2 minutes of 
application. 

Tube contents should not touch stopper or the end of the needle during the collection 
procedure. 
Blood Collection Instructions: 
**Arrange for the same day shipment! 

Confirm blood tube is not expired. Expired tubes should not be used for blood collection. 

Draw whole blood sample into 10 mL Streck Cell-Free DNA BCT tube (*see note 
regarding prevention of backflow). Fill tube until blood flow stops. NOTE: Epic requires 
a minimum of 4 mL blood per sample, but a full 10 mL tube of blood should be provided 
when possible. 

Remove tube from adapter and immediately mix by gentle inversion 8 to 10 times. Tube 
inversion prevents clotting. Inadequate or delayed mixing may result in inaccurate test 
results. 

Label the tube with subject’s identification and date and time of blood draw. Unlabeled 
blood tubes may not be processed. 

Keep sample at room temperature and ship on day of collection in shipper with ambient 
gel packs. 
Specimen Shipment Logistics 
All shipments must include requisition forms that contain Patient ID, Collection Date and time, 
Collection Site (including address), Time Point (if applicable), and the appropriate trial code 
(20C0012/ Epic Internal ID: NE-003). Clinical sites should provide email notification of sample 
shipment to Epic Sciences on the day of collection. The email should contain: 

Trial codes (20C0012/ Epic Internal ID: NE-003) 

Patient ID 

Collection date and time* 

Time point/Visit 


39
Abbreviated Title: Phase II M7824 in UC
Version Date: 06/23/2021

Tracking information 
If possible, include a scanned copy of the completed sample requisition form. Partner will be 
responsible for all blood collection supplies, shipping materials, and shipping expenses. 
* When collection time is not provided, Epic Sciences will assume the sample was collected at 
8:00AM (local time) on the date of collection.
Send notification to: partners@epicsciences.com 
Ship to: Epic Science
Attn: (20C0012/Epic internal ID: NE-003)
9381 Judicial Dr. Suite 200
Sand Diego, CA 92121
Contact phone number is: 1-858-356-6610
Epic Science will promptly notify the project stakeholders via email  of any holiday closures.
5.1.6
c-Met analysis by RT-PCR
Peripheral blood for analysis of c-Met mRNA will be collected in a PAXgene tube (PreAnalytix; 
2.5 cc peripheral blood per tube) per the manufacturer’s instructions.  After the blood is drawn, the 
tube should be inverted several times, placed at 4°C.  RNA will be isolated using the PAXgene 
Blood RNA Kit according to the manufacturer’s instructions. The first strand cDNA will be 
synthesized from total RNA by using a HC reverse transcription kit (Applied Biosystems). The 
reaction mixture is diluted to 100 μL with TE. PCR will be performed using the c-met primers).  
Sample Transport/Storage:
Blood/plasma samples will be stored by Dr. Figg’s laboratory and processed and analyzed by the 
Dr. Liang Cao’s laboratory. 
For Figg lab, please e-mail NCIBloodcore@mail.nih.gov at least 24 hours before transporting 
samples (the Friday before is preferred). 
For sample pickup, page 102-11964. For immediate help, call 240-760-6180 (main blood 
processing core number) or, if no answer, 240-760-6190 (main clinical pharmacology lab number).  
For questions regarding sample processing, contact NCIBloodcore@mail.nih.gov by e-mail or at 
240-858-3191.
5.1.7
Tumor Studies
5.1.7.1
RNA-Seq, TCR sequencing, and MET Protein

Single Cell RNA-Seq: from RNA extracted from fresh frozen tumor tissue for 
transcriptome sequencing (RNA-Seq) to evaluate if RNA gene expression profiling that 
measure responsive genes relative to antigen presentation, chemokine expression, 
cytotoxic activity and adaptive immune resistance are correlated with clinical response.

TCR Sequencing: from RNA extracted from fresh frozen tumor tissue: To evaluate and 
characterize the clonality of the T-cell population as a way to infer the peripheral expansion 
of tumor-reactive T-cell clones in response to study drug combination.


40
Abbreviated Title: Phase II M7824 in UC
Version Date: 06/23/2021

MET protein: MET protein evaluated from tumor biopsies will be correlated with clinical 
responses
Tumor tissue will be prioritized (highest to lowest): 
1) Formalin fixed for diagnostic and DNA/RNA extraction from FFPE (20 slides total)
•
10 unstained FFPE slides (room temperature) will be sent to Laboratory of Pathology. 
Please contact Dr. Jun Wei (weij@mail.nih.gov), prior to transport. Telephone: 240-
760-7428.
•
10 unstained FFPE slides (room temperature) will be stored in the Laboratory of 
Pathology for additional tumor testing
2) Three cores will be collected when possible and flash frozen for RNA extraction
•
For frozen tumor, place 1 core in 1.5mL Eppendorf or 15mL conical tube or 1-2 blocks 
on dry ice. DNA and RNA extracted by Laboratory of Pathology and sent to 
Oncogenomics Section for exome sequencing, and TCR sequencing (contact Dr. 
Young Song, songyo@mail.nih.gov). Single Cell RNA Seq will be performed in the 
Single 
Cell 
Analysis 
Facility 
(SCAF) 
(contact 
Dr. 
Michael 
Kelly, 
michael.kelly3@nih.gov / 240-760-6301).
•
1-2 frozen cores will be stored by Dr. Bottaro’s lab for additional testing. Please contact 
Rene Costello (rene.costello@nih.gov / 301-443-6915) to arrange for pick-up of 
sample)
FFPE:
In the case of exisiting (pre-treatment) FFPE slide/blocks already available for the consenting 
patients, the sample will be transferred to the Laboratory of Pathology (LP). 
Collection and handling 
For DNA and RNA to be extracted from FFPE tissues the Laboratory of Pathology in consultation 
with the surgical pathologist will evaluate specimen for adequacy and diagnosis. For the majority 
of cases the Laboratory of Pathology will perform both the extraction and quality control (QC) of 
nucleic acids. This will include DNA and RNA from tumor, and DNA from germline tissue 
(matched normal, blood,or other tissues). The DNA will be used for exome sequencing, and RNA 
sequencing will be performed in a research setting. Final approval to proceed to sequencing will 
be determined by passing all QCs according to the SOPs.  
Fresh/Frozen Tissue: 
If a pre-treatment biopsy is performed, the surgical sample will be obtained by the interventional 
radiology or surgical dissection/resection, and the sample collection will be processed as follows: 
Interventional Radiologist: Recommend 19 gauge needle or larger in caliber after discussion and 
at the discretion of the intervention radiologist
Contact Research Nurse or Rene Costello to be present at time of procedure.


41
Abbreviated Title: Phase II M7824 in UC
Version Date: 06/23/2021
1. 1-2 cores snap frozen sent to OncoGenomics (contact Dr. Young Song, 
songyo@mail.nih.gov). Transport to OncoGenomics in 4°C wet ice.
2. 1-2 cores in container cooled in dry ice for flash freezing. Transport to Don Bottaro’s 
lab in dry ice. (contact Rene Costello, rene.costello@nih.gov). 
Sample Transport/Storage:
Laboratory of Pathology (LP) will arrange transportation of the DNA (and RNA sample) to the 
Genetics Branch. Building 37, Room 6144, Bethesda, MD 20892. Please contact Dr. Jun Wei 
(weij@mail.nih.gov), prior to transport. Telephone: 240-760-7428. Dr. Wei will ensure that the 
patient has been consented and that he has been emailed a copy of the consent form before the 
samples are processed for RNA sequencing
The primary purpose of the studies is to utilize Omics high throughput techniques to identify novel 
biomarkers and targets of response to this study drug. 

Transcriptome sequencing (RNA-Seq) from RNA extracted from blood and fresh frozen 
tumor tissue: To evaluate if RNA gene expression profiling that measure responsive genes 
relative to antigen presentation, chemokine expression, cytotoxic activity and adaptive 
immune resistance are correlated with clinical response.

T-cell receptor (TCR) sequencing from RNA extracted from fresh frozen tumor tissue: 
To evaluate and characterize the clonality of the T-cell population as a way to infer the 
peripheral expansion of tumor-reactive T-cell clones in response to study drug.
5.1.7.2
Genomics studies– TrueSight Oncology
Pre-treatment tissue biopsy and/or tissue availability is mandatory. On-treatment biopsy is required 
unless obtaining biopsy is not technically or clinically feasible. Post-treatment biopsy is optional.

10 unstained FFPE slides (room temperature) from in-house surgery and outside materials 
will be brought directly to General Surgical Pathology office - 10/Room 2S262. 
Paraffin-embedded tissue specimens from outside must be formalin fixed. They will be submitted 
either as a tissue block containing >20% tumor, or a minimum of 10 FFPE unstained slides for 
molecular pathology testing and surgical pathology review.
Alterations to the above requirements on sample submission will be at the discretion of the 
Laboratory of Pathology. 
The TruSight Oncology 500 (TSO-500) is a next-generation sequencing (NGS) assay that analyzes 
cancer-relevant genes from both DNA and RNA in one integrated workflow. During library 
preparation, enrichment chemistry is optimized to capture nucleic acid targets from formalin-fixed, 
paraffin-embedded (FFPE) tissues. With simultaneous analysis of both DNA and RNA, various 
types of biomarkers relevant to a given tumor type (single nucleotide variants (SNVs), indels, 
fusions, splice variants, tumor mutation burden (TMB), and microsatellite instability (MSI)) can 
be assessed from the same sample in a single assay. The RNA panel uses a probe design that 
enables capture of both known fusions and novel fusion partners. The TSO500 panel includes 523 
genes for DNA mutation detection and 55 genes for fusion and splice variant detection.


42
Abbreviated Title: Phase II M7824 in UC
Version Date: 06/23/2021
The new molecular pathology report is also incorporated with reporting software for clinical 
actionability as Tier levels of FDA-approved drug and clinical trials, and pathogenicity based on 
AMP/ASCO/CAP/ACMG guidelines.
NIH Clinical Record Interactive System (CRIS) orders will be placed to notify the laboratory of 
pathology.
Collection and handling:
Please contact Mark Raffeld, mraff@mail.nih.gov at 301-480-8927.
5.1.8
Multiplex Immunohistochemistry
To correlate baseline expression of PD-L1 (on tumor cells, tumor-infiltrating immune cells or 
both) with activity of study drug. To evaluate modulation of intratumoral immune contexture / 
immunophenotype (i.e. CD3, CD8, CD4, FoxP3) in response to study drug compared with 
baseline.
•
In the case of exisiting (pre-treatment) FFPE slide/blocks already available for the 
consenting patients, the sample will be transferred to the Laboratory of Pathology (LP). 
•
For patients undergoing dedicated research biopsies (baseline or on-treatment C3D1), 
tissue will be sent to the Laboratory of Pathology (LP) for accessioning, processing 
overnight in formalin and embedding in paraffin (FFPE).
Plan for analysis and quantification: 
Multiplex Immunohistochemistry: 4-5 micron thick sections of tissue (from FFPE blocks 
mentioned above) will be mounted on 25 x 75mm, charged glass slides (routinely used in 
Laboratory of Pathology). These unstained slides (US) will undergo several cycles of 
immunostaining using the Opal Method after initial deparaffinization and hydration. In brief, the 
tissue will be subject to heat induced epitope retrieval (HIER), followed by blocking agent, then 
primary and secondary (HRP) antibody incubation. This is followed by signal amplification using 
tyramide based fluorophores which will covalently bind to tissue at the site of primary antibody 
attachement (antigen of interest). This is followed by stripping of antibodies using HIER, to allow 
for 2nd round of new antibodies of intetest. These steps are repeated for total of 6-7 times to allow 
detection of 6-7 markers. This is followed by DAPI (4',6-diamidino-2-phenylindole) counterstain 
to allow for nuclear detection. Once all antigens of interest are stained, a multiplex scanning 
protocol will be created on Vectra Polaris scanner (Perkinelmer), to allow for whole slide imaging 
at 10-20X. This is followed by higher resolution of regions of interest (ROIs) picked by trained 
research pathologist (Dr. H. Sater). The scans genetrated at high resolution are called multispectral 
images (MSIs) and have the im3 format. These can only be analyzed using inform software 
(available in Dr. Sater’s Lab). The software allows for spectral unmixing based on a spectral library 
built from single stains with each fluorophore used and scanned with multiplex protocol as MSI. 
The initial step will be to create monoplex IHC using CD3 antibody on all available cases. These 
will be scanned and MSIs will be generated to achieve the primary endpoint analysis (CD3+ cell 
density). Quantification of cells expressing CD3 will be perfomed on inform using training sets of 
images to create an algorithm. The algorithm, will be used for quantifying the cell number per 
area. Representative ROIs (planned to be 5 in number and randomly selected) might vary based 
on tissue size. Once CD3+ staining is verified for accuracy and integrity of images, we will move 
to next step which is multiplexing. The antibodies of interest are based on preclinical data or 


43
Abbreviated Title: Phase II M7824 in UC
Version Date: 06/23/2021
hypothesis driven. We plan to investigate a panel of multiple immune cell susbets such as T-helper 
cells (CD4+), T regulatory cells (CD4+FOXP3+), Cytotoxic T cells (CD3+CD8+), NK cells 
(CD56+), macrophages (CD68), B cells (CD19+) and other immune activation/immunsuppresive 
markers (IDO, PD-1, PD-L1, Ki67, ICOS, CD69, CD27, CD16 and other T cell activation 
markers) as well as tumor cell markers (Cytokeratin, Vimentin, etc) in a multiplex staining method. 
This method ensures simultaneous staining of different markers in the same tissue plane for 
colocaliztion and near neighbor analysis. The staining will be done in a panel like fashion where 
6-7 immunohistochemical (IHC) markers plus DAPI are chosen in any single slide.
All images are analyzed and saved in a secure server, accessible and monitored by Dr. H. Sater.
Collection and handing:
The Sater Lab will request 4-5 micron thick recuts of 5-10 FFPE slides by submitting a Tissue 
Resource Committee (TRC) request for Human Biological Materials for Research form. These 
biopsies will be examined by a research pathologist (Dr. H Sater) for the presence of tumor and 
tissue integrity and at least 5 consecutive recuts of each biopsy is deemed optimal for analysis. 
Hematoxyln and Eosin staining will be first done on the deepest level cut to reassess integrity of 
tissue for further analysis.
Please contact:
Dr. Houssein A. Sater MD / Beatriz Walters (GMC, CCR/NCI)
10 Center Drive, Building 10, Room 6B12
Bethesda, MD 20892
E-mail: houssein.abdulsater@nih.gov
5.1.9
Imaging 
Background
Magnetic resonance imaging (MRI) offers a high tissue contrast which allows direct imaging of 
the bones and soft tissues. Application of whole-body MRI approach has been shown to be 
clinically useful in certain diseases such as myeloma, lung cancer, lymphoma at both initial 
diagnosis/staging and treatment follow up [42-44]. In addition to anatomic pulse sequences, 
inclusion of diffusion weighted MRI (DW MRI) has also been documented to improve disease 
detection and monitoring steps. In this protocol the whole-body MR imaging protocol will include 
two different anatomic pulse sequences in coronal planes (T1W MRI and Short TI Inversion 
Recovery [STIR]) and a functional imaging pulse sequence (b800 diffusion weighted MRI). The 
DW MRI enables detection of lesions/foci with increased cellularity whereas the two anatomic 
pulse sequences will enable characterization of these lesions/foci detected on DW MRI. There will 
be no intravenous gadolinium injection-based imaging sequences, therefore it is a relatively less 
invasive novel imaging technique for patients with urothelial carcinoma especially considering the 
need for follow up imaging.
Methods
Whole body MRIs will be performed in B3 Molecular Imaging Clinic using a clinical 3 Tesla 
scanner. The patients will be imaged in supine position using surface coils and no intravenous 
contrast injection will be utilized. The imaging will be done in 5 stacks (head/neck, chest, 
abdomen, pelvis, thighs) for T1W MRI and STIR and in 4 stacks (head/neck, chest, abdomen, 
pelvis/thighs) for DW MRI. For chest, abdomen and pelvis stacks the patient will be asked to hold 


44
Abbreviated Title: Phase II M7824 in UC
Version Date: 06/23/2021
breath for a few times. The active scan time is planned to be 18-25 minutes. The entire imaging 
session is planned to be 40 minutes.
Timepoints: Please refer to Section 5.2 and Appendix A: Study Calendar for timepoints. 


45
Abbreviated Title: Phase II M7824 in UC
Version Date: 06/23/2021
MPI MRI WB Protocol Parameters
Coronal 5 stacks: Thighs, Pelvis, Abdomen, Chest, Head/neck
Axial DWIBS 4 stacks: Head/Neck, Chest, Abdomen, Pelvis/thighs.
Sequence
Plane
FOV
Slice 
Thickness
TR/TE/TI
Voxel size
Matrix
Flip 
Angle
Scan Time
T1W
Coronal
5 stacks
450 L-R
300 H-F   
6 mm
694/8/N/A
Scan 1.6x1.6
Recon1.17x1.17
188x247
90
4 minutes
STIR
Coronal
5 stacks
450 L-R
300 H-F   
6 mm
8399/70/230
Scan 1.6x1.6
Recon 1.0x1.0
188x248
125
4 minutes
DWIBS 
(DWI b-
value 800)
Axial
4 stacks
450 L-R
300 H-F   
6 mm
7730/66/220
Scan 3.5x3.5
Recon 1.7x1.7
128x81
N/A
10 minutes


46
Abbreviated Title: Phase II M7824 in UC
Version Date: 06/23/2021
5.2
SAMPLE COLLECTION SCHEDULE 
All cycles (28 days)
Test/Location
Baseline (C1D1)
C1D15
C2D1
C3D1
C4D1
C5D1
C6D1
and 
beyond
EOT visit
Correlative Research Studies (Blood-based)
X
X
X
X
X
X
X
X
Immune subsets
5.1.1
Peripheral Blood 
Mononuclear Cells 
(PBMCs)
Frederick/Schlom 
Lab 
6x10 mL
Sodium 
Heparin 
green top
6x10 mL
Sodium 
Heparin 
green top
6x10 mL
Sodium 
Heparin 
green top
6x10 mL
Sodium 
Heparin 
green top
6x10 mL
Sodium 
Heparin 
green top
6x10 mL
Sodium 
Heparin 
green top
6x10 mL
Sodium 
Heparin 
green top
6x10 mL
Sodium 
Heparin 
green top
X
X
X
X
X
X
X
X
Cytokine / Chemokine 
Plasma
5.1.2
Figg/Cao Lab
1x4 mL
 EDTA- 
Vacutaine
r tube 
(lavender 
top)
1x4 mL
 EDTA- 
Vacutain
er tube 
(lavender 
top)
1x4 mL
 EDTA- 
Vacutaine
r tube 
(lavender 
top)
1x4 mL
 EDTA- 
Vacutaine
r tube 
(lavender 
top)
1x4 mL
 EDTA- 
Vacutaine
r tube 
(lavender 
top)
1x4 mL
 EDTA- 
Vacutaine
r tube 
(lavender 
top)
1x4 mL
 EDTA- 
Vacutaine
r tube 
(lavender 
top)
1x4 mL
 EDTA- 
Vacutaine
r tube 
(lavender 
top)
X
X
X
X
X
cfDNA
Plasma
5.1.3
Figg/Cao Lab
1x10 mL
EDTA- 
Vacutaine
r tube 
(lavender 
top)
1x10 mL
EDTA- 
Vacutainer 
tube 
(lavender 
top)
1x10 mL
EDTA- 
Vacutainer 
tube 
(lavender 
top)
1x10 mL
EDTA- 
Vacutainer 
tube 
(lavender 
top)
1x10 mL
EDTA- 
Vacutainer 
tube 
(lavender 
top)
X
X
X
X
X
X
X
X
HGF and MET
Plasma
5.1.4
Figg/Cao
1x10mL
EDTA- 
Vacutaine
r tube 
(lavender 
top)
1x10mL
EDTA- 
Vacutaine
r tube 
(lavender 
top)
1x10mL
EDTA- 
Vacutainer 
tube 
(lavender 
top)
1x10mL
EDTA- 
Vacutainer 
tube 
(lavender 
top)
1x10mL
EDTA- 
Vacutainer 
tube 
(lavender 
top)
1x10mL
EDTA- 
Vacutainer 
tube 
(lavender 
top)
1x10mL
EDTA- 
Vacutainer 
tube 
(lavender 
top)
1x10mL
EDTA- 
Vacutainer 
tube 
(lavender 
top
X
X
X
X
c-Met analysis
Blood
5.1.6
Figg/Cao Lab
2x 5ml
PAXGene 
RNA
2x 5ml
PAXGene 
RNA
2x 5ml
PAXGene 
RNA
2x 5ml
PAXGene 
RNA
X
X
X
X
Circulating Tumor 
Cells (CTCs) 
5.1.5
Peripheral Blood
EPIC
1x10mL
Streck 
Brown-
Black tube
1x10mL
Streck 
Brown-
Black 
tube
1x10mL
Streck 
Brown-
Black tube
1x10mL
Streck 
Brown-
Black tube


47
Abbreviated Title: Phase II M7824 in UC
Version Date: 06/23/2021
All cycles (28 days)
Test/Location
Baseline (C1D1)
C1D15
C2D1
C3D1
C4D1
C5D1
C6D1
and 
beyond
EOT visit
Total Research Blood 
Volume per 
Timepoint (mL)
118
88
98
118
78
108
78
118
Correlative Research Studies (Tumor-based)
Single cell RNA-Seq
5.1.7.2
3 cores snap frozen 
tissue Kelly Lab
X
X*
TCR-Seq
5.1.4
Fresh frozen 1 core 
biopsy tissue
LP
X
X*
TSO
5.1.7.2
FFPE/Core biopsy 
fresh tissue
Raffeld lab
X**
MET protein
5.1.7.1
10 Slides and/or 1-2 
cores
Bottaro lab
X
X*
Multiplex IHC
5.1.8
FFPE tissue, at least 5 
consecutive slides
Sater lab
X
X*
Correlative Research Studies (Imaging-based)
Whole body 
MRI***
5.1.9
MIP, Turkbey
X
X
*Between cycles 2 and 4
** Optional collection based on history of prior tumor sequencing or clinical indication at the PI’s discretion.
*** Mandatory unless the participant is unable to lay flat or be in a confined space for the duration of the 
procedure.


48
Abbreviated Title: Phase II M7824 in UC
Version Date: 06/23/2021
5.3
SAMPLE STORAGE, TRACKING AND DISPOSITION
Samples will be ordered in CRIS and tracked through a Clinical Trial Data Management system. 
Should a CRIS screen not be available, the CRIS downtime procedures will be followed. Samples 
will not be sent outside the National Institutes for Health (NIH) without appropriate approvals 
and/or agreements, if required.
5.3.1
Laboratory of Pathology
All consenting patients with available tissue will undergo comprehensive Omics analysis on the 
tumor and normal DNA, RNA. Samples collected from patients for Omics studies will be labeled 
with the medical record number, patient name, accessioning with SoftPath, barcode generated by 
Labmatrix and an assigned unique identifier. 
This information will not be released to patients or families as these results are considered 
exploratory and of no established clinical utility. Research samples will be labeled with the Study 
ID number, barcode from Labmatrix and samples ID which is sequentially determined (e.g. 
CL0001, CL0002, etc., which is automatically coded by the LIMS system utilized ). Laboratory 
personnel will store the key to the code in a secure, password protected database accessible only 
to them.
The entire DNA and RNA sequence data will be deposited in secure OncoGenomics server which 
exists within the NIH firewall. All data is coded and stripped of identifiable information. The code 
is kept by the principal investigator  and the companion protocol PI and/or enrolling investigator. 
The data is stored in the form of coded BAM files, and processed vcf files contacting all calls in 
the germline and tumor DNA. The investigator will have access only to the subdirectory that 
contains the data from his/her patients. The folder can only be accessed using the investigators 
NIH username and password. All data will be coded and stripped of identifiable information.
Tissues designated for clinical diagnostics are transported to the Laboratory of Pathology (LP) 
where they are examined grossly and relevant portions are fixed, embedded in paraffin and 
sectioned and stained for diagnostic interpretation. Unutilized excess tissue that is not placed in 
paraffin blocks  is stored in formalin for up to three months, in accordance with College of 
American Pathologists/Joint Commission on Accreditation of Healthcare Organizations 
(CAP/JCAHO) guidelines, and then discarded. Following completion of the diagnostic workup, 
the slides and tissue blocks are stored indefinitely in the LP’s clinical archives. All specimens are 
catalogued and retrieved utilizing the clinical laboratory information systems, in accordance with 
CAP/JCAHO regulations. The use of any stored specimens for research purposes is only allowed 
when the appropriate IRB approval has been obtained. In some cases, this approval has been 
obtained via the original protocol on which the patient was enrolled. 
5.3.2
Bottaro 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. 
Please contact Dr. Bottaro to notify of biopsy date and time at 240-858-3967 or Rene Costello at 
240-858-3889 and to arrange for pick-up of sample.


49
Abbreviated Title: Phase II M7824 in UC
Version Date: 06/23/2021
5.3.3
Figg lab 
All samples sent to the Blood Processing Core (BPC) will be barcoded, with data entered and 
stored in the Labmatrix utilized by the BPC. This is a secure program, with access to Labmatrix 
limited to defined Figg lab personnel, who are issued individual user accounts. Installation of 
Labmatrix is limited to computers specified by Dr. Figg. These computers all have a password 
restricted login screen. 
Labmatrix creates a unique barcode ID for every sample and sample box, which cannot be traced 
back to patients without 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 barcoded 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.  
Access to stored clinical samples is restricted. Samples will be stored until requested by a 
researcher named on the protocol. All requests are monitored and tracked in 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 BPC. 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. 
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. If, at any time, a patient withdraws 
consent, the participants 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. The PI will record any 
loss or unanticipated destruction of samples as a deviation. Reporting will be per the requirements 
of Section 7.2.
Sample barcodes are linked to patient demographics and limited clinical information. This 
information will only be provided to investigators listed on this protocol, via registered use of the 
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 
pharmacokinetic data with these variables.
5.3.4
Clinical Services Program
All data associated with the patient samples is protected by using a secure database. All Clinical 
Support Laboratory Staff receive annual training in maintaining records’ confidentiality. All 
samples drawn at the NIH Clinical Center will be transported to the Clinical Support Laboratory 
at the Frederick National Laboratory for Cancer Research by couriers.


50
Abbreviated Title: Phase II M7824 in UC
Version Date: 06/23/2021
Samples will be tracked and managed by Central Repository database, where there is no link to 
personal identifiable information. All samples will be stored in either a -80ºC freezer or vapor 
phase liquid nitrogen. These freezers are located at NCI Frederick Central Repository in Frederick, 
Maryland.
NCI Frederick Central Repositories (managed under a subcontract) store, among other things, 
biological specimens in support of NIH clinical studies. All specimens are stored in secure, limited-
access facilities with sufficient security, backup, and emergency support capability and monitoring 
to ensure long-term integrity of the specimens for research. 
Specimens are stored in accordance with applicable HHS and FDA Protection of Human Subjects 
Regulations in accordance with the subcontractor’s Federal-wide Assurance. The subcontractor’s 
role limited to clinical research databases and repositories containing patient specimens. The 
subcontractor does not conduct or have any vested interest in research on human subjects but does 
provide services and support the efforts of its customers, many of which are involved in research 
on human subjects. 
It is the intent and purpose of the subcontractor to accept only coded, linked samples and sample 
information. To the limit of our ability, every effort will be made to ensure that protected 
information is not sent electronically or by hard copy or on vial labels. 
Sample data is stored in the Biospecimen Inventory System II (BSI). This inventory tracking 
system is used to manage the storage and retrieval of specimens as well as to maintain specimen 
data. BSI is designed for controlled, concurrent access. It provides a real-time, multi-user 
environment for tracking millions of specimens. The system controls how and in what order 
database updates and searches are performed. This control prevents deadlocks and race conditions. 
For security, BSI has user password access, 3 types of user access levels, and 36 user permissions 
(levels of access) that can be set to control access to the system functions. BSI provides audit 
tracking for processes that are done to specimens including shipping, returning to inventory, 
aliquoting, thawing, additives, and other processes. BSI tracks the ancestry of specimens as they 
are aliquoted, as well as discrepancies and discrepancy resolution for specimens received by the 
repository. If a specimen goes out of the inventory, the system maintains data associated with the 
withdrawal request. Vials are labeled with a unique BSI ID which is printed in both eye-readable 
and bar-coded format. No patient-specific information is encoded in this ID. 
Investigators are granted view, input, and withdrawal authority only for their specimens. They may 
not view specimen data or access specimens for which they have not been authorized. Access to 
specimen storage is confined to repository staff. Visitors to the repositories are escorted by 
repository staff at all times.
5.4
SAMPLES FOR GENETIC/GENOMIC ANALYSIS
5.4.1
Description of the scope of genetic/genomic analysis
Using the tissue, and blood samples we will perform next research generation sequencing (NGS) 
of DNA (Exome or Panel).


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5.4.2
Privacy and Confidentiality of medical information/biological specimens
Initially the samples of each patient will be barcoded. At no time will patient’s names be used on 
the blood and tissue samples. Sometimes, because a group collaboration or journal policy requires 
it, a subject’s genetic data will be deposited in a database such as dbGaP. Although there is 
controlled access to such a database, such a submission carries theoretical risks of revealing the 
identity of the subject. This is discussed in the consent.
5.4.3
Management of Results
Subjects will be contacted if a clinically actionable gene variant is discovered. Clinically 
actionable findings for the purpose of this study are defined as disorders appearing in the 
American College of Medical Genetics and Genomics recommendations for the return of 
incidental findings that is current at the time of primary analysis. (A list of current guidelines is 
maintained on the CCR intranet:
https://ccrod.cancer.gov/confluence/display/CCRCRO/Incidental+Findings+Lists).
Subjects will be contacted at this time with a request to provide a blood sample to be sent to a 
CLIA certified laboratory. 
If the research findings are verified in the CLIA certified lab, the subject will be offered the 
opportunity to come to NIH (at our expense) to have genetic education and counseling with the 
NCI Genetics Branch to explain this result. If the subject does not want to come to NIH, a referral 
to a local genetic healthcare provider will be provided (at their expense). This is the only time 
during the course of the study that incidental findings will be returned. No interrogations 
regarding clinically actionable findings will be made after the primary analysis.
5.4.4
Genetic counseling
The costs of CLIA testing will be paid for by the Center for Cancer Research, the Branch, or the 
Principal Investigator.  If the health history, family history, or tumor diagnosis from the Laboratory 
of Pathology at the NIH Clinical Center suggests that the participant might benefit from genetic 
testing, we will discuss this with him/her.
6
DATA COLLECTION AND EVALUATION 
6.1
DATA COLLECTION
The PI will be responsible for overseeing entry of data into an in-house password protected 
electronic system (C3D) and ensuring data accuracy, consistency and timeliness. The principal 
investigator, associate investigators/research nurses and/or 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.
All adverse events, including clinically significant abnormal findings on laboratory evaluations, 
regardless of severity, will be followed until return to baseline or stabilization of event.
Document AEs from the first study drug administration, Study Day 1, through 30 days after the 
end of treatment. Beyond 30 days after the last dose of study drug, only adverse events which are 
serious and related to the study intervention need to be recorded.


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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. 
6.1.1
Tumor data
The tumor disease information that will be documented and verified at the screening visit for 
each subject includes the following. All these details will be documented in patient’s history 
and physical exam and also recorded in the C3D database.
Detailed history of the tumor, including histopathological diagnosis, grading and staging in 
accordance with the Union Internationale Contre le Cancer Tumor Node Metastasis 
Classification at diagnosis (UICC TNM).
o The T and M category (T1-3 vs T4 and M0 or M1) of the tumor at the time of study entry, 
based on screening assessments
All therapy used for prior treatment of the tumor (including surgery, radiotherapy and 
chemotherapy, immunotherapy).
Any other conditions that were treated with chemotherapy, radiation therapy, or 
immunotherapy.
6.1.2
Concomitant Medications and Therapies
All concomitant medications taken by the subject during the trial, from the date of signature of 
informed consent are to be recorded in the appropriate section of the eCRF, noting the name, dose, 
duration and indication of each drug. Nondrug interventions (other than vitamins) and any changes 
to a concomitant medication or other intervention should also be recorded in the eCRF.
6.1.3
DATA ELEMENTS

Documentation of dosage and timing of drug administration

Outside laboratory, radiologic, and pathology results will be sent to the PI and entered into 
NCI C3D at NIH


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Abbreviated Title: Phase II M7824 in UC
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
NIH labs and tests will be downloaded into C3D
6.2
DATA SHARING PLANS
6.2.1
Human Data Sharing Plan
Human data generated in this research for future research will be shared as follows:

Coded, linked data in an NIH-funded or approved public repository.  

Coded, linked data in another public repository.  

Identified or coded, linked data in BTRIS (automatic for activities in the Clinical Center)
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.
Data will 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 8 weeks. After 
one year response evaluation will be done every 12 weeks. In addition to a baseline scan, 
confirmatory scans should also be obtained 4-8 weeks (not less than 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) [45]. 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: 

By CT scan: 
o
Scan slice thickness 5 mm or under: as >10 mm
o
Scan slice thickness >5 mm: double the slice thickness 


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Abbreviated Title: Phase II M7824 in UC
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
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 
preferred to evaluation by clinical examination unless the lesion(s) being followed cannot be 
imaged but are assessable by clinical exam.


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Abbreviated Title: Phase II M7824 in UC
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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.
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.
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).
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.    


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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).
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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Abbreviated Title: Phase II M7824 in UC
Version Date: 06/23/2021
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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Abbreviated Title: Phase II M7824 in UC
Version Date: 06/23/2021
For Patients with Non-Measurable Disease (i.e., Non-Target Disease)
Non-Target Lesions
New Lesions
Overall Response
CR
No
CR
Non-CR/non-PD
No
Non-CR/non-PD*
Not all evaluated
No
not evaluated
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
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 will be defined as the duration of time from start of treatment to time of progression or death, 
whichever occurs first.
6.3.6
Response Review
6.3.6.1
Best overall response (BOR) 
The duration of best overall response is measured from the time measurement criteria are met for 
CR, PR or SD (whichever is first recorded) until the first date that recurrent or progressive disease 
is objectively documented (taking as reference for progressive disease the smallest measurements 
recorded since the treatment started).
The duration of overall CR is measured from the time measurement criteria are first met for CR 
until the first date that progressive disease is objectively documented.


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6.3.6.2
Duration of stable disease 
Stable disease is measured from the start of the treatment until the criteria for progression are met, 
taking as reference the smallest measurements recorded since the treatment started, including the 
baseline measurements. Stable Disease (SD) when sum of all target lesions does not qualify for 
CR/PR/PD for Target Lesion Response and Persistence of non-target lesions on Non-Target 
Lesion Response.
6.4
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). 
7
NIH REPORTING REQUIREMENTS/DATA AND SAFETY MONITORING PLAN
7.1
DEFINITIONS
Please refer to definitions provided in Policy 801: Reporting Research Events found here.
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 here. 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 here.
7.3
NCI CLINICAL DIRECTOR REPORTING
Problems expeditiously reported to the OHSRP in iRIS will also be reported to the NCI Clinical 
Director. A separate submission is not necessary as reports in iRIS will be available to the Clinical 
Director.
In addition to those reports, all deaths that occur within 30 days after receiving a research 
intervention should be reported via email to the Clinical Director unless they are due to progressive 
disease.  
To report these deaths, please send an email describing the circumstances of the death to Dr. Dahut 
at NCICCRQA@mail.nih.gov within one business day of learning of the death.


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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. 
8
SPONSOR PROTOCOL/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 
a clinically significant 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 Events (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 Section 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 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.


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
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).
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.

M7824 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 


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Abbreviated Title: Phase II M7824 in UC
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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.
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  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 8.1.6.
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 overall survival which includes death due to disease progression is part of the study objectives, 
and captured as an endpoint in this study, death due to disease progression will not be reported in 
expedited manner to the sponsor. However, if there is evidence suggesting a casual 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
Reporting will be per the collaborative agreement.


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Abbreviated Title: Phase II M7824 in UC
Version Date: 06/23/2021
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 (Section 8.1.2) should be reported as SAEs. 
The outcome of all pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, 
normal birth, or congenital abnormality) 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 125 
days after treatment.
Pregnancy of the patient’s partner is not considered to be an AE. However, the outcome of all 
pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, normal birth, or 
congenital abnormality) occurring from the date of the first dose until 125 days after the last dose 
should, if possible, be followed up and documented.
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 in expedited manner to the FDA in accordance 
to 21 CFR 31.2.32.  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
SPONSOR PROTOCOL NON-ADHERENCE REPORTING
Protocol non-adherence is defined as any noncompliance with the clinical trial protocol, 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 non-adherence identified by the 
Staff or the site Monitor on the OSRO Site Protocol Non-Adherence Log.  The protocol-specific, 
cumulative non-adherence log should be maintained in the site essential documents file and 
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month over the duration of the study. In addition, any non-adherence to the protocol should be 
documented in the participant’s source records and reported to the local IRB per their guidelines. 
OSRO required protocol non-adherence 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
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 that 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) Monitoring 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. The intensity and frequency of monitoring will 
be based on several factors, including study type, phase, risk, complexity, expected enrollment 
rate, and any unique attributes of the study and the site. OSRO Monitoring visits and related 
activities will be conducted throughout the life cycle of each protocol, with the first activity being 
before study start 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 take place at the study 
site(s).  Monitoring visit reports will describe visit activities, observations, findings of protocol 
non-adherence and associated action items or follow-up required for resolution of findings.  
Monitoring reports will be distributed to the study PI, NCI CCR QA, coordinating center (if 
applicable) and the OSRO regulatory file.
If protocol non-adherence is identified by the Monitor (i.e., any noncompliance with the clinical 
trial protocol, GCP, or protocol-specific procedural requirements on the part of the participant, the 
Investigator, or the site Staff) the Monitor will note the observation, review with site Staff and if 
unresolved, request that the Staff document the non-adherence on the protocol-specific OSRO Site 
Protocol Non-Adherence Log (see Section 8.8).
10 STATISTICAL CONSIDERATIONS  
10.1 STATISTICAL HYPOTHESIS
10.1.1 Primary Endpoint(s) 
The primary endpoint of this trial is to evaluate the activity of bintrafusp alfa (M7824) as 
determined by objective response rate (ORR) in two metastatic urothelial carcinoma cohorts:
o
Cohort 1: Checkpoint inhibitor naïve

Cohort 1A: cisplatin ineligible

Cohort 1B: refractory post-platinum therapy


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o
Cohort 2: Checkpoint inhibitor previously treated patients

Cohort 2A: previously achieved a CR/PR 

Cohort 2B: previously had SD/PD
10.1.2 Secondary Endpoint(s)

To evaluate the activity of bintrafusp alfa (M7824) in urothelial carcinoma patients as 
determined by progression free survival (PFS) and overall survival (OS).

To obtain additional data to evaluate the safety of bintrafusp alfa (M7824) in urothelial 
carcinoma 
10.2 SAMPLE SIZE DETERMINATION
10.2.1 Cohort 1A: Checkpoint inhibitor naïve patients who are cisplatin-ineligible
In this cohort, it would be desirable to demonstrate that the treatment exceeds a 30% response rate. 
As such, in this cohort, this trial will be conducted using a Simon minimax two-stage phase II trial 
design (Simon R, Controlled Clinical Trials 10:1-10, 1989) to rule out an unacceptably low 
PR+CR rate of 15% (p0=0.15) in favor of an improved response rate of 40% (p1=0.40). With 
alpha=0.10 (probability of accepting a poor treatment=0.10) and beta = 0.20 (probability of 
rejecting a good treatment=0.20), the first stage will enroll 9 evaluable patients, and if 0 to 1 of 9 
have a clinical response, then no further patients will be accrued in this trial.  If 2 or more of the 
first 9 patients have a response, then accrual would continue until a total of 16 evaluable patients 
have been treated. As it may take up to several months to determine if a patient has experienced a 
response, a temporary pause in the accrual may be necessary to ensure that enrollment to the 
second stage is warranted. If there are 2 to 4 patients with a response out of 16 patients, this would 
be an uninterestingly low response rate. If there were 5 or more of 16 (31.3%) who experienced a 
response, this would be sufficiently interesting to warrant further study in later trials. Under the 
null hypothesis (15% response rate), the probability of early termination is 60.0%.
10.2.2 Cohort 1B: Checkpoint inhibitor naïve patients who are refractory post-platinum therapy
In this cohort, it would be desirable to demonstrate that the treatment exceeds a 20% response rate. 
As such, in this cohort, this trial will be conducted using a Simon minimax two-stage phase II trial 
design (Simon R, Controlled Clinical Trials 10:1-10, 1989) to rule out an unacceptably low 
PR+CR rate of 10% (p0=0.10) in favor of an improved response rate of 40% (p1=0.40). With 
alpha=0.10 (probability of accepting a poor treatment=0.10) and beta = 0.10 (probability of 
rejecting a good treatment=0.10), the first stage will enroll 8 evaluable patients, and if 0 of 8 have 
a clinical response, then no further patients will be accrued in this cohort.  If 1 or more of the first 
8 patients have a response, then accrual would continue until a total of 15 evaluable patients have 
been treated. As it may take up to several months to determine if a patient has experienced a 
response, a temporary pause in the accrual may be necessary to ensure that enrollment to the 
second stage is warranted. If there are 1 to 3 patients with a response out of 15 patients, this would 
be an uninterestingly low response rate. If there were 4 or more of 15 (26.7%) who experienced a 
response, this would be sufficiently interesting to warrant further study in later trials. Under the 
null hypothesis (10% response rate), the probability of early termination is 43.1%.


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10.2.3 Cohort 2A: Checkpoint inhibitor refractory patients with Complete Response (CR) or 
Partial Response (PR) as per RECIST 1.1
In this cohort, it would be desirable to demonstrate that the treatment exceeds a 15% response rate. 
As such, in this cohort, this trial will be conducted using a Simon minimax two-stage phase II trial 
design (Simon R, Controlled Clinical Trials 10:1-10, 1989) to rule out an unacceptably low 
PR+CR rate of 5% (p0=0.05) in favor of an improved response rate of 25% (p1=0.25). With 
alpha=0.10 (probability of accepting a poor treatment=0.10) and beta = 0.20 (probability of 
rejecting a good treatment=0.20), the first stage will enroll 12 evaluable patients, and if 0 of the 12 
have a clinical response, then no further patients will be accrued in this trial.  If 1 or more of the 
first 12 patients have a response, then accrual would continue until a total of 16 evaluable patients 
have been treated. As it may take up to several months to determine if a patient has experienced a 
response, a temporary pause in the accrual may be necessary to ensure that enrollment to the 
second stage is warranted. If there are 1 to 2 patients with a response out of 16 patients, this would 
be an uninterestingly low response rate. If there were 3 or more of 16 (18.8%) who experienced a 
response, this would be sufficiently interesting to warrant further study in later trials. Under the 
null hypothesis (5% response rate), the probability of early termination is 54.0%.
10.2.4 Cohort 2B. Checkpoint inhibitor refractory patients with Stable Disease (SD) or 
Progressive Disease (PD) as per RECIST 1.1
In this cohort, it would be desirable to demonstrate that the treatment exceeds a 5% response rate.  
As such, in this cohort, this trial will be conducted using a Simon minimax two-stage phase II trial 
design (Simon R, Controlled Clinical Trials 10:1-10, 1989) to rule out an unacceptably low 
PR+CR rate of 5% (p0=0.05) in favor of an improved response rate of 20% (p1=0.20). With 
alpha=0.10 (probability of accepting a poor treatment=0.10) and beta = 0.20 (probability of 
rejecting a good treatment=0.20), the first stage will enroll 12 evaluable patients, and if 0 of the 12 
have a clinical response, then no further patients will be accrued in this trial.  If 1 or more of the 
first 12 patients have a response, then accrual would continue until a total of 21 evaluable patients 
have been treated. As it may take up to several months to determine if a patient has experienced a 
response, a temporary pause in the accrual may be necessary to ensure that enrollment to the 
second stage is warranted. If there are 1 to 2 patients with a response out of 21 patients, this would 
be an uninterestingly low response rate. If there were 3 or more of 21 (14.3%) who experienced a 
response, this would be sufficiently interesting to warrant further study in later trials. Under the 
null hypothesis (5% response rate), the probability of early termination is 54.0%.
These phase II cohorts treated with TGFB trap alone may require up to 15+16+16+21=68 
evaluable patients. To allow for a small number of inevaluable patients, this trial of up to 4 different 
cohorts will have an accrual ceiling of 75 patients. It is expected that 2-3 patients per month may 
enroll onto the trial; thus, it is expected that this trial may complete accrual in 2 to 3 years.
10.3 POPULATIONS FOR ANALYSES
Modified intention to treat: all patients who receive at least one dose of each agent will be included 
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10.4 STATISTICAL ANALYSES
10.4.1 General Approach
Response fractions, and time to event endpoints will be reported along with appropriate confidence 
intervals.
10.4.2 Analysis of the Primary Endpoints
Separately by cohort, the fraction of patients in phase II cohorts who experience a PR or CR using 
the study treatment will be determined by dividing the number responders by the total evaluable 
patients. The fraction will be reported along with 80% and 95% two-sided confidence intervals. 
10.4.3 Analysis of the secondary efficacy endpoints
Progression-free survival (PFS) will be determined using the Kaplan-Meier method, considering 
those who progress or die without progression as failures, and censoring those who do not.
Overall survival (OS) will be determined using the Kaplan-Meier method.
Each of these will be calculated starting from the date the patient enrolled onto the trial. 
Appropriate confidence intervals will be reported for each of these measures.
10.4.4 Baseline Descriptive Statistics
Demographic and baseline clinical characteristics of all patients will be reported.
10.4.5 Planned Interim Analyses
As indicated above, for each phase II cohort, using a Simon two-stage design, after the required 
number of evaluable patients have been enrolled in the first stage, an analysis of the response rate 
will be undertaken to determine if there are sufficient responses to proceed to the second stage. 
10.4.6 Sub-Group Analyses
Analyses will be performed by arm without further sub-analyses.
10.4.7 Tabulation of Individual Participant Data
None will be provided.
10.4.8 Exploratory Analyses
1. Determine peripheral immune modulation using: 

Multi-parametric flow cytometry – immune subset analysis

Cytokine/chemokine analysis  (i.e TGF-, IFN-, IL-6, IL-8, etc.)

Blood-based immune parameters (neutrophil-to-lymphocyte ratio)

Circulating Tumor Cells (CTCs) and circulating cell-free tumor DNA (cfDNA)
2. Determine immune status of the tumor microenvironment using:

Multiplex IHC for PD-L1 expression, CD8, CD4, FoxP3 T-cell infiltration

RNA-Seq transcriptome sequencing for tumor/immune gene expression profile 
(and peripheral blood mononuclear cells

T-cell receptor (TCR) sequencing for T-cell clonality and MET protein levels

Next generation sequencing (TSO-500) for tumor biomarkers in tumor samples


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Any of these exploratory evaluations which generate quantitative measures will be done using 
descriptive statistics including confidence intervals when appropriate. Any statistical tests 
performed for evaluation of exploratory objectives will be done without formal adjustment for 
multiple comparisons, but in the context of the number of tests performed. 
11 COLLABORATIVE AGREEMENTS 
11.1 CRADA
This study will receive the investigational study agent under a Cooperative Research and 
Development Agreement (CRADA) with EMD Serono. CRADA Number: 02666. 
12 HUMAN SUBJECTS PROTECTIONS 
12.1 RATIONALE FOR SUBJECT SELECTION
Cisplatin ineligible or platinum refractory metastatic urothelial cancer patients may have received 
pior checkpoint inhibitor therapy or be checkpoint inhibitor naïve to enroll. Patients with 
metastatic urothelial cancer who received prior checkpoint inhibitors are left with limited options 
and the effect of subsequent immunotherapy treatment is unknown. While current PD-1/PD-L1 
checkpoint inhibtors have shown efficacy in checkpoint naïve patients who are either cisplatin 
ineligible or refractory response rates response rates are about 20% [46]. Therefore, it is imperative 
to improve on this response rate with drugs like M7824 that have potential of increasing response 
rates through immunomodulation. These reasons express the need to determine M7824 activity in 
our patient population. 
Participants who do not accept blood transfusions will be excluded. As there is a risk of severe 
bleeding with this study drug, 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 or adverse event data are currently available on the use of M7824 in patients 
less than 18 years of age, children are excluded from this study.
12.3
 PARTICIPATION OF SUBJECTS UNABLE TO GIVE CONSENT
Adults unable to give consent are excluded from enrolling in the protocol. However, it is possible 
that subjects enrolled in the protocol may permanently lose the capacity to consent for themselves 
during the course of this study. In the event this occurs, the subjects will remain in the study 
because there is a prospect of direct benefit (Section 12.5.2) from research participation. 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 
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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 to assess ongoing capacity of the subjects and to identify an LAR, as needed.
Please see Section 12.6.1 for consent procedure.
12.4 EVALUATION OF BENEFITS AND RISKS/DISCOMFORTS
Patients will receive evaluation of their disease at the National Cancer Institute’s Clinical Center.  
Potential adverse reactions attributable to the administration of the study drug utilized in this trial 
are discussed in Section 14. All care will be taken to minimize side effects, but they can be 
unpredictable in nature and severity. Patients will be examined and evaluated prior to enrollment. 
All evaluations to monitor the treatment of patients will be recorded in the patient chart. If patients 
suffer any physical injury as a result of the participation in this study, immediate medical treatment 
is available at the Clinical Center, National Cancer Institute, Bethesda, Maryland.
The potential benefit to a patient that goes onto study is a reduction in the bulk of their tumor 
which may or may not have favorable impact on symptoms and/or survival.
Although no compensation is available, any injury will be evaluated and treated in keeping with 
the benefits or care to which patients are entitled under applicable regulations. In all publications 
and presentations resulting from this trial, patients’ anonymity will be protected to the maximum 
extent possible. Authorized personnel from the National Cancer Institute (NCI) and Food and Drug 
Administration (FDA) or other regulatory authorities may have access to research files in order to 
verify that patients’ rights have been safeguarded. In addition, patient names will be given to the 
Central Registration to register patients onto the study.
12.5 RISKS/BENEFITS ASSESSMENT
12.5.1 Known Potential Risks
The primary risk to patients participating in this research study is the potential toxicity of the 
M7824. Potential adverse reactions attributable to the administration of the study drug utilized in 
this trial are discussed in Section 14.1.2. The protocol provides detailed and careful monitoring of 
all patients to assess for toxicity. Toxicity data will be collected and reviewed to ensure that there 
were no severe toxicities that would preclude further patient enrollment. Patients will be treated 
with therapeutic intent and response to the therapy will be closely monitored. 
12.5.1.1 Blood Sampling
Side effects of blood draws include pain and bruising, lightheadedness, and rarely, fainting. 
12.5.1.2 Electrocardiogram
Some skin irritation can occur where the ECG/EKG electrodes are placed. The test is completely 
painless, and generally takes less than a minute to perform.
12.5.1.3 Tumor Biopsy 
Needle biopsy is minimally invasive and is typically a very safe procedure. Depending upon the 
site being biopsied and the type of biopsy being performed, risks can include infection of the 


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biopsy site, development of a hematoma, and bleeding. Rarely more significant complications can 
occur when structures near the biopsy target are entered with the needle (e.g. puncture of lung or 
bowel). Surgical procedures for biopsy specimens will not be conducted for the sole purpose of 
research specimen collection, although when surgical biopsies are performed for clinical or NCI 
protocol requirements, samples may be requested as part of participation on this trial. In this 
instance, no added risk is incurred.
12.5.1.4 Imaging
In addition to the radiation risks discussed below, CT scans may include the risks of an allergic 
reaction to the contrast. Participants might experience hives, itching, headache, difficulty 
breathing, increased heartrate and swelling.
12.5.1.5 MR Imaging
The risks of MR imaging are relatively small. Participants undergoing gadolinium enhanced MRIs 
may also be at risk for kidney damage.MRIs include the additional risk of damage to hearing.
12.5.1.6 Risks of exposure to ionizing radiation 
This research study involves up to 7 CT C/A/P scans and up to 3 CT-guided biopsies. Pre-treatment 
tissue biopsy and tissue availability is mandatory. On-treatment biopsy is required unless obtaining 
biopsy is not technically or clinically feasible. Post-treatment biopsy is optional. Subjects will be 
exposed to up to approximately 10.1 rem.
12.5.1.7 Non-Physical Risks of Genetic Research
12.5.1.7.1 Risk of receiving unwanted information
Anxiety and stress may arise as a result of the anticipation that unwanted information regarding 
disease related DNA sequencing or disease tendencies, or misattributed paternity. Patients will be 
clearly informed that the data related to DNA sequencing and genetic analysis is coded, 
investigational and will not be shared with patients, family members or health care providers.
12.5.1.7.2 Risk related to possibility that information may be released
This includes the risk that data related to genotype, DNA sequencing or risk for disease tendency 
or trait can be released to members of the public, insurers, employers, or law enforcement agencies. 
Although there are no plans to release results to the patients, family members or health care 
providers, this risk will be included in the informed consent document.
12.5.1.7.3 Risk to family or relatives
Family members or relatives may or may not want to be aware of familial tendencies or genetic 
risks of disease which may cause anxiety about possible future health problems. As previously 
noted, patients will be notified of any medically significant and actionable incidental findings. 
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12.5.2 Known Potential Benefits
Patients who previously received checkpoint therapy may benefit from receiving further 
checkpoint block with M7824 they would otherwise not obtain in a standard of care setting. 
Immediate potential benefits include potential response to tumor progression, palliation of 
symptoms, and improved outcomes. Long range potential benefits of this study will build on 
knowledge and the science used to develop therapies for future cancer patients
12.5.3 Assessment of Potential Risks and Benefits
A number of clinically appropriate strategies to minimize risk to patients have been built into the 
protocol through the means of inclusion/exclusion criteria, monitoring strategies, and management 
guidelines. Overall, the potential benefits of M7824 for patients retaining the ability to consent and 
those who lose capacity to consent during the course of the trial outweigh the risks associated with 
the proposed entry into this trial.
12.6 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 
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.
Note: When required, witness signature will be obtained similarly as described for the investigator 
and participant as described below.
Consent will be documented with required signatures on the physical document (which includes 
the printout of an electronic document sent to participant) or on the electronic document. 
Signatures on electronic documents are described below.  Note: FDA only regulates electronic 
signatures (i.e., an electronic timestamp is generated at the time of signature) in FDA regulated 
research. 
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 Adobe platform (which is not 21 CFR Part 11 
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During the consent process, participants and investigators will view individual copies of the 
approved consent document on screens at their respective locations.
Both the investigator and the subject will sign the document with a hand signature using a finger, 
stylus or mouse.
Electronic signature on electronic document
When permitted by the NIH Clinical Center, electronic signatures may be obtained using the 
iMedConsent platform once it is designated as 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.
The identity of the participant will be determined by a prompt which will require the provision of 
information from a form of government issued identification prior to obtaining the signature. If 
participant does not have such identification available, security questions will be used to confirm 
identity.
Both the investigator and the subject will sign the document electronically per system prompts.
12.6.1 Consent Process for Adults Who Lack Capacity to Consent to Research Participation
For participants addressed in Section 12.3, an LAR will be identified consistent with Policy 403 
and informed consent obtained from the LAR, as described in Section 12.6.
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) 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

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).


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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 Conference 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 NCI 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.
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 


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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 AND INVESTIGATIONAL DEVICE INFORMATION  
14.1 M7824 (BINTRAFUSP ALFA, MSB0011359C) (IND # 149968)
14.1.1 Source/Acquisition and Accountability 
M7824 is manufactured and supplied for the trial by EMD Serono Research and Development 
Institute. The investigational product will be dispensed at the direction of an investigator for 
administration to a study participant enrolled on the clinical trial. Disposal of expired or unused 
product will be returned to the manufacturer or disposed of according to standard site procedures 
based on agreement between the manufacturer and the site.
14.1.2 Toxicity 
In a phase 1, open-label 3+3 dose-escalation study of M7824 in 16 patients, 3 patients experienced 
grade 3 drug-related adverse events including skin infection secondary to grade 2 cccc, lipase 
increased, and colitis with associated anemia. There were no grade 4 – 5 treatment related adverse 
events. Please see table below for details:


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Treatment-related TEAE Leading to Permanent Treatment Discontinuation by System 
Organ Class and Preferred Term in ≥ 2 participants in the Pooled Analysis of Dose 
Expansion Cohorts (Source: Investigator Brochure v6)


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As of the data cutoff of 24 August 2018, 7 deaths (1.1%) were reported as due to treatment-related 
TEAE, however an additional death (primary cause of intra-abdominal hemorrhage, assessed as 
treatment-related) started more than 30 days after the end of treatment and is therefore is not 
included in above count of treatment-related death. In Study EMR200647-001, 3 participants had 
a treatment-related death: 1 participant had dyspnea, hemolysis and thrombocytopenia, 1 
participant had an intracranial tumor hemorrhage and 1 participant had pneumonia. In Study 
MS200647-0008, 4 participants had a treatment-related death: 2 participants died due to ILD, 1 
participant due to sudden death and 1 participant due to septic shock. Please refer to IB v 6.0 
Section 5.2.2.9 for a summary of the SAEs from the Sponsor’s Global Drug Safety database from 
25 August 2018 to 31 December 2019 for ongoing studies.  
In dose escalation phase of M7824 studies, 2 DLTs were observed at 20mg/kg dose level . One (1) 
subject (20 mg/kg, with underlying cervical cancer and medical history of radiation therapy was 
diagnosed with colitis (with subsequent bleeding and anemia) during the 21 day DLT observation 
period of the escalation part of the study. Colitis and associated secondary events of Grade 3 
anemia and Grade 3 rectal hemorrhage (which occurred in a previously radiated area) were 
considered dose limiting. Other subject (20 mg/kg) with past history of recurrence of parotid 
cancer in the left mastoid sinus after heavy particle therapy and multiple chemotherapies 
experienced fainting and fall, CT scan revealed Grade 3 intracranial tumor hemorrhage in left 
mastoid sinus.  The event occurred after 24 hours from first dose of M7824 during the 21-day DLT 
observation period of the escalation part of the study and was assessed as related to M7824.
Highest dose tested was 30mg/kg , and no MTD observed for M7824.
Based on accrued safety profile of M7824 in phase I studies, and with scientific rationale and 
consistency with observed safety findings with similar class drugs ( anti PD-1/PDL-1 and anti-
TGF-β targeting therapies), important identified and potential risks  for M7824 were determined. 
Important identified Risks includes Infusion related reactions (IRR), immune related adverse 
events (irAE) & skin adverse events due to anti-TGF-β action of M7824 and are adverse drug 
reactions for M7824.
IRR is a composite term which includes Reactions: Anaphylactic reaction, Drug hypersensitivity, 
Hypersensitivity, Infusion related reaction, Type I hypersensitivity and Signs and Symptoms: 
Abdominal pain, Back pain, Chills, Dyspnoea, Flushing, Hypotension, Pyrexia, Urticaria, 
Wheezing. 
irAEs identified risk for M7824 (based on PDL-1blockade) are Thyroiditis, autoimmune 
thyroiditis, hypothyroidism, hyperthyroidism, Diabetes mellitus, Type I diabetes, type I diabetes 
mellitus, adrenal insufficiency, adrenalitis, Colitis Enteritis, enterocolitis, Nephritis, acute kidney 
injury,  Myositis, Retinal microvasculitis, retinal vasculitis, rash, rash generalized, maculo-papular 
rash, erythematous, rash, pruritic rash, pemphigoid, Pneumonitis Interstitial pneumonitis, 
Interstitial lung disease.
irAEs potential risks for M7824 are Guillain-Barré syndrome, uveitis, pancreatisis, myasthenia 
gravis/myasthenic syndrome.
Skin AE ( TGF-β blockade mediated) include rash with hyperkeratosis, cutaneous squamous cell 
carcinoma, keratoacanthoma.


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Important potential risks includes treatment related anemia, delay in wound healing and 
embryofetal toxicity.
As of October 2018, more than 670 patients have been treated with M7824 1200mg flat dose q2w 
across multiple solid tumor expansion cohorts. 
The safety profile is consistent with other monotherapy checkpoint inhibitors, with the exception 
of keratoacanthomas and cutaneous squamous cell carcinomas ( similar to anti-TGF-β targeting 
therapy Fresolimumab and TGF-β genetic mutation inheritance -Ferguson- Smith Syndrome) 
which have occurred in approximately  7% of M7824 treated patients, and are well managed with 
surgical excision. These lesions have not been a criterion for treatment discontinuation.
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, mild and moderate mucosal bleedings, 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 (e.g., gum bleeding, nose bleeds, coughing up blood, blood in their urine, 
or blood in the stool).
14.1.3 Formulation and preparation 
M7824 drug product is provided as a sterile liquid formulation. 
The Concentrate for Solution for Infusion (liquid formulation) is packaged at a 10 mg/mL 
concentration in USP / Ph. Eur. type I 50R or 20R vials which are filled with drug product solution 
to allow an extractable volume of 60 mL (600 mg/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 aluminum crimp seal closure. 
14.1.4 Stability and Storage 
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.
The liquid formulation is diluted directly with 0.9% saline solution. The chemical and physical in-
use stability for the infusion solution of M7824 in 0.9% saline solution has been demonstrated for 
a total of 72 hours at 2°C to 8°C and 24 hours at room temperature. However, from a 
microbiological point of view, the diluted solution should be used immediately and is not intended 
to be stored unless dilution has taken place in controlled and validated aseptic conditions. If not 


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used immediately, in-use storage times and conditions prior to administration are the responsibility 
of the user. Do not freeze or shake the diluted solution.
No other drugs should be added to the infusion containers containing M7824.
14.1.5 Administration procedures
M7824 will be administered as a 1-hour an intravenous (IV) infusion once every two weeks of 
each cycle. M7824 is administered as IV infusion via a peripheral or central vascular access device 
(VAD). Confirm patient has a port with titanium as the main material before accessing the Central 
VAD. 
A 
0.2 
micron 
polyethersulfone 
(PES) 
in-line 
filter 
is 
mandatory 
for 
administration.Premedications may be administered per Section 3.3.1.1.
As with all monoclonal antibody therapies, there is a risk of allergic reaction including 
anaphylactic shock. M7824 should be administered in a setting that allows for immediate access 
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. 
Patients must be observed for 2 hours after the first M7824 dose. If no reactions are observed, the 
patients need to be monitored for only 30 minutes after subsequent doses. 
If an allergic reaction occurs, the subject must be treated according to the best available medical 
practice. Please see the guidelines for handling of infusion-related reaction in Section 3.3.1.4.
Investigators should also monitor subjects closely for potential irAEs, which may become manifest 
after several weeks of treatment. Such events may consist of persistent rash, diarrhea and colitis, 
autoimmune hepatitis, arthritis, glomerulonephritis, cardiomyopathy, or uveitis and other 
inflammatory eye conditions. 
Vital signs must be measured within 30 minutes before and 30 minutes following M7824 infusions. 
In addition, at least one time during the infusion of M7824.
14.1.6 Incompatibilities 
None known


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052): a multicentre, single-arm, phase 2 study. Lancet Oncol 2017, 18(11):1483-1492.
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Iglesias M, Sevillano M, Ibiza S, Canellas A, Hernando-Momblona X et al: TGFbeta 


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drives immune evasion in genetically reconstituted colon cancer metastasis. Nature 
2018.
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Lan Y, Zhang D, Xu C, Hance KW, Marelli B, Qi J, Yu H, Qin G, Sircar A, Hernandez 
VM et al: Enhanced preclinical antitumor activity of M7824, a bifunctional fusion 
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medicine 2018, 10(424).
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Grenga I, Donahue RN, Gargulak ML, Lepone LM, Roselli M, Bilusic M, Schlom J: 
Anti-PD-L1/TGFbetaR2 (M7824) fusion protein induces immunogenic modulation 
of human urothelial carcinoma cell lines, rendering them more susceptible to 
immune-mediated recognition and lysis. Urologic oncology 2017.
25.
Strauss J, Heery C, Schlom J, Madan RA, Cao L, Kang Z, Lamping E, Marte JL, 
Donahue RN, Grenga I et al: Phase 1 trial of M7824 (MSB0011359C), a bifunctional 
fusion protein targeting PD-L1 and TGF-beta, in advanced solid tumors. Clin 
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immune-mediated recognition and lysis. Urologic oncology 2018, 36(3):93.e91-93.e11.
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David JM, Dominguez C, McCampbell KK, Gulley JL, Schlom J, Palena C: A novel 
bifunctional anti-PD-L1/TGF-β Trap fusion protein (M7824) efficiently reverts 
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6(10):e1349589-e1349589.
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Jochems C, Tritsch SR, Pellom ST, Su Z, Soon-Shiong P, Wong HC, Gulley JL, Schlom 
J: Analyses of functions of an anti-PD-L1/TGFβR2 bispecific fusion protein 
(M7824). Oncotarget 2017, 8(43):75217-75231.
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Gatti-Mays ME, Gulley JL: M7824: A promising new strategy to combat cancer 
immune evasion. Oncoscience 2018, 5(11-12):269-270.
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Galsky MD, Hahn NM, Rosenberg J, Sonpavde G, Hutson T, Oh WK, Dreicer R, 
Vogelzang N, Sternberg C, Bajorin DF et al: A consensus definition of patients with 
metastatic urothelial carcinoma who are unfit for cisplatin-based chemotherapy. 
Lancet Oncol 2011, 12(3):211-214.
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Strauss J, Heery CR, Schlom J, Madan RA, Cao L, Kang Z, Lamping E, Marte JL, 
Donahue RN, Grenga I et al: Phase I Trial of M7824 (MSB0011359C), a Bifunctional 
Fusion Protein Targeting PD-L1 and TGFbeta, in Advanced Solid Tumors. Clin 
Cancer Res 2018.


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34.
Guleria I, Khosroshahi A, Ansari MJ, Habicht A, Azuma M, Yagita H, Noelle RJ, Coyle 
A, Mellor AL, Khoury SJ et al: A critical role for the programmed death ligand 1 in 
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Lepone LM, Donahue RN, Grenga I, Metenou S, Richards J, Heery CR, Madan RA, 
Gulley JL, Schlom J: Analyses of 123 Peripheral Human Immune Cell Subsets: 
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Not Detected in Analysis of Standard Immune Cell Types. J Circ Biomark 2016, 5:5.
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Messiou C, Hillengass J, Delorme S, Lecouvet FE, Moulopoulos LA, Collins DJ, 
Blackledge MD, Abildgaard N, Ostergaard B, Schlemmer HP et al: Guidelines for 
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Petralia G, Padhani AR, Pricolo P, Zugni F, Martinetti M, Summers PE, Grazioli L, 
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Taylor SA, Mallett S, Ball S, Beare S, Bhatnagar G, Bhowmik A, Boavida P, 
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Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, 
Arbuck S, Gwyther S, Mooney M et al: New response evaluation criteria in solid 


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tumours: revised RECIST guideline (version 1.1). European journal of cancer 
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Niglio SA, Jia R, Ji J, Ruder S, Patel VG, Martini A, Sfakianos JP, Marqueen KE, 
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Ligand-1 Blockade in Patients with Platinum-resistant Metastatic Urothelial 
Cancer: A Systematic Review and Meta-analysis. European Urology.


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16 APPENDICES
16.1 APPENDIX A: STUDY CALENDAR
All Cycles (28 days each)
Screening2
C1
D1
C1
D15
C2
D1
C2
D15
C3
D1
C3
D15
C4
D1
C4
D15
C5
D1
C5
D15
C6
D1
C6
D15& 
Beyond
EOT visit
Follow up9,11
History/PE incl 
weight and skin 
assessment 12
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Confirmation of 
pathology/Biopsy1
X
X
X
ECOG, Vital Signs
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Tumor evaluation/
measurements
X
X
X
X8,9
M78243,4 
X
X
X
X
X
X
X
X
X
X
X
X
Lab assessments5 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Pregnancy test6 
X
X
X
X
X
X
X
Lymphocyte 
phenotyping7 
X
ECG
X
CT C/A/P or 
CT C+MRI A/P8,9,10 
X
X
X
X8,9
X
Follow-up Phone 
calls/emails
X9
Correlative Studies
Please refer to Section 5.2


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1.
Pre-treatment tissue biopsy and/or tissue availability is mandatory. On-treatment biopsy is required unless obtaining biopsy is not technically 
or clinically feasible. Post-treatment biopsy is optional.
2.
Tests done at screening do not need to be repeated on baseline (C1D1) if performed within 21 days prior to initiation of study therapy.
3.
M7824 will be delivered intravenously every 2 weeks (+/- 3 days).
4.
Vital signs must be measured within 30 minutes before and 30 minutes following M7824 infusions. In addition, at least one time during the 
infusion of M7824.
5.
Laboratory assessments: CBC with differential, acute care panel (sodium, potassium, chloride, total CO2 (Bicarbonate), creatinine, glucose, 
urea nitrogen), mineral panel (albumin, calcium total, magnesium total, phosphorus), hepatic panel (alkaline phosphatase, ALT/GPT, 
AST/GOT, total bilirubin, direct bilirubin), ionized calcium, amylase, lipase, TSH with reflex T3 and T4, LDH, total protein, GGT, PT/INR, 
PTT, and urine analysis. Hepatitis B and C will be done at screening only.
6.
For females of childbearing-potential (within 3 days prior to initiation of study therapy).
7.
Lymphocyte phenotyping tests will be done to check the eligibility of HIV positive patients. HIV-positive patients are eligible only if CD4 
counts are greater than 350 cells/mm3 and viral load is undetectable.
8.
CT of chest, abdomen and pelvis with IV contrast (oral contrast as indicated) or CT of the chest without contrast and MRI abdomen/pelvis 
with tumor measurements. For this study patients should be re-evaluated for response every 8 weeks (+/- 10 days). If a scan identifies 
objective response or progressive disease, a confirmatory scan should be obtained 4-8 weeks following initial documentation of objective 
response or progression. In patients with clinical progression or unequivocal scan, confirmatory progression scan can be deferred. Scans 
will continue every 8 weeks until disease progression or start of a new anti-cancer treatment.
9.
After disease progression or in those subjects who were removed from study therapy for reasons other than disease progression, subjects 
will be followed every 12 weeks in clinic or by telephone/email for assessment of survival status, related adverse events and documentation 
of initiation of new anti-cancer therapy.
10. If appropriate screening imaging is done within 21 days of C1D1 repeat screening imaging is not required.
11. All SAEs ongoing at the 30-day (+/- 10 days) safety follow-up visit must be monitored and followed up by the investigator until stabilization 
or until the outcome is known, unless the subject is documented as “lost to follow-up.” In addition, all trial drug-related SAEs occurring 
after 30 day safety follow up visit and ongoing at the Safety Follow-up visit have to be followed up in the same manner.
12. 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).
.


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16.2 APPENDIX B: 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.


87
Abbreviated Title: Phase II M7824 in UC
Version Date: 06/23/2021
Appendix C: Management of ir AEs
16.2.1 Table A1
Management of Skin irAEs in Patients Treated With ICPis
1.0 Skin Toxicities
1.1 Rash/inﬂammatory dermatitis
Deﬁnition: Erythema multiforme minor (a targetoid reaction in the skin and mucous membranes usually triggered 
by infections, such as herpes simplex viruses, but can be associated with an immune-related drug eruption and if 
progresses to erythema multiforme major, it and can be a harbinger of SCAR, such as SJS), lichenoid (resembling 
the ﬂat-topped, polygonal, and sometimes scaly or hypertrophic lesions of lichen-planus), eczematous 
(inﬂammatory dermatitis characterized by pruritic, erythematous, scaly, or crusted papules or plaques on the skin, 
which is vulnerable to superinfection, psoriasiform [resembling the well-demarcated, erythematous, and scaly 
papules and plaques of psoriasis], morbilliform [a nonpustular, nonbullous measles-like exanthematous rash of the 
skin often referred to as “maculopapular” and without systemic symptoms or laboratory abnormalities, excluding 
occasional isolated peripheral eosinophilia, palmoplantar erythrodysesthesia [hand-foot syndrome; redness, 
numbness, burning, itching, and superﬁcial desquamation of the palms and soles], neutrophilic dermatoses [eg, 
Sweet syndrome], and others)
Diagnostic workshop
Pertinent history and physical examination
Rule out any other etiology of the skin problem, such as an infection, an effect of another drug, or a skin condition 
linked to another systemic disease or unrelated primary skin disorder
If needed, a biologic checkup, including a blood cell count and liver and kidney tests
Directed serologic studies if an autoimmune condition is suspected, such as lupus or dermatomyositis: a screening 
antinuclear antibody test, SS-A/Anti-Ro, SS-B/Anti-La if predominantly photodistributed/photosensitivity, 
antihistone, double-stranded DNA, and other relevant serologies. Consider expanding serologic studies or 
diagnostic work-up if other autoimmune conditions are considered based on signs, symptoms Skin biopsy
Consider clinical monitoring with use of serial clinical photography
Review full list of patient medications to rule out other drug-induced cause for photosensitivity
Grading
Management
Grading according to CTCAE is a challenge for skin. 
Instead, severity may be based on BSA, tolerability, 
morbidity, and duration.
G1: Symptoms do not affect the quality of life or 
controlled with topical regimen and/or oral antipruritic
Continue ICPi
Treat with topical emollients and/or mild-moderate 
potency topical corticosteroids
Counsel patients to avoid skin irritants and sun 
exposure
G2: Inﬂammatory reaction that affects quality of life and 
equires intervention based on diagnosis
Consider holding ICPi and monitor weekly for 
improvement. If not resolved, interrupt treatment until 
skin AE has reverted to Grade 1
Consider initiating prednisone (or equivalent) at dosing 
1 mg/kg, tapering over at least 4 weeks
In addition, treat with topical emollients, oral 
antihistamines, and medium- to high-potency topical 
corticosteroids
G3: As G2 but with failure to respond to indicated 
interventions for a G 2 dermatitis
Hold ICPi therapy and consult with dermatology to 
determine appropriateness of resuming
Treat with topical emollients, oral antihistamines, and 
high-potency topical corticosteroids
Initiate (methyl)prednisolone (or equivalent) 1-2 mg/kg, 
tapering over at least 4 weeks
G4: All severe rashes unmanageable with prior 
interventions and intolerable
Immediately hold ICPi and consult dermatology to 
determine appropriateness of resuming ICPi therapy 


88
Abbreviated Title: Phase II M7824 in UC
Version Date: 06/23/2021
1.0 Skin Toxicities
upon resolution of skin toxicity and once corticosteroids 
are reduced to prednisone (or equivalent) ≤ 10 mg
Systemic corticosteroids: IV (methyl)prednisolone (or 
equivalent) dosed at 1-2 mg/kg with slow tapering when 
the toxicity resolves
Monitor closely for progression to severe cutaneous 
adverse reaction
Should admit patient immediately with direct oncology 
involvement and with an urgent consult by dermatology
Consider alternative antineoplastic therapy over 
resuming ICPis if the skin irAE does not resolve to G1 
or less; if ICPIs are the patient’s only option, consider 
restarting once these adverse effects have resolved to 
a G1 level
1.2 Bullous dermatoses
Deﬁnition: Including bullous pemphigoid or other autoimmune bullous dermatoses, bullous drug reaction
Diagnostic work-up
Physical examination
Rule out any other etiology of the skin problem, such as an infection, an effect of another drug, or a skin condition 
linked to another systemic disease
If needed, a biologic checkup, including a blood cell count, liver, and kidney tests; consider serum antibody tests to 
rule out bullous pemphigoid or, under the guidance of dermatology, sending patient serum for indirect 
immunoﬂuorescent testing to rule out other autoimmune blistering diseases
Referral to dermatology for blisters that are not explained by infectious or transient other causes (eg, herpes 
simplex, herpes zoster, bullous impetigo, bullous insect bite, friction or pressure blister)
Consider skin biopsy (both hematoxylin and eosin evaluation of lesional skin and direct immunoﬂuorescence 
evaluation of perilesional skin)
Grading
Management
G1: Asymptomatic, blisters covering < 10% BSA and no 
associated erythema
If blisters are < 10% BSA, asymptomatic, and 
noninﬂammatory (such as the case with friction blisters 
or pressure blisters), cessation of ICPi is not necessary, 
and only observation and/or local wound care is 
warranted.
When symptomatic bullae or erosions, which are 
deroofed vesicles or bullae, are observed on the skin or 
mucosal surfaces, the cutaneous irAE is by deﬁnition 
considered at least G2
See G2 management recommendations
G2: Blistering that affects quality of life and requires 
intervention based on diagnosis not meeting criteria for 
Grade > 2
Blisters covering 10%-30% BSA
Hold ICPi therapy and consult with dermatology for 
work-up and to determine appropriateness of resuming
Attention given to general local wound care, which 
includes plain petrolatum ointment and bandages or 
plain petrolatum ointment gauze and bandage over any 
open erosions, which are left over on the skin after the 
blister has popped or if the roof of the blister easily 
sloughs off
Counsel patients to avoid skin irritants and 
overexposure to sun, wear protective clothing, use 
sunscreens
Work-up for autoimmune bullous disease as above
Initiate Class 1 high-potency topical corticosteroid (eg, 
clobetasol, betamethasone or equivalent) and reassess 
every 3 days for progression or improvement


89
Abbreviated Title: Phase II M7824 in UC
Version Date: 06/23/2021
1.0 Skin Toxicities
Low threshold to initiate treatment with prednisone (or 
equivalent) at 0.5-1 mg/kg dosing and taper over at 
least 4 weeks
Monitor patients with G2 irAEs closely for progression 
to involvement of greater BSA and/or mucous 
membrane involvement. Consider following patients 
closely using serial photography
Primer on monitoring for complicated cutaneous 
adverse drug reactions:
Review of systems: Skin pain (like a sunburn), fevers, 
malaise, myalgias, arthralgias, abdominal pain, 
ocular discomfort or photophobia, sores or 
discomfort in the nares, sores or discomfort in the 
oropharynx, odynophagia, hoarseness, dysuria, 
sores or discomfort in the vaginal area for women or 
involving the meatus of the penis for men, sores in 
the perianal area, or pain with bowel movements
Physical examination: Include vital signs and a full skin 
examination speciﬁcally evaluating all skin surfaces 
and mucous membranes (eyes, nares, oropharynx, 
genitals, and perianal area). Assess for 
lymphadenopathy, facial or distal extremity swelling 
(may be signs of DIHS/DRESS). Assess for 
pustules or blisters or erosions in addition to areas 
of “dusky erythema,” which may feel painful to 
palpation. To assess for a positive Nikolsky sign, 
place a gloved ﬁnger tangentially over erythematous 
skin and apply friction parallel to the skin surface. 
Nikolsky sign is positive if this results in detached or 
sloughing epidermis demonstrating poor attachment 
of the epidermis to the dermis, which is the case in 
some autoimmune disorders (eg, pemphigus) and 
SJS/TEN
G3: Skin sloughing covering > 30% BSA with 
associated pain and limiting self-care ADL
Hold ICPi therapy and consult with dermatology to 
determine appropriateness of resuming
Administer IV (methyl)prednisolone (or equivalent) 1-2 
mg/kg, tapering over at least 4 weeks
If bullous pemphigoid is diagnosed, it may be possible 
to avoid long-term use of systemic corticosteroids and 
treat with rituximab, as an alternative approach to 
treating the irAE
Seek infectious disease consultation if patient might 
have secondary cellulitis or if patient has other infection 
risk factors, such as neutropenia, etc.
G4: Blisters covering > 30% BSA with associated ﬂuid 
or electrolyte abnormalities
Permanently discontinue ICPi
Admit patient immediately and place under supervision 
of a dermatologist
Administer IV (methyl)prednisolone (or equivalent) 1-2 
mg/kg with tapering over at least 4 weeks when the 
toxicity resolves
If bullous pemphigoid is diagnosed, it may be possible 
to avoid long-term use of systemic corticosteroids and 
treat with rituximab as an alternative approach to 
treating the irAE


90
Abbreviated Title: Phase II M7824 in UC
Version Date: 06/23/2021
1.0 Skin Toxicities
Seek infectious disease consultation if patient might 
have secondary cellulitis or if patient has other infection 
risk factors, such as neutropenia, etc
1.3 SCARs, including SJS, TEN, acute generalized exanthematous pustulosis, and DRESS/DIHS
Deﬁnition: Severe changes in either structure or functions of skin, the appendages or the mucous membranes due 
to a drug
Diagnostic work-up
Total body skin examination with attention to examining all mucous membranes as well as complete review of 
systems
Rule out any other etiology of the skin problem, such as an infection, an effect of another drug, or a skin condition 
linked to another systemic disease
A biologic checkup, including a CBC with differential test, and liver and kidney function tests, including urinalysis, 
in addition to the blood work; if the patient is febrile, blood cultures should be considered as well
Skin biopsies to assess for full-thickness epidermal necrosis, as is seen in SJS/TEN, as well as other possible 
etiologies like paraneoplastic pemphigus or other autoimmune blistering dermatoses or other drug reactions, such 
as acute generalized exanthematous pusulosis
Consider following patients closely using serial clinical photography
If mucous membrane involvement or blistering is observed on the skin, consider early admission to a burn center 
for further monitoring and management Primer on monitoring for complicated cutaneous adverse drug reactions:
Review of systems: Skin pain (like a sunburn), fevers, malaise, myalgias, arthralgias, abdominal pain, ocular 
discomfort or photophobia, sores or discomfort in the nares, sores or discomfort in the oropharynx, odynophagia, 
hoarseness, dysuria, sores or discomfort in the vaginal area for women or involving the meatus of the penis for 
men, sores in the perianal area, or pain with bowel movements
Physical examination: Include vital signs and a full skin examination speciﬁcally evaluating all skin surfaces and 
mucous membranes (eyes, nares, oropharynx, genitals, and perianal area). Assess for lymphadenopathy, facial or 
distal extremity swelling (may be signs of DIHS/DRESS). Assess for pustules or blisters or erosions in addition to 
areas of “dusky erythema,” which may feel painful to palpation. To assess for a positive Nikolsky sign, place a 
gloved ﬁnger tangentially over erythematous skin and apply friction parallel to the skin surface. Nikolsky sign is 
positive if this results in detached or sloughing epidermis demonstrating poor attachment of the epidermis to the 
dermis, which is the case in some autoimmune disorders (eg, pemphigus) and SJS/TEN
Grading
Management
All Grades
In cases of suspected SJS or any mucous membrane 
involvement, discontinue ICPi treatment and monitor 
closely for improvement, regardless of grade
G1: NA
For SCARs, there is no G1 category; if lower BSA is 
involved with bullae or erosions, there should remain a 
high concern that this reaction will progress to G3 or G4
G2: Morbilliform (“maculopapular”) exanthem covering 
10%-30% BSA with systemic symptoms, 
lymphadenopathy, or facial swelling
Hold ICPi and monitor patients closely every 3 days 
with G2 irAEs for progression to involvement of greater 
BSA and/or mucous membrane involvement
Consider following patients closely using serial 
photography
Initiate therapy with topical emollients, oral 
antihistamines, and medium- to high-strength topical 
corticosteroids
Consider initiation of prednisone (or equivalent) 0.5-1 
mg/kg tapered over at least 4 weeks
G3: Skin sloughing covering < 10% BSA with mucosal 
involvement associated signs (eg, erythema, purpura, 
epidermal detachment, mucous membrane 
detachment)
Hold ICPi therapy and consult with dermatology
Treat skin with topical emollients and other petrolatum 
emollients, oral antihistamines, and high-strength 
topical corticosteroids; dimethicone may also be offered 
as an alternative to petrolatum


91
Abbreviated Title: Phase II M7824 in UC
Version Date: 06/23/2021
1.0 Skin Toxicities
Administer IV (methyl)prednisolone (or equivalent) 0.5-1 
mg/kg and convert to oral corticosteroids on response, 
wean over at least 4 weeks
Admit to burn and/or consult wound services with 
attention to supportive care, including ﬂuid and 
electrolyte balance, minimizing insensible water losses, 
and preventing infection
Given the immune mechanism of action of these 
medicines, use of immune suppression is warranted 
and should be offered
For mucous membrane involvement of SJS or TEN, 
appropriate consulting services should be offered to 
guide management in preventing sequelae from 
scarring (eg, ophthalmology; ear, nose, and throat; 
urology; gynecology; etc, as appropriate)
G4: Skin erythema and blistering/sloughing covering ≥ 
10% to > 30% BSA with associated signs (eg, 
erythema, purpura, epidermal detachment, mucous 
membrane detachment) and/or systemic symptoms and 
concerning associated blood work abnormalities (eg, 
liver function test elevations in the setting of 
DRESS/DIHS)
Permanently discontinue ICPi
Admit patient immediately to a burn unit or ICU with 
consulted dermatology and wound care services
Consider further consultations based on management 
of mucosal surfaces
(eg, ophthalmology; urology; gynecology; ear, nose, 
and throat surgery; etc) Initiate IV (methyl)prednisolone 
(or equivalent) 1-2 mg/kg, tapering when toxicity 
resolves to normal
IVIG or cyclosporine may also be considered in severe 
or corticosteroid-unresponsive cases
Consider pain/palliative consultation and/or admission 
in patients presenting with DRESS manifestations
Additional considerations: The usual prohibition of corticosteroids for SJS is not relevant here, as the underlying 
mechanism is a T-cell immunodirected toxicity
Adequate suppression is necessary with corticosteroids or other agents and may be prolonged in cases of 
DRESS/DIHS
All recommendations are expert consensus based, with beneﬁts outweighing harms, and strength of 
recommendations are moderate
Abbreviations: ADL, activities of daily living; AE, adverse event; BSA, body surface area; CBC, complete blood 
count; CTCAE, Common Terminology Criteria for Adverse Events; DIHS, drug-induced hypersensitivity syndrome; 
DRESS, drug reaction with eosinophilia and systemic symptoms; G, Grade; ICPi, immune checkpoint inhibitor; 
ICU, intensive care unit; irAE, immune-related adverse event; IV, intravenous; IVIG, intravenous immunoglobulin; 
NA, not applicable; SCAR, severe cutaneous adverse reactions; SJS, Stevens-Johnson syndrome; TENS, toxic 
epidermal necrolysis.


92
Abbreviated Title: Phase II M7824 in UC
Version Date: 06/23/2021
16.2.2 Table A2
Management of GI irAEs in Patients Treated With ICPis
2.0 GI Toxicities
2.1 Colitis
Deﬁnition: A disorder characterized by inﬂammation of the colon
Diagnostic work-up
G2
Work-up of blood (CBC, comprehensive metabolic panel, TSH, ESR, CRP), stool (culture, Clostridium difficile, 
parasite, CMV or other viral etiology, ova and parasite) should be performed
Consider testing for lactoferrin (for patient stratiﬁcation to determine who needs more urgent endoscopy) and 
calprotectin (to follow-up on disease activity)
Screening laboratories (HIV, hepatitis A and B, and blood quantiferon for TB) to prepare patients to start inﬂiximab 
should be routinely done in patients at high risk for those infections and appropriately selected patients based on 
infectious disease expert’s evaluation
Imaging (eg, CT scan of abdomen and pelvis and GI endoscopy with biopsy) should be considered as there is 
evidence showing that the presence of ulceration in the colon can predict a corticosteroid-refractory course, which 
may require early inﬂiximab
Consider repeating endoscopy for patients who do not respond to immunosuppressive agents; repeating 
endoscopy for disease monitoring can be considered when clinically indicated and when planning to resume 
therapy
G3-4
All the work-up listed for G2 (blood, stool, imaging, and scope with biopsy) should be completed immediately
Consider repeating endoscopy for patients who do not respond to immunosuppressive agents; repeating 
endoscopy for disease monitoring should only be considered when clinically indicated and when planning to 
resume ICPi
Grading (based on CTCAE for diarrhea, as most often 
used clinically)
Management
All patients
Counsel all patients to be aware of and inform their 
health care provider immediately if they experience:
Abdominal pain, nausea, cramping, blood or mucus in 
stool or changes in bowel habits, fever, abdominal 
distention, obstipation, constipation
For G2 or higher, consider permanently discontinuing 
CTLA-4 agents and may restart PD-1, PD-L1 agents if 
patient can recover to G1 or less; concurrent 
immunosuppressant maintenance therapy should be 
considered only if clinically indicated in individual cases
G1: Increase of fewer than four stools per day over 
baseline; mild increase in ostomy output compared with 
baseline
Continue ICPi; alternatively, ICPi may be held 
temporarily and resumed if toxicity does not exceed
G1
Monitor for dehydration and recommend dietary 
changes Facilitate expedited phone contact with 
patient/caregiver May obtain gastroenterology consult 
for prolonged G1 cases
G2: Increase of four to six stools per day over baseline; 
moderate increase in ostomy output compared with 
baseline
Should hold ICPi temporarily until patient’s symptoms 
recover to G1; can consider permanently
discontinuing CTLA-4 agents and may restart PD-1, 
PD-L1 agents if patient can recover to G1 or less
Concurrent immunosuppressant maintenance therapy (, 
10 mg prednisone equivalent dose) may be offered only 
if clinically indicated in individual cases


93
Abbreviated Title: Phase II M7824 in UC
Version Date: 06/23/2021
2.0 GI Toxicities
May also include supportive care with medications such 
as Imodium if infection has been ruled out
Should consult with gastroenterology for G2 or higher
Administer corticosteroids, unless diarrhea is transient, 
starting with initial dose of 1 mg/kg/day prednisone or 
equivalent
When symptoms improve to G1 or less, taper 
corticosteroids over at least 4-6 weeks before resuming 
treatment, although resuming treatment while on low-
dose corticosteroid may also be an option after an 
evaluation of the risks and beneﬁts
EGD/colonoscopy, endoscopy evaluation should be 
highly recommended for cases Grade $ 2 to stratify 
patients for early treatment with inﬂiximab based on the 
endoscopic ﬁndings and to determine the safety of 
resuming PD-1, PD-L1 therapy
Stool inﬂammatory markers can be considered 
(lactoferrin and calprotectin) in cases of G2 or higher to 
differentiate functional versus inﬂammatory diarrhea, 
and use calprotectin to monitor treatment response if 
provider prefers
Repeat colonoscopy is optional for cases of G2 or 
higher for disease activity monitoring to achieve 
complete remission, especially if there is a plan to 
resume ICPi
G3: Increase of seven or more stools per day over 
baseline, incontinence, hospitalization indicated, severe 
increase in ostomy output compared with baseline, 
limiting self-care ADL
Should consider permanently discontinuing CTLA-4 
agents and may restart PD-1, PD-L1 agents if patient 
can recover to G1 or less.
Administer corticosteroids (initial dose of 1-2 mg/kg/d 
prednisone or equivalent)
Consider hospitalization or outpatient facility for patients 
with dehydration or electrolyte imbalance
If symptoms persist $ 3-5 days or recur after 
improvement, consider administering IV corticosteroid 
or noncorticosteroid (eg, inﬂiximab)
Consider colonoscopy in cases where patients have 
been on immunosuppression and may be at risk for 
opportunistic infections as an independent cause for 
diarrhea (ie, CMV colitis) and for those who are anti-
TNF or corticosteroid refractory
G4: Life-threatening consequences; urgent intervention 
indicated
Permanently discontinue treatment
Should admit patient when clinically indicated; patients 
managed as outpatients should be very closely 
monitored
Administer 1-2 mg/kg/d methylprednisolone or 
equivalent until symptoms improve to G1, and then start 
taper over 4-6 weeks
Consider early inﬂiximab 5-10 mg/kg if symptoms 
refractory to corticosteroid within 2-3 days Consider 
lower GI endoscopy if symptoms are refractory despite 
treatment or there is concern of new infections
Additional considerations
The use of vedolizumab may be considered in patients refractory to inﬂiximab and/or contraindicated to TNF-a 
blocker. The decision should be made on an individual basis from gastroenterology and oncology evaluation. This 
is based on case series showing promising results


94
Abbreviated Title: Phase II M7824 in UC
Version Date: 06/23/2021
2.0 GI Toxicities
Patients with hepatitis and irAE colitis are rare, and management should include permanently discontinuing ICPi 
and offering other immunosuppressant agents that work systemically for both conditions
Currently, enteritis alone as the cause of diarrhea is uncommon and requires small bowel biopsy as the evaluation 
tool. It may be managed similar as colitis,including corticosteroid and/or inﬂiximab, etc
2.2 Hepatitis
Deﬁnition: A disorder characterized by a viral pathologic process involving the liver parenchyma
Diagnostic work-up
Monitor patient for abnormal liver blood tests: AST, ALT, and bilirubin prior to each infusion and/or weekly if G1 
liver function test elevations. No treatment is recommended for G1 liver function test abnormality
For G2 or higher:
Work-up for other causes of elevated liver enzymes should be tested, viral hepatitis, alcohol history, iron study, 
thromboembolic event, liver ultrasound, cross-sectional imaging for potential liver metastasis from primary 
malignancy. If suspicion for primary autoimmune hepatitis is high, can consider ANAs, antismooth muscle 
antibodies, antineutrophil cytoplasmic antibodies. If patients with elevated alkaline phosphatase alone, g-glutamyl 
transferase should be tested. For isolated elevation of transaminases, consider checking CK for other etiologies
Grading
Management
All patients
Counsel all patients to be aware of and inform their 
health care provider immediately if they experience:
Yellowing of skin or whites of the eyes Severe nausea 
or vomiting
Pain on the right side of the abdomen Drowsiness
Dark urine (tea colored)
Bleeding or bruising more easily than normal Feeling 
less hungry than usual
G1: Asymptomatic (AST or ALT > ULN to 3.0 x ULN 
and/or total bilirubin > ULN to 1.5 x ULN)
Continue ICPi with close monitoring; consider alternate 
etiologies
Monitor laboratories one to two times weekly
Manage with supportive care for symptom control
G2: Asymptomatic (AST or ALT > 3.0 to ≤ 5 x ULN 
and/or total bilirubin > 1.5 to ≤ 3 x ULN)
Hold ICPi temporarily and resume if recover to G1 or 
less on prednisone ≤ 10 mg/d
For Grade 2 hepatic toxicity with symptoms, may 
administer corticosteroid 0.5-1 mg/kg/d prednisone or 
equivalent if the abnormal elevation persists with 
signiﬁcant clinical symptoms in 3-5 days Increase 
frequency of monitoring to every 3 days
Inﬂiximab might not be the most appropriate treatment 
option in the situation of immune-mediated hepatitis 
given the potential risk of idiosyncratic liver failure 
(Note: No clear evidence shows the liver toxicity from 
inﬂiximab from other studies)
In follow-up, may resume ICPi treatment followed by 
taper only when symptoms improve to G1 or less and 
corticosteroid ≤ 10 mg/d; taper over at least 1 month
Patients should be advised to stop unnecessary 
medications and any known hepatotoxic drugs
G3: Symptomatic liver dysfunction, ﬁbrosis by biopsy, 
compensated cirrhosis, reactivation of chronic hepatitis 
(AST or ALT 5-20 x ULN and/or total bilirubin 3-10x3 
ULN)
Permanently discontinue ICPi
Immediately start corticosteroid 1-2 mg/kg 
methylprednisolone or equivalent
If corticosteroid refractory or no improvement after 3 
days, consider mycophenolate mofetil or azathioprine (if 
using azathioprine should test for thiopurine 
methyltransferase deﬁciency)


95
Abbreviated Title: Phase II M7824 in UC
Version Date: 06/23/2021
2.0 GI Toxicities
Laboratories at daily or every other day; consider 
inpatient monitoring for patients with AST/ALT > 8 x 
ULN and/or elevated TB 3 x ULN
Increase frequency of monitoring to every 1-2 days
Inﬂiximab might not be the most appropriate treatment 
option in the situation of immune-mediated hepatitis 
given the potential risk of liver failure (Note: No clear 
evidence shows that the liver toxicity from inﬂiximab 
from other studies); alternatives include non–TNF-a 
agents as systemic immunosuppressants If no 
improvement is achieved with corticosteroids or for 
patients on combination therapy with a novel agent, 
with standard chemotherapy, or with targeted therapy, 
refer to hepatologist for further pathologic evaluation of 
hepatitis
Corticosteroid taper can be attempted around 4-6 
weeks; re-escalate if needed; optimal duration unclear
G4: Decompensated liver function (eg, ascites, 
coagulopathy, encephalopathy, coma; AST or ALT > 20 
x ULN and/or total bilirubin > 10 x ULN)
Permanently discontinue ICPi
Administer 2 mg/kg/d methylprednisolone equivalents
If corticosteroid refractory or no improvement after 3 
days, consider mycophenolate mofetil
Monitor laboratories daily; consider inpatient monitoring
Avoid the use of inﬂiximab in the situation of immune-
mediated hepatitis
Hepatology consult if no improvement was achieved 
with corticosteroid
Corticosteroid taper can be attempted around 4-6 
weeks when symptoms improve to G1 or less; re-
escalate if needed; optimal duration unclear
Consider transfer to tertiary care facility if necessary
All recommendations are expert consensus based, with beneﬁts outweighing harms, and strength of 
recommendations is moderate.
Abbreviations: ADL, activities of daily living; ALT, alanine aminotransferase; ANA, antinuclear antibody; AST, 
aspartate aminotransferase; CBC, complete blood count, CK, creatine kinase; CMV, cytomegalovirus; CRP, 
C-reactive protein; CT, computed tomography; CTCAE, Common Terminology Criteria for Adverse Events; CTLA-
4, cytotoxic T-cell lymphocyte-4; EGD, esophagogastroduodenoscopy; ESR, erythrocyte sedimentation rate; G, 
Grade; GI, gastrointestinal; HIV, human immunodeficiency virus; ICPi, immune checkpoint inhibitor; irAE, immune-
related adverse event; IV, intravenous; PD-1; programmed death 1; PD-L1, programmed death ligand 1; TB, 
tuberculosis; TNF, tumor necrosis factor; TSH, thyroid-stimulating hormone; ULN, upper limit of normal.


96
Abbreviated Title: Phase II M7824 in UC
Version Date: 06/23/2021
16.2.3 Table A3
Management of Lung irAEs in Patients Treated With ICPis
3.0 Lung Toxicities
3.1 Pneumonitis
Deﬁnition: Focal or diffuse inﬂammation of the lung parenchyma (typically identiﬁed on CT imaging)
No symptomatic, pathologic, or radiographic features are pathognomonic for pneumonitis
Diagnostic work-up
Should include the following: CXR, CT, pulse oximetry
For G2 or higher, may include the following infectious work-up: nasal swab, sputum culture and sensitivity, blood 
culture and sensitivity, urine culture and sensitivity
Grading
Management
G1: Asymptomatic, conﬁned to one lobe of the lung or 
< 25% of lung parenchyma, clinical or diagnostic 
observations only
Hold ICPi with radiographic evidence of pneumonitis 
progression
May offer one repeat CT in 3-4 weeks; in patients who 
have had baseline testing, may offer a repeat 
spirometry/DLCO in 3-4 weeks
May resume ICPi with radiographic evidence of 
improvement or resolution. If no improvement, should 
treat as G2
Monitor patients weekly with history and physical 
examination and pulse oximetry; may also offer CXR
G2: Symptomatic, involves more than one lobe of the 
lung or 25%-50% of lung parenchyma, medical 
intervention indicated, limiting instrumental ADL
Hold ICPi until resolution to G1 or less
Prednisone 1-2 mg/kg/d and taper by 5-10 mg/wk over 
4-6 weeks Consider bronchoscopy with BAL
Consider empirical antibiotics
Monitor every 3 days with history and physical 
examination and pulse oximetry, consider CXR; no 
clinical improvement after 48-72 hours of prednisone, 
treat as G3
G3: Severe symptoms, hospitalization required, 
involves all lung lobes or 50% of lung parenchyma, 
limiting self-care
ADL, oxygen indicated
G4: Life-threatening respiratory compromise, urgent 
intervention indicated (intubation)
Permanently discontinue ICPi
Empirical antibiotics; (methyl)prednisolone IV 1-2 
mg/kg/d; no improvement after 48 hours, may add 
inﬂiximab 5 mg/kg or mycophenolate mofetil IV 1 g 
twice a day or IVIG for 5 days or cyclophosphamide; 
taper corticosteroids over 4-6 weeks
Pulmonary and infectious disease consults if necessary
Bronchoscopy with BAL 6 transbronchial biopsy
Patients should be hospitalized for further management
Additional considerations
GI and Pneumocystis prophylaxis with PPI and Bactrim may be offered to patients on prolonged corticosteroid use 
(> 12 weeks), according to institutional guidelines
Consider calcium and vitamin D supplementation with prolonged corticosteroid use
The role of prophylactic ﬂuconazole with prolonged corticosteroid use (> 12 weeks) remains unclear, and 
physicians should proceed according to institutional guidelines
Bronchoscopy + biopsy; if clinical picture is consistent with pneumonitis, no need for biopsy
All recommendations are expert consensus based, with beneﬁts outweighing harms, and strength of 
recommendations are moderate.
Abbreviations: ADL, activities of daily living; BAL, bronchoalveolar lavage; CT, computed tomography; CXR, chest 
x-ray; DLCO, diffusing capacity of lung for carbon monoxide; G, Grade; GI, gastrointestinal; ICPi, immune 
checkpoint inhibitor; irAE, immune-related adverse event; IV, intravenous; IVIG, intravenous immunoglobulin; PPI, 
proton pump inhibitor.


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16.2.4 Table A4
Management of Endocrine irAEs in Patients Treated With ICPis
4.0 Endocrine Toxicity
Counsel patients to inform their health care provider immediately if they experience any changes in their health 
since their last visit, especially any of the following:
Headaches that will not go away or unusual headache 
patterns
Vision changes
Rapid heartbeat
Increased sweating
Extreme tiredness or weakness
Muscle aches
Weight gain or weight loss
Dizziness or fainting
Feeling more hungry or thirsty than usual
Hair loss
Changes in mood or behavior, such as decreased sex 
drive, irritability, or forgetfulness Feeling cold
Constipation
Voice gets deeper
Urinating more often than usual
Nausea or vomiting
Abdominal pain
4.1 Thyroid
4.1.1 Primary hypothyroidism
Deﬁnition: Elevated TSH, normal or low FT4
Diagnostic work-up
TSH and FT4 every 4-6 weeks as part of routine clinical monitoring on therapy or for case detection in 
symptomatic patients
Grading
Management
G1: TSH < 10 mIU/L and asymptomatic
G2: Moderate symptoms; able to perform ADL; TSH 
persistently > 10 mIU/L
Should continue ICPi with close follow-up and 
monitoring of TSH, FT4 May hold ICPi until symptoms 
resolve to baseline
Consider endocrine consultation
Prescribe thyroid hormone supplementation in 
symptomatic patients with any degree of TSH elevation 
or in asymptomatic patients with TSH levels that persist 
> 10 mIU/L (measured 4 weeks apart)
Monitor TSH every 6-8 weeks while titrating hormone 
replacement to normal TSH FT4 can be used in the 
short term (2 weeks) to ensure adequacy of therapy in 
those with frank hypothyroidism where the FT4 was 
initially low
Once adequately treated, should monitor thyroid 
function (at least TSH) every 6 weeks while on active 
ICPi therapy or as needed for symptoms to ensure 
appropriate replacement; repeat testing annually or as 
indicated by symptoms once stable
G3-4: Severe symptoms, medically signiﬁcant or life-
threatening consequences, unable to perform ADL
Hold ICPi until symptoms resolve to baseline with 
appropriate supplementation
Endocrine consultation


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4.0 Endocrine Toxicity
May admit for IV therapy if signs of myxedema 
(bradycardia, hypothermia) Thyroid supplementation 
and reassessment as in G2
Additional considerations
For patients without risk factors, full replacement can be estimated with an ideal body weight–based dose of 
approximately 1.6 µg/kg/d
For elderly or fragile patients with multiple comorbidities, consider titrating up from low dose, starting at 25-50 mg
Extreme elevations of TSH can be seen in the recovery phase of thyroiditis and can be watched in asymptomatic 
patients to determine whether there is recovery to normal within 3-4 weeks
Under guidance of endocrinology, consider tapering hormone replacement and retesting in patients with a history 
of thyroiditis (initial thyrotoxic phase)
Adrenal dysfunction, if present, must always be replaced before thyroid hormone therapy is initiated 
4.1.2 Hyperthyroidism
Deﬁnition: Suppressed TSH and high normal or elevated FT4 and/or triiodothyronine
Diagnostic work-up
Monitor TSH, FT4 every 4-6 weeks from the start of therapy or as needed for case detection in symptomatic 
patients
Consider TSH receptor antibodies if there are clinical features and suspicion of Grave disease (eg, 
ophthalmopathy)
Close monitoring of thyroid function every 2-3 weeks after diagnosis to catch transition to hypothyroidism in 
patients with thyroiditis and hyperthyroidism
Grading
Management
G1: Asymptomatic or mild symptoms
Can continue ICPi with close follow-up and monitoring 
of TSH, FT4 every 2-3 weeks until it is clear whether 
there will be persistent hyperthyroidism (see below) or 
hypothyroidism (see 4.1.1)
Consider holding ICPi until symptoms return to baseline
Consider endocrine consultation
b-Blocker (eg, atenolol, propranolol) for symptomatic 
relief
Hydration and supportive care
Corticosteroids are not usually required to shorten 
duration
For persistent hyperthyroidism (> 6 weeks) or clinical 
suspicion, work-up for Graves disease (TSI or TRAb) 
and consider thionamide (methimazole or PTU) Refer 
to endocrinology for Graves disease
G3-4: Severe symptoms, medically signiﬁcant or life-
threatening consequences, unable to perform ADL
Hold ICPi until symptoms resolve to baseline with 
appropriate therapy
Endocrine consultation
b-Blocker (eg, atenolol, propranolol) for symptomatic 
relief
For severe symptoms or concern for thyroid storm, 
hospitalize patient and initiate prednisone 1-2 mg/kg/d 
or equivalent tapered over 1-2 weeks; consider also 
use of SSKI or thionamide (methimazole or PTU).
Additional considerations
Thyroiditis is transient and resolves in a couple of weeks to primary hypothyroidism or normal. Hypothyroidism can 
be treated as above. Graves disease is generally persistent and is due to increased thyroid hormone production 
that can be treated with antithyroid medical therapy. Physical examination ﬁndings of ophthalmopathy or thyroid 
bruit are diagnostic of Graves and should prompt early endocrine referral.
4.2 Adrenal – primary adrenal insufﬁciency


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4.0 Endocrine Toxicity
Deﬁnition: Adrenal gland failure leading to low morning cortisol, high morning ACTH, as well as hyponatremia and 
hyperkalemia with orthostasis and volume depletion due to loss of aldosterone
Diagnostic work-up for patients in whom adrenal 
insufﬁciency is suspected:
Evaluate ACTH (AM), cortisol level (AM)
Basic metabolic panel (Na, K, CO2, glucose)
Consider ACTH stimulation test for indeterminate 
results
If primary adrenal insufﬁciency (high ACTH, low 
cortisol) is found biochemically:
Evaluate for precipitating cause of crisis such as 
infection Perform an adrenal CT for 
metastasis/hemorrhage
Grading
Management
G1: Asymptomatic or mild symptoms
Consider holding ICPi until patient is stabilized on 
replacement hormone
Endocrine consultation
Replacement therapy with prednisone (5-10 mg daily) 
or hydrocortisone (10-20 mg orally every morning, 5-10 
mg orally in early afternoon)
May require ﬂudrocortisone (0.1 mg/d) for 
mineralocorticoid replacement in primary adrenal 
insufﬁciency
Titrate dose up or down as symptoms dictate
G2: Moderate symptoms, able to perform ADL
Consider holding ICPi until patient is stabilized on 
replacement hormone
Endocrine consultation
Initiate outpatient treatment at two to three times 
maintenance
(if prednisone, 20 mg daily; if hydrocortisone, 20-30 mg 
in the morning, and 10-20 mg in the afternoon) to 
manage acute symptoms.
Taper stress-dose corticosteroids down to maintenance 
doses over 5-10 days
Maintenance therapy as in G1.
G3-4: Severe symptoms, medically signiﬁcant or life-
threatening consequences, unable to perform ADL
Hold ICPi until patient is stabilized on replacement 
hormone
Endocrine consultation
See in clinic or, for after hours, make an emergency 
department referral for normal saline (at least 2 L) and 
IV stress-dose corticosteroids on presentation 
(hydrocortisone 100 mg or dexamethasone 4 mg (if the 
diagnosis is not clear and stimulation testing will be 
needed)
Taper stress-dose corticosteroids down to maintenance 
doses over 7-14 days after discharge
Maintenance therapy as in G1
Additional considerations
Primary and secondary adrenal insufﬁciency can be distinguished by the relationship between ACTH and cortisol. 
If the ACTH is low with low cortisol, then management is as per 4.3.
Patients on corticosteroids for management of other conditions will have low morning cortisol as a result of 
iatrogenic, secondary adrenal insufﬁciency. ACTH will also be low in these patients. A diagnosis of adrenal 
insufﬁciency is challenging to make in these situations (see next section on hypophysitis).


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4.0 Endocrine Toxicity
Emergent therapy for someone with suspected adrenal insufﬁciency is best done with dexamethasone as a 
stimulation test can still be performed. If the diagnosis is already conﬁrmed, can use hydrocortisone 100 mg.
All patients need education on stress dosing and a medical alert bracelet for adrenal insufﬁciency to trigger stress-
dose corticosteroids by EMS.
Endocrine consultation prior to surgery or any procedure for stress-dose planning.
4.3 Pituitary - hypophysitis
Deﬁnition: Inﬂammation of the pituitary with varying effects on hormone function. Most commonly presenting with 
central adrenal insufﬁciency. May also have central hypothyroidism, diabetes insipidus, and hypogonadism. 
Diagnostic work-up
Diagnosis: Low ACTH with a low cortisol. Low or normal TSH with a low FT4. Hypernatremia and volume depletion 
with diabetes insipidus. Low testosterone or estradiol with low LH and FSH.
Testing:
Evaluate ACTH, cortisol (AM), TSH, FT4, electrolytes
Consider evaluating LH, FSH, and testosterone levels in males or estrogen in premenopausal females with 
fatigue, loss of libido, and mood changes Consider MRI of the brain with or without contrast with pituitary/sellar 
cuts in patients with multiple endocrine abnormalities 6 new severe headaches or complaints of vision changes
Grading
Management
G1: Asymptomatic or mild symptoms
Consider holding ICPi until patient is stabilized on 
replacement hormones
Endocrine consultation
Hormonal supplementation as in G1
G3-4: Severe symptoms, medically signiﬁcant or life-
threatening consequences, unable to perform ADL
Hold ICPi until patient is stabilized on replacement 
hormones
Endocrine consultation
Hormonal supplementation as in G1
Consider initial pulse dose therapy with prednisone 1-2 
mg/kg oral daily (or equivalent) tapered over at least 1-
2 weeks
Additional considerations
Be aware of the need to start corticosteroids ﬁrst when planning hormone replacement therapy for multiple 
deﬁciencies
All patients need instruction on doubling doses for illness (stress dosing) and a medical alert bracelet for adrenal 
insufﬁciency to trigger stress-dose corticosteroids by EMS
Corticosteroid use can cause isolated central adrenal insufﬁciency
Work-up cannot be done with a simple AM cortisol in a patient on corticosteroids for other conditions
Laboratory conﬁrmation of adrenal insufﬁciency should not be attempted until treatment with corticosteroids for 
other disease is ready to be discontinued. For long-term exposure, consult endocrinology for recovery and 
weaning protocol using hydrocortisone.
4.4 Diabetes
Deﬁnition: T2DM is a combination of insulin resistance and insufﬁciency that may require oral or insulin therapy. It 
may be new onset or exacerbated during therapy for nonimmunologic reasons, such as corticosteroid exposure.
Autoimmune T1DM results from islet cell destruction and is often acute onset, with ketosis and an insulin 
requirement
Diagnostic work-up
Monitor patients for hyperglycemia or other signs and symptoms of new or worsening DM, including measuring 
glucose at baseline and with each treatment cycle during induction for 12 weeks, then every 3-6 weeks thereafter. 
To guide the work-up in new-onset hyperglycemia, clinicians should consider a patient’s medical background, 
exposure history, and risk factors for each subtype of DM.
Laboratory evaluation in suspected T1DM should include testing for ketosis in urine and an assessment of the 
anion gap on a metabolic panel. Anti–glutamic acid decarboxylase, anti–islet cell, or anti–insulin antibodies are 
highly speciﬁc for autoimmune diabetes. Insulin and C-peptide levels can also assist in the diagnosis.


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Abbreviated Title: Phase II M7824 in UC
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4.0 Endocrine Toxicity
Grading
Management
G1: Asymptomatic or mild symptoms; fasting glucose 
value > ULN (160 mg/dL); fasting glucose value > ULN 
(8.9 mmol/L); no evidence of ketosis or laboratory 
evidence of T1DM
Can continue ICPi with close clinical follow-up and 
laboratory evaluation
May initiate oral therapy for those with new-onset T2DM
Screen for T1DM if appropriate, for example, acute 
onset with prior normal values or clinical concern for 
ketosis
G2: Moderate symptoms, able to perform ADL, fasting 
glucose value > 160-250 mg/dL; fasting glucose value> 
8.9-13.9 mmol/L, ketosis or evidence of T1DM at any 
glucose level
May hold ICPi until glucose control is obtained
Titrate oral therapy or add insulin for worsening control 
in T2DM Should administer insulin for T1DM (or as 
default therapy if there is confusion about type)
Urgent endocrine consultation for any patient with 
T1DM; in the absence of endocrinology, internal 
medicine may sufﬁce
Consider admission for T1DM if early outpatient 
evaluation is not available or signs of ketoacidosis are 
present
G3-4: Severe symptoms, medically signiﬁcant or life-
threatening consequences, unable to perform ADL
G3: > 250-500 mg/dL (> 13.9-27.8 mmol/L)
G4: > 500 mg/dL (> 27.8 mmol/L)
Hold ICPi until glucose control is obtained on therapy 
with reduction of toxicity to G1 or less
Urgent endocrine consultation for all patients
Initiate insulin therapy for all patients
Admit for inpatient management: Concerns for 
developing DKA, Symptomatic patients regardless of 
diabetes type, New-onset T1DM unable to see 
endocrinology
Additional considerations
Insulin therapy can be used as the default in any case with hyperglycemia
Long-acting therapy alone is not usually sufﬁcient for T1DM, where half of daily requirements are usually given in 
divided doses as prandial coverage and half as long acting.
Insulin doses will be lower in T1DM because of preserved sensitivity (total daily requirement can be estimated at 
0.3-0.4 units/kg/d).
In T2DM, sliding-scale coverage with meals over a few days provides data to estimate a patient’s daily 
requirements and can be used to more rapidly titrate basal needs.
All recommendations are expert consensus based, with beneﬁts outweighing harms, and strength of 
recommendations are moderate.
Abbreviations: ACTH, adrenocorticotropic hormone; ADL, activities of daily living; CT, computed tomography; 
DKA, diabetic ketoacidosis; DM, diabetes mellitus; EMS, emergency medical services; FSH, follicle-stimulating 
hormone; FT4, free thyroxine; G, Grade; ICPi, immune checkpoint inhibitor; irAE, immune-related adverse event; 
LH, luteinizing hormone; MRI, magnetic resonance imaging; PTU, propylthiouracil; 2L, second-line; SSKI, 
potassium iodide; T1DM, type 1 diabetes mellitus; T2DM, type 2 diabetes mellitus; TRAb, thyroid-stimulating 
hormone receptor antibody; TSH, thyroid-stimulating hormone; TSI, thyroid-stimulating immunoglobulin; ULN, 
upper limit ofnormal.


102
Abbreviated Title: Phase II M7824 in UC
Version Date: 06/23/2021
16.2.5 Table A5
Management of Musculoskeletal irAEs in Patients Treated With ICPis
5.0 Musculoskeletal Toxicities
5.1 Inﬂammatory arthritis
Deﬁnition: A disorder characterized by inﬂammation of the joints
Clinical symptoms: Joint pain accompanied by joint swelling; inﬂammatory symptoms, such as stiffness after 
inactivity or in the morning, lasting > 30 minutes to 1 hour; improvement of symptoms with NSAIDs or 
corticosteroids but not with opioids or other pain medications may also be suggestive of inﬂammatory arthritis.
Diagnostic work-up
G1
Complete rheumatologic history and examination of all peripheral joints for tenderness, swelling, and range of 
motion; examination of the spine Consider plain x-ray/imaging to exclude metastases and evaluate joint damage 
(erosions), if appropriate
Consider autoimmune blood panel including ANA, RF, and anti-CCP, and anti-inﬂammatory markers (ESR and 
CRP) if symptoms persist; if symptoms are suggestive of reactive arthritis or affect the spine, consider HLA B27 
testing
G2
Complete history and examination as above; laboratory tests as above
Consider US 6 MRI of affected joints if clinically indicated (eg, persistent arthritis unresponsive to treatment, 
suspicion for differential diagnoses such as metastatic lesions or septic arthritis)
Consider early referral to a rheumatologist, if there is joint swelling (synovitis) or if symptoms of arthralgia persist 
> 4 weeks
G3-4
As for G2
Seek rheumatologist advice and review
Monitoring: Patients with inﬂammatory arthritis should be monitored with serial rheumatologic examinations, 
including inﬂammatory markers, every 4-6 weeks after treatment is instituted.
Grading
Management
All Grades
Clinicians should follow reports of new joint pain to 
determine whether inﬂammatory arthritis is present; 
question whether symptom new since receiving ICPi
G1: Mild pain with inﬂammation, erythema, or joint 
swelling
Continue ICPi
Initiate analgesia with acetaminophen and/or NSAIDs
G2: Moderate pain associated with signs of 
inﬂammation, erythema, or joint swelling, limiting 
instrumental ADL
Hold ICPi and resume upon symptom control and on 
prednisone ≤ 10 mg/d 
Escalate analgesia and consider higher doses of 
NSAIDS as needed
If inadequately controlled, initiate prednisone or 
prednisolone 10-20 mg/d or equivalent for 4-6 weeks
If improvement, slow taper according to response 
during the next 4-6 weeks; if no improvement after initial 
4-6 weeks, treat as G3
If unable to lower corticosteroid dose to < 10 mg/d after 
3 months, consider DMARD
Consider intra-articular corticosteroid injections for large 
joints
Referral to rheumatology
G3-4: Severe pain associated with signs of 
inﬂammation, erythema, or joint swelling; irreversible 
joint damage; disabling; limiting self-care ADL
Hold ICPi temporarily and may resume in consultation 
with rheumatology, if recover to G1 or less
Initiate oral prednisone 0.5-1 mg/kg
If failure of improvement after 4 weeks or worsening in 
meantime, consider synthetic or biologic DMARD
Synthetic: methotrexate, leﬂunomide


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5.0 Musculoskeletal Toxicities
Biologic: consider anticytokine therapy such as TNF-a 
or IL-6 receptor inhibitors. (Note: As caution, IL-6 
inhibition can cause intestinal perforation; while this is 
extremely rare, it should not be used in patients with 
colitis.) Test for viral hepatitis B, C, and latent/active TB 
test prior to DMARD treatment
Referral to rheumatology.
Additional considerations
Early recognition is critical to avoid erosive joint damage.
Corticosteroids can be used as part of initial therapy in inﬂammatory arthritis, but due to likely prolonged treatment 
requirements, physicians should consider starting corticosteroid-sparing agents earlier than one would with other 
irAEs
Oligoarthritis can be treated early on with intra-articular corticosteroids; consider early referral.
Consider PCP prophylaxis for patients treated with high dose of corticosteroids for 12 weeks, as per local 
guidelines.
5.2 Myositis
Deﬁnition: A disorder characterized by muscle inﬂammation with weakness and elevated muscle enzymes (CK). 
Muscle pain can be present in severe cases. Can be life threatening if respiratory muscles or myocardium are 
involved
Diagnostic work-up
Complete rheumatologic and neurologic history regarding differential diagnosis; rheumatologic and neurologic 
examination, including muscle strength; and examination of the skin for ﬁndings suggestive of dermatomyositis. 
Muscle weakness is more typical of myositis than pain. Consider preexisting conditions that can cause similar 
symptoms.
Blood testing to evaluate muscle inﬂammation
CK, transaminases (AST, ALT), LDH, and aldolase can also be elevated
Troponin to evaluate myocardial involvement and other cardiac testing, such as echocardiogram, as needed
Inﬂammatory markers (ESR and CRP)
Consider EMG, imaging (MRI), and/or biopsy on an individual basis when diagnosis is uncertain and overlap with 
neurologic syndromes, such as myasthenia gravis, is suspected
Consider paraneoplastic autoantibody testing for myositis and neurologic conditions, such as myasthenia gravis 
Monitoring: CK, ESR, CRP
G1: Complete examination and laboratory work-up as above
G2: Complete history and examination as above; autoimmune myositis blood panel; EMG, MRI of affected joints
Early referral to a rheumatologist or neurologist
G3-4: As for G2
Urgent referral to a rheumatologist or neurologist
Grading
Management
G1: Mild weakness with or without pain
Continue ICPi
If CK is elevated and patient has muscle weakness, 
may offer oral corticosteroids, and treat as G2
Offer analgesia with acetaminophen or NSAIDs if there 
are no contraindications
G2: Moderate weakness with or without pain, limiting 
age-appropriate instrumental ADL
Hold ICPi temporarily and may resume upon symptom 
control, if CK is normal and prednisone dose 10 mg; if 
worsens, treat as per G3
NSAIDs as needed
Referral to rheumatologist or neurologist
If CK is elevated three times or more), initiate 
prednisone or equivalent at 0.5-1 mg/kg
May require permanent discontinuation of ICPi in most 
patients with G2 symptoms and objective ﬁndings 


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5.0 Musculoskeletal Toxicities
(elevated enzymes, abnormal EMG, abnormal muscle 
MRI or biopsy)
G3-4: Severe weakness with or without pain, limiting 
self-care ADL
Hold ICPi until G1 or less while off immune suppression 
and permanently discontinue if any evidence of 
myocardial involvement
Consider hospitalization for severe weakness
Referral to rheumatologist or neurologist
Initiate prednisone 1 mg/kg or equivalent. Consider 1-2 
mg/kg of methylprednisolone IV or higher-dose bolus if 
severe compromise
(weakness severely limiting mobility, cardiac, 
respiratory, dysphagia) Consider plasmapheresis
Consider IVIG therapy
Consider other immunosuppressant therapy, such as 
methotrexate, azathioprine, or mycophenolate mofetil, if 
symptoms and CK levels do not improve or worsen 
after 4-6 weeks; rituximab is used in primary myositis 
but caution is advised given its long biologic duration
Additional considerations: Caution is advised with rechallenging
5.3 Polymyalgia-like syndrome
Deﬁnition: Characterized by marked pain and stiffness in proximal upper and/or lower extremities and no signs of 
true muscle inﬂammation such as CK elevation or EMG ﬁndings of myositis. No true muscle weakness, difﬁculty in 
active motion related to pain
Diagnostic work-up
G1
Complete rheumatologic history regarding differential diagnosis and examination of all joints and skin
Check for symptoms of temporal arteritis, such as headache or visual disturbances; refer to ophthalmologist if 
present, and consider temporal artery biopsy ANA, RF, anti-CCP
CK to evaluate differential diagnosis of myositis
Inﬂammatory markers (ESR, CRP)
Monitoring: ESR, CRP
G2: Complete history and examination as above; autoimmune tests as required for differential diagnosis; early 
referral to a rheumatologist
G3-4: As for G2; see rheumatologist advice and review
Grading
Management
G1: Mild stiffness and pain
Continue ICPi
Initiate analgesia with acetaminophen and/or NSAIDs if 
there are no contraindications
G2: Moderate stiffness and pain, limiting age-
appropriate instrumental ADL
Consider holding ICPi and resuming upon symptom 
control, prednisolone < 10 mg; if worsens, treat as per 
G3
Initiate prednisone 20 mg/d or equivalent; if symptoms 
improve, start to taper dose after 3-4 weeks
If no improvement or need for higher dosages after 4 
weeks, escalate to G3 Consider referral to 
rheumatology
G3-4: Severe stiffness and pain, limiting self-care ADL
Hold ICPi and may resume, in consultation with 
rheumatology, if recover toG1 or less; however, note 
that cases of toxicity returning upon rechallenge have 
been reported.
Referral to rheumatology


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5.0 Musculoskeletal Toxicities
Should initiate prednisone 20 mg/d or equivalent. If no 
improvement or need for higher dosages for prolonged 
time, may offer a corticosteroid-sparing agent such as 
methotrexate or IL-6 inhibition with tocilizumab
(Note: As caution, IL-6 inhibition can cause intestinal 
perforation; while this is extremely rare, it should not be 
used in patients with colitis or GI metastases). Consider 
admission for pain control
All recommendations are expert consensus based, with beneﬁts outweighing harms, and strength of 
recommendations are moderate.
Abbreviations: ADL, activities of daily living; ALT, alanine aminotransferase; ANA, antinuclear antibodies; AST, 
aspartate aminotransferase; CCP, citrullinated protein antibody; CK, creatine kinase; CRP, C-reactive protein; 
DMARD, disease-modifying antirheumatic drug; EMG, electromyography; ESR, erythrocyte sedimentation rate; G, 
Grade; HLA, human leukocyte antigen; ICPi, immune checkpoint inhibitor; IL, interleukin; irAE, immune-related 
adverse event; IV, intravenous; IVIG, intravenous immunoglobulin; LDH, lactate dehydrogenase; MRI, magnetic 
resonance imaging, NSAID, nonsteroidal anti-inﬂammatory drug; PCP, Pneumocystis pneumonia; RF, rheumatoid 
factor; TB, tuberculosis; TNF, tumor necrosis factor.


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Abbreviated Title: Phase II M7824 in UC
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16.2.6 Table A6
Management of Renal irAEs in Patients Treated With ICPis
6.0 Renal Toxicities
Nephritis and renal dysfunction: diagnosis and monitoring
For any suspected immune-mediated adverse reactions, exclude other causes
Monitor patients for elevated serum creatinine prior to every dose
Routine urinalysis is not necessary, other than to rule out UTIs, etc; nephrology may consider further
If no potential alternative cause of AKI identiﬁed, then one should forego biopsy and proceed directly with 
immunosuppressive therapy Swift treatment of autoimmune component important
6.1 Nephritis
Deﬁnition: Inﬂammation of the kidney affecting the structure
Grading
Management
G1: Creatinine level increase of > 0.3 mg/dL; creatinine 
1.5-2.0 3 over baseline
Consider temporarily holding ICPi, pending 
consideration of potential alternative etiologies (recent 
IV contrast, medications, ﬂuid status) and baseline renal 
function. A change that is still < 1.5 ULN could be 
meaningful
G2: Creatinine 2-3 x above baseline
Hold ICPi temporarily
Consult nephrology
Evaluate for other causes (recent IV contrast, 
medications, ﬂuid status, etc); if other etiologies ruled 
out, administer 0.5-1 mg/kg/d prednisone equivalents
If worsening or no improvement: 1 to 2 mg/kg/d 
prednisone equivalents and permanently discontinue 
treatment
If improved to G1 or less, taper corticosteroids over 4-6 
weeks If no recurrence of chronic renal insufﬁciency, 
discuss resumption of ICPI with patient after taking into 
account the risks and beneﬁts.
G3: Creatinine > 3 x baseline or > 4.0 mg/dL; 
hospitalization indicated
Permanently discontinue ICPi
G4: Life-threatening consequences; dialysis indicated
Consult nephrology
Evaluate for other causes (recent IV contrast, 
medications, ﬂuid status, etc)
Administer corticosteroids (initial dose of 1-2 mg/kg/d 
prednisone or equivalent)
Additional considerations
Monitor creatinine weekly
Reﬂex kidney biopsy should be discouraged until corticosteroid treatment has been attempted
6.2 Symptomatic nephritis: follow-up
Grading
Management
G1
Improved to baseline, resume routine creatinine 
monitoring
G2
If improved to G1, taper corticosteroids over at least 3 
weeks before resuming treatment with routine 
creatinine monitoring If elevations persist > 7 days or 
worsen and no other cause found, treat as G3
G3
If improved to G1, taper corticosteroids over at least 4 
weeks 
If elevations persist 3-5 days or worsen, consider 
additional immunosuppression (eg, mycophenolate)


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6.0 Renal Toxicities
G4
If improved to G1, taper corticosteroids over at least 4 
weeks
If elevations persist 2-3 days or worsen, consider 
additional immunosuppression (eg, mycophenolate)
All recommendations are expert consensus based, with beneﬁts outweighing harms, and strength of 
recommendations are moderate.
Abbreviations: AKI, acute kidney injury; G, Grade; ICPi, immune checkpoint inhibitor; irAE, immune-related 
adverse event; IV, intravenous; ULN, upper limit of normal; UTI, urinary tract infection.


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16.2.7 able A7
Management of Nervous System irAEs in Patients Treated With ICPis
7.0 Nervous System Toxicities
7.1 Myasthenia gravis
Deﬁnition: Fatigable or ﬂuctuating muscle weakness, generally more proximal than distal. Frequently has ocular 
and/or bulbar involvement (ptosis, extraocular movement abnormalities resulting in double vision, dysphagia, 
dysarthria, facial muscle weakness). May have neck and/or respiratory muscle weakness. (Note: May occur with 
myositis and/or myocarditis. Respiratory symptoms may require evaluation to rule out pneumonitis, myocarditis. 
Miller Fisher variant of Guillain-Barré syndrome (ophthalmoparesis) and the oculobulbar myositis (ptosis, 
ophthalmoparesis, dysphagia, neck and respiratory weakness) with ICPi may have overlapping symptoms.
Diagnostic work-up
AChR and antistriated muscle antibodies in blood; if AChR antibodies are negative, consider muscle speciﬁc 
kinase and lipoprotein-related 4 antibodies in blood Pulmonary function assessment with NIF and VC
CPK, aldolase, ESR, CRP for possible concurrent myositis
Consider MRI of brain and/or spine, depending on symptoms to rule out CNS involvement by disease or alternate 
diagnosis
If respiratory insufﬁciency or elevated CPK, troponin T, perform cardiac examination with ECG and TTE for 
possible concomitant myocarditis
Neurologic consultation
Electrodiagnositic studies, including neuromuscular junction testing with repetitive stimulation and/or jitter studies, 
NCS to exclude neuropathy, and needle EMG to evaluate for myositis
Grading
Management
All grades
All grades warrant work-up and intervention given 
potential for progressive myasthenia gravis to lead to 
respiratory compromise
No G1
G2: Some symptoms interfering with ADL MGFA 
severity class 1 (ocular symptoms and ﬁndings only) 
and MGFA severity class 2 (mild generalized 
weakness)
Hold ICPi and may resume in G2 patients (MGFA 1 and 
2) only if symptoms resolve 
Should consult neurology
Pyridostigmine starting at 30 mg orally three times a 
day and gradually increase to maximum of 120 mg 
orally four times a day as tolerated and based on 
symptoms Administer corticosteroids (prednisone, 1-1.5 
mg/kg orally daily) if symptoms G2; wean based on 
symptom improvement
G3-4: Limiting self-care and aids warranted, weakness 
limiting walking, ANY dysphagia, facial weakness, 
respiratory muscle weakness, or rapidly progressive 
symptoms, or MGFA severity class 3-4 moderate to 
severe generalized weakness to myasthenic crisis
Permanently discontinue ICPi
Admit patient, may need ICU-level monitoring
Neurology consult
Continue corticosteroids and initiate IVIG 2 g/kg IV over 
5 days (0.4 g/kg/d) or plasmapheresis for 5 days
Frequent pulmonary function assessment
Daily neurologic review
Additional considerations
Avoid medications that can worsen myasthenia: b-blockers, IV magnesium, ﬂuoroquinolones, aminoglycosides, 
and macrolides Initially a 5-day course of plasmapheresis or a 2 g/kg course of IVIG over 5 days
1-2 mg/kg methylprednisolone daily, wean based on symptom improvement
Pyridostigmine, wean based on improvement
ICPi-associated myasthenia gravis may be monophasic, and additional corticosteroid-sparing agents may not be 
required
7.2 Guillain-Barré syndrome
Deﬁnition: Progressive, most often symmetrical muscle weakness with absent or reduced deep tendon reﬂexes. 
Often starts with sensory symptoms/neuropathic pain localized to lower back and thighs. May involve extremities 


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(typically ascending weakness but not always), facial, respiratory, and bulbar and oculomotor nerves. May have 
dysregulation of autonomic nerves.
Diagnostic work-up
Neurologic consultation
MRI of spine with or without contrast (rule out compressive lesion and evaluate for nerve root 
enhancement/thickening)
Lumbar puncture: CSF typically has elevated protein and often elevated WBCs; even though this is not typically 
seen in classic Guillain-Barré syndrome, cytology should be sent with any CSF sample from a patient with cancer.
Serum antibody tests for Guillain-Barré syndrome variants (GQ1b for Miller Fisher variant a/w ataxia and 
ophthalmoplegia) Electrodiagnostic studies to evaluate polyneuropathy
Pulmonary function testing (NIF/VC)
Frequent neurochecks
Grading
Management
All grades
Warrant work-up and intervention given potential for 
progressive Guillain-Barré syndrome to lead to 
respiratory compromise
Note: There is no G1 toxicity
G1: Mild, none
NA
G2: Moderate, some interference with ADL, symptoms 
concerning to patient
Discontinue ICPi
G3-4: Severe, limiting self-care and aids warranted, 
weakness, limiting walking, ANY dysphagia, facial 
weakness, respiratory muscle weakness, or rapidly 
progressive symptoms
Admission to inpatient unit with capability of rapid 
transfer to ICU-level monitoring Start IVIG (0.4 g/kg/d 
for 5 days for a total dose of 2 g/kg) or plasmapheresis. 
Corticosteroids are usually not recommended for 
idiopathic Guillain-Barré syndrome; however, in ICPi-
related forms, a trial is reasonable (methylprednisolone 
2-4 mg/kg/d), followed by slow corticosteroid taper
Pulse corticosteroid dosing (methylprednisolone 1 g/d 
for 5 days) may also be considered for G3-4 along with 
IVIG or plasmapheresis
Frequent neurochecks and pulmonary function 
monitoring
Monitor for concurrent autonomic dysfunction
Nonopioid management of neuropathic pain
Treatment of constipation/ileus
Additional considerations
Slow prednisone taper after corticosteroid pulse plus IVIG or plasmapheresis May require repeat IVIG courses
Caution with rechallenging for severe cases
7.3 Peripheral neuropathy
Deﬁnition: Can present as asymmetric or symmetric sensory, motor, or sensory motor deﬁcit. Focal 
mononeuropathies, including cranial neuropathies (eg, facial neuropathies/Bell palsy) may be present. Numbness 
and paresthesias may be painful or painless. Hypo- or areﬂexia or sensory ataxia may be present.
Diagnostic work-up
G1
Screen for reversible neuropathy causes: diabetic screen, B12, folate, TSH, HIV, consider serum protein 
electrophoresis, and other vasculitic and autoimmune screen Neurologic consultation
Consider MRI of spine with or without contrast
G2: in addition to above
MRI spine advised/MRI of brain if cranial nerve Consider EMG/NCS
Consider neurology consultation
G3-4: go to Guillain-Barré syndrome algorithm


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Grading
Management
G1: Mild, no interference with function and symptoms 
not concerning to patient. Note: Any cranial nerve 
problem should be managed as moderate
Low threshold to hold ICPi and monitor symptoms for a 
week If to continue, monitor very closely for any 
symptom progression
G2: Moderate, some interference with ADL, symptoms 
concerning to patient (ie, pain but no weakness or gait 
limitation)
Hold ICPi and resume once return to G1
Initial observation OR initiate prednisone 0.5-1 mg/kg (if 
progressing from mild)
Neurontin, pregabalin, or duloxetine for pain
G3-4: Severe, limiting self-care and aids warranted, 
weakness limiting walking or respiratory problems (ie, 
leg weakness, foot drop, rapidly ascending sensory 
changes) Severe may be Guillain-Barré syndrome and 
should be managed as such
Permanently discontinue ICPi
Admit patient
Neurologic consultation
Initiate IV methylprednisolone 2-4 mg/kg and proceed 
as per Guillain-Barré syndrome management
7.4 Autonomic neuropathy
Deﬁnition: Nerves that control involuntary bodily functions are damaged. This may affect blood pressure, 
temperature control, digestion, bladder function, and sexual function. A case of severe enteric neuropathy with 
ICPi has been reported. Can present with GI difﬁculties such as new severe constipation, nausea, urinary 
problems, sexual difﬁculties, sweating abnormalities, sluggish pupil reaction, and orthostatic hypertension.
Diagnostic work-up
An evaluation by neurologist or relevant specialist, depending on organ system, with testing that may include
Screening for other causes of autonomic dysfunction: diabetic screen, adrenal insufﬁciency, HIV, paraproteinemia, 
amyloidosis, botulism; consider chronic diseases such as Parkinson and other autoimmune screening
AM orthostatic vitals
Consider electrodiagnostic studies to evaluate for concurrent polyneuropathy
Consider paraneoplastic Lambert-Eaton myasthenic syndrome, antineutrophil cytoplasmic antibodies, and 
ganglionic AChR antibody testing
Grading
Management
G1: Mild, no interference with function and symptoms 
not concerning to patient
Low threshold to hold ICPi and monitor symptoms for a 
week; if to continue, monitor very closely for any 
symptom progression
G2: Moderate, some interference with ADL, symptoms 
concerning to patient
Hold ICPi and resume once return to G1
Initial observation OR initiate prednisone 0.5-1 mg/kg (if 
progressing from mild)
Neurologic consultation
G3-4: Severe, limiting self-care and aids warranted
Permanently discontinue ICPi
Admit patient
Initiate methylprednisolone 1 g daily for 3 days followed 
by oral corticosteroid taper Neurologic consultation
7.5 Aseptic meningitis
Deﬁnition: may present with headache, photophobia, and neck stiffness; often afebrile but may be febrile. There 
may be nausea/vomiting. Mental status should be normal (distinguishes from encephalitis).
Diagnostic work-up
MRI of brain with or without contrast + pituitary protocol
AM cortisol, ACTH to rule out adrenal insufﬁciency
Consider lumbar puncture: measure opening pressure; check cell count and protein glucose; and perform Gram 
stain, culture, PCR for HSV, and other viral PCRs depending on suspicion, cytology
May see elevated WBC count with normal glucose, normal culture, and Gram stain; may see reactive lymphocytes 
or histiocytes on cytology


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Grading
Management
G1: Mild, no interference with function and symptoms 
not concerning to patient. Note: Any cranial nerve 
problem should be managed as moderate.
G2: Moderate, some interference with ADL, symptoms 
concerning to patient (ie, pain but no weakness or gait 
limitation)
G3-4: Severe, limiting self-care and aids warranted
Hold ICPi and discuss resumption with patient only after 
taking into account the risks and beneﬁts
Consider empirical antiviral (IV acyclovir) and 
antibacterial therapy until CSF results Once bacterial 
and viral infection are negative, may closely monitor off 
corticosteroids or consider oral prednisone 0.5-1 mg/kg 
or IV methylprednisolone 1 mg/kg if moderate/severe 
symptoms
7.6 Encephalitis
Deﬁnition: As for aseptic meningitis, need to exclude infectious causes, especially viral (ie, HSV).
Confusion, altered behavior, headaches, seizures, short-term memory loss, depressed level of consciousness, 
focal weakness, speech abnormality Diagnostic work-up
Diagnostic work-up
Neurologic consultation
MRI of brain with or without contrast may reveal T2/ﬂuid-attenuated inversion recovery changes typical of what is 
seen in autoimmune encephalopathies or limbic encephalitis or may be normal
Lumbar puncture: check cell count and protein glucose and perform Gram stain, culture, PCR for HSV and other 
viral PCRs depending on suspicion, cytology, oligoclonal bands, autoimmune encephalopathy, and paraneoplastic 
panels.
May see elevated WBC count with lymphocytic predominance and/or elevated protein
EEG to evaluate for subclinical seizures
Blood: metabolic, CBC, ESR, CRP, ANCA (if suspect vasculitic process), thyroid panel including TPO and 
thyroglobulin Rule out concurrent anemia/thrombocytopenia, which can present with severe headaches and 
confusion
Grading
Management
G1: Mild, no interference with function and symptoms 
not concerning to patient. Note: Any cranial nerve 
problem should be managed as moderate.
G2: Moderate, some interference with ADL, symptoms 
concerning to patient (ie, pain but no weakness or gait 
limitation)
G3-4: Severe, limiting self-care and aids warranted
Hold ICPi and discuss resumption with patient only after 
taking into account the risks and beneﬁts
As above for aseptic meningitis, suggest concurrent IV 
acyclovir until PCR results obtained and negative
Trial of methylprednisolone 1-2 mg/kg
If severe or progressing symptoms or oligoclonal bands 
present, consider pulse corticosteroids 
methylprednisolone 1 g IV daily for 3-5 days plus IVIG 2 
g/kg over 5 days If positive for autoimmune 
encephalopathy antibody and limited or no 
improvement, consider rituximab or plasmapheresis in 
consultation with neurology
7.7 Transverse myelitis
Deﬁnition: Acute or subacute weakness or sensory changes bilateral, often with increased deep tendon reﬂexes
Diagnostic work-up
Neurologic consultation
MRI of spine (with thin axial cuts through the region of suspected abnormality) and MRI of brain
Lumbar puncture: cell count, protein, glucose, oligoclonal bands, viral PCRs, cytology, onconeural antibodies 
Blood: B12, HIV, RPR, ANA, Ro/La, TSH, aquaporin-4 IgG
Evaluation for urinary retention, constipation
Grading
Management
G1: Mild, no interference with function and symptoms 
not concerning to patient. Note: Any cranial nerve 
problem should be managed as moderate.
Permanently discontinue ICPi
Methylprednisolone 2 mg/kg
Strongly consider higher doses of 1 g/d for 3-5 days 
Strongly consider IVIG


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G2: Moderate, some interference with ADL, symptoms 
concerning to patient (ie, pain but no weakness or gait 
limitation)
G3-4: Severe, limiting self-care and aids warranted
All recommendations are expert consensus based, with beneﬁts outweighing harms, and strength of 
recommendations are moderate.
Abbreviations: AChR, acetylcholine receptor; ACTH, adrenocorticotropic hormone; ADL, activities of daily living; 
ANA, antinuclear antibody; ANCA, antineutrophil cytoplasmic antibodies; CBC, complete blood count; CNS, 
central nervous system; CPK, creatine phosphokinase; CRP, C-reactive protein; CSF, cerebrospinal fluid; ECG, 
electrocardiogram; EEG, electroencephalogram; EMG, electromyography; ESR, erythrocyte sedimentation rate; G, 
Grade; GI, gastrointestinal; HIV, human immunodeficiency virus; HSV, herpes simplex virus; ICPi, immune 
checkpoint inhibitor; ICU, intensive care unit; IgG, immunoglobulin G; IV, intravenous; IVIG, intravenous 
immunoglobulin; irAE, immune-related adverse event; MGFA, Myasthenia Gravis Foundation of America; MRI, 
magnetic resonance imaging; NA, not applicable; NCS, nerve conduction study; NIF, negative inspiratory force; 
PCR, polymerase chain reaction; RPR, rapid plasma reagin, TPO, thyroid peroxidase; TSH, thyroid-stimulating 
hormone; TTE, transthoracic echocardiogram; VC, vital capacity; WBC, white blood cell count.


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16.2.8 Table A8
Management of Hematologic irAEs in Patients Treated With ICPis
8.0 Hematologic Toxicities
8.1 Autoimmune hemolytic anemia
Deﬁnition: A condition in which RBCs are destroyed and removed from the blood stream before their normal 
lifespan is over. Symptoms include weakness, paleness, jaundice, dark-colored urine, fever, inability to do physical 
activity, and heart murmur.
Diagnostic work-up
History and physical examination (with special consideration of history of new drugs and insect, spider, or snake 
bites)
Blood chemistry, CBC with evidence of anemia, macrocytosis, evidence of hemolysis on peripheral smear; LDH, 
haptoglobin, bilirubin, reticulocyte count, free Hgb DIC panel, which could include PTNIR infectious causes
Autoimmune serology
Paroxysmal nocturnal hemoglobinuria screening
Direct and indirect bilirubin; LDH; direct agglutinin test; and if no obvious cause, bone marrow analysis, 
cytogenetic analysis to evaluate for myelodysplastic syndromes
Evaluation for viral/bacterial (mycoplasma, etc) causes of hemolysis studies
Protein electrophoresis, cryoglobulin analysis
Work-up for bone marrow failure syndrome if refractory, including B12, folate, copper, parvovirus, FE, thyroid, 
infection
Glucose-6-phosphate dehydrogenase
Evaluation of common drug causes (ribavirin, rifampin, dapsone, interferon, cephalosporins, penicillins, NSAIDs, 
quinine/quinidine, ﬂudarabine, ciproﬂoxacin, lorazepam, diclofenac, etc)
Assessment of methemoglobinemia
Grading
Management
G1: Hgb < LLN to 10.0 g/dL; < LLN to 6.2 mmol/L; < 
LLN to 100 g/L
Continue ICPi with close clinical follow-up and 
laboratory evaluation
G2: Hgb < 10.0 to 8.0 g/dL; < 6.2to4.9mmol/L; < 100 to 
80 g/L
Hold ICPi and strongly consider permanent 
discontinuation
Administer 0.5-1 mg/kg/d prednisone equivalents
G3: Hgb < 8.0 g/dL; < 4.9 mmol/L; < 80 g/L; transfusion 
indicated
Permanently discontinue ICPi
Should use clinical judgment and consider admitting the 
patient
Hematology consult
Prednisone 1-2 mg/kg/d (oral or IV depending on 
symptoms/speed of development)
If worsening or no improvement, 1-2 mg/kg/d 
prednisone equivalents and permanently discontinue 
ICPi treatment
Consider RBC transfusion per existing guidelines; do 
not transfuse more than the minimum number of RBC 
units necessary to relieve symptoms of anemia or to 
return a patient to a safe Hgb range (7-8 g/dL in stable, 
noncardiac inpatients)
Should offer patients supplementation with folic acid 1 
mg once daily
G4: Life-threatening consequences, urgent intervention 
indicated
Permanently discontinue ICPi
Admit patient
Hematology consult
IV prednisone corticosteroids 1-2 mg/kg/d
If no improvement or if worsening while on 
corticosteroids or severe symptoms on presentation, 
initiate other immunosuppressive drugs, such as 


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rituximab, IVIG, cyclosporin A, and mycophenolate 
mofetil
RBC transfusion per existing guidelines; discuss with 
blood bank team prior to transfusions that a patient with 
possible ICPi serious AE is in house.
Additional considerations: Monitor Hgb levels on a weekly basis until the corticosteroid tapering process is 
complete; thereafter, less-frequent testing is needed
8.2 Acquired TTP
Deﬁnition: A disorder characterized by the presence of microangiopathic hemolytic anemia, thrombocytopenic 
purpura, fever, renal abnormalities, and neurologic abnormalities, such as seizures, hemiplegia, and visual 
disturbances. It is an acute or subacute condition. 
Diagnostic work-up
History with speciﬁc questions related to drug exposure (eg, chemotherapy, sirolimus, tacrolimus, opana ER 
antibiotics, quinine) Physical examination, peripheral smear
ADAMTS13 activity level and inhibitor titer
LDH, haptoglobin, reticulocyte count, bilirubin, urinalysis to rule out other causes
PT, activated PTT, ﬁbrinogen
Blood group and antibody screen, direct antiglobulin test, CMV serology
Consider CT/MRI brain, echocardiogram, ECG
Viral studies
Note: This disorder is usually associated with a severe drop in platelets and hemolysis/anemia precipitously
Grading
Management
All grades
The ﬁrst step in the management of TTP is a high index 
of suspicion for the diagnosis and timely recognition; 
hematology consult should immediately be called, as 
delay in identiﬁcation is associated with increased 
mortality/morbidity.
Initially, the patient should be stabilized and any critical 
organ dysfunction stabilized
G1: Evidence of RBC destruction (schistocytosis) 
without anemia, renal insufﬁciency, or 
thrombocytopenia clinically
G2: Evidence of RBC destruction (schistocytosis) 
without clinical consequence with G2 anemia and 
thrombocytopenia
Hold ICPi and discuss resumption with patient only after 
taking into account the risks and beneﬁts, noting that 
there are currently no data to recommend restarting 
ICPi therapy Hematology consult
Administer 0.5-1 mg/kg/d prednisone
G3: Laboratory ﬁndings with clinical consequences (G3 
thrombocytopenia, anemia, renal insufﬁciency > 2)
G4: Life-threatening consequences (eg, CNS 
hemorrhage or thrombosis/embolism or renal failure)
Hold ICPi and discuss resumption with patient only after 
taking into account the risks and beneﬁts, noting that 
there are currently no data to recommend restarting 
ICPi therapy
Hematology consult
In conjunction with hematology, initiate PEX according 
to existing guidelines with further PEX dependent on 
clinical progress
Administer methylprednisolone 1 g IV daily for 3 days, 
with the ﬁrst dose typically administered immediately 
after the ﬁrst PEX
May offer rituximab
8.3 Hemolytic uremic syndrome
Deﬁnition: A disorder characterized by a form of thrombotic microangiopathy with renal failure, hemolytic anemia, 
and severe thrombocytopenia. Signs and symptoms of hemolytic uremic syndrome can include:
Bloody diarrhea
Decreased urination or blood in the urine


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Abdominal pain, vomiting, and occasionally fever
Pallor
Small, unexplained bruises or bleeding from the nose and mouth Fatigue and irritability
Confusion or seizures
High blood pressure
Swelling of the face, hands, feet, or entire body
Diagnostic work-up
History and physical examination (special consideration for new history of high-risk drugs, hypertension, or cardiac 
causes) CBC with indices
Blood smear morphology. Note that the presence of schistocytes on smear is critical for diagnosis.
Serum creatinine
ADAMTS13 (to rule out TTP)
Homocysteine/methylmalonic acid
Complement testing C3, C4, CH50 (complement inhibitory antibodies for suspected familial)
Evaluate reticulocyte count and mean corpuscular volume
Evaluation of infectious cause, including screening for EBV, CMV, HHV6
Evaluation for nutritional causes of macrocytosis (B12 and folate)
Pancreatic enzymes
Evaluation for diarrheal causes, shiga toxin, Escherichia coli 0157, etc
Direct antibody test (Coombs test), haptoglobin, LDH, and other etiologies of anemia
Evaluation for common drugs causing hemolysis (tacrolimus, cyclosporine, sirolimus, etc)
Evaluation for concurrent confusion
Grading
Management
G1-2: Evidence of RBC destruction (schistocytosis) 
without clinical consequences of anemia, 
thrombocytopenia Grade 2
G3: Laboratory ﬁndings with clinical consequences (eg, 
renal insufﬁciency, petechiae)
G4: Life-threatening consequences (eg, CNS 
thrombosis/ embolism or renal failure)
Continue ICPi with close clinical follow-up and 
laboratory evaluation
Supportive care Permanently discontinue ICPi
Begin therapy with eculizumab therapy 900 mg weekly 
for four doses, 1,200 mg week 5, then 1,200 mg every 2 
weeks
Red blood transfusion according to existing guidelines
8.4 Aplastic anemia
Deﬁnition: Condition in which the body stops producing enough new blood cells 
Diagnostic work-up
History and physical examination (close attention to medications, exposure to radiation, toxins, recent viral 
infections) CBC, smear, reticulocyte count
Viral studies, including CMV, HHV6, EBV, parvovirus
Nutritional assessments including B12, folate, iron, copper, ceruloplasmin, vitamin D
Serum LDH, renal function
Work-up for infectious causes
Identify marrow hypo/aplasia
Bone marrow biopsy and aspirate analysis
Peripheral blood analysis, including neutrophil count, proportion of GPI-negative cells by ﬂow for PNH
Flow cytometry to evaluate loss of GPI-anchored proteins
Type and screen patient for transfusions and notify blood bank that all transfusions need to be irradiated and 
ﬁltered
Grading
Management
G1: Nonsevere, < 0.5 polymorphonuclear cells x 109/L 
hypocellular marrow, with marrow cellularity < 25%, 
peripheral platelet count . 20,000, reticulocyte count 
< 20,000
Hold ICPi and provide growth factor support and close 
clinical follow-up, and laboratory evaluation 
Supportive transfusions as per local guidelines


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G2: Severe, hypocellular marrow < 25% and two of the 
following: ANC < 500, peripheral platelet < 20,000, and 
reticulocyte < 20,000
Hold ICPi and provide growth factor support and close 
clinical laboratory evaluations daily
Administer ATG + cyclosporine; HLA typing and 
evaluation for bone marrow transplantation if patient is 
candidate; all blood products should be irradiated and 
ﬁltered
Supportive care with granulocyte colony-stimulating 
factor may be added in addition
G3-4: Very severe, ANC > 200, platelet count > 20,000, 
reticulocyte count > 20,000, plus hypocellular marrow > 
25%
Hold ICPi and monitor weekly for improvement; if not 
resolved, discontinue treatment until AE has reverted to 
G1
Hematology consult, growth factor support
Horse ATG plus cyclosporine
If no response, repeat immunosuppression with rabbit 
ATG plus cyclosporine, cyclophosphamide
For refractory patients, consider eltrombopag plus 
supportive care
8.5 Lymphopenia
Deﬁnition: An abnormally low level of lymphocytes in PB; for adults, counts of < 1,500/mm3 
Diagnostic work-up
History and physical examination (special attention for lymphocyte-depleting therapy such as ﬂudarabine, ATG, 
corticosteroids, cytotoxic chemotherapy, radiation exposure, etc, as well as history of autoimmune disease, family 
history of autoimmune disease) Evaluation of nutritional state as cause
Spleen size
CBC with differential, peripheral smear and reticulocyte counts
CXR for evaluation of presence of thymoma
Bacterial cultures and evaluation for infection (fungal, viral, bacterial speciﬁcally CMV/HIV)
Grading
Management
G1-2: 500-1,000 PB lymphocyte count
G3: 250-499 PB lymphocyte count
G4: < 250 PB lymphocyte count
Continue ICPi
Continue ICPi, checking CBC weekly for monitoring, 
initiation of CMV screening Consider holding ICPi
Initiate Mycobacterium avium complex prophylaxis and 
Pneumocystis jirovecii prophylaxis, CMV screening. 
HIV/hepatitis screening if not already done
May consider EBV testing if evidence of 
lymphadenopathy/hepatitis, fevers, hemolysis 
consistent with lymphoproliferative disease
8.6 Immune thrombocytopenia
Deﬁnition: An autoimmune disorder characterized by immunologic destruction of otherwise normal platelets 
Diagnostic work-up
History and physical examination (special attention for lymphocyte-depleting therapy, such as ﬂudarabine, ATG, 
corticosteroids, cytotoxic therapy) Family history of autoimmunity or personal history of autoimmune disease
History of viral illness
CBC
Peripheral blood smear, reticulocyte count
Bone marrow evaluation only if abnormalities in the above test results and further investigation is necessary for a 
diagnosis
Patients with newly diagnosed immune thrombocytopenia should undergo testing for HIV, hepatitis C virus, 
hepatitis B virus, and Helicobacter pylori Direct antigen test should be checked to rule out concurrent Evan 
syndrome
Nutritional evaluation


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Bone marrow evaluation if other cell lines affected and concern for aplastic anemia
Grading
Management
G1: Platelet count < 100/µL
G2: Platelet count < 75/µL
Continue ICPi with close clinical follow-up and 
laboratory evaluation
Hold ICPi but monitor for improvement; if not resolved, 
interrupt treatment until AE has reverted to G1
Administer prednisone 1 mg/kg/d (dosage range, 0.5-2 
mg/kg/d) orally for 2-4 weeks after which time this 
medication should be tapered over 4-6 weeks to the 
lowest effective dose IVIG may be used in conjunction 
with corticosteroids if a more-rapid increase in platelet 
count is required.
G3: Platelet count < 50/µL
Hold ICPi but monitor for improvement; if not resolved, 
interrupt treatment until AE has reverted to G1
G4: Platelet count < 25/µL
Hematology consult
Prednisone 1-2 mg/kg/d (oral or IV depending on 
symptoms)
If worsening or no improvement, 1-2 mg/kg/d 
prednisone equivalents and permanently discontinue 
treatment
IVIG used with corticosteroids when a more-rapid 
increase in platelet count is required
If IVIG is used, the dose should initially be 1 g/kg as a 
one-time dose. This dosage may be repeated if 
necessary
If previous treatment with corticosteroids and/or IVIG 
unsuccessful, subsequent treatment may include 
rituximab, thrombopoietin receptor agonists, or more-
potent immunosuppression (From American Society of 
Hematology guideline on immune thrombocytopenia97; 
consult for further details)
8.7 Acquired hemophilia
Deﬁnition: Disorder caused by the development of autoantibodies (inhibitors) directed against plasma coagulation 
factors 
Diagnostic work-up
Full blood count to assess platelet number, ﬁbrinogen, PT, PTT, INR; the typical ﬁnding in patients with acquired 
hemophilia A is a prolonged activated PTT with a normal PT
MRI, CT, and ultrasonography may be indicated to localize, quantify, and serially monitor the location and 
response of bleeding Medication review to assess for alternative causes
Determination of Bethesda unit level of inhibitor
Grading
Management
G1: Mild, 5%-40% of normal factor activity in blood, 
0.05-0.4 IU/mL of whole blood
Hold ICPi and discuss resumption with patient only after 
taking into account the risks and beneﬁts
Administer 0.5-1 mg/kg/d prednisone
Transfusion support as required
Treatment of bleeding disorders with hematology 
consult
G2: Moderate, 1%-5% of normal factor activity in blood, 
0.01- 0.05 IU/mL of whole blood
Hematology consult
Administration of factor replacement (choice based on 
Bethesda unit of titer)
Administer 1 mg/kg/d prednisone 6 rituximab (dose, 375 
mg/m2 weekly for 4 weeks) and/or cyclophosphamide 


118
Abbreviated Title: Phase II M7824 in UC
Version Date: 06/23/2021
8.0 Hematologic Toxicities
(dose, 1-2 mg/kg/d); choice of rituximab v 
cyclophosphamide is patient speciﬁc and should be 
done with assistance of hematology consult; 
prednisone, rituximab, and cyclophosphamide should 
be given for at least 5 weeks
Factors should be provided to increase level during 
bleeding episodes, with choice of factor based on 
presence or absence of inhibitor
G3-4: Severe, < 1% of normal factor activity in blood, < 
0.01 IU/mL of whole blood
Permanently discontinue ICPi
Admit patient
Hematology consult
Administration of factor replacement, choice based on 
Bethesda unit level of inhibitor Bypassing agents may 
be used (factor VII, factor VIII inhibitor bypass activity); 
caution should be taken in the elderly and those with 
coronary artery disease
Prednisone 1-2 mg/kg/d (oral or IV depending on 
symptoms) 6 rituximab (dose, 375 mg/m2 weekly for 4 
weeks) and/or cyclophosphamide (dose, 1-2 mg/kg/d).
Transfusion support as required for bleeding
If worsening or no improvement add cyclosporine or 
immunosuppression/immunoadsorption
Additional considerations: The American Heart Association requires specialist clinical and laboratory expertise. 
Consult and/or transfer to a specialist center is often appropriate. If consultation with or transfer to a hemophilia 
center is not immediately possible, then investigation and treatment should be initiated while a liaison is being 
established.
All recommendations are expert consensus based, with beneﬁts outweighing harms, and strength of 
recommendations are moderate.
Abbreviations: AE, adverse event; ANC, absolute neutrophil count; ATG, antithymocyte globulin; CBC, complete 
blood count; CMV, cytomegalovirus; CNS, central nervous system; CT, computed tomography; CXR, chest x-ray; 
DIC, disseminated intravascular coagulation; EBV, Epstein-Barr virus; ECG, electrocardiogram; ER, extended 
release; FE, ferritin; G, Grade; GPI, glycosylphosphatidylinositol; Hgb, hemoglobin; HHV6, human herpesvirus 6; 
HIV, human immunodeficiency virus; HLA, human leukocyte antigen; ICPi, immune checkpoint inhibitor; INR, 
international normalized ratio; irAE, immune-related adverse event; IV, intravenous; IVIG, intravenous 
immunoglobulin; LDH, lactate dehydrogenase; LLN, lower limit of normal; MRI, magnetic resonance imaging; 
NSAID, nonsteroidal anti-inﬂammatory drug; PB, peripheral blood; PEX, plasma ex-change; PNH, paroxusmal 
nocturnal hemoglobinuria; PT, prothrombin time; PTT, partial thromboplastin time; RBC, red blood cell count; TTP, 
thrombotic thrombocytopenic purpura.


119
Abbreviated Title: Phase II M7824 in UC
Version Date: 06/23/2021
16.2.9 Table A9
Management of Cardiovascular irAEs in Patients Treated With ICPis
9.0 Cardiovascular Toxicities
9.1 Myocarditis, pericarditis, arrhythmias, impaired ventricular function with heart failure and vasculitis
Deﬁnition: Signs and symptoms may include chest pain, arrhythmia, palpitations, peripheral edema, progressive or 
acute dyspnea, pleural effusion, fatigue
Diagnostic work-up
At baseline
ECG
Consider troponin, especially in patient treated with combination immune therapies Upon signs/symptoms 
(consider cardiology consult)
ECG
Troponin
BNP Echocardiogram CXR
Additional testing to be guided by cardiology and may include
Stress test
Cardiac catherization Cardiac MRI
Grading
Management
G1: Abnormal cardiac biomarker testing, including 
abnormal ECG
G2: Abnormal screening tests with mild symptoms
G3: Moderately abnormal testing or symptoms with mild 
activity
G4: Moderate to severe decompensation, IV medication 
or intervention required, life-threatening conditions
All grades warrant work-up and intervention given 
potential for cardiac compromise
Consider the following:
Hold ICPi and permanently discontinue after G1
High-dose corticosteroids (1-2 mg/kg of prednisone) 
initiated rapidly (oral or IV depending on symptoms)
Admit patient, cardiology consultation
Management of cardiac symptoms according to 
ACC/AHA guidelines and with guidance from cardiology
Immediate transfer to a coronary care unit for patients 
with elevated troponin or conduction abnormalities
In patients without an immediate response to high-dose 
corticosteroids, consider early institution of cardiac 
transplant rejection doses of corticosteroids 
(methylprednisolone 1 g every day) and the addition of 
either mycophenolate, inﬂiximab, or antithymocyte 
globulin
Qualifying statement: Treatment recommendations are based on anecdotal evidence and the life-threatening 
nature of cardiovascular complications. Holding checkpoint inhibitor therapy is recommended for all grades of 
complications. The appropriateness of rechallenging remains unknown. Note that inﬂiximab has been associated 
with heart failure and is contraindicated at high doses in patients with moderate-severe heart failure.
9.2 Venous thromboembolism
Deﬁnition: A disorder characterized by occlusion of a vessel by a thrombus that has migrated from a distal site via 
the blood stream. Clinical signs and symptoms are variable and may include pain, swelling, increased skin vein 
visibility, erythema, and cyanosis accompanied by unexplained fever for DVT and dyspnea, pleuritic pain, cough, 
wheezing, or hemoptysis for PE
Diagnostic work-up
Evaluation of signs and symptoms of PE or DVT may include Clinical prediction rule to stratify patients with 
suspected venous thromboembolism Venous ultrasound for suspected DVT
CTPA for suspected PE
Can also consider D-dimer for low-risk patients based on risk stratiﬁcation by clinical prediction rule for DVT/PE 
when CT or Doppler are not available or appropriate Ventilation/perfusion scan is also an option when CTPA is not 
appropriate
Consider other testing, including ECG, CXR, BNP and troponin levels, and arterial blood gas


120
Abbreviated Title: Phase II M7824 in UC
Version Date: 06/23/2021
9.0 Cardiovascular Toxicities
Grading
Management
G1: Venous thrombosis (eg, superﬁcial thrombosis)
Continue ICPi
Warm compress
Clinical surveillance
G2: Venous thrombosis (eg, uncomplicated DVT), 
medical intervention indicated
G3: Thrombosis (eg, uncomplicated PE [venous], 
nonembolic cardiac mural [arterial] thrombus), medical 
intervention indicated
Continue ICPi
Management according to CHEST, ACC, and/or AHA 
guidelines and consider consult from cardiology or 
other relevant specialties
LMWH is suggested over VKA, dabigatran, rivaroxaban 
apixaban, or edoxaban for initial and long-term 
treatment
IV heparin is an acceptable alternative for initial use, 
and oral anticoagulants are acceptable for the long term
G4: Life-threatening (eg, PE, cerebrovascular event, 
arterial insufﬁciency), hemodynamic or neurologic 
instability, urgent intervention indicated
Permanently discontinue ICPi
Admit patient and management according to CHEST, 
ACC, and/or AHA guidelines and with guidance from 
cardiology
Respiratory and hemodynamic support
LMWH is suggested over VKA, dabigatran, 
rivaroxaban, apixaban, or edoxaban for initial and long-
term treatment
IV heparin is an acceptable alternative for initial use, 
and oral anticoagulants are acceptable for the long term
Further clinical management as indicated based on 
symptoms
Additional considerations
While it may be impossible to determine the etiology of thromboembolic disease in patients with advanced cancer 
and the role, if any, that ICPi treatment plays, it is reasonable to remove the potential inciting agents given the 
severity and life-threatening potential of G4 complications. Clinicians are to use clinical judgment and take into 
account the risks and beneﬁts when deciding whether to discontinue ICPi treatment.
Anticoagulant therapy duration should continue for a minimum of 9-12 months to indeﬁnitely in the setting of active 
cancer unless patient is asymptomatic, doing well, or in remission.
All recommendations are expert consensus based, with beneﬁts outweighing harms, and strength of 
recommendations are moderate.
Abbreviations: ACC, American College of Cardiology; AHA, American Heart Association; BNP, brain natriuretic 
peptide; CT, computed tomography; CTPA, computed tomography pulmonary angiography; CXR, chest x-ray; 
DVT, deep vein thrombosis; ECG, electrocardiogram; G, Grade; ICPi, immune checkpoint inhibitor; irAE, immune-
related adverse event; IV, intravenous; LMWH, low-molecular-weight heparin; MRI, magnetic resonance imaging; 
PE, pulmonary embolism; VKA, vitamin K agonist.


121
Abbreviated Title: Phase II M7824 in UC
Version Date: 06/23/2021
16.2.10
 Table A10
Management of Ocular irAEs in Patients Treated With ICPis
10.0 Ocular Toxicities
Counsel all patients to inform their health care provider immediately if they experience any of the following ocular 
symptoms
Blurred vision
Change in color vision Photophobia
Distortion
Scotomas
Visual ﬁeld changes Double vision Tenderness
Pain with eye movement Eyelid swelling Proptosis
Evaluation, under the guidance of ophthalmology
Check vision in each eye separately
Color vision
Red reﬂex
Pupil size, shape, and reactivity
Fundoscopic examination
Inspection of anterior part of eye with penlight
Prior conditions
Exclude patients with history of active uveitis
History of recurrent uveitis requiring systemic immunosuppression or continuous local therapy
Additional considerations
Ocular irAEs are many times seen in the context of other organ irAEs
High level of clinical suspicion as symptoms may not always be associated with severity Best to treat after 
ophthalmologist eye examination
10.1 Uveitis/iritis
Deﬁnition: Inﬂammation of the middle layer of the eye Diagnostic work-up: as per above
Grading
Management
G1: Asymptomatic
Continue ICPi
Refer to ophthalmology within 1 week
Artiﬁcial tears
G2: Medical intervention required, anterior uveitis
Hold ICPi temporarily until after ophthalmology consult
Urgent ophthalmology referral
Topical corticosteroids, cycloplegic agents, systemic 
corticosteroids
May resume ICPi treatment once off systemic 
corticosteroids, which are purely indicated for ocular 
adverse effects or once corticosteroids for other 
concurrent systemic irAEs are reduced to # 10 mg; 
continued topical/ocular corticosteroids are permitted 
when resuming therapy to manage and minimize local 
toxicity Re-treat after return to G1 or less
G3: Posterior or panuveitis
Permanently discontinue ICPi
Urgent ophthalmology referral.
Systemic corticosteroids and 
intravitreal/periocular/topical corticosteroids
G4: 20/200 or worse
Permanently discontinue ICPi
Emergent ophthalmology referral
Systemic corticosteroids (IV prednisone 1-2 mg/kg or 
methylprednisolone 0.8-1.6 mg/kg) and 


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Version Date: 06/23/2021
10.0 Ocular Toxicities
intravitreal/periocular/topical corticosteroids per 
ophthalmologist opinion
Additional considerations: Consider use of inﬂiximab or other TNF-a blockers in cases that are severe and 
refractory to standard treatment
10.2 Episcleritis
Deﬁnition: Inﬂammatory condition affecting the episcleral tissue between the conjunctiva and the sclera that occurs 
in the absence of an infection Diagnostic work-up: As per 10.0
Grading
Management
G1: Asymptomatic
Continue ICPi
Refer to ophthalmology within 1 week
Artiﬁcial tears
G2: Vision 20/40 or better
Hold ICPi therapy temporarily until after ophthalmology 
consult
Urgent ophthalmology referral
Topical corticosteroids, cycloplegic agents, systemic 
corticosteroids
G3: Symptomatic and vision worse than 2/40
Permanently discontinue ICPi
Urgent ophthalmology referral.
Systemic corticosteroids and topical corticosteroids with 
cycloplegic agents
G4: 20/200 or worse
Permanently discontinue ICPi
Emergent ophthalmology referral.
Systemic corticosteroids and topical corticosteroids with 
cycloplegic agents
Additional considerations: Consider use of inﬂiximab or other TNF-α blockers in cases that are severe and 
refractory to standard treatment
10.3 Blepharitis
Deﬁnition: Inﬂammation of the eyelid that affects the eyelashes or tear production Diagnostic work-up: As per 10.0
Grading
Management
No formal grading system
Warm compresses and lubrication drops
Continue therapy unless persistent and serious
All recommendations are expert consensus based, with beneﬁts outweighing harms, and strength of 
recommendations are moderate.
Abbreviations: ICPi, immune checkpoint inhibitor; G, Grade; irAE, immune-related adverse event; IV, intravenous, 
TNF, tumor necrosis factor.

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: 06/23/2021
Page 1 of 21
CC ICF template v. 05.05.20
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
PRINCIPAL INVESTIGATOR:
Andrea B. Apolo, M.D
STUDY TITLE:
A Phase II Study of Bintrafusp alfa (M7824) in Checkpoint Inhibitor 
Naïve and Refractory Subjects with Urothelial Carcinoma
STUDY SITE:
NIH Clinical Center
Cohort: 
Affected Patients 
Consent Version:
June 23, 2021
WHO DO YOU CONTACT ABOUT THIS STUDY? 
Study PI:                            Andrea B. Apolo, M.D.
                                Phone:  301-480-0536 
                                Email:  andrea.apolo@nih.gov
KEY INFORMATION ABOUT THIS RESEARCH 
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). 
This section provides the information we believe is most helpful and important to you in making 
your decision about participating in this study. Additional information that may help you decide 
can be found in other sections of the document. Taking part in research at the NIH is your choice.
You are being asked to take part in this study because you have urothelial cancer that has spread 
to other parts of your body and you have been previously treated with chemotherapy or 
immunotherapy.
The purpose of this study is to learn if giving M7824 could help your immune system fight the 
cancer.
M7824 is a drug that blocks pathways that cancer cells use to prevent your immune system from 
fighting your cancer.
The use of M7824 in this study is considered investigational, which means that this drug has not 
been approved by the U.S. Food and Drug Administration (FDA) to treat urothelial cancer 
However, the FDA has given us permission to use M7824 in this study.
There are other standard of care drugs that can be given by your regular cancer doctor and could 
be more effective to treat your disease. If you decide to participate in this study, you will not be 
able to receive any of these conventional cancer treatments. Depending on your disease and 
prior treatments, these drugs could include chemotherapy and/or FDA approved immune check-
point inhibitors (“immunotherapy”). 
IRB NUMBER: 20C0142
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PATIENT IDENTIFICATION
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CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
Standard chemotherapies that are platinum-based (such as cisplatin or carboplatin) or taxane 
based (such as paclitaxel, abraxane or docetaxel) are some possible treatments that you could 
receive. Standard platinum-taxane-based chemotherapies are known to cause changes in blood 
counts, nausea, vomiting, fatigue, and neuropathy (tingling and/or numbness most often in the 
fingers and toes).  
If you have not already received immunotherapy, you may be eligible to receive it as a standard 
treatment.  This includes FDA approved drugs like atezolizumab, avelumab, durvalumab, 
nivolumab, and pembrolizumab. These drugs alter the immune system and may lead to known 
autoimmune side effects like fatigue, skin problems, diarrhea, liver damage, and lung 
inflammation. 
The treatment being given in this study and the side effects are different than if you were to 
receive standard care.
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.
If you decide to join this study, here are some of the most important things that you should know 
that will happen:
•
M7824 is given as an IV (intravenous) infusion. A small plastic tube is put into a vein in 
your arm and the medication is given once every two weeks.
•
You will be seen in the NIH Clinical Center by your study team every 2 weeks while you 
are receiving treatment. These clinic visits will take 2-4 hours. The treatments will be 
given in the Oncology Outpatient Center every two weeks during the treatment portion 
of the study and those visits will take 4-6 hours. Treatment will continue until your cancer 
worsens, you develop unacceptable side effects or you decide to stop receiving the study 
treatment. 
•
You will have clinical, laboratory, and imaging tests to see how you are doing and to 
assess your disease. We will also collect required samples from you (such as:  blood and 
tissue samples) for both clinical and research purposes.
•
After the study treatment has ended, you will be seen in the NIH Clinical Center by your 
study team after 30 days from the last dose of drug and then you will be followed 
indefinitely in clinic or over phone/email every 12 weeks. You will have tests done 
(physical exams and blood work) either at NIH or by your local provider to see how you 
are doing and to see how your disease is responding.
As described above and later in more detail in this consent form, you may experience side effects 
from taking part in this study. Some can be mild or very serious, temporary, long-lasting, or 
permanent, any may include death.  
IRB NUMBER: 20C0142
IRB APPROVAL DATE: 06/24/2021


PATIENT IDENTIFICATION
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CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
Just as we do not know what side effects you might have, we cannot know if you may benefit 
from taking part in this study. If you do not benefit, this study and the results from our research 
may help others in the future.
You are free to stop participating in the trial at any time.  If you decide to stop, the study doctor 
may ask you to agree to certain tests to make sure it is safe for you to stop.
The remaining document will now describe the research study in more detail.  This information 
should be considered before you make your choice. Members of the study team will talk with you 
about the information in this document. Some people have personal, religious, or ethical beliefs 
that may limit the kinds of medical or research interventions in which they would want to 
participate. Take the time you need to ask any questions and discuss this study with NIH staff, and 
with your family, friends, and personal health care providers.
If the individual being asked to participate in this research study is not able to give consent for 
themselves, you, as the Legally Authorized Representative, will be their decision-maker and you 
are being asked to give permission for this person to be in this study. For the remainder of this 
document, the term “you” refers to you as the decision-maker and/or the individual being asked to 
participate in this research. 
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?
The main purpose of this research study is to learn if giving M7824 could help your immune 
system’s ability to fight urothelial cancer.
We are asking you to join this research study because you have metastatic urothelial cancer that 
has not responded to previous treatment with chemotherapy and/or immunotherapy
M7824 is considered investigational, which means that it has not been approved by the U.S. Food 
and Drug Administration (FDA) to treat urothelial cancer. Prior clinical studies with M7824 have 
helped researchers learn about the recommended doses that are safe.
WHAT WILL HAPPEN DURING THE STUDY?
Before you begin the study 
Before beginning the study, you will be evaluated by a physician investigator, as well as other 
members of the research team for eligibility to participate in the study. We will discuss your medical 
history in detail and draw blood from a vein to perform laboratory tests to help determine whether you 
are eligible to participate. We will also need a small sample of tissue (biopsy) from your cancer in 
order to confirm your diagnosis. These tests and/or procedures will help your doctor verify whether 
you can participate. This is called screening. The exams, tests, and procedures you will have are 
IRB NUMBER: 20C0142
IRB APPROVAL DATE: 06/24/2021


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 06/23/2021
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MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
part of the usual approach for people who have genitourinary cancers. We will discuss these tests 
and the reasons they are required if you need to have them. Most scans must be performed within 21 
days before enrollment. Briefly, these tests, which will be performed under a separate protocol 
include:

Confirmation of diagnosis (You must provide a sample tumor tissue for formal evaluation 
by the NCI Laboratory of Pathology. The tissue may be from a previous surgery or biopsy.  
If none is available, we will ask you to have a biopsy to provide a fresh sample).  

Medical history and physical examination including weight, height and vital signs

Blood and urine lab tests

Pregnancy test in women who can have children. Pregnant women will not be allowed on 
study.

CT Scans or MRI if CT scans cannot be done

Electrocardiogram (ECG)

Tests for certain infections (Hepatitis B, Hepatitis C)
During the study
In this study, you will undergo a series of treatment cycles, each lasting 28 days. 
You will need to make several visits to the study center for testing during the treatment period. It 
is important that you come to all of these scheduled visits. 
At the visit to the study center after you first join the study, the study doctor will do the following 
tests and procedures. Some tests or procedures done at screening may not be repeated on this day. 
Your doctor will let you know which ones.:

Perform a complete physical examination

Assess your Eastern Cooperative Oncology Group (ECOG) performance status. ECOG 
measures your ability to perform your normal activities.

Record your vital signs (blood pressure, heart rate, body temperature, and breathing rate)

Pregnancy test, if applicable

Routine blood tests

M7824 will be given once every 2 weeks through an IV (infusion). This procedure takes 
about 1 hour.  

For the prevention of infusion-related adverse effects and possible allergic reactions, you 
will receive an antihistamine drug (e.g. Benadryl) and an anti-inflammatory drug (e.g. 
acetaminophen) before the first 2 infusions of M7824. Based on how your body reacts to 
the first 2 infusions, the study doctor will see if you will need to continue receiving these 
medication drugs before your other infusions.

You will continue to be treated with M7824 until your disease gets worse, you have 
unacceptable side effects or you decide to stop receiving the study treatment.
Follow-up tests
Every two weeks:

Medical history and physical exam
IRB NUMBER: 20C0142
IRB APPROVAL DATE: 06/24/2021


PATIENT IDENTIFICATION
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CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY

Blood tests

Vital signs
Every 4 weeks:

Pregnancy test, if you are a woman who could possibly become pregnant
Every 8 weeks

Imaging scans to look at tumor growth (CAT scans)
Additional research testing
In addition to the tests that we will conduct to determine whether you are having side effects or if 
you are responding to the study therapy, we will also collect samples from you. The samples are 
being collected to look at the effects of therapy on your immune system and markers of tumor 
activity, including collecting and testing tumor cells. Unless noted otherwise below, the samples 
will be collected at least once each cycle and at the time your disease responds to treatment or gets 
worse (required), and at the end of treatment (optional).
Research imaging:

Whole body MRI (also called diffusion weighted MRI or DW MRI) done before you start 
treatment at and at the start of cycle 3
Research samples include:

blood (around 2 cups in the first 8 weeks and then about 1 cup every 8 weeks after that 
while on treatment)

tissue (collected before you start treatment and at the start of cycle 3 (required, if your 
study doctor thinks it is feasible) and at your end of treatment visit - optional)
All of your samples collected for research purposes on this study (such as the tumor and normal 
tissue) may be used to look for specific changes in the DNA in tumors that could be used to develop 
new ways of diagnosing and treating cancer. DNA (also called deoxyribonucleic acid) in the cells 
carries genetic information and passes it from one generation of cells to the next – like an 
instruction manual. Normal tissue contains the DNA (instructions) that you were born with, DNA 
in tumor cells has changed – or mutated – and we think that change in the DNA is what causes 
tumors to form and to grow. 
To look at your DNA, we may use do what is called “whole genome sequencing” and “whole 
exome sequencing.”  This where we will do special tests in the lab to look at the entire sequence, 
or order, of how your DNA is put together.  This is what makes you unique.  
To determine which parts of the DNA have mutated, we will compare the DNA in your tumor cells 
to DNA from your normal cells. We will then analyze the results from similar tumors to see if 
there are any changes in the DNA that are common to a particular type of tumor. To examine the 
tumor and normal tissue we may use several different techniques depending on the type of tissue 
we collect. These could include growing cell lines (cells which keep dividing and growing in the 
laboratory, sometimes for years allowing us to continually study those cells), xenograft studies 
IRB NUMBER: 20C0142
IRB APPROVAL DATE: 06/24/2021


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
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CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
(placing or growing cells in another animal, such as mice), and looking in detail at the parts of the 
genes that produce specific proteins.
However, you should know that the analyses that we perform in our laboratory are for research 
purposes only; they are not nearly as sensitive as the tests that are performed in a laboratory that 
is certified to perform genetic testing or testing for routine clinical care. For these reasons, we will 
not give you the results of the research tests done on your research samples in most cases.  There 
may be exceptions to what we share with you and this is described later in this consent form in the 
section for “Return of research results.” 
End of treatment visit
When you stop taking the study drug for any reasons, you will be asked to return to the study 
center for the end of treatment visit. This end of treatment visit should occur within 30 days after 
you stop taking the study drugs and, if possible, prior to starting any new therapy for your cancer. 
At this visit, the study doctor/study team will do the following:

Perform a complete physical examination and medical history 

Record your vital signs (blood pressure, heart rate, body temperature, and breathing rate) 
and body weight.

EKG

CT scans 

Collect blood (around ¼ cup) for safety laboratory assessments and research studies.

Collect a urine sample

Collect tissue samples (optional) for post-treatment research studies.
Long-term follow-up visit
You will be followed every 12 weeks in the clinic or by telephone/email for review of survival 
status, adverse events and information about new anti-cancer therapy you may have started. The 
study doctor will continue to follow-up with you indefinitely.
HOW LONG WILL THE STUDY TAKE?
You will continue to receive the study drug (in repeated 28-day cycles) until the cancer worsens, 
you have unacceptable side effects, you decide to no longer take part in the study or your study 
doctor decides it is no longer suitable for you to continue. 
HOW MANY PEOPLE WILL PARTICIPATE IN THIS STUDY?
We plan to have approximately 75 people participate in this study at the NIH. 
WHAT ARE THE RISKS AND DISCOMFORTS OF BEING IN THE STUDY?
There are risks, discomforts, and inconveniences associated with any research study. These 
deserve careful thought. You should talk with the investigator if you have any questions.
It is probable that you will experience some of the side effects listed, but it is unlikely that you will 
experience all of them. You will be watched closely, and we will give you medicines to try and 
prevent or reverse the side effects. However, doctors don’t know all the side effects that may 
happen. Side effects may be mild or very serious. In some cases, side effects can be serious, long 
IRB NUMBER: 20C0142
IRB APPROVAL DATE: 06/24/2021


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
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lasting, or may never go away. We will tell you if we learn any new information that may affect 
your health, welfare, or decision to stay in this study. You should talk to your study doctor about 
any side effects that you have while taking part in the study.
M7824
Common (occurring in more than 5 % of patients)

Tiredness 

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

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

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've had a life-long problem 
of frequent or excessive bleeding or bruising, or if you take aspirin or prescription 
medication to thin your blood.
Occasional (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
IRB NUMBER: 20C0142
IRB APPROVAL DATE: 06/24/2021


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
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
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

Stroke

Slow wound healing

Thickening of the skin, nails

Certain type of a skin cancer

Abdominal pain

Non-cardiac chest pain

Anemia or low blood cell count

Allergic reactions or reactions related to the infusions might occur during treatment. 
Usually, these reactions are mild to moderate and can be treated with drugs, but could also 
be severe to life-threatening which could require advanced cardiac life support and even 
fatal reactions might occur. 
For the prevention of infusion-related side effects and possible allergic reactions you will 
receive of an antihistamine drug (Benadryl® or similar) and acetaminophen (Tylenol® or 
similar) 30 to 60 minutes before the first 2 infusions of M7824. Based on how your body 
reacts to the first 2 infusions, the study doctor will see if you will need to continue receiving 
these medication drugs before your other infusions In addition, as a preventive measure, 
you may be asked to stay overnight in the hospital for observation after the first two 
infusions of the study drug.  For other doses, you will be asked to remain in the study center 
for at least 2 hours after the end of the infusion.
There is a risk of tumor lysis syndrome due to tumor shrinkage. This complication is caused by 
the breakdown products of dying cells and includes elevated blood potassium, elevated blood 
phosphorus, elevated blood uric acid and elevated urine uric acid, low blood calcium, and 
consequent acute kidney failure.
In addition, immune-related side effects might be possible. These adverse events are caused by 
over activity of your body’s immune system. The immune system normally protects you from 
infections and foreign substances, such as cancer. If the immune system is overactive, it may think 
that parts of the body are foreign substances and attack them.
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:

pneumonitis (inflammatory disease of the lung): 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
IRB NUMBER: 20C0142
IRB APPROVAL DATE: 06/24/2021


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
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
hypothyroidism (decreased function of the thyroid gland)

hyperthyroidism (increased function of thyroid gland)

thyroiditis (inflammatory disease of the thyroid gland)

hepatitis (inflammation of the liver). 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)

adrenal insufficiency: inability of the adrenal glands (triangle-shaped glands located on top 
of the kidneys) to produce a normal quantity of hormones. It 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 (inflammatory disease of muscles characterized by pain and tenderness)

colitis (inflammatory disease of the large intestine). 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 (marked inflammation and damage to the heart)

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.

Hypopituitarism (problems with the pituitary gland). 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
IRB NUMBER: 20C0142
IRB APPROVAL DATE: 06/24/2021


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
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Risks of study research procedures
Blood draws
Risks include temporary discomfort, pain, redness, bleeding, bruising, and swelling at the site 
where the needle is inserted, and/or very rarely inflammation/infection of the vein, which could 
require antibiotics. You may also experience dizziness, nausea, or rarely, fainting during blood 
taking. Please tell the study doctor if you do not feel well after having your blood drawn.
Electrocardiogram (ECG)
Some skin irritation can occur where the ECG/EKG electrodes are placed. Once the electrodes are 
placed, the test will begin, is completely painless, and generally takes less than a minute to perform. 
After the test, the electrodes are removed.
Tumor biopsy 
If your doctor determines it is safe, we will obtain a piece of your tumor (biopsy) using a needle 
with minimal risk to you. You will be given local anesthesia (numbing medicine) and a sedative 
prior to the biopsy.  The biopsy will be taken through a needle put through the skin into your tumor. 
Depending upon the location of your tumor, a CT scan may be used to assist the biopsy. After the 
procedure the nurses will watch your blood pressure and other vital signs.  Two biopsies are 
mandatory, and one is optional. These biopsies will be used for conducting research and making 
clinical decisions. If an attempt at biopsy is unsuccessful, you will still be eligible for treatment. 
There may be some temporary pain or discomfort during the procedure and afterwards in the area 
where the tissue was removed. You may also experience some bruising around the biopsy site over 
the following days. In rare cases an infection or bleeding may occur. Your doctor will give you a 
separate surgical consent form for this hospital procedure.
Imaging/scans
CT and/or MRI scans are used to monitor your disease while you are in this study. You may receive 
a contrast agent as part of your CT scan or MRI. Contrast agents can cause allergic reactions and 
kidney damage. Allergic reactions can include mild itching associated with hives but can also 
result in a serious life-threatening emergency from difficulty breathing. If this occurs, it is 
treatable. Please ask the study doctor if you have questions about the risks of these scans. If done, 
MRI scans do not involve radiation risk. The scans that you will receive during this study are 
considered standard for your type of disease.  
MRI scans cannot be done on people who have:
o
a cardiac pacemaker, 
o
neural pacemaker, 
o
surgical metal clips in the brain or on blood vessels, 
o
cochlear implants, 
o
or foreign metal objects within the eye.  
At the time of your MRI, you will be asked about these things.
IRB NUMBER: 20C0142
IRB APPROVAL DATE: 06/24/2021


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
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What are the risks related to pregnancy? 
If you are able to become pregnant, we will ask you to have a pregnancy test before starting this 
study. You will need to practice an effective form of birth control before starting study treatment, 
during study treatment, and for 65 days after you finish study treatment (the restricted period). 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 during the restricted period. If you think or know you have become pregnant during the 
restricted period, please contact a study team member as soon as possible.
If you are a sexually active person with a partner able to become pregnant, it is important that your 
partner not become pregnant during the restricted period (at least 125 days after the last dose of 
the study drug - restricted period for male participants). It is equally important that you do not 
donate sperm for the same time period. 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. If you think your partner has become pregnant during the restricted period, please contact 
study team as soon as possible. If you and your partner plan for your partner to become pregnant 
after the restricted period (male or female as applicable), please discuss this with the study team.
What are the risks of radiation from being in the study? 
During your participation in this research study, you will be exposed to radiation from up to 7 CT 
scans of chest, abdomen and pelvis and up to 3 CT guided biopsies.  The amount of radiation 
exposure you will receive from these procedures is equal to approximately 10.1 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 scans that you get in this study will expose you to the roughly the same amount of radiation 
as 33.7 years 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 1.0 out of 100 (1.0%) and of getting a fatal cancer is 0.5 out of 100 (0.5%). 
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 
IRB NUMBER: 20C0142
IRB APPROVAL DATE: 06/24/2021


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
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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. 
Privacy Risks Associated with Return of Incidental or Secondary Findings
Although your genetic information is unique to you, you do share some genetic information with 
your children, parents, brothers, sisters, and other blood relatives. Consequently, it may be possible 
that genetic information from them could be used to help identify you. Similarly, it may be possible 
that genetic information from you could be used to help identify them.  Patterns of genetic variation 
also can be used by law enforcement agencies to identify a person or his/her blood relatives.  
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 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.
WHAT ARE THE BENEFITS OF BEING IN THE STUDY?
You might not benefit from being in this study. 
However, the potential benefit to you might be shrinking of your tumor or decrease in 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.
Are there any potential benefits to others that might result from the study?
In the future, other people might benefit from this study because what we learn in this study may 
eventually be used to treat others with your disease.
WHAT OTHER OPTIONS ARE THERE FOR YOU?
Before you decide whether or not to be in this study, we will discuss other options that are 
available to you. Instead of being in this study, you could 

choose to be treated with surgery, radiation or with drugs already approved by the FDA for 
your disease

choose to take part in a different study, if one is available

choose not to be treated for cancer but you may want to receive comfort care to relieve 
symptoms.
IRB NUMBER: 20C0142
IRB APPROVAL DATE: 06/24/2021


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
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DISCUSSION OF FINDINGS
New information about the study
If we find out any new information that may affect your choice to participate in this study, we 
will get in touch with you to explain what we have learned. This may be information we have 
learned while doing this study here at the NIH or information we have learned from other 
scientists doing similar research in other places.
Return of research results
When we are examining your DNA, it is possible that we could identify possible changes in other 
parts of your DNA that are not related to this research. These are known as “incidental medical 
findings”. 
These include: 

Changes in genes that are related to diseases other than cancer 

Changes in genes that are not known to cause any disease. These are known as normal 
variations. 

Changes in genes that are new and of uncertain clinical importance. This means that we do 
not know if they could cause or contribute to a disease or if they are normal variations. 
Since the analyses that we perform in our laboratory are not nearly as sensitive as the tests that are 
performed in a laboratory that is certified to perform genetic testing, the genetic changes that we 
find may or may not be valid.  Therefore, we do not plan to inform you of all of the genetic results 
of testing on your tissue and blood that is performed in our research lab. However, in the unlikely 
event that we discover a finding 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 have an additional tube of blood drawn to verify the findings we have seen in 
our lab. If the results are verified, you will be re-contacted and offered a referral to a genetic 
healthcare provider to discuss the results.
EARLY WITHDRAWAL FROM THE STUDY 
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 worsens or comes back during treatment

if you have side effects from the treatment that your doctor thinks are too severe

if you become pregnant

if the M7824 may become unavailable

if new information shows that another treatment would be better for you

if you do not follow the study rules

if the study is stopped for any reason
In this case, you will be informed of the reason therapy is being stopped.  
After therapy is stopped, we would like to see you for a safety visit 30 days after your last dose.
IRB NUMBER: 20C0142
IRB APPROVAL DATE: 06/24/2021


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 06/23/2021
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MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
You can stop taking part in the study at any time. However, if you decide to stop taking part in the 
study, we would like you to talk to the study doctor and your regular doctor first.
If you decide at any time to withdraw your consent to participate in the trial, we will not collect 
any additional medical information about you. However, according to FDA guidelines, 
information collected on you up to that point may still be provided to EMD Serono or designated 
representatives.
STORAGE, SHARING AND FUTURE RESEARCH USING YOUR SPECIMENS AND 
DATA
Will Your Specimens or Data Be Saved for Use in Other Research Studies?
As part of this study, we are obtaining specimens and data from you. We will remove all the 
identifiers, such as your name, date of birth, address, or medical record number and label your 
specimens and data with a code so that you cannot easily be identified. However, the code will 
be linked through a key to information that can identify you. We plan to store and use these 
specimens and data for studies other than the ones described in this consent form that are going 
on right now, as well as studies that may be conducted in the future. These studies may provide 
additional information that will be helpful in understanding urothelial cancer, or other diseases 
or conditions. This could include studies to develop other research tests, treatments, drugs, or 
devices, that may lead to the development of a commercial product by the NIH and/or its research 
or commercial partners. There are no plans to provide financial compensation to you if this 
happens. Also, it is unlikely that we will learn anything from these studies that may directly 
benefit you.
I give permission for my coded specimens and data to be stored and used for future research as 
described above.
_____ Yes
_____ No
Initials
Initials
Will Your Specimens or Data Be Shared for Use in Other Research Studies?
We may share your coded specimens and data with other researchers.  If we do, while we will 
maintain the code key, we will not share it, so the other researchers will not be able to identify 
you.  They may be doing research in areas that are similar to this study or in other unrelated 
areas. These researchers may be at NIH, other research centers and institutions, or commercial 
entities. 
I give permission for my coded specimens and data to be shared with other researchers and used 
by these researchers for future research as described above.
_____ Yes 
_____ No
Initials
Initials
IRB NUMBER: 20C0142
IRB APPROVAL DATE: 06/24/2021


PATIENT IDENTIFICATION
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If you change your mind and do not want us to store and use your specimens and data for future 
research, you should contact the research team member identified at the top of this document. 
We will do our best to comply with your request but cannot guarantee that we will always be 
able to destroy your specimens and data. For example, if some research with your specimens and 
data has already been completed, the information from that research may still be used. Also, for 
example, if the specimens and data have been shared already with other researchers, it might not 
be possible to withdraw them. 
In addition to the planned use and sharing described above, we might remove all identifiers and 
codes from your specimens and data and use or share them with other researchers for future 
research at the NIH or other places.  When we or the other researchers access your anonymized 
data, there will be no way to link the specimens or data back to you.  We will not contact you to 
ask your permission or otherwise inform you before we do this.  We might do this even if you 
answered "no" to the above questions.  If we do this, we would not be able to remove your 
specimens or data to prevent their use in future research studies, even if you asked, because we 
will not be able to tell which are your specimens or data.
NIH policies require that your clinical and other study data be placed in an internal NIH database 
that is accessible to other NIH researchers for future research. Usually, these researchers will not 
have access to any of your identifiers, such as your name, date of birth, address, or medical 
record number; and your data will be labeled with only a code. We cannot offer you a choice of 
whether your data to be placed in this database or not.  If you do not wish to have your data 
placed in this database, you should not enroll in this study.  
Will Your Genomic Data Be Shared Outside of This Study?
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.  
How Long Will Your Specimens and Data be Stored by the NIH?
Your specimens and data may be stored by the NIH indefinitely. 
IRB NUMBER: 20C0142
IRB APPROVAL DATE: 06/24/2021


PATIENT IDENTIFICATION
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File in Section 4: Protocol Consent (1)
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Risks of Storage and Sharing of Specimens and Data
When we store your specimens and data, we take precautions to protect your information from 
others that should not have access to it. When we share your specimens and data, we will do 
everything we can to protect your identity, for example, when appropriate, we remove information 
that can identify you. Even with the safeguards we put in place, we cannot guarantee that your 
identity will never become known or someone may gain unauthorized access to your information. 
New methods may be created in the future that could make it possible to re-identify your specimens 
and data.
PAYMENT
Will you receive any type of payment for taking part in this study?
You will not receive any payment for taking part in this study. 
REIMBURSEMENT
Will you receive reimbursement or direct payment by NIH as part of your participation?
On this study, the NCI will reimburse the cost for some of your expenses such as those for hotel, 
travel, meals. Some of these costs may be paid directly by the NIH and some may be reimbursed 
after you have paid. The amount and form of these payments are determined by the NCI Travel 
and Lodging Reimbursement Policy. You will be given a summary of the policy which provides 
more information.
If your travel to the NIH Clinical Center (e.g. flight, hotel) is arranged and paid for by the NIH, 
the agency making the reservations and their representatives will have access to your identifiable 
information..
COSTS
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.
CONFLICT OF INTEREST (COI) 
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 or the guidelines of their home institution, but they 
do not need to report their personal finances to the NIH.
IRB NUMBER: 20C0142
IRB APPROVAL DATE: 06/24/2021


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
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CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
The NIH and the research team for this study have developed a drug being used in this study. This 
means it is possible that the results of this study could lead to payments to NIH. By law, the 
government is required to share such payments with the employee inventors. You will not receive 
any money from the development of M7824.
The NIH and the research team for this study are using M7824 developed by EMD Serono through 
a joint study with your study team and the company. The company also provides financial support 
for this study.
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  
Some of your health information, and/or information about your specimen, from this study will 
be kept in a central database for research. Your name or contact information will not be put in 
the database. Your test results will be identified by a unique code and the list that links the code 
to your name will be kept separate from your sample and health information. Your information 
may be given out if required by law. For example, certain states require doctors to report to health 
boards if they find a disease like tuberculosis. However, the researchers will do their best to 
make sure that any information that is released will not identify you.
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

The study Sponsor, Center for Cancer Research or their agent(s)

Qualified representatives from EMD Serono, the pharmaceutical company who 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, 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 
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. 
IRB NUMBER: 20C0142
IRB APPROVAL DATE: 06/24/2021


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 06/23/2021
Page 18 of 21
CC ICF template v. 05.05.20
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
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 information 
that 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 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.
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.
IRB NUMBER: 20C0142
IRB APPROVAL DATE: 06/24/2021


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 06/23/2021
Page 19 of 21
CC ICF template v. 05.05.20
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
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, Andrea B. 
Apolo, andrea.apolo@nih.gov, at 301-480-0536. 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: 20C0142
IRB APPROVAL DATE: 06/24/2021


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 06/23/2021
Page 20 of 21
CC ICF template v. 05.05.20
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.
IRB NUMBER: 20C0142
IRB APPROVAL DATE: 06/24/2021


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 06/23/2021
Page 21 of 21
CC ICF template v. 05.05.20
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
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: 20C0142
IRB APPROVAL DATE: 06/24/2021