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12.3 participation of subjects unable

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 Research Participation" form so that another person can make decisions about their medical care in the event that they become incapacitated or cognitively impaired during the course of the study. Note: The PI or AI will contact the NIH Ability to Consent Assessment Team (ACAT) for evaluation to assess ongoing capacity of the subjects and to identify an LAR, as needed. Please see Section **12.6.1** for consent procedure.
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12.4 evaluation of benefits and

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.
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12.5 risks/benefits assessment 12.5.1 known

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 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.
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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.
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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
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12.5.1.7.1 risk of receiving unwanted

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.
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12.5.1.7.2 risk related to possibility

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.
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12.5.1.7.3 risk to family or

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. Study results will not be shared with patients.
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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.
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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 compliant) to obtain the required signatures. 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**.
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13 regulatory and operational considerations

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

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.
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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.
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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 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.
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14 pharmaceutical and investigational device

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.
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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:
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)  
| Expansion Cohorts (Source: Investigator Brochure v6)   |            |           |            |
|--------------------------------------------------------|------------|-----------|------------|
| MS200647-0008                                          |            |           |            |
| EMR200647-001                                          | Total      |           |            |
| Primary System Organ Class                             | (N = 539)  | (N = 91)  | (N = 630)  |
| Dictionary-Derived Term                                | N (%)      | N (%)     | N (%)      |
| Participants with any SAE                              | 321 (59.6) | 50 (54.9) | 371 (58.9) |
| Blood and lymphatic system                             | 27 (5.0)   | 0         | 27 (4.3)   |
| disorders                                              |            |           |            |
| Anaemia                                                | 19 (3.5)   | 0         | 19 (3.0)   |
| Endocrine disorders                                    | 1 (2.0)    | 2 (2.2)   | 13 (2.1)   |
| Adrenal insufficiency                                  | 5 (0.9)    | 2 (2.2)   | 7 (1.1)    |
| Gstrointestinal disorders                              | 64 (11.9)  | 13 (14.3) | 77 (12.2)  |
| Abdominal pain                                         | 5 (0.9)    | 1 (1.1)   | 6 (1.0)    |
| Gastrointestinal haemorrhage                           | 7 (1.3)    | 1 (1.1)   | 8 (1.3)    |
| Upper gastrointestinal                                 | 2 (0.4)    | 4 (4.4)   | 6 (1.0)    |
| haemorrhage                                            |            |           |            |
| Vomiting                                               | 6 (1.1)    | 0         | 6 (1.0)    |
| General disorders and administration                   | 70 (13.0)  | 10 (11.0) | 80 (12.7)  |
| site conditions                                        |            |           |            |
| Disease progression                                    | 43 (8.0)   | 6 (6.6)   | 49 (7.8)   |
| General physical health                                | 6 (1.1)    | 0         | 6 (1.0)    |
| detenoration                                           |            |           |            |
| Pyrexia                                                | 8 (1.5)    | 1 (1.1)   | 9 (1.4)    |
| Hepatobiliary disorders                                | 10 (1.9)   | 8 (8.8)   | 18 (2.9)   |
| Cholangitis                                            | 2 (0.4)    | 5 (5.5)   | 7 (1.1)    |
| Infections and infestations                            | 54 (10.0)  | 9 (9.9)   | 63 (10.0)  |
| Pneumonia                                              | 14 (2.6)   | 3 (3.3)   | 17 (2.7)   |
| Sepsis                                                 | 8 (1.5)    | 0         | 8 (1.3)    |
| Metabolism and nutrition disorders                     | 25 (4.6)   | 3 (3.3)   | 28 (4.4)   |
| Decreased appetite                                     | 5 (0.9)    | 3 (3.3)   | 8 (1.3)    |
| Neoplasms benign, malignant and                        | 61 (11.3)  | 69 (11.0) |            |
| 8 (8.8)                                                |            |           |            |
| unspecified (incl cysts and polyps)                    |            |           |            |
| Keratoacanthoma                                        | 9 (1.7)    | 0         | 9 (1.4)    |
| Squamous cell carcinoma of skin                        | 2 (4.1)    | 1 (1.1)   | 23 (3.7)   |
| Tumour haemorrhage                                     | 8 (1.5)    | 2 (2.2)   | 10 (1.6)   |
| Renal and urinary disorders                            | 14 (2.6)   | 0         | 14 (2.2)   |
| Acute kidney injury                                    | 10 (1.9)   | 0         | 10 (1.6)   |
| Respiratory, thoracic and mediastinal                  | 68 (12.6)  | 6 (6.6)   | 74 (11.7)  |
| disorders                                              |            |           |            |
| Dyspnoea                                               | 26 (4.8)   | 0         | 26 (4.1)   |
| Pneumothorax                                           | 6 (1.1)    | 1 (1.1)   | 7 (1.1)    |
| Pulmonary embolism                                     | 9 (1.7)    | 0         | 9 (1.4)    |  
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. 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-PDL1 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 drugrelated (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 inuse 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 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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15 references

1. von der Maase H, Hansen SW, Roberts JT, Dogliotti L, Oliver T, Moore MJ, Bodrogi I,
Albers P, Knuth A, Lippert CM *et al*: **Gemcitabine and cisplatin versus methotrexate,**
vinblastine, doxorubicin, and cisplatin in advanced or metastatic bladder cancer: results of a large, randomized, multinational, multicenter, phase III study. J Clin Oncol 2000, 18(17):3068-3077.  
2. Sternberg CN, de Mulder P, Schornagel JH, Theodore C, Fossa SD, van Oosterom AT,
Witjes JA, Spina M, van Groeningen CJ, Duclos B *et al*: **Seven year update of an** EORTC phase III trial of high-dose intensity M-VAC chemotherapy and G-CSF versus classic M-VAC in advanced urothelial tract tumours. European journal of cancer (Oxford, England : 1990) 2006, 42(1):50-54.  
3. Sonpavde G, Watson D, Tourtellott M, Cowey CL, Hellerstedt B, Hutson TE, Zhan F,
Vogelzang NJ: **Administration of cisplatin-based chemotherapy for advanced** urothelial carcinoma in the community. *Clinical genitourinary cancer* 2012, 10(1):1-5.  
4. Bellmunt J, Choueiri TK, Fougeray R, Schutz FA, Salhi Y, Winquist E, Culine S, von der Maase H, Vaughn DJ, Rosenberg JE: **Prognostic factors in patients with advanced** transitional cell carcinoma of the urothelial tract experiencing treatment failure with platinum-containing regimens. *J Clin Oncol* 2010, 28(11):1850-1855.  
5. Galsky MD, Hahn NM, Rosenberg J, Sonpavde G, Hutson T, Oh WK, Dreicer R,
Vogelzang N, Sternberg CN, Bajorin DF *et al*: **Treatment of patients with metastatic** urothelial cancer "unfit" for Cisplatin-based chemotherapy. *J Clin Oncol* 2011, 29(17):2432-2438.  
6. Morales A, Eidinger D, Bruce AW: **Intracavitary Bacillus Calmette-Guerin in the**
treatment of superficial bladder tumors. *The Journal of urology* 1976, 116(2):180-183.  
7. Pardoll DM: **The blockade of immune checkpoints in cancer immunotherapy**. *Nature* reviews Cancer 2012, 12(4):252-264.  
8. Bellmunt J, de Wit R, Vaughn DJ, Fradet Y, Lee JL, Fong L, Vogelzang NJ, Climent MA, Petrylak DP, Choueiri TK *et al*: Pembrolizumab as Second-Line Therapy for Advanced Urothelial Carcinoma. *The New England journal of medicine* 2017, 376(11):1015-1026.  
9. Rosenberg JE, Hoffman-Censits J, Powles T, van der Heijden MS, Balar AV, Necchi A,
Dawson N, O'Donnell PH, Balmanoukian A, Loriot Y *et al*: **Atezolizumab in patients** with locally advanced and metastatic urothelial carcinoma who have progressed following treatment with platinum-based chemotherapy: a single-arm, multicentre, phase 2 trial. *Lancet* 2016, 387(10031):1909-1920.  
10. Sharma P, Retz M, Siefker-Radtke A, Baron A, Necchi A, Bedke J, Plimack ER, Vaena D, Grimm MO, Bracarda S *et al*: Nivolumab in metastatic urothelial carcinoma after platinum therapy (CheckMate 275): a multicentre, single-arm, phase 2 trial. Lancet Oncol 2017, 18(3):312-322.  
11. Powles T, O'Donnell PH, Massard C, Arkenau HT, Friedlander TW, Hoimes CJ, Lee JL,
Ong M, Sridhar SS, Vogelzang NJ *et al*: Efficacy and Safety of Durvalumab in Locally Advanced or Metastatic Urothelial Carcinoma: Updated Results From a Phase 1/2 Open-label Study. *JAMA oncology* 2017, 3(9):e172411.  
12. Apolo AB, Infante JR, Balmanoukian A, Patel MR, Wang D, Kelly K, Mega AE, Britten CD, Ravaud A, Mita AC *et al*: Avelumab, an Anti-Programmed Death-Ligand 1 Antibody, In Patients With Refractory Metastatic Urothelial Carcinoma: Results From a Multicenter, Phase Ib Study. *J Clin Oncol* 2017, 35(19):2117-2124.  
13. Patel MR, Ellerton J, Infante JR, Agrawal M, Gordon M, Aljumaily R, Britten CD, Dirix L, Lee KW, Taylor M *et al*: **Avelumab in metastatic urothelial carcinoma after** platinum failure (JAVELIN Solid Tumor): pooled results from two expansion cohorts of an open-label, phase 1 trial. *Lancet Oncol* 2018, 19(1):51-64.  
14. Balar AV, Galsky MD, Rosenberg JE, Powles T, Petrylak DP, Bellmunt J, Loriot Y,
Necchi A, Hoffman-Censits J, Perez-Gracia JL *et al*: **Atezolizumab as first-line** treatment in cisplatin-ineligible patients with locally advanced and metastatic urothelial carcinoma: a single-arm, multicentre, phase 2 trial. *Lancet* 2017, 389(10064):67-76.  
15. Balar AV, Castellano D, O'Donnell PH, Grivas P, Vuky J, Powles T, Plimack ER, Hahn NM, de Wit R, Pang L *et al*: First-line pembrolizumab in cisplatin-ineligible patients with locally advanced and unresectable or metastatic urothelial cancer (KEYNOTE052): a multicentre, single-arm, phase 2 study. *Lancet Oncol* 2017, 18(11):1483-1492.  
16. Chen W, Jin W, Hardegen N, Lei KJ, Li L, Marinos N, McGrady G, Wahl SM:
Conversion of peripheral CD4+CD25- naive T cells to CD4+CD25+ regulatory T cells by TGF-beta induction of transcription factor Foxp3. The Journal of experimental medicine 2003, 198(12):1875-1886.  
17. Ohtani T, Mizuashi M, Nakagawa S, Sasaki Y, Fujimura T, Okuyama R, Aiba S: TGFbeta1 dampens the susceptibility of dendritic cells to environmental stimulation, leading to the requirement for danger signals for activation. *Immunology* 2009, 126(4):485-499.  
18. Thomas DA, Massague J: **TGF-beta directly targets cytotoxic T cell functions during**
tumor evasion of immune surveillance. *Cancer cell* 2005, 8(5):369-380.  
19. Marchioni M, Nazzani S, Preisser F, Bandini M, Karakiewicz PI: **Therapeutic strategies**
for organ-confined and non-organ-confined bladder cancer after radical cystectomy. *Expert review of anticancer therapy* 2018, 18(4):377-387.  
20. Budhu S, Schaer DA, Li Y, Toledo-Crow R, Panageas K, Yang X, Zhong H, Houghton AN, Silverstein SC, Merghoub T *et al*: Blockade of surface-bound TGF-beta on regulatory T cells abrogates suppression of effector T cell function in the tumor microenvironment. *Science signaling* 2017, 10(494).  
21. Mariathasan S, Turley SJ, Nickles D, Castiglioni A, Yuen K, Wang Y, Kadel Iii EE,
Koeppen H, Astarita JL, Cubas R *et al*: **TGFbeta attenuates tumour response to PDL1 blockade by contributing to exclusion of T cells**. *Nature* 2018.  
22. Tauriello DVF, Palomo-Ponce S, Stork D, Berenguer-Llergo A, Badia-Ramentol J,
Iglesias M, Sevillano M, Ibiza S, Canellas A, Hernando-Momblona X *et al*: TGFbeta drives immune evasion in genetically reconstituted colon cancer metastasis. *Nature* 2018.  
23. 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 protein simultaneously targeting PD-L1 and TGF-beta. Science translational medicine 2018, 10(424).  
24. 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 Cancer Res 2018.  
26. Nishijima TF, Shachar SS, Nyrop KA, Muss HB: **Safety and Tolerability of PD-1/PDL1 Inhibitors Compared with Chemotherapy in Patients with Advanced Cancer: A**
Meta-Analysis. *The oncologist* 2017, 22(4):470-479.  
27. 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* 2018, 36(3):93.e91-93.e11.  
28. 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** mesenchymalization of human lung cancer cells. *Oncoimmunology* 2017, 6(10):e1349589-e1349589.  
29. Mariathasan S, Turley SJ, Nickles D, Castiglioni A, Yuen K, Wang Y, Kadel EE, III,
Koeppen H, Astarita JL, Cubas R *et al*: **TGFbeta attenuates tumour response to PDL1 blockade by contributing to exclusion of T cells**. *Nature* 2018, 554(7693):544-548.  
30. 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.  
31. Gatti-Mays ME, Gulley JL: M7824: A promising new strategy to combat cancer immune evasion. *Oncoscience* 2018, 5(11-12):269-270.  
32. 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.  
33. 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.  
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 fetomaternal tolerance. *The Journal of experimental medicine* 2005, 202(2):231-237.  
35. Leber A, Teles A, Zenclussen AC: **Regulatory T cells and their role in pregnancy**. Am J Reprod Immunol 2010, 63(6):445-459.  
36. Wafula PO, Teles A, Schumacher A, Pohl K, Yagita H, Volk HD, Zenclussen AC: PD-1 but not CTLA-4 blockage abrogates the protective effect of regulatory T cells in a pregnancy murine model. *Am J Reprod Immunol* 2009, 62(5):283-292.  
37. Zenclussen AC: **Adaptive immune responses during pregnancy**. Am J Reprod Immunol 2013, 69(4):291-303.  
38. Hilbish KG, Martin JA, Stauber AJ, Edwards TL, Breslin WJ: TGF-beta1 monoclonal antibody: Assessment of embryo-fetal toxicity in rats and rabbits. *Birth Defects Res* B Dev Reprod Toxicol 2016, 107(4-5):174-184.  
39. Donahue RN, Lepone LM, Grenga I, Jochems C, Fantini M, Madan RA, Heery CR,
Gulley JL, Schlom J: Analyses of the peripheral immunome following multiple administrations of avelumab, a human IgG1 anti-PD-L1 monoclonal antibody. J Immunother Cancer 2017, 5:20.  
40. 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: Defining Differences with Age and between Healthy Donors and Cancer Patients Not Detected in Analysis of Standard Immune Cell Types. *J Circ Biomark* 2016, 5:5.  
41. Werner SL, Graf RP, Landers M, Valenta DT, Schroeder M, Greene SB, Bales N,
Dittamore R, Marrinucci D: Analytical Validation and Capabilities of the Epic CTC Platform: Enrichment-Free Circulating Tumour Cell Detection and Characterization. *J Circ Biomark* 2015, 4:3.  
42. Messiou C, Hillengass J, Delorme S, Lecouvet FE, Moulopoulos LA, Collins DJ,
Blackledge MD, Abildgaard N, Ostergaard B, Schlemmer HP *et al*: **Guidelines for**
Acquisition, Interpretation, and Reporting of Whole-Body MRI in Myeloma:
Myeloma Response Assessment and Diagnosis System (MY-RADS). *Radiology* 2019, 291(1):5-13.  
43. Petralia G, Padhani AR, Pricolo P, Zugni F, Martinetti M, Summers PE, Grazioli L,
Colagrande S, Giovagnoni A, Bellomi M *et al*: **Whole-body magnetic resonance** imaging (WB-MRI) in oncology: recommendations and key uses. *Radiol Med* 2019, 124(3):218-233.  
44. Taylor SA, Mallett S, Ball S, Beare S, Bhatnagar G, Bhowmik A, Boavida P,
Bridgewater J, Clarke CS, Duggan M *et al*: Diagnostic accuracy of whole-body MRI
versus standard imaging pathways for metastatic disease in newly diagnosed nonsmall-cell lung cancer: the prospective Streamline L trial. *Lancet Respir Med* 2019, 7(6):523-532.  
45. 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 tumours: revised RECIST guideline (version 1.1). *European journal of cancer* (Oxford, England : 1990) 2009, 45(2):228-247.  
46. Niglio SA, Jia R, Ji J, Ruder S, Patel VG, Martini A, Sfakianos JP, Marqueen KE,
Waingankar N, Mehrazin R *et al*: Programmed Death-1 or Programmed Death Ligand-1 Blockade in Patients with Platinum-resistant Metastatic Urothelial Cancer: A Systematic Review and Meta-analysis. European Urology.