Clinical trial NCT04560686
Conditions: Resectable Lung Non-Small Cell Carcinoma Stage I Lung Cancer AJCC v8 Stage IA1 Lung Cancer AJCC v8 Stage IA2 Lung Cancer AJCC v8 Stage IA3 Lung Cancer AJCC v8 Stage IB Lung Cancer AJCC v8 Stage II Lung Cancer AJCC v8 Stage IIA Lung Cancer AJCC v8 Stage IIB Lung Cancer AJCC v8 Stage IIIA Lung Cancer AJCC v8 Stage IIIB Lung Cancer AJCC v8
Sponsor: M.D. Anderson Cancer Center
Start date: 2020-08-05; Completion date: 2021-07-01
Enrollment: 2 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This phase II trial studies how well bintrafusp alfa before surgery works in treating patients with non-small cell lung cancer for which the patient has not received treatment in the past (untreated) and that can be removed by surgery (resectable). Immunotherapy with bintrafusp alfa may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving bintrafusp alfa before surgery may help lower the risk of the cancer coming back after surgery.

Detailed description:
PRIMARY OBJECTIVE:

I. To evaluate the rate of major pathologic response (MPR).

OUTLINE:

Patients receive bintrafusp alfa intravenously (IV) on days 1, 15, and 29 in the absence of unacceptable toxicity. Within 4-6 weeks after last dose of bintrafusp alfa, patients undergo surgery at the discretion of the treating surgeon. Within 8 weeks after surgery, patients may receive chemotherapy or undergo radiation therapy at the discretion of the treating physician.

After completion of study treatment, patients are followed for up to 5 years.

Arms: arm 1: Patients receive bintrafusp alfa IV on days 1, 15, and 29 in the absence of unacceptable toxicity. Within 4-6 weeks after last dose of bintrafusp alfa, patients undergo surgery at the discretion of the treating surgeon. Within 8 weeks after surgery, patients may receive chemotherapy or undergo radiation therapy at the discretion of the treating physician.
Interventions: intervention 1: Bintrafusp Alfa intervention 2: Therapeutic Conventional Surgery
Intervention descriptions: intervention 1: Given IV intervention 2: Undergo surgery

Protocol documents:
Prot_SAP_000.pdf: 
Clinical Study Protocol 9.0                                                      
MDA Cancer Center 
Bintrafusp Alpha- M7824                    
 
 15 June 2020 
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MD Anderson IND Sponsor Cover Sheet 
Protocol ID 
2019-0910 
Protocol Title 
Phase II Study of Neoadjuvant Immune Checkpoint Blockade-based 
Therapy with M7824 (bintrafusp alpha) For Untreated Resectable-Small 
Cell Lung Cancers 
Strategic Alliance: EMD Serono 
Protocol Version 
9.0 
Version Date 
06/15/2020 
Protocol PI 
Tina Cascone, MD 
Department 
Thoracic Head & Neck 
IND Sponsor 
MD Anderson Cancer Center 
IND # 
146722 


Clinical Study Protocol 9.0                                                      
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Bintrafusp Alpha- M7824                    
 
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Clinical Study Protocol 
Drug Substance: Bintrafusp alpha 
Study Code: 
M7824 
Version: 
8.0 
Date:                     20 May 2020 
 
PHASE II STUDY OF NEOADJUVANT IMMUNE CHECKPOINT BLOCKADE-BASED 
THERAPY WITH M7824 (bintrafusp alpha) FOR UNTREATED RESECTABLE NON-SMALL 
CELL LUNG CANCERS 
 
Sponsor & Study center: 
The University of Texas MD Anderson Cancer Center 
1515 Holcombe Blvd. 
Houston, TX 77030 
 
 
Principal Investigator 
Tina Cascone, MD, PhD 
The University of Texas MD Anderson Cancer Center 
Department of Thoracic/Head and Neck Medical Oncology 
1515 Holcombe Blvd. Unit 432 
Houston, TX 77030 
 
 
 
Co-Principal Investigator 
Boris Sepesi, MD 
Department of Cardiothoracic Surgery 
The University of Texas MD Anderson Cancer Center 
1515 Holcombe Blvd. Unit 432 
Houston, TX 77030 
 
 
 
 
 
 
 
 
 
 
 


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                                                   Table of Contents 
Clinical Study Protocol .................................................................................................................................. 2 
PHASE II STUDY OF NEOADJUVANT IMMUNE CHECKPOINT BLOCKADE-BASED 
THERAPY WITH M7824 (bintrafusp alpha) FOR UNTREATED RESECTABLE NON-SMALL 
CELL LUNG CANCERS ............................................................................................................................ 2 
Principal Investigator .............................................................................................................................. 2 
Co-Principal Investigator ....................................................................................................................... 2 
1 Protocol Summary ........................................................................................................................................ 7 
1.3 Study Schema .......................................................................................................................................... 11 
2. 
Sponsor, Investigators and Trial Administrative Structure ............................................................. 11 
3. 
BACKGROUND .................................................................................................................................... 11 
3.1 
Adjuvant platinum-based chemotherapy ........................................................................................ 11 
3.2 
Neoadjuvant (induction) platinum-based chemotherapy ............................................................... 11 
3.3 
Investigational agent M7824 .................................................................................................... 12 
3.4 
Preclinical studies with M7824 in cancer ............................................................................. 12 
3.5 
Pharmacokinetics / Immunogenicity Findings ............................................................................... 13 
3.6 
Toxicology .......................................................................................................................................... 14 
3.7 
Safety of M7824 ................................................................................................................................. 14 
3.8 
Efficacy of M7824 in solid tumors ................................................................................................... 16 
3.9 Summary of Clinical Findings for M7824 in NSCLC ............................................................... 17 
3.10 
Combination of immune checkpoint blockade and platinum-based chemotherapy for NSCLC18 
3.12 
Neoadjuvant immune checkpoint blockade in resectable NSCLC ............................................... 20 
3.13 
TCD8+ TILs as a prognostic marker. ............................................................................................. 20 
4. 
RATIONALE OF THE STUDY .......................................................................................................... 20 
5. 
HYPOTHESIS ....................................................................................................................................... 21 
5.1 
Overall Benefit and Risk ................................................................................................................... 21 
Infusion-related Reactions / Hypersensitivity ................................................................................. 22 
Immune-related Adverse Events / Autoimmune Disorders ......................................................... 22 
Anemia ...................................................................................................................................................... 22 
Alterations in Wound Healing or Repair of Tissue Damage ........................................................ 22 
Embryofetal Toxicity.............................................................................................................................. 23 
Mild to Moderate Mucosal Bleeding Events .................................................................................... 23 
5.2 
Potential Benefit ................................................................................................................................ 23 
6. 
STUDY ENDPOINTS ........................................................................................................................... 24 
6.2 
Secondary Endpoints ........................................................................................................................ 24 


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6.3 
Exploratory Endpoints ..................................................................................................................... 24 
6.4 
Additional assessments ................................................................................................................. 26 
7. 
ETHICAL CONSIDERATIONS ......................................................................................................... 27 
8. 
STUDY DESIGN AND PLAN ............................................................................................................. 27 
8.1 
Modular design of neoadjuvant signal-finding study platform ................................................ 27 
8.2 
Study Plan .......................................................................................................................................... 27 
Arm A — M7824 monotherapy ..................................................................................................................... 28 
9. 
TREATMENT ....................................................................................................................................... 28 
9.2 
Surgery ............................................................................................................................................... 28 
9.3 
Post-operative (Adjuvant) Systemic Therapy ............................................................................. 28 
9.4 
Post-operative (Adjuvant) Radiation Therapy ................................................................................... 28 
10 
ELIGIBILITY CRITERIA ........................................................................................................... 29 
10.1 
Inclusion Criteria ............................................................................................................................ 29 
10.2 
Exclusion Criteria .............................................................................................................................. 30 
11. 
STUDY ASSESSMENTS .................................................................................................................. 31 
11.1 
Performance status ........................................................................................................................ 31 
11.2 
Clinical Laboratory Tests ............................................................................................................. 31 
11.3 
Symptoms and toxicity assessment .............................................................................................. 31 
11.4 
Radiology assessments .................................................................................................................. 31 
11.5 
Mediastinal Staging ........................................................................................................................... 32 
11.6 Surgical Pathology ................................................................................................................................ 32 
11.7 Correlative Research: Biomarkers profiling ...................................................................................... 32 
11.7.1   Tumor tissue collection, processing and analysis .......................................................................... 32 
11.7.1.1 
Pre-Surgery ................................................................................................................................ 32 
11.7.1.2 
Surgery ....................................................................................................................................... 33 
11.7.1.3 
Tissue Research Correlatives Analysis .................................................................................... 33 
11.7.2 
Blood-based biomarkers ........................................................................................................... 34 
11.7.3 
Stool-based biomarkers ............................................................................................................ 34 
11.7.4 
CT imaging-based biomarkers ................................................................................................. 34 
11.7.5 Pharmacokinetics and Anti-Drug Antibody .................................................................................... 34 
13 
Study Intervention Compliance ....................................................................................................... 36 
13.1 Overdose................................................................................................................................................. 36 
14. 
Concomitant Therapy ....................................................................................................................... 36 
14.1 
Permitted Medicines ......................................................................................................................... 37 
14.2 
Prohibited Medicines ........................................................................................................................ 37 


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14.3 
Permitted/Prohibited Procedures .................................................................................................... 37 
14.4 
Other Interventions ........................................................................................................................... 38 
14.5 
Dose Selection and Modification ...................................................................................................... 38 
14.6 
Study Intervention after the End of the Study ............................................................................... 39 
14.7 
Special Precautions ........................................................................................................................... 39 
14.7.2 
Immune-related Adverse Events .............................................................................................. 42 
14.7.3 
Potential TGFβ-mediated Skin Adverse Events ......................................................................... 43 
14.7.4 
Anemia ........................................................................................................................................... 43 
15 
Management of Adverse Events of Interest ................................................................................ 43 
15.2 
Potential Risks ................................................................................................................................... 45 
15.3 
Adverse Drug Reactions Requiring Treatment Discontinuation .................................................. 45 
16 
Discontinuation of Study Intervention and Participant Discontinuation/Withdrawal ............... 47 
16.2 
Participant Discontinuation/Withdrawal from the Study ............................................................. 47 
17 
Lost to Follow-up ............................................................................................................................... 47 
18 
Long-term follow-up ......................................................................................................................... 48 
19 
Data Sharing ...................................................................................................................................... 48 
20 
Study Medication - Pharmaceutical Formulation .......................................................................... 51 
20.1 
Study Medication - Handling of the Dosage Form ......................................................................... 51 
20.2 
Study Medication - Instructions for Storage .................................................................................. 51 
21 STUDY ASSESSMENTS AND PROCEDURES .................................................................................... 52 
Baseline evaluation: ............................................................................................................................... 52 
22 
STATISTICALCONSIDERATIONS.............................................................................................. 56 
Analysis of primary efficacy endpoint: .................................................................................................... 56 
Table 3. Predictive probabilities of true MPR rates. .............................................................................. 56 
Analysis of Secondary/Exploratory Endpoints: ...................................................................................... 57 
23 
STUDY MONITORING AND EARLYSTOPPING RULES .......................................................................... 58 
24 
Data Confidentiality Plan ................................................................................................................. 60 
Confidentiality of Data .......................................................................................................................... 60 
Confidentiality of Participant Records .............................................................................................. 60 
25 
REFERENCES ...................................................................................................................................... 61 
Appendix 1 The Recommendations for irAE Management, in Accordance with the Joint American 
Society of Clinical Oncology Clinical Practice Guidelines and National Comprehensive Cancer 
Network .......................................................................................................................................................... 62 
Tables of Management of irAEs in Patients Treated with ICPis: ............................................... 62 
Table A1 
Management of Skin irAEs in Patients Treated With ICPis ................................. 63 


Clinical Study Protocol 9.0                                                      
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Table A2 
Management of GI irAEs in Patients Treated With ICPis ..................................... 70 
Table A3 
Management of Lung irAEs in Patients Treated With ICPis ................................ 76 
Table A4 
Management of Endocrine irAEs in Patients Treated With ICPis ...................... 78 
Table A5 
Management of Musculoskeletal irAEs in Patients Treated With ICPis ........... 85 
Table A6 
Management of Renal irAEs in Patients Treated With ICPis ............................... 90 
Table A7 
Management of Nervous System irAEs in Patients Treated With ICPis .......... 92 
Table A8 
Management of Hematologic irAEs in Patients Treated With ICPis .................. 98 
Table A9 
Management of Cardiovascular irAEs in Patients Treated With ICPis ........... 106 
Table A10 
Management of Ocular irAEs in Patients Treated With ICPis ........................... 109 
Appendix 2 Adverse Events: Definitions and Procedures for Recording, Evaluating, 
Follow-up, and Reporting ................................................................................................................... 112 
Abnormal Laboratory Findings and Other Abnormal Investigational Findings ................... 113 
Serious Adverse Events ..................................................................................................................... 113 
Events that Do Not Meet the Definition of an SAE ....................................................................... 114 
Events Not to Be Considered as AEs/SAEs .................................................................................. 114 
AE/SAEs Observed in Association with Disease Progression................................................. 114 
Adverse Events of Special Interest.................................................................................................. 114 
Recording and Follow-Up of AE and/or SAE ................................................................................. 115 
Reporting Serious Adverse Events and Adverse Events of Special Interest Serious 
Adverse Events ..................................................................................................................................... 115 
• 
Additionally, any serious adverse events that occur after the 100 day time period that 
are related to the study treatment must be reported to the IND Office. This may include 
the development of a secondary malignancy. .............................................................................. 116 
Pregnancy and Reporting .................................................................................................................. 116 
Adverse Events of Special Interest.................................................................................................. 117 
Serious Adverse Event (SAE) Reporting ........................................................................................ 118 
Reporting to FDA:................................................................................................................................. 118 
It is the responsibility of the PI and the research team to ensure serious adverse events 
are reported according to the Code of Federal Regulations, Good Clinical Practices, the 
protocol guidelines, the sponsor’s guidelines, and Institutional Review Board policy. ... 119 
 
 
 
 
 


Clinical Study Protocol 9.0                                                      
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Bintrafusp Alpha- M7824                    
 
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1 Protocol Summary 
1.1 SYNOPSIS 
Clinical Trial Protocol Number 
 2019-0910 
Title 
Phase II study of neoadjuvant immune 
checkpoint blockade-based therapy with 
M7824 (bifunctional anti-PD-L1/ TGF-β Trap 
fusion protein) for untreated stage I-IIIA non- 
small cell lung cancers amenable for surgical 
resection 
Trial Phase 
II 
IND Number 
146722 
 
 
Coordinating Investigator 
Tina Cascone, MD, PhD 
The University of Texas – MD Anderson 
Cancer Center 
Houston, TX USA 
Sponsor 
The University of Texas – MD Anderson 
Cancer Center, Houston, TX 
Trial center/country 
Single institution trial / United States 
Planned trial period 
(first subject in-last subject out) 
TBD 
Trial Registry 
Pending NCT identifier 
Endpoints:  
Primary 
Endpoints: 
To evaluate the rate of major pathologic response, defined as ≤ 10% viable tumor cells in the 
resected specimen using the methods described by Pataer et al. in patients treated with 
induction M7824 monotherapy. 
 
Secondary 
Endpoints: To 
estimate: 
Toxicity (assessed by the NCI CTCAE v. 
5) Peri-operative morbidity and mortality 
Response rates to induction treatment (by RECIST version 1.1) (1) 
Recurrence-free survival and Overall survival 
Survival rates at 12, 18 and 24 months 
To correlate major pathologic response with recurrence-free and overall survival 
Complete resection (R0) rate 
Pathologic complete response (pCR) in resected tumor specimens 


Clinical Study Protocol 9.0                                                      
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Bintrafusp Alpha- M7824                    
 
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To correlate response assessed by imaging studies with outcomes (both major 
pathologic response to treatment and long-term recurrence-free survival) 
CD8+ TILs in resected tumor tissues of patients treated with M7824 
Exploratory Endpoints: 
PD-L1 expression in tumor tissue 
Multi-region next generation DNA and/or RNA sequencing in tumor tissue (including whole 
exome and/or whole genome sequencing) and in blood/normal tissue, so that tumor 
heterogeneity and mutational load can be correlated with efficacy of immunotherapy and/or 
other correlative markers 
Immunophenotyping or characterization of the immune cell subsets in tumor tissue, including 
markers of T cell exhaustion, T cell activation, T regulatory cells, T cell function, antigen 
presenting cells, as well as CD20, Ki67, granzyme B, IFN-γ, TGF-beta, GATA-3, RORgt, BCL2, 
as well as CD68 and other markers relevant to immune profiling 
Expression of immunoregulatory and co-stimulatory markers in TILs by flow cytometry, 
including, but not limited to, PD1, CTLA4, LAG3, 41BB, and TCR zeta chain 
RNA and protein expression in tumor and adjacent normal tissue, including assessment of 
immune/inflammatory pathways 
Immunophenotyping or characterization of the immune cell subsets in the periphery, including, 
but not limited to, T cells, B cells, NK cells, or subpopulations of the aforementioned immune cell 
types 
Single cell genomics in tumor (including tumor positive nodes) and adjacent normal tissue 
Serum soluble factors, including IFN-gamma and interferon inducible factors (such as CXCL9 
and CXCL10), PD-L1, PD-1, anti-tumor antibodies, microRNAs (such as miR-513, and miR19b), 
IL-12, TNFα, IL-10, TGF-β, VEGF, IL-6, IL-8, IL-17, IL-18, C-reactive protein and, as well as 
other cytokines, chemokines, inflammatory factors and immune mediators 
T cell receptor repertoire (TCR) sequencing in tumor tissue, adjacent normal lung and the 
periphery (pre- and post-neoadjuvant therapy) 
Next generation sequencing of cell-free circulating DNA 
Immunopeptidome analysis 
Enteric microbiome analysis 
CT imaging analysis. 
Methodology and design: 
This is an open label, phase 2 study with modular design assessing the experimental agent 
M7824 in the neoadjuvant setting. We will start investigating M7824 monotherapy (Arm 
A) induction treatment in patients with resectable NSCLC, with the primary objective to 
estimate the MPR in each arm. After confirmation of eligibility criteria, patients will be 
enrolled in Arm A. Sequential arms investigating induction M7824-based strategies may be 
added after completion of enrollment in Arm A (23 patients) based on emerging data with a 
protocol   amendment 


Clinical Study Protocol 9.0                                                      
MDA Cancer Center 
Bintrafusp Alpha- M7824                    
 
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Planned number of subjects: 
Arm A: 23 
Investigational Medicinal Product: M7824 
Dose/mode of administration/ dosing schedule: 
M7824 will be administered intravenously at a dose of 1200 mg every 14 days (+/- 3 days). 
Planned trial and treatment duration per subject: 
Subjects will receive M7824 monotherapy for three doses prior to surgery. Administration will 
be stopped due to documented progressive disease, unacceptable toxicity, consent 
withdrawal, or any criterion for withdrawal as outlined in this protocol. 
Statistical methods 
The study is a phase II trial with a modular design. Currently, eligible patients will be accrued 
to the M7824 monotherapy (Arm A). The primary objective is to evaluate the rate of MPR, 
rather than hypothesis testing with pre-specified null and alternative MPR rates. There will be 
no interim futility nor efficacy monitoring. A sample size of 23 patients is proposed for the 
study. With an estimated accrual rate of approximately 2 patients a month, the accrual period 
is approximately 15-24 months. 
Analysis of primary endpoint of major pathologic response (MPR): 
The primary endpoint is major pathologic response (MPR). We will estimate the MPR rate 
with a 95% credible interval (CI) assuming that the MPR rate follows a prior beta distribution 
(0.5, 0.5). For example, if the M7824 monotherapy indeed has a true MPR rate of 30% and 7 
patients with MPR are observed in this study, the corresponding 95% CI of the observed 
MPR rate would be (14.8%, 50.7%). Furthermore, we calculated predictive probability of 
Prob(p > 0.15 | data and true MPR rate) for a variety of true MPR rates, where p is the MPR 
rate. As shown in Statistical consideration section in Table 3, there will be a fairly high 
chance (81 – 89%) for the study to observe a MPR rate > 15% with a sample size of 23 
patients if the true MPR rates are 25% and higher. We chose to use 15% MPR rate as cutoff 
because a historic MPR rate to neoadjuvant chemotherapy alone of 19% is observed (as 
described by Pataer et al.) (2). However, some patients that receive neoadjuvant chemotherapy 
may not receive surgery for one reason or another, and these cases will be considered 
treatment failure. Assuming the 19% major pathologic response rate is calculated from 80% of 
patients who receive surgery, a conservative estimate of the major pathologic response is 
15%. 
 
Analysis of Secondary/Exploratory Endpoints: 
Analysis for the secondary/exploratory endpoints will be descriptive and exploratory in 
nature. Descriptive statistics will be provided to summarize the data distribution. Association 
analysis by Pearson or Spearman correlation coefficient will be calculated for continuous 
data and chi-square or Fisher's exact test for categorical data. Time-to-event endpoints will 
be computed using the Kaplan-Meier method. 
Toxicity monitoring: A Bayesian method to monitor the toxicity in the perioperative phase will 
be used. We consider that neoadjuvant therapy with either one of the regimens is not 
feasible if it results in unacceptable toxicities in at least 20% of the patients with 70% 
or higher probability. The toxicity monitoring will start after a minimum of 6 patients have 


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Clinical Study Protocol 9.0                                                      
MDA Cancer Center 
Bintrafusp Alpha- M7824                    
 
 15 June 2020 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
been enrolled.  With a prior probability of toxicity as Beta (0.5,0.5), the toxicity stopping 
boundaries are defined as seeing unacceptable toxicity in >= 3 of 6-7, 4 of 8-10, 5 of 11-13, 
6 of 14-16, 7 of 17-19, 8 of 20-22 or 9 of 23 patients. When the true toxicity rates are 0.1, 
0.3, and 0.5, the probabilities of early stopping are 0.04, 0.56, and 0.97 with the 
corresponding average sample sizes of 22.4, 15.1 and 8.0, respectively. 


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Clinical Study Protocol 9.0                                                      
MDA Cancer Center 
Bintrafusp Alpha- M7824                    
 
 15 June 2020 
 
 
 
1.3 Study Schema 
 
 
 


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Clinical Study Protocol 9.0                                                      
MDA Cancer Center 
Bintrafusp Alpha- M7824                    
 
 15 June 2020 
 
 
 
 
2. Sponsor, Investigators and Trial Administrative Structure 
 
This clinical trial will be sponsored by: 
The University of Texas - MD Anderson Cancer Center. The trial will be conducted within the 
Department of Thoracic/Head and Neck Medical Oncology at the University of Texas - MD 
Anderson Cancer Center in Houston, TX. 
All clinical assessments will be performed in the outpatient clinic setting. 
Study drug will be administered in the Cancer Therapy and Research Center (CTRC), an 
outpatient infusion center at MD Anderson. 
Additional sites may be added in the future upon agreement with the study sponsors and the 
conducting investigator. 
The Principal Investigator represents all Investigators for decisions and discussions regarding 
this trial, consistent with the International Conference on Harmonisation (ICH) Topic E6 Good 
Clinical Practice (GCP; hereafter referred to as ICH GCP). 
The trial will appear in the following clinical trial registry: www.clinicaltrials.gov 
 
 
3. 
BACKGROUND 
Surgical resection remains the preferred treatment approach for patients with stage I, II, and 
selected stage III non-small cell lung cancers. Nonetheless, a substantial number of patients will 
recur after surgical resection alone. As such, the use of perioperative cytotoxic therapy has 
been developed to improve outcomes in this setting. 
 
3.1 
Adjuvant platinum-based chemotherapy 
Cisplatin-based adjuvant chemotherapy has become the standard of care treatment following 
surgical resection of patients with lymph node positive non-small cell lung cancer, based on data 
from three randomized controlled studies (3-5). A meta- analysis including 4584 patients and 5 
trials demonstrated a hazard ratio (HR) for death of 0.89 in favor of adjuvant chemotherapy 
compared to surgery alone (95% CI 0.82-0.96, p=0.005), which translates to an absolute 
improvement in 5-year overall survival of 5.4% (6). 
 
3.2 
Neoadjuvant (induction) platinum-based chemotherapy 
Early randomized, single-institution, small-scale studies evaluating the role of induction 
chemotherapy in patients with stage III NSCLC provided evidence for potential benefits from 
systemic therapy prior to surgical resection. Despite the small sample size, Roth et al., and  
Rosell et al. found statistically significant improvements in overall survival for patients assigned to 
receive induction treatment, compared to the control arm of surgery alone (7, 8). Following this 
experience, several multi- institutional, randomized, phase III studies were launched to evaluate 
the effects of induction chemotherapy in patients with stage I-III NSCLC (9-13). Collectively,  
these studies demonstrated that (1) induction treatment had activity in NSCLC and elicited 
objective responses in at least 40% of the patients; (2) there was no significant increase in 


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Clinical Study Protocol 9.0                                                      
MDA Cancer Center 
Bintrafusp Alpha- M7824                    
 
 15 June 2020 
 
 
 
perioperative mortality; (3) induction chemotherapy did not seem to negatively impact disease 
resectability. Furthermore, a meta-analysis including seven induction randomized trials (988 
patients), demonstrated a HR for death of 0.82 (95% CI 0.69-0.97, p=0.002) in favor of induction 
treatment, translating into an absolute improvement of overall survival at 5 years of 6% (14). 
Since these figures are very similar to the benefits seen in the adjuvant chemotherapy meta- 
analysis, one could argue that chemotherapy, either before or after surgery, are reasonable 
treatment options in patients that are candidate for peri-operative systemic therapy. 
Potential advantages of neoadjuvant compared to adjuvant treatment include: (1) the ability to 
deliver treatment with higher dose intensity, due to better tolerability (12); (2) the ability to 
demonstrate sensitivity to treatment in vivo (since one can follow response to therapy by imaging 
studies, and assess pathologic response in the resected specimen) – the in vivo assessment of 
treatment efficacy provides important prognostic information, since patients with a partial or 
complete radiographic response to treatment (15), and patients with lymph node pathologic 
downstaging after therapy have been shown to have improved survival (16-18); (3) the ability to 
study biomarker modulation in response to therapy, and correlate them with short- term (i.e., 
response rates), and long-term (i.e., disease-free or overall survival) efficacy outcomes, thus 
streamlining translational research. 
Induction systemic therapy may be particularly important in the setting of immune checkpoint 
inhibitor use. One might postulate that, in contrast to the adjuvant setting (in which only micro- 
metastatic disease is present), the higher tumor burden present at the time of induction treatment 
may be necessary for abundant antigen release and presentation to the immune system, and 
consequently, development of a robust immune response. The possible superiority of induction 
immune therapy, as compared to adjuvant immune therapy, is currently being investigated in pre-
clinical models at MD Anderson (Cascone et al, AACR 2018, manuscript in preparation). 
 
3.3 Investigational agent M7824 
 
M7824 (MSB0011359C, bintrafusp alfa) is an innovative first-in-class bifunctional fusion  
protein composed of the extracellular domain of TGFβ receptor II (TGFβRII or TGFβ Trap) 
covalently linked via a flexible linker to the C-terminus of each heavy chain of an 
immunoglobulin (IgG1) antibody blocking programmed death-ligand 1 (anti-PD-L1). Bintrafusp 
alfa is the proposed international nonproprietary name for M7824. Complete information on the 
chemistry, pharmacology, efficacy, and safety of M7824 is in the Investigator’s Brochure”. This 
anti-PD-L1 / TGFβ-Trap molecule is designed to target 2 major mechanisms of 
immunosuppression in the tumor microenvironment. 
 
3.4 Preclinical studies with M7824 in cancer 
 
A recent report found that blockade of TGFβ signaling in T cells or deletion of TGFβ1 from T 
cells in a mouse model led to diminished PD-1 expression in tumor-infiltrating CD8+ T cells. 
Concomitant PD-1 and TGFβ blockade can restore pro-inflammatory cytokines. In a murine 
model of hepatocellular carcinoma, TGFβ appeared to increase the expression of PD-L1 in 
dendritic cells, which in turn promoted T-cell apoptosis and increased percentage of CD25+, 
Foxp3+ T regulatory cells (19). Higher levels of circulating myeloid-derived suppressor cells 
(MDSCs), a significant source of TGFβ, are associated with failure to respond to anti-PD-1 


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Clinical Study Protocol 9.0                                                      
MDA Cancer Center 
Bintrafusp Alpha- M7824                    
 
 15 June 2020 
 
 
 
therapy. Experiments demonstrate that M7824 strongly enhances antitumor activity and 
prolongs survival in mouse tumor models above the effect of either the anti-PD-L1 antibody, or 
TGFβRII control alone. Tumor rechallenge experiments in cured mice show durable protective 
immunity. In vivo studies showed that the antitumor effects were mediated by CD8+ T cells and 
NK cells. CD8+ T-cell tumor infiltrates were observed and, overall, the CD8+ response was 
associated with long-term protective immunity. Importantly, in the MC38 model, M7824 showed 
significantly improved efficacy than the combination of avelumab plus TGFβ Trap control, 
supporting the rationale of combining the 2 active moieties in 1 molecule. 
 
Given the emerging picture for PD-1 / PD-L1 class, in which responses are apparent but with 
room for increase in effect size, it is assumed that co-targeting a complementary immune 
modulation step will improve tumor response. A similar TGF-targeting agent, fresolimumab, 
which is a monoclonal antibody targeting TGFβ1, 2, and 3, showed initial evidence of tumor 
response in a Phase I trial in subjects with melanoma. The objective response was observed 
in 1 of 28 subjects with 6 subjects showing stable disease. Internal data shows that the 
TGFβRII portion of M7824 has dose dependent antitumor activity in a mouse pharyngeal 
carcinoma xenograft model, similar to antitumor findings with soluble receptor reported 
elsewhere. Given the preclinical and clinical evidence of both pathways, it is anticipated that 
M7824 may have enhanced antitumor activity compared with immunotherapy agents which 
target a single pathway and is an attractive anticancer strategy. 
 
3.5 Pharmacokinetics / Immunogenicity Findings 
 
Preclinical PK data and PK / PharmDyn analysis for M7824 is available from mice and 
cynomolgus monkeys. The single-dose data in monkey shows non-linearity between the low 
doses of 0.8 and 4 mg/kg versus the high dose of 20 mg/kg, which had reduced clearance, 
suggesting a saturable component. The TGFβ-1 binding was assessed and showed 
suppression for prolonged periods beyond drug exposure at all dose levels;   however, 
baseline data contained data below lower limit of quantification and therefore these data were 
not considered relevant for PK/PharmDyn projections. The fusion protein appeared stable 
since there was no evidence of intralinker cleavage. Mouse PK  /  PharmDyn  models for 
tumor and peripheral blood (CD3+ splenic) PD-L1 occupancy were also generated. 
 
A brief summary of PK and PK / PharmDyn is as follows: 
• The predicted human terminal half-life (t1/2) for M7824 is approximately 6 days 
• Simulations predict that a 1 mg/kg dose will provide an average exposure of 
approximately 7 μg/mL in humans 
• Based on PK / PharmDyn modeling and human 
projections: 
o At a human dose of 0.1 mg/kg, 95% PD-L1 total occupancy at maximum serum 
concentration observed post-dose (Cmax) is expected in PBMCs, providing 
approximately 60% total occupancy in tumor 


14 
Clinical Study Protocol 9.0                                                      
MDA Cancer Center 
Bintrafusp Alpha- M7824                    
 
 15 June 2020 
 
 
 
o At a human dose of 1.0 mg/kg, more than 95% of PD-L1 total occupancy at Cmax is 
expected in PBMCs and tumor 
o At a human dose of 1.0 mg/kg, 20%  effect  is  projected  in  tumor  regression in 
the PK / PharmDyn model compared with 95% at 7.5 mg/kg 
• Human projections indicate a dose of 7.5 mg/kg and higher (range 4 to 20 
mg/kg), on a biweekly schedule is needed to achieve full efficacy based on a 
mouse tumor model in which complete tumor regressions were observed. 
 
Anti-drug antibodies were observed in some animals; however, the impact on PK or PK / 
PharmDyn is not known. Preclinical antidrug antibody formation is not predictive of human 
antibodies. 
 
3.6 Toxicology 
The toxicological profile of M7824 was investigated in vivo in mice and cynomolgus 
monkeys. In addition, an optimized in vitro cytokine release assay in human PBMCs as well as 
tissue cross-reactivity studies in normal human and cynomolgus monkey tissues were 
performed. 
 
Investigations of local tolerance were integrated in the repeat-dose toxicity studies. The 
investigation of safety pharmacology relevant parameters (CNS, respiratory, cardiovascular) 
was included in the pivotal 4-week intravenous (IV) repeat-dose toxicity study in cynomolgus 
monkeys. Please refer to the investigator brochure for M7824 for further details (M7824 IB v 
4.0). 
 
3.7 Safety of M7824 
 
A reasonable safety profile is anticipated when targeting these pathways. The safety of the 
PD-1 / PD-L1 class continues to emerge but appears to be substantially less adverse 
compared with the CTLA-4 class of T cell checkpoint inhibitors. TGFβ inhibiting biologics 
administered in clinical trials also showed an acceptable human safety profile in humans. 
Fresolimumab was studied in Phase I trial in subjects with cancer (28 with melanoma, 1 with 
renal cell carcinoma). No DLTs were observed and 15 mg/kg, the highest dose tested, was 
determined to be safe. The major AE was emergent skin tumors and hyperkeratosis. In a small 
trial of idiopathic pulmonary fibrosis, the most common AE was fatigue (20). In a study of 16 
subjects with focal segmental glomerulosclerosis, the only AE was pustular rash in 2 subjects 
(21). TβM1, an antibody inhibiting the TGFβII receptor, was well tolerated when studied at doses 
as high as 240 mg with diarrhea as the only DLT event. Notably, one event of low hemoglobin 
(Hgb) was observed in the high dose group. Importantly, the preclinical profile of M7824 is 
predominantly benign and highly comparable to that of other checkpoint inhibitors. 
Overall, evidence suggests non-overlapping toxicity profiles for anti-PD-L1 and anti-TGFβ agent 
classes. There is a theoretical potential of immune-related adverse events (irAEs) that would be 
the consequence of a double blockade of negative regulatory loops of the immune system; 
however, taken together, the preclinical profile of M7824 and clinical evidence of each 


15 
Clinical Study Protocol 9.0                                                      
MDA Cancer Center 
Bintrafusp Alpha- M7824                    
 
 15 June 2020 
 
 
 
pathway suggests a low risk of synergistic toxicity stemming from the dual-functionality of 
M7824. The safety profile is described in the IB for M7824 and is briefly summarized here (refer 
to M7824 IB v5). Safety tolerability, PK, and biological and clinical activity of M7824 have been 
evaluated in subjects with metastatic or locally advanced solid tumors and expansion to 
selected indications in the global Phase I Study EMR200647-001 in subjects with metastatic or 
locally advanced solid tumors, and the phase I study MS200647-0008 in subjects with 
metastatic or locally advanced solid tumors in Asia. To date, over 700 patients have been 
treated with M7824 and an acceptable safety profile has been observed. Randomized phase 2 
trials have recently been initiated using M7824. The dose selection for the dose expansion 
cohorts and phase 2 studies was based on the review of the available clinical  
safety/tolerability, pharmacokinetic (PK), and pharmacodynamic (PD) (PD-L1 TO and TGFβ 
concentrations in PBMCs and plasma, respectively) data from the ongoing Phase I Study 
EMR200647-001 informed by population PK (popPK), modeling and simulation approaches and 
a translational PK/efficacy model from mouse studies. 
 
Analysis of the available preliminary PK data in dose escalation cohorts of Study EMR200647- 
001 at doses from 1 to 20 mg/kg supports flat dosing approach. The dose for the expansion 
cohorts of both studies has been selected as 1200 mg/infusion (flat dose) iv once every 2 
weeks. The safety summary for this Investigator’s Brochure includes data from 377 subjects 
treated in the pooled expansion cohort from the ongoing Phase I EMR200647-001 (as of interim 
analysis at 3 months after the 30th or 40th subject’s 1st dose). The pooled safety data are from 
10 expansion cohorts including hepatocellular carcinoma (HCC) second-line (2L), NSCLC 2L, 
NSCLC anti-PD-L1 failure, melanoma anti-PD-L1 failure, pancreatic adenocarcinoma 2L, 
colorectal cancer (CRC) 3L or greater, triple-negative breast cancer (TNBC) 2L, esophageal 
adenocarcinoma 2L or greater, glioblastoma 2L, squamous cell carcinoma head and neck 
(SCCHN) 2L or greater. 
 
In EMR200647-001 pooled expansion cohort of the first 377 subjects, 364 (96.6%) subjects 
experienced TEAE, treatment-related Grade ≥ 3 TEAEs occurred in 58 (15.4%) subjects, 
treatment related SAEs were reported in 28 (7.4%) subjects, and 16 (4.2%) subjects had 
treatment discontinuations due to treatment related TEAEs (M7824 IB v 4.0). The preliminary 
safety assessment of M7824 from EMR200647-001 and MS200647-0008 studies suggested an 
acceptable safety profile in subjects with advanced or metastatic solid tumors. Overall, the 
patterns of TEAEs in both studies are consistent with the types of AEs commonly observed in 
subjects with advanced or metastatic malignancies that have progressed after ≥ 1 lines of prior 
anticancer therapy with the exception of the identified risks of M7824. 
 
Based on medical assessment (regular and periodic safety review which also includes external 
experts) of safety data emerging from the ongoing clinical studies with M7824, supported by 
scientific evidence from biological mechanism, observations with other check point inhibitors  
as well as TGFβ inhibitor, fresolimumab, the following events in the 3 AESI categories were 
reclassified as important identified risks (adverse reactions) at the end of safety reporting period 
(23 July 2017), the frequency and intensity are summarized in this Investigator’s Brochure 
(M7824 IB v4). 


16 
Clinical Study Protocol 9.0                                                      
MDA Cancer Center 
Bintrafusp Alpha- M7824                    
 
 15 June 2020 
 
 
• Infusion-related reactions (IRRs) including hypersensitivity (immediate): Signs and 
symptoms may include but are not limited to pyrexia, chills, flushing, hypotension, 
dyspnea, wheezing, back pain, abdominal pain, and urticarial 
 
• Immune-related adverse events (irAEs) including colitis, pneumonitis/interstitial lung 
disease, endocrinopathies (thyroid disorders including hyperthyroidism, hypothyroidism, 
autoimmune thyroiditis and adrenal insufficiency), Type I diabetes mellitus, renal 
disorders (acute renal injury), hepatitis (increased transaminase), retinal 
microvasculitis, myositis, skin reactions like rash (generalized, maculo-papula, 
erythematous, pemphigoid). 
 
• Skin lesions with hyperkeratosis, keratoacanthoma, cutaneous squamous cell 
         carcinoma possibly due to TGFβ inhibition. 
 
Treatment-related anemia treatment-emergent adverse events (TEAEs), alterations in wound 
healing or repair of tissue damage and embryofetal toxicity remain important potential risks. 
Respective risk mitigation measures have been implemented in the protocols. TEAEs of 
special interest (AESI) are IRRs, irAEs, skin TEAEs, and treatment-related anemia TEAEs. 
Most of the AESI incidents were well managed or resolved. IRRs occurred in 23 (6.1%) 
subjects. All of the events were Grade 1 or 2 in intensity. Treatment-related irAE of any grade 
occurred in 34 (9.0%) subjects. Most irAEs were of Grade 1 or 2 in intensity, 7 (1.9%) subjects 
experienced treatment related Grade 3 irAEs. No subject experienced Grade 4 or 5 irAEs. The 
treatment-related irAEs that occurred in 2 or more subjects were rash maculo-papular in 11 
(2.9%) subjects, rash in 4 (1.1%) subjects, pruritus in 3 (0.8%) subjects, and rash macular in 3 
(0.8%) subjects, and hypothyroidism in 3 (0.8%) subjects. Skin AESIs include skin AEs possibly 
due to TGFβ inhibition (rash with hyperkeratosis, keratoacanthoma, and squamous cell 
carcinoma of the skin) and immune-related skin AEs possibly mediated by PD-L1 inhibition. 
Treatment-related skin AESIs that are possibly due to TGFβ inhibition included 
keratoacanthoma in 11 (2.9%) subjects, squamous cell carcinoma of skin in 2 (0.5%) subjects, 
hyperkeratosis in 3 (0.8%) subjects, and actinic keratosis in 2 (0.5%) subjects. Treatment- 
related anemia AESIs occurred in 24 (6.4%) subjects including anemia in 23 (6.1%) subjects 
(Grade ≥ 3 in 13 subjects), and Grade 5 hemolysis in 1 (0.3%) subject. 
 
3.8 Efficacy of M7824 in solid tumors 
 
The efficacy data is based on the available data from the dose escalation cohorts of 
EMR200647-001 and MS200647-0008 presented at the ASCO annual meeting 2018. The 
clinical efficacy data of the dose expansion cohorts will be reported at a later point in time. 
Based on the limited efficacy data, initial signals of tumor response are evident. The subjects 
enrolled in the dose escalation cohorts in the two studies represent a variety of primary tumor 
types and had locally advanced, inoperable or metastatic disease with at least 1 type prior 
anticancer treatment. 
 
In dose escalation cohorts of EMR200647-001, confirmed responses were complete response 
(CR) in 1 subject with cervical cancer who received M7824 at 10 mg/kg and partial response (PR) 
in 2 subjects (3 and 10 mg/kg). Stable disease (SD) was achieved in 6 subjects, in 


17 
Clinical Study Protocol 9.0                                                      
MDA Cancer Center 
Bintrafusp Alpha- M7824                    
 
 15 June 2020 
 
 
 
particular 2 subjects with progressive disease at study entry achieved prolonged SD following 
treatment with M7824. 
 
In dose escalation cohorts of MS200647-0008, confirmed responses were PR in 2 subjects (1 
subject with colorectal cancer, who received 3 mg/kg and the other with ovarian cancer, who 
received 20 mg/kg M7824). Both PRs were ongoing beyond the data cutoff. SD was achieved 
in 3 subjects including 2 subjects at 3 mg/kg dose level, and 1 subject at 10 mg/kg dose level. 
 
Overall, considering the preliminary clinical activity of M7824 observed in both EMR200647- 001 
and MS200647-0008 dose escalation cohorts, together with the safety profile that appears to be 
manageable given the advanced disease of the studied patient populations, the benefit/risk 
evaluation is considered favorable for continued clinical development of M7824. 
 
 
3.9 Summary of Clinical Findings for M7824 in NSCLC 
 
Results of the expansion cohort of the ongoing, phase 1 trial NCT02517398 evaluating M7824 in 
refractory solid tumors were recently presented at ASCO Annual Meeting 2018 (22). Patients with 
advanced NSCLC unselected for PD-L1 who progressed following first-line standard treatment 
(no prior immunotherapy) were randomized to receive M7824 500 mg (n = 40) or 1200 mg (n = 
40) intravenously q2 week until disease progression, unacceptable toxicity, or trial withdrawal. 
The primary objective is to assess best objective responses (BOR) per RECIST v1.1; other 
objectives include dose exploration and safety/tolerability assessment. Tumor cell PD-L1 
expression was evaluable in 75 patients (Ab clone 73-10 [ > 80% = > 50% with 22C3]). As of 
October 25, 2017, 80 patients received M7824 for a median of 11.9 (range, 2-48) weeks, with a 
median follow-up of 35.2 weeks; 17 patients remain on treatment. Investigator-assessed 
unconfirmed ORR was 25.0% (500 mg ORR, 22.5%; 1200 mg ORR, 27.5%). Clinical activity was 
observed across PD-L1 expression levels (Table 1); ORR was 40.7% in PD-L1+ and 71.4% in 
PD-L1–high patients at 1200 mg dose. The most common treatment-related adverse events 
(TRAEs) were pruritus (18.8%), maculopapular rash (17.5%), and decreased appetite (12.5%). 
Grade ≥3 TRAEs occurred in 20 pts (25.0%). 6 pts (500 mg, n = 2; 1200 mg, n = 4) discontinued 
treatment due to TRAEs. No treatment-related deaths occurred. M7824 monotherapy has shown 
promising efficacy across PD-L1 subgroups, with an ORR at the RP2D of 1200 mg of 40.7% and 
71.4% in PD-L1+ and –high patients, respectively and with overall good tolerance. 
 
 
Table 1. Investigator-assessed efficacy of M7824 observed in NSCLC patients across PD-L1 
expression levels 
 
500 mg Q2W 
N=40 
1200 mg Q2W 
N=40 
Overall 
N=40 
Best overall response, n (%) 
Complete response 
Partial response  
Stable disease 
Progressive disease 
 
0 (0) 
8 (20.0) 
3 (7.5) 
22 (55.5) 
 
1 (2.5) 
10 (25.0) 
7 (17.5) 
21 (52.5) 
 
1 (1.3) 
18 (22.5) 
10 (12.5) 
43 (53.8) 


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Clinical Study Protocol 9.0                                                      
MDA Cancer Center 
Bintrafusp Alpha- M7824                    
 
 15 June 2020 
 
 
 
  Not evaluable 
7 (17.5) 
1 (2.5) 
8 (10.0) 
  Investigator-assessed ORR, n      
  (%) 
  All 
  PD-L1+ (≥1%) 
  PD-L1–high (≥80%) 
8/40 (20.0) 
6/31 (19.4) 
2/6 (33.3) 
11/40 (27.5) 
11/27 (40.7) 
5/7 (71.4) 
19/80 (23.8) 
17/58 (29.3) 
7/13 (53.8) 
  Disease control rate, n (%) 
  All 
  PD-L1+ (≥1%) 
  PD-L1–high (≥80%) 
11 (27.5) 
9 (29.0) 
2 (33.3) 
18 (45.0) 
15 (55.6) 
5 (71.4) 
29 (36.3) 
24 (41.4) 
7 (53.8) 
  Median PFS, months (95% CI) 
  All 
  PD-L1+ 
  PD-L1–high 
1.4 (1.3-2.7) 
1.6 (1.3-3.3) 
1.5 (0.2-NR) 
2.7 (1.3-8.1) 
6.8 (2.6-NR) 
NR (2.7-NR) 
2.1 (1.4-2.9) 
2.7 (1.6-6.8) 
8.1 (1.4-NR) 
  Median OS, months 
  All 
  PD-L1+ 
  PD-L1–high 
10.9 (4.6-NR) 
10.3 (4.5-NR) 
NR (1.0-NR) 
NR (11.8-NR) 
NR (12.2-NR) 
NR (12.2-NR) 
12.2 (10.5-NR) 
NR (10.3-NR) 
NR (9.5-NR) 
 
 
3.10 Combination of immune checkpoint blockade and platinum-based chemotherapy for 
NSCLC 
 
The PD-1 inhibitor pembrolizumab has shown superior efficacy as monotherapy in previously 
untreated patients with advanced NSCLC and a PD-L1 tumor proportion score ≥50% compared 
with standard platinum-based chemotherapy, with fewer toxicities (23). Based on this results, the 
investigators of the Keynote-021 phase II study assessed the efficacy of pembrolizumab added to 
platinum-doublet chemotherapy as first line therapy for advanced non-squamous NSCLC patients 
(24). The objective response rate was 55% in the pembrolizumab plus chemotherapy group 
compared with 29% in the chemotherapy alone group (p=0.0016) with an overall tolerable toxicity 
profile. More recently, the IMpower150 phase 3 trial evaluated the addition of the PD-L1 inhibitor 
atezolizumab (atezo) to carboplatin (C) + paclitaxel (P) ± bevacizumab (bev) in chemo- naive 
patients with metastatic non-squamous NSCLC. Patients who had not previously received 
chemotherapy were randomly assigned to receive atezolizumab plus carboplatin plus paclitaxel 
(ACP), bevacizumab plus carboplatin plus paclitaxel (BCP), or atezolizumab plus BCP (ABCP) 
every 3 weeks for four or six cycles, followed by maintenance therapy with atezolizumab, 
bevacizumab, or both. The two primary end points were investigator-assessed PFS both among 
patients in the intention-to-treat population who had a wild-type genotype (WT population; patients 
with EGFR or ALK genetic alterations were excluded) and among patients in the WT population 
who had high expression of an effector T-cell (Teff) gene signature in the tumor (Teff- high WT 
population) and OS in the WT population. The median PFS was longer in the ABCP group than in 
the BCP group (8.3 months vs. 6.8 months; HR 0.62; 95% CI, 0.52 to 0.74; 


19 
Clinical Study Protocol 9.0                                                      
MDA Cancer Center 
Bintrafusp Alpha- M7824                    
 
 15 June 2020 
 
 
 
p<0.001); the corresponding values in the Teff-high WT population were 11.3 months and 6.8 
months (HR 0.51; 95% CI, 0.38 to 0.68; p<0.001). PFS was also longer in the ABCP group than 
in the BCP group in the entire intention-to-treat population and among patients with low or 
negative programmed death ligand 1 (PD-L1) expression, those with low Teff gene-signature 
expression, and those with liver metastases. Median OS among the patients in the WT 
population was longer in the ABCP group than in the BCP group (19.2 months vs. 14.7 months; 
HR, 0.78; 95% CI, 0.64 to 0.96; p=0.02). The safety profile of ABCP was consistent with 
previously reported safety risks of the individual agents (25). 
 
The phase III trial, KEYNOTE-189, was a randomized, double blind, placebo controlled, study 
investigating pembrolizumab in combination with pemetrexed and cisplatin or carboplatin 
compared with pemetrexed and cisplatin or carboplatin alone in previously untreated patients 
with wild type (WT) advanced or metastatic nonsquamous NSCLC, regardless of PD-L1 
expression (NCT02578680). The results of this phase 3 trial have been recently reported and 
demonstrated that in patients with previously untreated metastatic nonsquamous NSCLC without 
EGFR or ALK mutations, the addition of pembrolizumab to standard pemetrexed plus platinum-
based chemotherapy resulted in significantly longer OS and PFS than chemotherapy alone. After 
a median follow-up of 10.5 months, the 12-month OS rate was 69.2% (95% CI, 64.1 to 73.8) in 
the pembrolizumab-combination group vs. 49.4% (95% CI, 42.1 to 56.2) in the placebo-
combination group (HR for death, 0.49; 95% CI, 0.38 to 0.64; p<0.001). Median PFS was 8.8 
months (95% CI, 7.6 to 9.2) in the pembrolizumab-combination group and 4.9 months (95% CI, 
4.7 to 5.5) in the placebo-combination group (HR for disease progression or death, 0.52; 95% CI, 
0.43 to 0.64; p<0.001) (26). 
Another phase III trial, CheckMate 227, compared nivolumab, or nivolumab plus ipilimumab, or 
nivolumab plus platinum-based chemotherapy versus platinum-based chemotherapy in patients 
with chemotherapy-naïve stage IV recurrent NSCLC (NCT02477826). Results have been 
recently reported and demonstrated that PFS among patients with a high tumor mutational 
burden was significantly longer with nivolumab plus ipilimumab than with chemotherapy. The 1- 
year PFS rate was 42.6% with nivolumab plus ipilimumab vs. 13.2% with chemotherapy, and the 
median PFS was 7.2 months (95% CI, 5.5 to 13.2) vs. 5.5 months (95% CI, 4.4 to 5.8) (HR 
for disease progression or death, 0.58; 97.5% CI, 0.41 to 0.81; p<0.001). The ORR was 45.3% 
with nivolumab plus ipilimumab and 26.9% with chemotherapy (27). 
Collectively, these results and the ongoing studies support investigation of checkpoint inhibitors 
with or without platinum-based chemotherapy in the pre-operative setting. Given the platform 
design of this study, additional arms evaluating M7824-based combinations, including, but not 
limited to, platinum-based chemotherapy, will be launched with a protocol amendment based on 
ememrging results of combinatorial strategies in the metatstic setting. 
 
3.11 
Major pathologic response as a marker of induction chemotherapy efficacy  
 
Several small studies have suggested that the degree of tumor regression after induction therapy, 
as determined by histopathologic findings in the resected tumor, may be an objective 
criterion of chemotherapy response and may correlate with long-term treatment outcomes (28- 
31). This issue was comprehensively evaluated recently by Pataer et al. in a retrospective study 


20 
Clinical Study Protocol 9.0                                                      
MDA Cancer Center 
Bintrafusp Alpha- M7824                    
 
 15 June 2020 
 
 
 
with 192 patients treated with induction chemotherapy and 166 patients treated with surgery 
upfront at MD Anderson Cancer Center (2).Using a score system that quantifies the percentage of 
viable tumor cells in at least 1 section per cm of tumor greatest diameter (5-30 slides examined 
for each case), the authors demonstrated that in patients that received induction treatment, there 
is a statistically significant correlation between higher percentage of viable cells and shorter 
disease-free and overall survival. This correlation was not evident in patients treated with surgery 
upfront. In this cohort, 89% of the neoadjuvantly treated patients received a platinum and a 
taxane-based regimen, and a pathologic response (defined as ≤ 10% viable tumor cells) occurred 
in 19% of the patients. The 5-year recurrence-free survival for patients with and without a 
pathologic response were 78% and 35%, respectively (p<0.001). The 5-year overall survival for 
patients with and without a pathologic response were 85% and 40%, respectively (p<0.0001). 
Taken together, these results support the use of major pathologic response as a surrogate 
endpoint for recurrence-free and overall survival in patients with NSCLC treated with neoadjuvant 
chemotherapy. 
 
3.12 Neoadjuvant immune checkpoint blockade in resectable NSCLC 
 
Recently published results of a small, pilot study evaluating the safety and feasibility of 
neoadjuvant nivolumab as monotherapy for a limited number of patients with resectable NSCLC 
has demonstrated that nivolumab is safe, does not delay surgery, and induces a major 
pathological response in 9 of 20 resected tumors (45%) (32). Translational analyses revealed a 
significant correlation between the pathological response and the pretreatment tumor mutational 
burden, and the number of T-cell clones that were found in both the tumor and peripheral blood 
expanded significantly after neoadjuvant nivolumab therapy in 8/9 patients evaluated. These 
remarkable results highlights the need to test additional immunotherapy- based combination in 
the neoadjuvant setting to discover efficacy signal of compounds to be tested in larger trials. 
 
3.13 TCD8+ TILs as a prognostic marker. 
Several studies have demonstrated that TCD8+ TILs are associated with improved outcomes in 
resected NSCLCs (33-35). PD-1 and/or CTLA4 blockade are expected to recruit antigen specific 
TCD8+ cells to the tumor microenvironment, and therefore contribute to an enhanced immune 
response. As such, automated quantification of TCD8+ cells in resected specimens following 
induction immunotherapy may provide evidence for its role as a surrogate marker of efficacy of 
these drugs, and is included as a secondary endpoint in this study. Additionally, phenotypic 
characterization of the immune infiltrate (such as evaluation of exhausted T cells) may also be 
important to evaluate potential differences in outcomes to single agent versus combined immune 
checkpoint blockade (36). 
 
4. RATIONALE OF THE STUDY 
 
Immunotherapy with anti-PD1 therapy has shown to improve response rates and survival 
outcomes in NSCLC patients. TGFβ, being a central determinant of an immune suppressive 
tumor microenvironment (TME) may be a key resistance mechanism in PD-L1 therapy 


21 
Clinical Study Protocol 9.0                                                      
MDA Cancer Center 
Bintrafusp Alpha- M7824                    
 
 15 June 2020 
 
 
 
strategies. TGFβ signaling may promote an immune suppressive microenvironment by directly 
inducing T cells to differentiate into Tregs or indirectly via attraction of immunosuppressive 
immature myeloid and MDSCs into the TME. Upregulation of TGF-β signaling has been 
associated with primary (de novo) resistance to anti-PD-1 treatment in patients with metastatic 
melanoma and following development of acquired resistance to these agents following an initial 
response to therapy.  Given the ability of M7824 to sequester TGF-β in the circulation away from 
the TME, we hypothesize that M7824 may promote T cell effector function via disruption of PD-
1/PD-L1 axis to enhance anti-tumor response in patients with surgically resectable NSCLC. 
 
 
 
5. HYPOTHESIS 
The primary research question to be tested in this study is whether in patients with stage I- 
IIIA NSCLC amenable for surgical resection, induction immunotherapy with 3  doses  of 
M7824 monotherapy will produce major pathologic responses in resected tumors as 
determined by Pataer et al. (JTO 2012). 
 
The secondary research question to be tested in this study is that immunotherapy with 
M7824 will induce immune responses (as assessed by CD8+ TILs), tumor shrinkage (as 
assessed by CT), and improve recurrence-free survival (RFS) and overall survival (OS) in a 
subset of patients; analysis of correlative studies in these patients will assist in developing 
biomarkers predictive of response to immunotherapeutic agents in NSCLC and will assist in 
determining immune modulation by M7824. 
 
5.1 Overall Benefit and Risk 
The risk-benefit ratio has been carefully considered in the planning of the trial. Based on the 
preclinical data available to date, the conduct of the trial is considered justifiable using the dose 
and schedule of M7824 as specified in this protocol. The trial will be discontinued in the event of 
any new findings that indicate a relevant deterioration of the risk-benefit ratio and would render 
continuation of the trial unjustifiable. The following are considered potential risks of  
exposure to M7824: 
• Infusion-related reactions including hypersensitivity 
• irAEs / autoimmune disorders 
• Anemia 
• Rash with hyperkeratosis, keratoacanthoma, and squamous cell carcinoma of the 
skin 
• Alterations in wound healing or repair of tissue damage 
• Embryofetal toxicities 
• Mild to Moderate Mucosal Bleeding Events 
 
Respective safety measures that comprise inclusion / exclusion criteria for participation in clinical 
trials with M7824, guidance for prevention, monitoring, and medical management of 


22 
Clinical Study Protocol 9.0                                                      
MDA Cancer Center 
Bintrafusp Alpha- M7824                    
 
 15 June 2020 
 
 
 
potential risks, as well as guidance on study treatment interruption or discontinuation. See 
Section 3 above for a summary of clinical safety findings observed with M7824. 
 
 
Infusion-related Reactions / Hypersensitivity 
Infusion-related reactions hypersensitivity are a risk inherent to the administration of any 
recombinant protein to humans. Incidence of immunogenicity and character or severity of 
immunogenicity-induced side effects cannot be predicted by animal models because humanized 
or fully human proteins usually provoke a much stronger immune-response in rodents or 
non- human primates than in humans. The parent antibody caused lethal immune-mediated 
anaphylactic hypersensitivity reactions in mice after repeated application, while a control antibody 
lacking pharmacological activity only triggered a moderate immune reaction. However, in 
primates (cynomolgus monkeys), as a species closer to human, neither in the pilot 4-week IV 
repeat-dose toxicity trial nor in the pivotal 13-week IV infusion repeat-dose toxicity trial, clinical 
signs of hypersensitivity have been seen at dose levels of 20, 60, and 140 mg/kg, respectively. 
 
Immune-related Adverse Events / Autoimmune Disorders 
Since inhibition of PD-L1 and TGFβ signaling stimulates the immune system, irAEs may occur. 
Treatment of irAEs is mainly dependent upon severity (NCI-CTCAE grade): 
• Grade 1 to 2: treat symptomatically or with moderate dose steroids, more 
frequent monitoring 
• Grade 1 to 2 (persistent): manage similar to high grade AE (Grade 3 to 4) 
• Grade 3 to 4: treat with high dose corticosteroids 
Treatment of irAEs should follow guidelines set forth in the dedicated section of the protocol. 
 
Anemia 
As the 4-week toxicology studies in cynomolgus monkeys demonstrated reversible decreases 
in red blood cell counts, as well as corresponding Hgb and hematocrit, anemia is 
considered a potential risk. Inclusion criteria for the study will require adequate entry Hgb value. 
Risk management measures are provided in the dedicated section. The amount of  blood drawn 
during the study for non-essential biomarkers will be carefully considered, especially given the 
preclinical finding of reduced Hgb levels. 
 
Alterations in Wound Healing or Repair of Tissue Damage 
 
Alternations of wound healing and tissue damage repair are considered a potential risk given 
the TGFβ mechanism. Management should be discussed with the principal investigator on a 
case-by-case basis. 
 
 
 
 


23 
Clinical Study Protocol 9.0                                                      
MDA Cancer Center 
Bintrafusp Alpha- M7824                    
 
 15 June 2020 
 
 
Rash with HyperKeratosis / Keratoacanthoma /Squamous Cell Carcinoma of the Skin 
 
Phase I information from a TGF antibody showed excess keratoacanthomas, some with atypical 
features, and one confirmed  squamous  cell carcinoma  (Morris  2014). A genetic  disorder in the 
TGF pathway is also known to be associated with skin tumors (Goudie 2011). In the NSCLC 2L 
cohort of EMR200647-001, 7% of patients treated with M7824 developed these events. No 
patients were required to be discontinued from trial due to these lesions: they were typically well 
managed with simple excision and/or observation (22). Based on this information, skin tumors 
are considered a potential risk. Monitoring will include skin assessments as defined in the 
schedule of assessments. Management should be discussed with the on a case-by-case basis. 
Dermatological consults should be requested as needed. Rash with hyperkeratosis / 
keratoacanthoma / squamous cell carcinoma of the skin are considered as AESIs requiring 
expedited reporting from the Investigator to the Sponsor. Any suspicious lesion should be 
biopsied. For non-serious AESIs, an AESI Report Form has to be completed; for serious events, 
an SAE Report Form has to be used. 
 
Embryofetal Toxicity 
Embryofetal toxicities are a known risk of the PD-1 / PD-L1 targeting class. Animal models link 
the PD-1 / PD-L1 signaling pathway with maintenance of pregnancy through induction of maternal 
immune tolerance to fetal tissue. Based on its mechanism of action (MoA), M7824 may cause 
fetal harm when administered to a pregnant female. An appropriate contraception warning is 
provided in this clinical protocol. Subjects with pregnancy or in lactation period are prohibited 
from being enrolled in clinical trials. 
 
Mild to Moderate Mucosal Bleeding Events 
 
Mucosal 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. 
 
5.2 Potential Benefit 
Although considerable progress has occurred in understanding the biological characteristics of 
cancer as well as the development of more effective treatment regimens, most patients with 
locally advanced NSCLC succumb to their disease. Thus, there is a substantial need for novel 
therapeutic strategies to improve the outcome for this potentially curable patient population. 
 
Immune checkpoint blockade with anti-PD-1 therapy offers the chance to improve outcomes of 
patients with NSCLC treated with surgical resection on an outpatient basis. Treatment with 
M7824 may have the potential to provide significant benefit by shrinking tumors and preventing 
loco-regional and/or distant metastasis by inhibiting TGFβ, a pivotal factor involved in 
establishing an immune suppressive tumor microenvironment and a potential mechanism of 
resistance in PD-L1 therapy strategies. M7824 therapy has the ability to sequester TGF-β in the 
circulation far from the tumor microenvironment and may promote T cell effector function via 
disruption of PD-1/PD-L1 axis to enhance anti-tumor responses in the induction setting. 


24 
Clinical Study Protocol 9.0                                                      
MDA Cancer Center 
Bintrafusp Alpha- M7824                    
 
 15 June 2020 
 
 
 
Therefore, M7824, which targets a possible immunotherapy resistance mechanism in the form of 
TGFβ upregulation, may prove beneficial when administer as induction therapy in in early stage 
NSCLC patients. 
 
 
 
6. STUDY ENDPOINTS 
 
6.1 Primary Endpoints 
 
• Major pathologic response (MPR) rate in patients treated with induction 
M7824 monotherapy. 
 
MPR is defined as ≤ 10% viable tumor cells in the resected specimen using the methods 
described by Pataer et al (20). Briefly, at least 1 section per cm of tumor greatest diameter is 
evaluated, with a minimum of 5 slides. The percentage of residual tumor is determined by 
comparing the estimated cross sectional area of the viable tumor foci to estimated cross 
sectional areas of necrosis, fibrosis and inflammation on each slide. The results for all slides 
are averaged together to determine a mean value of viable tumor cells for each patient. 
 
6.2 Secondary Endpoints 
 
•      Toxicity (assessed by the NCI CTCAE version 5) 
•      Peri-operative morbidity and mortality 
•      Response rates to induction treatment (by RECIST version 1.1) (1) 
•      Recurrence-free survival and Overall survival 
•      Survival rates at 12, 18 and 24 months 
•      To correlate major pathologic response with recurrence-free and overall survival 
•      Complete resection (R0) rate 
•      Pathologic complete response (pCR) in resected tumor specimens 
•      To correlate response assessed by imaging studies with outcomes (both 
major pathologic response to treatment and long-term recurrence-free 
survival) 
•      CD8+ TILs in resected tumor tissues of patients treated with M7824 
Quantification of CD8+ TILs will be assessed by counting the cells positive for staining with an 
anti-CD8 antibody by immunohistochemistry and/or immunofluorescence in five random 
square areas (1 mm2 each) in both intratumoral and peritumoral compartments using 
anautomated system. 
 
6.3 Exploratory Endpoints 
An important aspect of this trial is to identify novel prognostic and predictive markers present at 
diagnosis, and to determine modulation of markers by induction M7824 monotherapy in order to 


25 
Clinical Study Protocol 9.0                                                      
MDA Cancer Center 
Bintrafusp Alpha- M7824                    
 
 15 June 2020 
 
 
inform future translational studies. As such, blood, stools, tumor tissue and adjacent normal 
lung tissues will be collected throughout the study period. The markers to be assessed in 
these 
specimens (likely with the use of high throughput technology) will be determined according to 
the best scientific knowledge and technology available at the time of batch analysis. 
Correlative studies will be interpreted as hypothesis- generating data, to be validated in 
subsequent trials. Candidate markers to be evaluated include (but are not restricted to): 
 
•    PD-L1 expression in tumor tissue 
• 
Multi-region next generation DNA and/or RNA sequencing in tumor tissue 
(including whole exome and/or whole genome sequencing) and in blood/normal 
tissue, so that tumor heterogeneity and mutational load can be correlated with 
efficacy of immunotherapy and/or other correlative markers 
• 
Immunophenotyping or characterization of the immune cell subsets in tumor 
tissue, including markers of T cell exhaustion (CD3, PD-1, CD4, CD8, CTLA-4, 
CD45), T cell activation (CD3, CD28, CD44, CD8, CD62L, CD45), T regulatory cells 
(CD3, FOXP3, CD8, CD4, CD25, CD45), T cell function (CD3, IFN-gamma, CD4, 
CD8, IL10, CD45), antigen presenting cells (CD11B, CD11C, GR-1, CD86, PD-L1, 
CD45), as well as CD20, Ki67, granzyme B, IFN-γ, TGF-beta, GATA-3, RORgt, BCL2 
(thus allowing for estimation of T cell activation, and Th1/Th2/Th17 bias), as well as 
CD68 and other markers relevant to immune profiing. 
• Expression of immunoregulatory and co-stimulatory markers in TILs by flow 
cytometry, including, but not limited to, PD1, CTLA4, LAG3, 41BB, and TCR zeta 
chain 
• RNA and protein expression in tumor and adjacent normal 
tissue, including assessment of immune/inflammatory pathways 
• Immunophenotyping or characterization of the immune cell subsets in the 
periphery, including, but not limited to, T cells, B cells, NK cells, or subpopulations 
of the aforementioned immune cell types 
• Single cell genomics in tumor (including tumor positive nodes, where available) 
and adjacent normal tissue 
• Serum soluble factors, including IFN-gamma and interferon inducible factors (such 
as CXCL9 and CXCL10), PD-L1, PD-1, anti-tumor antibodies, microRNAs (such 
as miR-513, and miR19b), IL-12, TNFα, IL-10, TGF-β, VEGF, IL-6, IL-8, IL-17, IL-
18, C-reactive protein and, as well as other cytokines, chemokines, inflammatory 
factors and immune mediators T cell receptor repertoire sequencing in tumor 
tissue and the periphery 
• Next generation sequencing of cell-free circulating DNA 
• Immunopeptidome analysis 
• Enteric microbiome analysis 
• CT imaging analysis 
• To correlate blood, tissue, and stool-based biomarkers with efficacy and toxicity 


26 
Clinical Study Protocol 9.0                                                      
MDA Cancer Center 
Bintrafusp Alpha- M7824                    
 
 15 June 2020 
 
 
6.4 Additional assessments 
In addition to the endpoints described above, post-treatment TILs will also be isolated, 
expanded and evaluated for anti-tumor activity in vitro. TILs may also be stored for future re- 
infusion into patients that develop disease recurrence as part of a separate clinical trial. We 
hypothesize that the efficiency of TIL isolation and efficacy of adoptive T-cell therapy will be 
 
improved when cells are collected post exposure to checkpoint inhibitors, thus providing further 
rationale for developing induction immunotherapy strategies in resectable NSCLCs. 


27 
Clinical Study Protocol 9.0                                                      
MDA Cancer Center 
Bintrafusp Alpha- M7824                    
 
 15 June 2020 
 
 
7. ETHICAL CONSIDERATIONS 
The study will be conducted in accordance with Good Clinical Practice (GCP), as defined by the 
International Conference on Harmonization (ICH), WHO and any local directives, and In 
compliance with the protocol. 
 
The protocol, any amendments, and the subject informed consent will receive Institutional 
Review Board/Independent  Ethics Committee (IRB/IEC)  approval/favorable  opinion before 
initiation of the study. 
 
8. STUDY DESIGN AND PLAN 
 
8.1 Modular design of neoadjuvant signal-finding study platform 
Given the promising activity and safety demonstrated by neoadjuvant nivolumab, several 
immunotherapy-based regimens are now being tested in the neoadjuvant setting in phase 2 
studies using the MPR as primary endpoint of efficacy. It follows that the best approach to 
expedite the evaluation of novel and active therapeutic strategies that merit further  
investigation in larger randomized trials, would be a modular platform clinical trial of single arm, 
signal-finding and efficacy-testing studies. M7824 has demonstrated promisingly clinical efficacy 
in NSCLC compared to prior immunotherapies, and therefore will be provide the backbone for 
this trial. Based on this modular design, upon completion of a proposed single arm study, a 
follow-on evaluation could result in either a randomized comparison, if a signal of activity is 
observed’ or the launch of another single arm study evaluating a new immunotherapy 
combination, if the proposed study fails to demonstrate a signal of activity. A new arm will be 
launched based on emerging data in a protocol amendment. 
 
8.2 Study Plan 
This is an open label, phase 2 platform study with modular design testing the experimental agent 
M7824 in the neoadjuvant setting. We  will start investigating M7824 monotherapy induction 
treatment in patients with resectable NSCLC, with the primary objective to determine the MPR in 
each arm, and compare it not between arms, but to the benchmark from historical controls of 
neoadjuvant chemotherapy. 
After confirmation of eligibility criteria, patients will be enrolled in Arm A. Sequential arms 
investigating induction M7824-based strategies may be added after completion of 
enrollment in Arm A.


28 
Clinical Study Protocol 9.0                                                      
MDA Cancer Center 
Bintrafusp Alpha- M7824                    
 
 15 June 2020 
 
Arm A — M7824 monotherapy 
 
 
9. TREATMENT 
 
9.1 Induction Treatment 
Patients will receive induction treatment, as follows: 
Arm A: M7824 1200 mg intravenously (IV) on days 1, 15, and 29 
 
 
9.2 Surgery 
Surgery will be performed after completion of induction therapy. It is strongly recommended 
that 3 doses of M7824 (Arm A) are administered prior to surgery. However, less than 3 
doses of M7824 will be allowed in case of excessive toxicities or other reasons identified by 
the treating physician that may lead to an unfavorable benefit/risk ratio of proceeding with 
therapy as planned per protocol, after discussing the case with the principal investigator. 
 
There must be at least 4 to 6 weeks M7824-free interval before surgery (i.e., surgery will only be 
performed at least 4 to 6 weeks after the last dose of M7824, unless there is a strong clinical 
indication to perform surgery sooner, in the opinion of the treating physician). It is strongly 
recommended that surgery be performed within 4 to 6 weeks after the last dose of M7824 
induction therapy. 
 
The operative approach (thoracoscopy versus thoracotomy) and the extent of surgical resection 
will be based on the treating surgeon’s judgment and may include wedge resection, 
segmentectomy, lobectomy, or pneumonectomy with mediastinal lymph node dissection of nodal 
stations 4, 7, 8, 9, 10, 11-14 for right sided resections, and nodal stations 5, 6, 7, 8, 9, 10, 11-14 
for left sided resection. 
 
9.3 Post-operative (Adjuvant) Systemic Therapy 
Since the primary efficacy endpoint of this study is major pathologic response (which will be 
assessed at the time of surgery), mandatory use or mandatory prohibition of post-operative 
(adjuvant) systemic therapy will not be defined by this protocol. Patients may receive adjuvant 
systemic therapy at the discretion of the treating physician. For patients with stage IB (with tumor 
size 4 cm or greater), II, and III, at least 3 cycles of adjuvant cisplatin- based chemotherapy are 
recommended. In case adjuvant systemic therapy is used, this information will be captured by 
retrospective chart review and may be used for interpretation of analysis of long-term treatment 
outcomes. 
 
9.4 Post-operative (Adjuvant) Radiation Therapy 
Since the primary efficacy endpoints of this study is major pathologic response (which will be 
assessed at the time of surgery), mandatory use or mandatory prohibition of post-operative 
(adjuvant) radiation therapy will not be defined by this protocol. Post-operative radiation therapy 


29 
Clinical Study Protocol 9.0                                                      
MDA Cancer Center 
Bintrafusp Alpha- M7824                    
 
 15 June 2020 
 
 
 
will be delivered according to institutional guidelines and the treating physician’s best judgement, 
preferably within 6 weeks of surgical resection or completion of adjuvant systemic therapy 
(whichever is longer). While radiation therapy is not formally required per protocol, it is strongly 
suggested that the following principles of radiation therapy be followed: 
 
• 
Consider post-operative radiation therapy in patients with pathologic confirmation of 
mediastinal lymph node involvement by cancer either before or after induction treatment. 
• 
Consider post-operative radiation therapy in patients with positive margins at surgical 
resection. 
• 
When recommended, deliver either photon- or proton-based external beam radiation 
therapy between 50-66 Gy depending on the completeness of tumor resection. Typically 
50 Gy in 25 fractions is given for R0 resection, 60 Gy in 30 fractions for R1, and 66 Gy in 
33 fractions for R2 resection. The final dose will be left up to the treating radiation 
oncologist. 
 
In case adjuvant radiation therapy is used, this information will be captured by retrospective 
chart review and may be used for interpretation of analysis of long-term treatment outcomes. 
 
10 ELIGIBILITY CRITERIA 
 
All eligibility criteria must be met prior to initiating treatment. 
 
10.1 Inclusion Criteria 
1. Age > 18 years 
2. Histologically or cytologically confirmed previously untreated NSCLC. If a diagnostic 
biopsy is available, a pre-treatment biopsy is not required. Patients with a suspected 
lung cancer are eligible, but pathology must be confirmed prior to initiating treatment 
on study. Neuroendocrine carcinomas (e.g. SCLC, large cell neuroendocrine 
carcinoma, atypical carcinoid, carcinoid) are not eligible. Non-small cell carcinomas 
with neuroendocrine differentiation are eligible. 
3. Patients with stage I-IIIA disease and IIIB (T3N2 only, and N2 single station), 
according to AJCC 8th edition, are eligible for arm A of the study. Patients with 
stage III, N2 single station, must not have more than one mediastinal lymph node 
station involved by tumor. 
4. All patients must have lymph node evaluation of contralateral stations 2 and/or 4 to 
exclude N3 disease. 
5. The patient must be a suitable candidate for surgery, in the opinion of the treating 
physician. 
6. Predicted FEV1 ≥ 50% 
7. Predicted DLCO ≥ 50% 
8. Signed and dated written informed consent must be provided by the patient prior to 
admission to the study in accordance with ICH-GCP guidelines and to the local 


30 
Clinical Study Protocol 9.0                                                      
MDA Cancer Center 
Bintrafusp Alpha- M7824                    
 
 15 June 2020 
 
 
 
legislation 
9. ECOG performance status score 0-1 
10. Patients must have organ and marrow function as defined below: 
9 
a. Absolute neutrophil count (ANC): ≥1.5 X 10 /L 
b. Hemoglobin: ≥9.0 g/dL 
9 
c. Platelets ≥100 X 10 /L 
d. Total bilirubin: ≤ 1.5 X ULN (except subjects with Gilbert Syndrome, who can have 
total bilirubin < 3.0 mg/dL) 
e. AST and ALT: ≤3 X ULN 
1 
f. 
Creatinine: ≤1.5 X ULN or Calculated creatinine clearance : ≥50 mL/min or 24-hour 
urine creatinine clearance: ≥50 mL/min 
1 
Cockcroft-Gault formula for creatinine clearance calculation: 
Female CrCl = (140 - age in years) x weight in kg x 0.85 
72 x serum creatinine in mg/dL 
Male CrCl = (140 - age in years) x weight in kg x 1.00 
72 x serum creatinine in mg/dL 
 
10.2 Exclusion Criteria 
1. Mixed SCLC and NSCLC histology. 
2. Major surgery within 4 weeks prior to the first dose of study intervention 
3. Thoracic RT of > 30 Gy within 6 months prior to the first dose of study intervention. 
4. Prior systemic therapy, including treatment with anti-PD-1/PD-L1 therapies and M7824, for 
treatment of the current lung cancer. 
5. Currently receiving cancer therapy (chemotherapy, radiation therapy, immunotherapy, or 
biologic therapy) or investigational anti-cancer drug. 
6. Previous malignant disease (other than the target malignancy to be investigated in this 
study) within the last 2 years. Participants with a history of cervical carcinoma in situ, 
superficial or noninvasive bladder cancer, or basal cell or squamous cell carcinoma in 
situ previously treated with curative intent are NOT excluded. Participants with other 
localized malignancies treated with curative intent need to be discussed with the PI of 
the study. 
7. Receipt of any organ transplantation, including allogeneic stem-cell transplantation, but 
with the exception of transplants that do not require immunosuppression (eg, corneal 
transplant, hair transplant). 
8. Has interstitial lung disease (ILD) OR has had a history of pneumonitis that has required 
oral or IV steroids 
9. Pregnant or lactating female: 
ï 
Women of childbearing potential (WOCB) must have a negative serum or urine 
pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 
72 hours prior to the start of immunotherapy. 
ï 
Women of childbearing potential is defined as any female who has experienced 
menarche and who has not undergone surgical sterilization (hysterectomy or 


30 
Clinical Study Protocol 9.0                                                      
MDA Cancer Center 
Bintrafusp Alpha- M7824                    
 
 15 June 2020 
 
 
 
bilateral oophorectomy) or who is not postmenopausal. Menopause is defined clinically as 12 
months of amenorrhea in a woman over 45 in the absence of other biological or physiological 
causes. 
10. Unwillingness or inability to follow the procedures required in the protocol. 
11. Any serious or uncontrolled medical disorder that, in the opinion of the investigator, may 
increase the risk associated with study participation or study drug administration, impair 
the ability of the subject to receive protocol therapy, or interfere with the interpretation of 
study results. Participants with history of bleeding diathesis or recent major bleeding 
events considered by the Investigator as high risk for investigational drug treatment are 
also excluded. 
12. Subjects with active, known or suspected autoimmune disease. Subjects with vitiligo, 
type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only 
requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions 
not expected to recur in the absence of an external trigger are permitted to enroll. 
13. Subjects with a condition requiring systemic treatment with either corticosteroids (>10 mg 
daily prednisone equivalents) or other immunosuppressive medications within 14 days of 
study drug administration. Inhaled or topical steroids and adrenal replacement doses > 10 
mg daily prednisone equivalents are permitted in the absence of active autoimmune 
disease. 
14. Subjects are permitted to use topical, ocular, intra-articular, intranasal, and inhalational 
corticosteroids (with minimal systemic absorption). Physiologic replacement doses of 
systemic corticosteroids are permitted, even if > 10 mg/day prednisone equivalents. A 
brief course of corticosteroids for prophylaxis (e.g., contrast dye allergy) or for treatment 
of non-autoimmune conditions (e.g., delayed-type hypersensitivity reaction caused by 
contact allergen) is permitted. 
15. History of positive hepatitis B virus surface antigen (HBV sAg) or hepatitis C virus 
ribonucleic acid indicating acute or chronic infection. 
16. History of positive human immunodeficiency virus or known acquired immunodeficiency 
syndrome. 
17. History of severe hypersensitivity reaction to any monoclonal antibody and/or to study 
drug components, any history of anaphylaxis, or recent (within 5 months) history of 
uncontrolled asthma. 
18. Serious illness or concomitant non-oncological disease such as neurologic, psychiatric, 
infectious disease or laboratory abnormality that may increase the risk associated with 
study participation or study drug administration and in the judgment of the investigator 
would make the patient inappropriate for entry into the study. 
19. Vaccine administration within 4 weeks of M7824 administration. Vaccination with live 
vaccines while on trial is prohibited. Administration of inactivated vaccines is allowed (for 
example, inactivated influenza vaccines). 
20. Patients who are sexually active, with preserved reproductive capacity, and unwilling to 
use a medically acceptable method of contraception (e.g. such as implants, injectables, 
combined oral contraceptives, some intrauterine devices or vasectomized partner for 
participating females, condoms for participating males) during and after the trial as 
detailed below: 


31 
Clinical Study Protocol 9.0                                                      
MDA Cancer Center 
Bintrafusp Alpha- M7824                    
 
 15 June 2020 
 
 
 
a. WOCBP should use an adequate method to avoid pregnancy for 65 days  
after the last dose of investigational drug. 
b. Men who are sexually active with WOCBP must use any contraceptive method 
with a failure rate of less than 1% per year. 
c. Men receiving immunotherapy and who are sexually active with WOCBP will 
be instructed to adhere to contraception for a period of 125 days after the last 
dose of investigational product. 
d. Women who are not of childbearing potential as well as azoospermic men do 
not require contraception. 
21. Psychological, familial, sociological or geographical factors potentially hampering 
compliance with the study protocol and follow-up schedule. 
 
11. STUDY ASSESSMENTS 
 
11.1 Performance status 
The performance status of all patients will be graded according to the ECOG PS scale. 
 
11.2 Clinical Laboratory Tests 
 
Clinical laboratory tests will be performed to assess eligibility for enrolment and will be repeated 
according to the schedule of assessment. Laboratory tests can be repeated more frequently, if 
clinically indicated. 
 
 
11.3 Symptoms and toxicity assessment 
 
The symptoms and adverse events of all patients will be graded at scheduled intervals according 
to the NCI CTCAE, v5.0. Patients will be monitored continuously throughout the study for the 
occurrence of adverse events. Planned medical interventions (e.g., planned surgical resection) 
will not be considered an adverse event. For the purpose of this study, adverse events that in the 
opinion of the treating investigator are related to planned surgical procedure (e.g., usual pain, 
usual bleeding, intra- or post-operative electrolyte imbalances and other clinically insignificant 
laboratory abnormalities) will not be captured and/or reported. Unexpected surgical complications 
will be retrospectively reviewed at the end of treatment assessments. 
 
11.4 Radiology assessments 
 
CT chest, PET-CT, and CT brain / MRI brain will be obtained according to the study calendar included 
in the clinical trial protocol. CT chest examinations maybe obtained with dual energy modality. 
Response and progression will be evaluated in the study using the international criteria 
proposed by the RECIST committee, and preferably by the same investigator or collaborator. 
Patients enrolled to this study may also be offered optional participation in a separate IRB- 
approved protocol evaluating additional imaging modalities for NSCLC. An independent informed 
consent process will be followed for accrual to such protocol. 
 


32 
Clinical Study Protocol 9.0                                                      
MDA Cancer Center 
Bintrafusp Alpha- M7824                    
 
 15 June 2020 
 
 
11.5 Mediastinal Staging 
 
Mediastinal staging should be accomplished by obtaining at least a CT chest or PET-CT. It is 
strongly recommended that patients with suspicious mediastinal lymph node involvement by 
PET-CT and/or CT chest undergo a mediastinoscopy or endobronchial ultrasound with biopsies for 
more detailed mediastinal  staging.  It is also strongly recommended that patients with clinical N1 
disease and/or central tumors undergo mediastinoscopy or endobronchial ultrasound with 
biopsies. Patients with clinical N0 disease and a peripheral lesion may not warrant 
mediastinoscopy or endobronchial ultrasound with biopsies, however this will be at the discretion 
of the treating physicians. 
 
11.6 Surgical Pathology 
 
To determine the pathologic response, specimens will be grossed and processed by the 
pathologists assistant under the supervision of the thoracic pathologist to include gross measurement 
of specimen and residual tumor size. At least 1 block/1 cm of tumor will be submitted (average 
of  5-10 blocks/patient). All slides prepared from blocks taken from each specimen will be 
reviewed by the thoracic pathologist, The surgical specimens will then be evaluated 
histopathologically as per routine surgical pathology standard to include tumor classification and 
evaluation of lymph node and margin status. In addition, specimens will be evaluated for pathologic 
complete response and quantification of percentage of viable tumor cells. Pathologic staging is 
performed as per AJCC staging for lung cancer (8th edition). 
 
11.7 Correlative Research: Biomarkers profiling 
 
All patients consented to collection and analysis of biospecimen for correlative research will have 
their respective sample(s) collected as outlined below. All biospecimen will utilize our institution’s 
approved biospecimen secured tracking platform such as BIMS or Prometheus. With each 
patient’s sample collection, unique sample identifier labels are generated with a 2-D barcode to 
link/associate with the specific biospecimen collection. For each biospecimen type, a 
collection/processing/storage SOP is generated. All tissue and microbiome samples will be 
stored at ITB until analysis. All blood samples will be processed and stored in Drs. Tran and 
Cascone’s Lab until analysis. At time of analysis, distribution of specific sample matrices to 
specified collaborator as described below. Again, the biospecimen tracking system will be used 
to provide the provision of the status in real-time of each and every collected, processed, and 
distributed biospecimen. 
 
11.7.1   Tumor tissue collection, processing and analysis 
11.7.1.1 
Pre-Surgery 
Archival tissue samples will be collected for histopathological examination and biomarkers, when 
available (at least 15 to 20 unstained slides and/or a tissue block are preferred). For patients 
without archival specimen, a new baseline tumor tissue sample from the primary tumor may be 
collected for histopathological examination and biomarkers. Samples will be obtained by an 
outpatient image-guided biopsy procedure (preferably core biopsy) or bronchoscopy. These 


33 
Clinical Study Protocol 9.0                                                      
MDA Cancer Center 
Bintrafusp Alpha- M7824                    
 
 15 June 2020 
 
specimens should be fixed in 10% formalin, preferably immediately and not more than 1 (one) 
hour after excision. Fixed biopsy samples will be processed for paraffin-embedding according to 
the Institutional Standard Operating Procedures. The paraffin blocks and slides should be 
labeled with the protocol number and the patient’s unique study identification number and stored 
at room temperature. A portion of the specimen obtained (or a second biopsy) will also be 
embedded in optimal cutting temperature compound and/or RNA later and/or culture media 
immediately after received and not more than 1 (one) hour after excision, frozen, and processed 
and/or stored at -80°C until analysis. All samples will be processed by and stored in ITB at -80°C 
should be placed in appropriate containers, labeled with the protocol number and the patient’s 
unique study identification number. Tissue obtained during mediastinal staging may also be 
collected for biomarker evaluation. 
 
11.7.1.2 
Surgery 
Tumor tissue will also be obtained at surgical resection and will be directly delivered to the 
pathology department to be processed as per Pathology SOP. The recommended procedure for 
obtaining the tissue specimens is as follows: a portion of the resected tumor tissue will be fixed 
in 10% formalin immediately after received and not more than 1 (one) hour after   excision. Fixed 
samples will be processed for paraffin-embedding according to the Institutional Standard 
Operating Procedures. The paraffin blocks and slides should be labeled with the protocol 
number and the patient’s unique study identification number and stored at room temperature. 
Another portion of the tumor specimen (preferably at least one sample ≥ 2 mm3 or 100 mg) will 
be embedded in optimal cutting temperature compound and/or RNA later and/or culture media 
immediately after received and not more than 1 (one) hour after excision, frozen and 
processed by and stored at -80°C in ITB until biomarkers analysis.  
 
11.7.1.3    Tissue Research Correlatives Analysis 
 
The following plan is for residual tissue collected for research of correlative analysis ONLY 
after all standard pathlological clinical care has been completed.  All residual tissue samples 
will be processed and stored in ITB until biomarkers analysis. The residual tumor tissues with or 
without adjacent lung tissue samples placed in culture media immediately after received will be 
processed for single cell suspension for single cell genomics and other biomarkers as specified 
below (37). Each cell will be bar-coded using 10x genomics technology (or other equivalent 
technologies) and libraries (RNA, DNA, or epigenomics) for sequencing. The sequenced data will 
be analyzed and we plan to associated sequencing data with clinical parameters. 
Based on pathologist’s assessment, clinical practice and discussion with pathology 
collaborator, if there are any residual normal lymph node tissue uninvolved by tumor may also 
be collected and processed by and stored in ITB until biomarker analysis. Additional analysis 
with new technical advancement and technologies  in collaborative efforts may occur; these will 
be completed according to institutional’s   guidelines and approvals such as alliance or 
agreements with outside vendor(s). 
Analyzed at UTMDACC labs based on availability of tumor tissue at each timepoint from pre-
surgery (archival, biopsy) and at surgical resection: 
a) whole exome (WES) and RNA sequencings: Ignacio Wistuba, Tina Cascone 
b) tumor infiltrating lymphocytes (TIL): Chantale Bernatchez 
c) single-cell RNA sequencing: Tina Cascone 
d) T-cell receptors repertoire (TCR): Tina Cascone


34 
Clinical Study Protocol 9.0                                                      
MDA Cancer Center 
Bintrafusp Alpha- M7824                    
 
 15 June 2020 
 
 
11.7.2 Blood-based biomarkers 
 
Blood will be collected (60 mL) – 4 x 10 mL sodium heparin, 1 x 10 mL STRECK or 
PAXGENE ctDNA, 1 x 10 mL EDTA, at scheduled intervals according to the study calendar as 
follows: 
a) prior to treatment initiation (+/- 7 days), 
b) within 7 days prior to dose #2 of M7842 
c) within 7 days prior to dose #3 of M7842 
d) at least 14 days after last dose of M7842 
e) within 8 weeks after surgery 
Blood samples collected and sent to the core laboratory to be processed and stored at -80oC or 
LN until analysis. 
All blood samples will be analyzed at UTMDACC labs based on availability of blood samples 
at each timepoint as listed above: 
a) cytokines and angiogenic factors (CAF) profiling: Hai Tran, Tina Cascone 
b) circulating tumor DNA (ct-DNA) profiling: Hai Tran, Tina Cascone 
c) circulating lymphocytes profiling: Chantale Bernatchez 
d) TCR sequencing/exome sequencing: Tina Cascone 
 
Additional analysis with new technical advancement and technologies in collaborative efforts may 
occur; these will be completed according to institutional’s guidelines and approvals such as alliance 
or agreements with outside vendor(s). 
 
11.7.3 Stool-based biomarkers 
 
Patients will provide their stool samples as detailed in the study calendar follows: 
a) prior to treatment initiation (+/- 7 days) 
b) at least 14 days after last dose of M7842 
Stool collection will be performed with commercially available collection kits OMNIgene-Gut 
from DNA Genotek company. These kits will be provided to patients at no cost. The collected 
stool samples will be stored by ITB until analysis 
a) microbiome profiling: Boris Sepesi, Tina Cascone. 
 
 
11.7.4 CT imaging-based biomarkers 
 
The imaging data will be saved to retrospectively reconstruct and post-process the images for 
further investigating advanced quantitative algorithms with the goal to improve detection and 
characterization of disease along with potential biomarkers to assess response to immune 
checkpoint blockade. 
 
11.7.5 Pharmacokinetics and Anti-Drug Antibody 
 
To evaluate population steady-state concentrations (PK) and potential development of anti-drug 
antibody (ADA), blood will be collected at the following timepoints as sponsor’s lab manual. 
 
 


34 
Clinical Study Protocol 9.0                                                      
MDA Cancer Center 
Bintrafusp Alpha- M7824                    
 
 15 June 2020 
 
 
Pharmacokinetics Samples: 
a) PK 1 - Dose #1 M7824: Prior to infusion of Dose #1 (60 minutes prior to infusion) 
b) PK 2 - Dose #1 M7824: immediately after infusion (within 60 minutes after infusion) 
c) PK 3 - Dose #2: Prior to infusion Dose #2 (60 minutes prior to infusion) 
d) PK 4 - Dose #3 M7824: Prior to infusion Dose #3 (60 minutes prior to infusion) 
e) PK 5 - Dose #3 M7824: immediately after infusion Dose #3 (within 60 minutes after infusion) 
f) 
PK 6 - at least 14 days after Dose #3 
 
Anti-Drug Antibody samples: 
g) ADA 1 - Dose #1 M7824: Prior to infusion of Dose #1 (60 minutes prior to infusion) 
h) ADA 2 - Dose #3 M7824: Prior to infusion Dose #3 (60 minutes prior to infusion) 
i) 
ADA 3 - at least 14 days after Dose #3 
 
 
12. 
Study Intervention(s) Preparation, Handling, Storage, and Accountability 
 
Further guidance and information for the preparation, handling, and storage of study 
intervention(s) are provided in the Pharmacy Manual. 
 
The Investigator and MD Anderson Cancer Center are responsible for study 
intervention accountability, reconciliation, and record maintenance (ie, receipt, 
reconciliation, and final disposition records). 
 
• Upon receipt of the study intervention(s), the Investigator or designee must 
confirm appropriate temperature conditions have been maintained during 
transit and any discrepancies are reported and resolved before use. Also, the 
responsible person will check for accurate delivery and acknowledge receipt by 
signing or initialing and dating the appropriate document and returning it to the 
location specified. A copy will be archived for the Investigator Site File. 
• Only participants enrolled in the study may receive study intervention(s) and 
only authorized site staff may supply or administer it. All study intervention(s) 
must be stored in a secure, environmentally-controlled, an monitored (manual 
or automated) area, in accordance with the labeled storage conditions, and with 
access limited to the Investigator and authorized site staff. 
• Dispensing will be recorded on the appropriate accountability forms so that 
accurate records will be available for verification at each monitoring visit. 
• Study intervention(s) accountability records at the study site will include the 
following: 
o Confirmation of receipt, in good condition and in the defined 
temperature range. 
o The inventory provided for the clinical study and prepared at the site. 
o The dose(s) each participant used during the study. 
o The disposition (including return, if applicable) of any unused study 
intervention(s). 
o Dates, quantities, batch numbers, container numbers, expiry dates, 
formulation (for study interventions prepared at the site), and the 


34 
Clinical Study Protocol 9.0                                                      
MDA Cancer Center 
Bintrafusp Alpha- M7824                    
 
 15 June 2020 
 
participant numbers. 
• The Investigator site will maintain records, which adequately documents that 
participants were provided the doses specified in this protocol, and all study 
intervention(s) provided were fully reconciled. 
• Unused study intervention(s) must not be discarded or used for any purpose 
other than the present study. No study intervention that is dispensed to a 
participant may be re-dispensed to a different participant. 
• Destruction of used and unused study intervention(s) should be performed at 
site if allowed by local law only after Sponsor authorization. 
 
13 Study Intervention Compliance 
 
In this study, participants will receive study intervention at the investigational site. Well- 
trained medical staff will monitor and perform the study intervention administration. The 
information of each administration including the date, time, and dose of study 
intervention will be recorded on the electronic Clinical Oncology research System (DMI). 
The Investigator will make sure that the information entered into the system regarding 
study intervention administration is accurate for each participant. Any reason for 
nonadherence should be documented. Nonadherence is defined as a participant 
missing > 1 cycle of study intervention for nonmedical reasons and barring any 
extenuating circumstances in the opinion of the Investigator. Extenuating circumstances 
should be documented, and when possible, discussed with the Sponsor in advance. If 1 
cycle was missed and the interval between the subsequent treatment cycle and the last 
administered treatment cycle is longer than 4 weeks for nonmedical reasons, the 
criterion for insufficient adherence is met as well. 
Consequences of noncompliance may lead to discontinuation of study interventions as 
described in the dedicated section. In case of overdose, see section below. 
 
13.1 Overdose 
 
Experience with overdose of M7824 is not available. In case of overdose symptomatic 
treatment has to be applied, there are no known antidotes for the compound. 
 
For this study, any dose of immunotherapy greater than 2 times more than the planned dose 
administered within a 24-hour time period will be considered an overdose. 
In event of overdose, infusion should be discontinued and participants should be observed 
closely for any signs of toxicity. Supportive treatment should be provided if clinically indicated. If 
an AE occurs resulting from overdose, it should follow SAE reporting criteria. 
If an incidence of overdose occurs meeting the protocol-defined definition without any 
association of symptoms or laboratory abnormalities, then it should be reported as a 
non-serious AESI, using the terminology “accidental or intentional overdose” without 
adverse effects 
 
14. Concomitant Therapy 
 
Record in the electronic system, the EMR, all concomitant therapies (e.g., medicines 
or nondrug interventions) used from the time the participant signs the informed 


34 
Clinical Study Protocol 9.0                                                      
MDA Cancer Center 
Bintrafusp Alpha- M7824                    
 
 15 June 2020 
 
consent until completion of the study, including any changes. For prescription and 
over-the-counter medicines, vaccines, vitamins, and herbal supplements, record the 
name, reason for use, dates administered, and dosing information. 
 
14.1 Permitted Medicines 
 
The only permitted medications are the following: 
 
1. Any medications (other than those excluded by the exclusion criteria or the 
prohibited medicines) that are considered necessary for the participants’ welfare and 
will not interfere with the study intervention may be given at the Investigator’s 
discretion. 
2. Other drugs to be used for prophylaxis, treatment of hypersensitivity reactions, and 
treatment of fever or flu-like symptoms are described as part of precautions 
 
Any medicines that are considered necessary to protect the participant’s welfare in 
emergencies may be given at the Investigator’s discretion, regardless if it results in a 
protocol deviation. 
 
14.2 Prohibited Medicines 
 
As stated for the exclusion criteria, participants must not have had prior systemic 
cytotoxic chemotherapy for their NSCLC OR any antibody or drug targeting T-cell 
coregulatory proteins (immune checkpoints) such as anti-PD-1, anti-PD-L1, or anti- 
CTLA-4 antibody OR concurrent anticancer treatment including: 
• Cytoreductive therapy 
• Radiotherapy delivered for non-palliative indications 
• Use of any investigational drug as specified in Schedule of Activities. 
• Immunotherapy, immunosuppressive drugs (that is, chemotherapy or systemic 
corticosteroids except for short-term treatment of allergic reactions or for the 
treatment of irAEs), or other experimental pharmaceutical products. Short-term 
administration of systemic steroid (that is, for allergic reactions or the 
management of irAEs is allowed). 
• Vaccine administration within 30 days before M7824 administration. 
• Vaccination with live vaccines while on study is prohibited. Administration of 
inactivated vaccines is allowed (for example, inactivated influenza vaccines). If 
the administration of a nonpermitted concomitant drug becomes necessary 
during the study, the participant will be withdrawn from study intervention and 
should complete the End-of-Treatment Visit and be followed for survival. 
 
14.3 Permitted/Prohibited Procedures 
 
Permitted Procedures 
Bone-directed organ-sparing radiotherapy may be administered for palliative and/or 
specific clinical indications during the study. The assessment of PD will be made 
according to RECIST 1.1 and not based on the necessity for palliative radiotherapy. 
The indication for palliative radiotherapy should be documented in the patient medical 


34 
Clinical Study Protocol 9.0                                                      
MDA Cancer Center 
Bintrafusp Alpha- M7824                    
 
 15 June 2020 
 
record. 
 
Prohibited Procedures 
The following nondrug therapies must not be administered during the study (or within 
28 days before enrollment): 
• Major surgery (excluding prior diagnostic biopsy and surgical resection of 
lung cancer for which patient is being treated on trial) within 4 weeks before 
the start of the study. 
` 
 
14.4 Other Interventions 
 
The following nondrug therapies must not be administered during the study: 
• Herbal remedies with immunostimulating properties (for example, mistletoe 
extract) or known to potentially interfere with major organ function (for 
example, hypericin). 
 
14.5 Dose Selection and Modification 
 
Justification for M7824 dose 
The RP2D for M7824 is 1200 mg administered as an iv infusion q2w. The selection of 
RP2D is based on the available clinical data from Phase I Study EMR200647-001 and 
Study MS200647-0008, including safety/tolerability, pharmacokinetics (PK), and 
pharmacodynamic (such as PDL1 target occupancy [TO] in PBMCs and TGFβ trapping 
in blood), as well as efficacy in 2L NSCLC cohorts from Study EMR200647- 
001. The selection of RP2D is also supported by population PK (pop PK) and 
exposure-response modeling and simulation. 
 
Safety/tolerability in Phase I 
The highest dose for M7824 tested in EMR200647-001 was 30 mg/kg, which 
corresponds to 2100 mg for a 70-kg participant (the median body weight in the current 
dataset) and to 2400 mg for an 80-kg participant (corresponding to a typical median 
body weight for solid tumor type participants) (Freshwater, 2017; Bajaj, 2017; Zhao, 
2017). Based on clinical observations, M7824 is well tolerated up to 30 mg/kg and the 
maximum tolerated dose was not reached. In addition, for the 2 dose levels evaluated 
in 2L NSCLC cohorts of Study EMR200647-001 (500 and 1200 mg iv q2w), there was 
no apparent dose-dependency in observed toxicities. 
 
Preclinical pharmacology and Phase I dose escalation PK and pharmacodynamics 
The PK dose-proportionality, peripheral PD-L1 TO/TGFβ trapping from the dose 
escalation phase of Study EMR200647-001 (at doses of 1, 3, 10, 20, and 30 mg/kg 
q2w), and preclinical pharmacology studies with M7824 supporting the RP2D of 1200 
mg q2w are described in the Investigator’s Brochure. In brief, the dose of 1200 mg q2w 
(corresponding to approximately 17 mg/kg for a 70-kg participant and to 15 mg/kg for 
an 80-kg participant) is within the efficacious dose range predicted based on modeling 
of preclinical pharmacology data in tumor-bearing mice. In participants with solid 
tumors, full pharmacological activity on PD-L1 in PBMC on TGFβ1 and 


34 
Clinical Study Protocol 9.0                                                      
MDA Cancer Center 
Bintrafusp Alpha- M7824                    
 
 15 June 2020 
 
TGFβ3 (in blood) were observed at doses ≥ 3 mg/kg. It is important to consider that full 
pharmacological activity, including PD-L1 TO and TGFβ trapping is required at the 
tumor site, for which no data are available for M7824 in humans. It is likely that doses 
higher than 3 mg/kg q2w are required for full pharmacological activity at the tumor site 
(refer to the M7824 IB v4). 
 
Flat dose rationale 
To achieve less variability in exposure, mitigate the risk of dosing errors, reduce the 
time necessary for dose preparation, and reduce drug wastage compared with th 
weight-based dosing, a flat dose approach was adopted for expansion phases of Phase 
I clinical studies. The flat dosing approach for Phase II is supported by pop PK 
modeling and simulation using data from 350 participants from the 2 Phase I clinical 
studies of M7824 in multiple solid tumor types, which showed that although body weight 
was found to be a covariate for clearance, the estimated magnitude of the body weight 
exponent on clearance is < 0.5, predicting less exposure variability from flat dosing than 
that from body weight-based dosing (Wang, 2009). 
Accordingly, simulations of AUC and Ctrough showed that variability in exposure was 
indeed slightly lower for flat dosing compared with weight-based dosing. 
 
 
Preliminary efficacy and exposure-response analysis 
Exposure-response and exposure-PFS assessments are based on data from 2L 
NSCLC 80 participants that were administered either 500 or 1200 mg of M7824 iv q2w) 
(n = 40 per cohort). As of the data cutoff of 25 October 2017, numerically higher 
confirmed ORR was observed in the 1200-mg cohort (25%), compared with the 500- 
mg cohort (20%) and the only CR was in the 1200-mg cohort. Similarly, there was a 
trend of longer PFS and OS in the 1200-mg cohort compared with the 500-mg cohort. 
 
14.6 Study Intervention after the End of the Study 
 
After a participant has completed the study at the postsurgical visit (approximately 
within 8 weeks after surgery) or has withdrawn early, participants may receive the care 
they and their physicians agree upon. Participants will be followed for survival and AEs. 
The overall end of the study is defined as when all protocol-defined assessments have 
been completed. 
 
 
14.7 Special Precautions 
 
As a part of precautionary safety measures, a risk management guidance is defined 
for M7824 treatment for IRRs and irAEs, which may arise due to the mAb inhibition of 
PD-L1. 
 
14.7.1 Infusion-related Reactions Including Immediate Hypersensitivity 
Infusion-related reactions including immediate hypersensitivity are defined in the 
dedicated section below and are important identified risks for M7824. 


34 
Clinical Study Protocol 9.0                                                      
MDA Cancer Center 
Bintrafusp Alpha- M7824                    
 
 15 June 2020 
 
 
Infusion reactions may vary in manifestation and timing, and signs and symptoms usually 
develop during or shortly after drug infusion which generally resolves completely within  
24 hours of completion of infusion. Infusion reactions like cytokine release syndrome may 
manifest similar signs and symptoms of an immediate hypersensitivity/allergic reaction. 
 
The study intervention will be administered on an outpatient basis. As a routine precaution, for the 
first 2 infusions, all participants enrolled in this study must be observed for 2 hours post end of 
infusion, in an area with resuscitation equipment and emergency agents. At all times during 
M7824 treatment, immediate emergency treatment of an IRR or a severe hypersensitivity 
reaction according to institutional standards must be assured. In order to treat possible 
hypersensitivity reactions like anaphylactic reactions, for instance, dexamethasone 10 mg and 
epinephrine in a 1:1000 dilution or equivalents should always be available along with equipment 
for assisted ventilation. If no IRRs are observed during the first 2 infusions, the mandated 2-hour 
post infusion observation time is no longer required. 
 
Premedication with an antihistamine and with paracetamol (acetaminophen) (for example,  
25 to 50 mg diphenhydramine and 500 to 650 mg paracetamol [acetaminophen] iv or oral 
equivalent) approximately 30 to 60 minutes prior to each dose of M7824 is mandatory for the 
first 2 infusions, after which premedication is optional and at the discretion of the Investigator. 
Steroids as premedication are not permitted. If Grade ≥ 2 infusion reactions are seen during the 
first 2 infusions, premedication should not be stopped. 
 
An assessment for possible IRR should be triggered based upon the development of specific 
symptoms within 24 hours of an infusion. These possible IRRs are identified based on a list of 
Medical Dictionary for Regulatory Activities (MedDRA) preferred terms and divided into 
reactions versus signs and symptoms. 
• 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 IRRs 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 are not limited to: rigors, chills, wheezing, pruritus, flushing, rash, 
hypotension, hypoxemia, fever, dyspnea, back pain, abdominal pain, and urticaria. 


41 
Clinical Study Protocol 9.0                                                      
MDA Cancer Center 
Bintrafusp Alpha- M7824                    
 
 15 June 2020 
 
 
 
Table 2. Treatment Modification for Symptoms of Infusion-related Reactions 
 
CI-CTCAE v5.0 Grade Treatment Modification 
Treatment modifications 
Grade 1 – mild 
Mild transient reaction; infusion interruption 
not indicated; intervention not indicated. 
Increased monitoring of vital signs as 
medically indicated, presuming these 
participants are deemed medically 
stable. 
Grade 2 – moderate 
• 
Therapy or infusion interruption 
indicated but if responds promptly to 
symptomatic treatment (for example, 
antihistamines, NSAIDs, narcotics, iv 
fluids); prophylactic medications indicated 
for 
≤ 24 hours. 
Stop M7824 infusion. 
Increased monitoring of vital signs as 
medically indicated as participants are 
deemed medically stable by attending 
Investigator. If symptoms resolve 
quickly or decreased to Grade 1, 
resume infusion at 50% of original rate 
with close monitoring of any worsening 
otherwise dosing held until resolution of 
symptoms with mandated 
premedication for the next schedule. If 
worsens to Grade 3 or 4, follow 
treatment modification guidelines 
accordingly. 
Grade 3 or Grade 4 – severe or life-threatening 
• Grade 3: Prolonged (for example, not rapidly 
responsive to symptomatic medication 
and/or brief interruption of infusion); 
recurrence of symptoms following initial 
improvement; hospitalization indicated for 
clinical sequelae. 
• Grade 4: Life-threatening consequences; 
urgent intervention indicated. 
Stop the M7824 infusion immediately 
and disconnect infusion tubing from 
the participant with additional 
appropriate medical measures and 
close monitoring until 
deemed medically stable by attending 
Investigator. Hospitalization may be 
indicated. Participants will be 
permanently withdrawn immediately 
from M7824 treatment and must not 
receive any further M7824 treatment 
iv = intravenous; NCI-CTCAE = National Cancer Institute-Common Terminology Criteria for 
Adverse Event; NSAIDs = nonsteroidal anti-inflammatory drugs. 
For Grade 3 or 4 infusion-related reactions, M7824 discontinuation is mandated. For all types 
and grades of infusion reactions, details about drug physical constitution, method of 
preparation and infusion must be recorded. 
 
In the event of a Grade 2 IRR that does not improve or worsens after implementation of the dose 
modifications indicated in Table 2 (including reducing the infusion rate by 50%), the Investigator 
may consider treatment with corticosteroids and the infusion should be stopped for that day. At 
the next infusion, the Investigator may consider the addition of H2 blocker antihistamines (for 
example, famotidine or ranitidine), in addition to premedication, for select participants. However, 
prophylactic steroids are NOT permitted. At next dose, if the participant has a second IRR Grade 
≥ 2 on the slower infusion rate, with the addition of further medication 


42 
Clinical Study Protocol 9.0                                                      
MDA Cancer Center 
Bintrafusp Alpha- M7824                    
 
 15 June 2020 
 
 
 
to premedication, the infusion should be stopped and the participant removed from treatment. 
 
Hypersensitivity Reaction 
If a hypersensitivity reaction occurs, the participant must be treated according to the best 
available medical practice. A complete guideline for the emergency treatment of anaphylactic 
reactions according to the Working Group of the Resuscitation Council (United Kingdom) and 
can be found at https://www.resus.org.uk/pages/reaction.pdf. Participants should be instructed 
to report any delayed reactions to the Investigator immediately. 
 
Symptoms may include, but are not limited to: 
• Impaired airway 
• Decreased oxygen saturation (< 92%) 
• Confusion 
• Lethargy 
• Hypotension 
• Pale/clammy skin 
• Cyanosis 
 
Management of hypersensitivity includes: 
1. Epinephrine injection and iv dexamethasone 
2. Participant should be placed on cardiac, blood pressure, heart rate, and oxygen saturation 
monitor immediately 
3. Alert intensive care unit for possible transfer if required. 
 
Prophylaxis of flu-like symptoms 
For prophylaxis of flu-like symptoms, a nonsteroidal anti-inflammatory drug (NSAID), for example, 
ibuprofen 400 mg or comparable NSAID dose, may be administered 2 hours before and 8 hours 
after the start of each iv infusion. 
 
14.7.2 Immune-related Adverse Events 
 
Immune-related AEs are specific to immunotherapies and vary by organ system. Immune- 
related AEs are important identified risks for M7824. 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) (NCCN Guidelines®), are listed in Appendix 1. These irAEs include: pneumonitis, 
colitis, hepatitis, endocrinopathies (including hypophysitis, thyroid disorders, type 1 diabetes 
mellitus), and nephritis. 
 
General management by NCI-CTCAE v5.0 grading, as per ASCO, is listed below: 
• Grade 1: study treatment should be continued with close monitoring, with the exception of 
some neurologic, hematologic, and cardiac toxicities. 
• Grade 2: study treatment may be suspended for most Grade 2 toxicities, with consideration of 
resuming when symptoms revert to Grade 1 or less. Corticosteroids may be administered 
(initial dose of 0.5 to 1 mg/kg/d of prednisone or equivalent). 


43 
Clinical Study Protocol 9.0                                                      
MDA Cancer Center 
Bintrafusp Alpha- M7824                    
 
 15 June 2020 
 
 
 
• 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 be initiated. 
Corticosteroids should be tapered over the course of at least 4 to 6 weeks. Some refractory 
cases may require infliximab or other immunosuppressive therapy. 
• Grade 4: in general, permanent discontinuation of study treatment is recommended, with the 
exception of endocrinopathies that have been controlled by hormone replacement. 
For organ/system specific management guidelines, review ASCO guideline tables in Appendix 1. 
 
14.7.3 Potential TGFβ-mediated Skin Adverse Events 
 
Skin AEs possibly due to TGFβ inhibition, including hyperkeratosis, KA and/or cutaneous 
squamous cell carcinomas (cSCC), are important identified risks for M7824 and are described in 
Section 6.9.1. Cases of KA and cSCC have also been reported for patients under treatment with 
other checkpoint inhibitors as well (Freites-Martinez, 2017; Bednarek, 2018). 
Skin assessments are performed at Baseline and 6 weekly for all participants (see Section 1.3 
[Schedule of Activities]). A detailed medical history of genetic or iatrogenic skin conditions, skin 
type, geographical location, occupational or environmental exposure to radiation or chemicals 
will be queried. For participants experiencing a dermatologic-related AE (hyperkeratosis, KA, or 
cSCC), initial biopsy with pathology report of initial AE is expected. 
Additional excisional biopsies of suspicious lesions should occur, and management discussed 
with the Medical Monitor provided by the IND office as indicated. Dermatology consultation is 
encouraged for diagnosis, 
outcome and follow-up. 
 
14.7.4 Anemia 
Notably, there are many reasons for anemia in patients with advanced cancer, which is why a 
thorough investigation of new anemia cases of unspecified etiology is requested. 
 
General Guidance for anemia management and evaluation: 
• Participants must enter the study with hemoglobin values at least 9 g/dL. 
• All relevant hematologic testing for treatment-related anemias should be done prior to blood 
transfusion, if clinically feasible. 
• Transfusion should be performed at the discretion of the Investigator, based on clinical 
assessment and considered when participant experiences significant anemia. 
 
15 Management of Adverse Events of Interest 
 
15.1 Adverse Events of Special Interest (AESI) 
 
Adverse events of special interest are serious or nonserious AE specific to the known 
mechanism of action of the treatment drug. These events are of clinical interest, which require 
close monitoring and rapid communication for optimal management. The method of AESI 
recording and reporting will follow the guideline for AE recording and reporting (refer to Appendix 
2). Safety measures to mitigate risks of AESIs include decisions for 


44 
Clinical Study Protocol 9.0                                                      
MDA Cancer Center 
Bintrafusp Alpha- M7824                    
 
 15 June 2020 
 
 
 
Inclusion/exclusion criteria prior to study enrollment and guidance for prevention, monitoring, 
diagnostic work-up and management of potential risks, as well as guidance on study 
intervention interruption or discontinuation for study participants. 
 
Infusion-related reactions, including immediate hypersensitivity 
Any signs or symptoms experienced by participants during the infusion or any event occurring 
during or within 1 day of drug administration should be evaluated as a potential IRR. IRRs are 
common adverse drug reactions (ADRs) with mAbs that occur temporally related to drug 
administration. Reported signs/symptoms have included anaphylaxis, anaphylactoid reactions, 
and cytokine release syndrome, among others. IRRs are an AESI for M7824, and important 
identified risks for M7824; precautions and management are discussed in the dedicated section. 
 
Immune-related adverse events 
Immune-related adverse events are defined as off-target immune-mediated side effect 
associated with exposure to an immunogenic drug. In the evaluation of irAEs, a full differential 
diagnosis should be considered in the diagnostic work-up, including possible etiologies such as 
neoplastic, infectious, metabolic, toxin, etc. Serologic, histologic (biopsy), and/or immunologic 
work-up should be performed as indicated to evaluate the differential diagnosis and/or support 
an immune-mediated cause. Immune-related AEs are AESIs for M7824 and important identified 
risks for M7824; the precautions and management are discussed in the dedicated section. 
 
Skin adverse events 
Skin AEs are AESIs for M7824 and include 2 potential mechanisms: 
1. Skin AEs possibly due to TGFβ inhibition are grouped as rash with hyperkeratosis, KA, and 
SCC of skin. Skin lesions with hyperkeratosis, KA, cutaneous squamous cell treatment- 
related skin AEs were well managed and did not require treatment discontinuation in Studies 
EMR200647-001 and MS200647-0008. Similar lesions have also been described with other 
immune checkpoint inhibitors; therefore, monitoring and diagnostic work-up is required for both 
treatment arms. 
2. Immune-related skin AEs possibly mediated by PD-L1 inhibition (events in this category 
are also reported under irAE). 
 
Treatment-related Anemia Adverse Events 
Anemia is considered a potential risk based on toxicologic findings with M7824 in cynomolgus 
monkey indicating a decrease in hemoglobin, red blood cell count (RBC), and hematocrit,  which 
was fully reversible or showed a trend toward recovery after treatment discontinuation. 
Treatment-related anemia AEs are AESIs for M7824. A consistent clinical risk of treatment- 
related anemia on M7824 was not observed in Study EMR200647-001. As summarized in the 
Investigator’s Brochure (Version 4), treatment-related anemia was reported in 6.1% of 
participants in pooled cohort data (n=23; 3.4% Grade 3+ (n=13). In the NSCLC 2L cohort of the 
study, treatment-related anemias were reported in 2 participants (2.5%), both of which were in the 
500-mg cohort (data cutoff 12 March 2018). No consistent and/or specific etiology was identified 
for related anemia events. For more information, refer to dedicated section in this protocol and 
the Investigator’s Brochure. 


45 
Clinical Study Protocol 9.0                                                      
MDA Cancer Center 
Bintrafusp Alpha- M7824                    
 
 15 June 2020 
 
 
15.2 Potential Risks 
 
Alterations in Wound Healing or Repair of Tissue Damage 
Due to the involvement of TGFβ in tissue and skin repair, alterations in wound healing or repair 
of tissue damage is considered an important potential risk. No relevant event is reported in the 
ongoing M7824 clinical studies. Monitoring of any surgical wounds while on study is 
recommended. In general, a 2-week delay from treatment is recommend following minor surgery 
and 4 week delay for major surgery. 
 
Embryo-fetal Toxicities 
Embryo-fetal toxicities are a known risk of the PD-1/PD-L1 targeting class. Animal models link 
the PD-1/PD-L1 signaling pathway with maintenance of pregnancy through induction of 
maternal immune tolerance to fetal tissue (Guleria, 2005; Leber, 2010; Wafula, 2009; 
Zenclussen, 2013). Embryo-fetal and reproductive toxicities have also been investigated in 
animal models for a humanized monoclonal antibody targeting TGFβ1. At doses as high as 30 
mg/kg, no maternal reproductive toxicity or embryo-fetal lethality were observed in rabbits 
(Hilbish, 2016). To mitigate these potential risks, pregnant participants are excluded from the 
study, and all participants of childbearing/conceiving potential must use highly-effective 
contraception. 
 
Mild to Moderate Mucosal Bleeding Events 
Mucosal 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. 
 
15.3 Adverse Drug Reactions Requiring Treatment Discontinuation 
Adverse drug reactions are defined in this study as any AEs related to study intervention 
assessed by the Investigator and/or Sponsor. Serious adverse reactions are ADRs which are 
assessed as serious. 
 
Immune-related AEs, IRRs, anemia, and potentially TGFβ-mediated skin AEs are managed and 
followed-up in their respective sections as indicated below. Permanent treatment discontinuation 
may be recommended, so the relevant section must be reviewed: 
• For management and guidance of suspected irAEs, see dedicated section in this protocol 
• For infusion-related reactions and hypersensitivity reactions guidance, see dedicated section in 
this protocol 
• For guidance and management for potentially TGFβ mediated skin AEs, see dedicated 
section in this protocol 
 
General guidance: 


46 
Clinical Study Protocol 9.0                                                      
MDA Cancer Center 
Bintrafusp Alpha- M7824                    
 
 15 June 2020 
 
 
 
• Inability to reduce corticosteroid dose to 10 mg or less of prednisone or equivalent per day 
within 12 weeks is an indication for permanent treatment discontinuation (except for use of 
steroids as hormone substitution). 
• Persistent Grade 2 or 3 adverse reactions (excluding endocrinopathies controlled with 
hormone replacement therapy) that do not recover to Grade 0 to 1 within 12 weeks after last 
dose of study intervention is an indication for permanent treatment discontinuation. 
 
Grade 4 ADRs: 
Participants with any Grade 4 ADRs require permanent treatment discontinuation except: 
a. isolated laboratory values out of normal range that do not have any clinical correlation. 
b. endocrinopathies controlled with hormone replacement therapy. 
See dedicated section for other suspected Grade 4 irAEs, as most require permanent treatment 
discontinuation. 
 
Grade 3 ADRs: 
1. Participants with any severe or Grade 3 treatment-related adverse reactions that recur 
should be permanently discontinued. Exceptions may be considered as follows: 
 
a. Transient (≤ 6 hours) Grade 3 flu-like symptoms or fever, which is controlled with 
medical management. 
b. Transient (≤ 24 hours) Grade 3 fatigue, local reactions, headache, nausea, emesis that 
resolves to ≤ Grade 1 or baseline. 
c. Tumor flare phenomenon defined as local pain, irritation, or rash localized at sites of 
known or suspected tumor. 
d. Grade 3 hemoglobin decrease (< 8.0 g/dL) that is clinically manageable with blood 
transfusions or erythroid growth factor. 
e. Increases in ECOG PS ≥ 3 that resolves to ≤ 2 by Day 1 of the next infusion (ie, 
infusions should not be given if the ECOG PS is ≥ 3 on the day of treatment and should 
be delayed until ECOG PS ≤ 2). 
f. Keratoacanthomas and/or cSCC (see Section 6.8.3 for management). 
 
2. See Appendix 1 for suspected Grade 3 irAEs as many require permanent treatment 
discontinuation, including pneumonitis and nephritis. 
 
a. AST or ALT > 5 times ULN or total bilirubin greater than 3 times ULN must be 
permanently discontinued, except for participants with liver metastases (for example) 
who begin treatment with Grade 2 AST or ALT. These participants should be 
discontinued if AST or ALT increases by ≥ 50% relative to baseline and lasts for at 
least 1 week. 
3. Persistent Grade 3 adverse reactions (excluding endocrinopathies controlled with hormone 
replacement therapy) that do not recover to Grade 0 to 1 within 12 weeks after dose of 
treatment. 
 
Grade 2 ADRs should be managed as follows: 


47 
Clinical Study Protocol 9.0                                                      
MDA Cancer Center 
Bintrafusp Alpha- M7824                    
 
 15 June 2020 
 
 
 
a. If a Grade 2 ADR resolves to Grade ≤ 1 by the day before the next infusion, treatment 
may continue. 
b. If a Grade 2 ADR does not resolve to Grade ≤ 1 by the day before the next infusion, but 
it is manageable and/or not clinically relevant, the PI should be consulted to assess if 
clinically reasonable to administer the following infusion. 
 
16 Discontinuation of Study Intervention and Participant Discontinuation/Withdrawal 
 
16.1 Discontinuation of Study Intervention 
 
Participants will be withdrawn from treatment for any of the following reasons: 
• A participant may withdraw from the study at any time, at his/her own request (ie, withdrawal of 
consent), and without giving a reason. 
• Occurrence of an exclusion criterion, which is clinically relevant and affects the participant’s 
safety, if discontinuation is considered necessary by the Investigator. 
 
The participant may be withdrawn at any time at the discretion of the Investigator for safety, 
behavioral, compliance, or administrative reasons. 
 
• Confirmed PD per RECIST 1.1 with the exception that participants receiving treatment may 
continue past PD if the participant’s ECOG PS has remained stable, and if in the opinion of 
the Investigator, the participant will benefit from continued treatment. 
• Some ADRs require withdrawal from treatment. 
• Drug must not be given to a known pregnant participant. 
• Use of a nonpermitted concomitant drug (without approval of MD Anderson and the Medical 
Monitor provided by the IND office), as defined in dedicated s of this protocol, where the 
predefined consequence is withdrawal from the study intervention. 
 
 
16.2 Participant Discontinuation/Withdrawal from the Study 
 
A participant must be withdrawn in the event of any of the following: 
• A participant may withdraw from the study at any time, at his/her own request (ie, withdrawal of 
consent), and without giving a reason. 
• The participant may be withdrawn at any time at the discretion of the Investigator for safety, 
behavioral, compliance, or administrative reasons. 
 
In case of withdrawal from treatment, the day of End-of-Treatment will correspond to the day of 
withdrawal (or within 7 days). 
 
17 Lost to Follow-up 
 
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site.


48 
Clinical Study Protocol 9.0                                                      
MDA Cancer Center 
Bintrafusp Alpha- M7824                    
 
 15 June 2020 
 
 
The following actions must be taken if a participant fails to return to the clinic for a required 
study visit: 
 
• The site must attempt to contact the participant and reschedule the missed visit as soon as 
possible, counsel the participant on the importance of maintaining the assigned visit schedule, 
and ascertain if the participant wants to or should continue in the study. 
 
• Before a participant is deemed “lost to follow-up”, the Investigator or designee must make 
every effort to regain contact with the participant: 1) where possible, make 3 telephone calls; 
2) if necessary, send a certified letter (or an equivalent local method) to the participant’s last 
known mailing address, and 3) if a participant has given the appropriate consent, contact the 
participant’s general practitioner for information. These contact attempts should be 
documented in the participant’s medical record. 
 
• Should the participant continue to be unreachable, he/she will be considered to have 
withdrawn from the study. 
 
18 Long-term follow-up 
 
After the End of Treatment evaluation, information on additional oncologic treatment (including 
post-operative systemic therapy and radiation therapy), time to disease progression/recurrence, 
sites of recurrence, development of second primary tumors, additional therapy for recurrence, 
long-term survival, and other relevant clinical data will be obtained. Patients (or their family 
members or designees) may be contacted by telephone or in writing or by electronic mail or 
during clinic visits after treatment discontinuation for collection of long-term follow-up data. 
Long-term follow-up clinical information may also be obtained through chart reviews. Long-term 
follow up will be conducted as long as needed to obtain relevant information for accurate 
interpretation of the study, but for no longer than five years. 
 
19 Data Sharing 
 
Researchers can do more powerful studies when they share with each other the information they 
get from studying human samples. NGS data may be placed in a local M.D. Anderson 
Institutional Data Repository, commonly referred to as BigData; where both deposition of and 
access to data require governance and approval. In some cases, grant requirements may require 
deposition of large-scale data into the public Genotypes and Phenotypes database (dbGaP) an 
access controlled database overseen by the National Center for Biotechnology Information 
(NCBI). In other cases peer reviewed Journals may require data to be shared through a resource 
such as dbGaP. Data submitted to those repositories will only be shared in a de-identified fashion 
and without associated clinical data or identifiers. This data will be used only for research 
purposes, and the data elements collected and analyzed   will only be those that are necessary to 
conduct this research. 
 
Database access additional protections: The precedent to publically broadcast sequence data 
has been set by large consortial projects, such as The Cancer Genome Atlas (TCGA) and the 
Encyclopedia of DNA Elements (ENCODE), in order to maximize data utility. However, we know 


49 
Clinical Study Protocol 9.0                                                      
MDA Cancer Center 
Bintrafusp Alpha- M7824                    
 
 15 June 2020 
 
there is the potential for privacy risks associated with the release of sequence data to databases 
and while the risk may be small, it could grow in the future as technology advances. To minimize 
this potential, we will implement good faith efforts to ensure patient confidentiality and reduce 
patient exposure. The database of Genotypes and Phenotypes and others like it are extremely 
access restricted. Only authorized researchers may deposit or access the data and either or both 
efforts require MD Anderson institutional approval. Sequence data will only be broadcast through 
secure transmission processes. All samples will be de-identified with access to the linking table 
available only to the MD Anderson PI and his/her designees. Only non- identifiable data will be 
deposited to dbGaP i.e., no linking table or access to a linking table will be available. Research 
records will be kept separate from medical records and patients will not have access to any of the 
research data. 
 
Protected health information (PHI) may be collected from medical records that are related to 
health and/or disease history including test results, medical procedures, and images (such as X- 
rays) in addition demographic and environmental factors may be requested. Researchers will use 
this information to better understand how genes affect health and response to treatment. 
All samples will be de-identified with access to the linking table available only to the MD Anderson 
PI and his/her designees.


51 
Clinical Study Protocol 9.0                                                      
MDA Cancer Center 
Bintrafusp Alpha- M7824                    
 
 15 June 2020 
 
 
20 Study Medication - Pharmaceutical Formulation 
 
Pharmaceutical Properties and Description of the Formulation M7824 
drug product is provided as either 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) or 20 mL (200 mg/20 mL), respectively. 
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. 
 
The excipients are viewed as standard, and therefore, not a safety risk. The estimated volumes of 
delivery are anticipated to be no more than 250 mL, which are clinically acceptable. 
 
20.1 Study Medication - Handling of the Dosage Form 
 
For applications in clinical studies the liquid formulation is diluted directly with 0.9% saline solution. 
The estimated volumes of delivery are anticipated to be no more than 250 mL, which are clinically 
acceptable. Detailed information on infusion bags and medical devices to be used for the preparation 
of the dilutions and subsequent administration will be provided in the manual of preparation. 
 
20.2 Study Medication - Instructions for 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. For application in clinical studies, 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 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 M782. 
 
 
 
 
 
 
 
 
 


52 
Clinical Study Protocol 9.0                                                      
MDA Cancer Center 
Bintrafusp Alpha- M7824                    
 
 15 June 2020 
 
 
21 STUDY ASSESSMENTS AND PROCEDURES 
 
Baseline evaluation: 
 
  Investigations 
Timing 
History and Physical   
Exam including: 
Treatment history 
Vital signs 
Medical history 
ECOG PS 
Smoking history 
TNM stage 
Height and weight 
Within 14 days  prior 
to treatment initiation 
Current Smoking Status     
and Tobacco Use 
Assessment of patient’s current smoking 
status and tobacco use 
Within 14 days    
prior to treatment 
initiation 
 Symptoms & Toxicities 
Evaluation and documentation of symptoms 
and toxicities using the NCI CTCAE v5.0 
Within 14 days 
prior to treatment 
initiation 
 Concomitant Medications 
Documentation of concomitant medications 
Within 14 days 
prior to treatment 
initiation 
 Hematology and 
Coagulation 
CBC with hemoglobin, platelets, and WBC 
with differential 
Prothrombin time (PT) / Partial 
thromboplastin time (PTT) 
Within 14 days 
prior to treatment 
initiation 
 Biochemistry 
Albumin 
Glucose 
Alkaline 
LDH 
phosphatase 
Potassium 
Total bilirubin,                     SGOT (AST) 
direct, indirect 
SGPT (ALT) 
BUN 
Sodium 
Creatinine 
Magnesium 
Total protein 
Uric acid 
Free T4, TSH 
Within 14 days 
prior to treatment 
initiation 


53 
Clinical Study Protocol 9.0                                                      
MDA Cancer Center 
Bintrafusp Alpha- M7824                    
 
 15 June 2020 
 
 
 
Pregnancy Test 
Urine or serum (for women of childbearing 
potential only) 
Within 48 hours 
prior to treatment 
initiation 
Radiology 
CT chest 
Within 30 days 
prior to treatment 
initiation 
Radiology 
PET-CT 
Within 60 days 
prior to treatment 
initiation 
Radiology 
MRI brain or CT brain (only for patients with 
stage II or III on pre-operative staging) 
Within 60 days 
prior to treatment 
initiation 
Mediastinal staging 
CT chest / PET-CT, mediastinoscopy, 
and/or endobronchial ultrasound 
Within 60 days 
prior to treatment 
initiation 
Pulmonary tests 
Complete pulmonary function test 
Within 60  days 
prior to treatment 
initiation 
Tumor/Adjacent Lung 
Tissue Collection for 
   Biomarkers 
Archival tissue or new biopsy of primary 
tumor for biomarker analysis (optional) 
Tissue obtained for mediastinal staging 
(optional) 
Prior to treatment 
initiation 
Blood-based biomarkers 
Blood sample 
Prior to treatment 
initiation 
Stool-based Microbiome 
Stool sample 
Prior to treatment 
initiation 
Pharmakokinetic (PK)  
studies 
Blood sample 
Prior to infusion 
and immediately 
after infusion of 
dose #1 of 
M7824 
Anti-Drug Antibodies (ADA) 
studies 
Blood sample 
Prior to infusion 
of dose #1 of 
M7824 


54 
Clinical Study Protocol 9.0                                                      
MDA Cancer Center 
Bintrafusp Alpha- M7824                    
 
 15 June 2020 
 
 
 
Evaluation during neoadjuvant treatment (prior to each M7824 infusion): 
 
Investigations 
Timing 
Physical Exam 
Including: 
BSA 
Vital signs 
Within 7 days prior to dose 
#2 and #3 of M7824 
Hematology 
CBC with hemoglobin, platelets, and 
WBC with differential 
Within 7 days prior to dose #2 
and #3 of M7824 
Pregnancy Test 
Urine or serum (for women of 
childbearing potential only) 
Within 7 days prior to dose #2 
and #3 of M7824 
1 
Biochemistry 
Albumin 
Alkaline 
phosphatase 
Total bilirubin, 
direct, indirect 
BUN 
Creatinine 
Total protein 
Free T4, TSH 
Glucose 
LDH 
Potassium 
SGOT (AST) 
SGPT (ALT) 
Sodium 
Magnesium 
Uric acid 
Within 7 days prior to dose #2 
and #3 of M7824 
1 
Radiology 
CT chest 
PET-CT 
At least 14 days after the last 
dose of M7824 
Symptoms 
& Toxicities 
Evaluation and documentation of 
symptoms and toxicities using the NCI 
CTCAE v5.0 
On an ongoing basis throughout 
the study until the final study 
visit 
Concomitant 
Medications 
Documentation of concomitant 
medications 
On an ongoing basis throughout 
the study until the final study 
visit 
Blood-based 
biomarkers1 
Blood sample 
Within 7 days prior to dose #2 
and #3 of M7824 and at least 14 
days after the last dose of M7824 


55 
Clinical Study Protocol 9.0                                                      
MDA Cancer Center 
Bintrafusp Alpha- M7824                    
 
 15 June 2020 
 
 
 
Pharmakokinetic 
(PK) studies 
Blood sample 
Prior to infusion of dose # 2 Prior 
to infusion and immediately after 
infusion of dose # 3 
At least 14 days after the last 
dose of M7824 
Anti-Drug Antibodies 
(ADA) studies 
Blood sample 
Prior to infusion of dose #3 of 
M7824 
At least 14 days after the last 
dose of M7824 
Pulmonary tests 
Complete pulmonary function test2 
At least 14 days after the last 
dose of M7824 
Stool-based 
Microbiome 
Stool sample 
At least 14 days after the last 
dose of M7824 
1 
If information / studies have already been obtained but therapy is delayed for any 
reason, repeated studies are not necessary prior to next cycle of therapy. 2Complete    
pulmonary function test may not be required if patient is no longer considered a 
surgical candidate post neoadjuvant therapy based on the treating physician’s 
discretion. 
 
 
 
Assessments at surgery: 
 
Investigations 
Timing 
Surgical procedure 
Title of operation 
Status of resection margins 
(R0, R1, R2) 
Through chart review 
Tumor 
Tissue 
Collection 
ypTNM 
Major pathologic response  
Percentage of viable tumor cells 
Nodal stations dissected / 
sampled and nodal status 
(positive vs. negative) at each 
station 
Evaluation of extra-capsular   
nodal spread 
As information becomes available 


56 
Clinical Study Protocol 9.0                                                      
MDA Cancer Center 
Bintrafusp Alpha- M7824                    
 
 15 June 2020 
 
 
 
End of treatment assessments: 
 
Investigations 
Timing 
Physical 
Exam 
Including
: 
Vital Signs 
Approximately within 8 weeks after 
surgery 
Blood-based 
biomarkers 
Blood sample 
Approximately within 8 weeks after 
surgery 
Symptoms & Toxicities Evaluation and documentation of 
symptoms and toxicities using the 
NCI CTCAE v5.0 
Retrospective evaluation of any 
Approximately within 8 weeks after 
surgery 
 
22 STATISTICALCONSIDERATIONS 
 
This is an open label phase II study with a modular design. Currently, eligible patients will be 
accrued to the M7824 monotherapy arm (Arm A). The primary objective is to evaluate the rate of MPR, 
rather than hypothesis testing with pre-specified null and alternative MPR rates. There will be no interim 
futility nor efficacy monitoring. The primary efficacy endpoint of the study is MPR evaluated in resected 
tumor tissues following neoadjuvant therapy and defined as ≤ 10% viable tumor cells in the 
resected specimen using the methods described by Pataer et al. (2). 
 
Analysis of primary efficacy endpoint: 
A sample size of 23 patients is proposed for each arm of the study. With an estimated accrual 
rate of 2-3 patients a month, the accrual period is approximately 15-24 months. We will estimate 
the MPR rate with a 95% credible interval (CI) assuming that the MPR rate follows a prior beta 
distribution (0.5, 0.5) with one patient worth of information. For example, if the M7824 
monotherapy indeed has a true MPR rate of 30% and 7 patients with MPR are observed in this 
study, the corresponding 95% CI of the observed MPR rate would be (14.8%, 50.7%). 
Furthermore, we calculated predictive probability of Prob (p > 0.15 | data and true MPR rate) for a 
variety of true MPR rates, where p is the MPR rate. As shown in the table below (Table 3), there 
will be a fairly high chance (81 – 89%) for the study to observe a MPR rate > 15% with a sample 
size of 23 patients if the true MPR rates are 25% and higher. 
 
Table 3. Predictive probabilities of true MPR rates. 
 
True MPR rate 
predictive probability of 
Prob( p > 0.15 | data and 
true MPR rate) where 
a0=0.5, b0=0.5 


57 
Clinical Study Protocol 9.0                                                      
MDA Cancer Center 
Bintrafusp Alpha- M7824                    
 
 15 June 2020 
 
 
 
0.05 
12% 
0.10 
30% 
0.15 
50% 
0.20 
67% 
0.25 
81% 
0.30 
89% 
 
We chose to use 15% MPR rate as cutoff because a historic major pathologic response rate 
to neoadjuvant chemotherapy alone of 19% is observed (as described by Pataer et al.) (2). 
However, some patients that receive neoadjuvant chemotherapy may not receive surgery for 
one reason or another, and these cases will be considered treatment failure. 
Assuming the 19% major pathologic response rate is calculated from 80% of patients who 
receive surgery, a conservative estimate of the major pathologic response is 15%. 
 
Analysis of Secondary/Exploratory Endpoints: 
 
Analysis for the secondary/exploratory endpoints will be descriptive and exploratory in nature. 
Descriptive statistics will be provided to summarize the data distribution. Association analysis by 
Pearson or Spearman correlation coefficient will be calculated for continuous data and chi- 
square or Fisher's exact test for categorical data. Time-to-event endpoints will be computed using 
the Kaplan-Meier method. Multivariate analysis will be used to explore the role of biomarkers in 
predicting pathologic response to treatment, in an exploratory way. The goals for these analyses 
are for hypothesis generating. The results will need to be confirmed by future   studies. 


58 
Clinical Study Protocol 9.0                                                      
MDA Cancer Center 
Bintrafusp Alpha- M7824                    
 
 15 June 2020 
 
 
 
23 STUDY MONITORING AND EARLYSTOPPING RULES 
 
To ensure the safety of the proposed treatment in the neoadjuvant setting, precautions have been 
taken into consideration and implemented: 
 
• A careful review of the literature has demonstrated that the use of neoadjuvant 
chemotherapy does not increase surgical morbidity or mortality (14). Because single 
agent M7824 has been found to have a more favorable adverse event profile than 
single agent chemotherapy (38, 39) it is expected that neoadjuvant immunotherapy will 
be feasible and safe. 
 
• A Bayesian method to monitor the toxicity in the perioperative phase will be used (40) 
 
Unacceptable toxicity is defined as: severe pneumonitis precluding performance of planned 
surgical resection, death during neoadjuvant treatment or within 30 days after surgery; severe post 
op acute respiratory distress syndrome (ARDS) not attributable to aspiration requiring prolonged 
ventilator support; development of broncho-pleural fistula not attributable to surgical technique; 
wound healing delays that require management with a major surgical procedure; wound infections 
that require intravenous antibiotic use for more than 21 days; re-operation for bleeding or infection 
deemed secondary other factors than surgical technique; empyema; stroke or myocardial 
infarction within 30  days after surgery; any treatment-related adverse events leading to a delay in 
surgery resulting in > 8 week interval between the last dose of neoadjuvant therapy and surgery, any 
surgical complication that is considered major by the treating physician and possibly, probably or 
definitely related the immunotherapy medications. The incidence of surgical complications for 
thoracoscopy/thoracotomy for non-small cell lung cancers is approximately 16-31% (41). We 
consider that neoadjuvant therapy with either one of the regimens is not feasible if it results in 
unacceptable toxicities in at least 20% of the patients with 70% or higher probability. 
 
We consider that neoadjuvant therapy with either one of the regimens is not feasible if it 
results in unacceptable toxicities in at least 20% of the patients with 70% or higher 
probability. The toxicity monitoring will start after a minimum of 6 patients have 
been enrolled with known toxicity outcome.  With a prior probability of toxicity as 
Beta(0.2,0.8), the toxicity stopping boundaries are defined as seeing unacceptable toxicity 
in >= 3 of 6-8, 4 of 9-12, 5 of 13-16, 6 of 17-20 or 7 of 21-23 patients. When the true 
toxicity rates are 0.1, 0.2, and 0.35, the probabilities of early stopping are 0.06, 0.34, and 
0.84 with the corresponding average sample sizes of 22.2, 18.6, and 11.2, respectively. In 
case one arm needs to be closed due to excessive toxicity, accrual to the remaining arm 
will continue in a non-randomized way. The calculation was performed using the Shiny 
Application: Bayesian Toxicity Monitoring version 2.1 (http://ibl.mdanderson.org/BTM/). 
 
 
The Investigator is responsible for completing an efficacy/safety summary report, and submitting 
it to the IND Office Medical Affairs and Safety Group, for review and approval. This should be 


59 
Clinical Study Protocol 9.0                                                      
MDA Cancer Center 
Bintrafusp Alpha- M7824                    
 
 15 June 2020 
 
submitted after the first 6 evaluable patients per study arm, complete 30 days after surgery, and 
every 3 evaluable patients per arm, thereafter. 
 
A copy of the cohort summary should be placed in the Investigator’s Regulatory Binder under 
“sponsor correspondence”. 


60 
Clinical Study Protocol 9.0                                                      
MDA Cancer Center 
Bintrafusp Alpha- M7824                    
 
 15 June 2020 
 
 
 
24 Data Confidentiality Plan 
 
Confidentiality of Data 
All clinical and research information/data will be collected and placed in our institution’s Data 
Management Initiative (DMI) supported by Biostatistical Department under Dr. Jack Lee’s 
oversight. This is a secured, password-protected intranet-based (UTMDACC only) database. 
Access to this database is restricted to the PI, protocol research nurse, protocol research data 
coordinator and DMI database analyst. 
The investigator affirms that information as pertains to the study will be maintained in 
confidence, and such information will be divulged to the IRB, IEC, or similar or expert 
committee; affiliated institution and employees, only under an appropriate understanding of 
confidentiality with such board or committee, affiliated institution and employees. Data 
generated by this study will be considered confidential by the investigator, except to the extent 
that it is included in a publication. 
 
Confidentiality of Participant Records 
The investigator agrees that the Sponsor (or Sponsor representative), IRB/IEC, or regulatory 
authority representatives may consult and/or copy study documents to verify worksheet/CRF 
data. By signing the consent form, the participant agrees to this process. If study documents will 
be photocopied during the process of verifying worksheet/CRF information, the participant will be 
identified by unique code only; full names/initials will be masked prior to transmission to the 
Sponsor. The investigator agrees to treat all participant data used and disclosed in connection 
with this study in accordance with all applicable privacy laws, rules and regulations. 


61 
Clinical Study Protocol 9.0                                                      
MDA Cancer Center 
Bintrafusp Alpha- M7824                    
 
 15 June 2020 
 
 
 
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2. 
Pataer A, Kalhor N, Correa AM, Raso MG, Erasmus JJ, Kim ES, et al. Histopathologic response 
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Clinical Study Protocol 9.0                                                      
MDA Cancer Center 
Bintrafusp Alpha- M7824                    
 
 15 June 2020 
 
 
 
14. 
Burdett S, Stewart LA, Rydzewska L. A systematic review and meta-analysis of the 
literature: chemotherapy and surgery versus surgery alone in non-small cell lung cancer. Journal 
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Garrido P, Gonzalez-Larriba JL, Insa A, Provencio M, Torres A, Isla D, et al. Long-term survival 
associated with complete resection after induction chemotherapy in stage IIIA (N2) and IIIB 
(T4N0-1) non small-cell lung cancer patients: the Spanish Lung Cancer Group Trial 9901. 
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Albain KS, Swann RS, Rusch VW, Turrisi AT, 3rd, Shepherd FA, Smith C, et al. Radiotherapy 
plus chemotherapy with or without surgical resection for stage III non-small-cell lung cancer: a 
phase III randomised controlled trial. Lancet. 2009;374(9687):379-86. 
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Betticher DC, Hsu Schmitz SF, Totsch M, Hansen E, Joss C, von Briel C, et al. Mediastinal lymph 
node clearance after docetaxel-cisplatin neoadjuvant chemotherapy is prognostic of survival in 
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Clinical Study Protocol 9.0                                                      
MDA Cancer Center 
Bintrafusp Alpha- M7824                    
 
 15 June 2020 
 
 
Appendix 1 The Recommendations for irAE Management, in Accordance with the Joint 
American Society of Clinical Oncology Clinical Practice Guidelines and National 
Comprehensive Cancer Network 
Reproduced from: Brahmer  JR. 
Management of Immune-Related Adverse Events in Patients Treated With Immune Checkpoint 
Inhibitor Therapy: American Society of Clinical Oncology Clinical Practice Guideline 
 
 
Tables of Management of irAEs in Patients Treated with ICPis: 
Table A1 Management of Skin irAEs in Patients Treated With ICPis 
Table A2 Management of GI irAEs in Patients Treated With ICPis  
Table A3 Management of Lung irAEs in Patients Treated With ICPis 
Table A4 Management of Endocrine irAEs in Patients Treated With ICPis  
Table A5 Management of Musculoskeletal irAEs in Patients Treated With ICPis 
Table A6 Management of Renal irAEs in Patients Treated With ICPis 
Table A7 Management of Nervous System irAEs in Patients Treated With ICPis 
Table A8 Management of Hematologic irAEs in Patients Treated With ICPis  
Table A9 Management of Cardiovascular irAEs in Patients Treated With ICPis  
Table A10 Management of Ocular irAEs in Patients Treated With ICPis


Clinical Study Protocol 9.0                                                      
MDA Cancer Center 
Bintrafusp Alpha- M7824                    
 
 15 June 2020 
 
 
  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 
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 


Clinical Study Protocol 9.0                                                      
MDA Cancer Center 
Bintrafusp Alpha- M7824                    
 
 15 June 2020 
 
 
 
                                                       1.0 Skin Toxicities 
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 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) 


Clinical Study Protocol 9.0                                                      
MDA Cancer Center 
Bintrafusp Alpha- M7824                    
 
 15 June 2020 
 
 
 
                                                         1.0 Skin Toxicities 
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 
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: 


Clinical Study Protocol 9.0                                                      
MDA Cancer Center 
Bintrafusp Alpha- M7824                    
 
 15 June 2020 
 
 
 
                                                          1.0 Skin Toxicities 
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 


Clinical Study Protocol 9.0                                                      
MDA Cancer Center 
Bintrafusp Alpha- M7824                    
 
 15 June 2020 
 
 
 
                                                            1.0 Skin Toxicities 
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 
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 


Clinical Study Protocol 9.0                                                      
MDA Cancer Center 
Bintrafusp Alpha- M7824                    
 
 15 June 2020 
 
 
 
                                                        1.0 Skin Toxicities 
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 
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) 


Clinical Study Protocol 9.0                                                      
MDA Cancer Center 
Bintrafusp Alpha- M7824                    
 
 15 June 2020 
 
 
 
                                                        1.0 Skin Toxicities 
 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. 


70 
Clinical Study Protocol 9.0                                                      
MDA Cancer Center 
Bintrafusp Alpha- M7824                    
 
 15 June 2020 
 
 
 
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 
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 


71 
Clinical Study Protocol 9.0                                                      
MDA Cancer Center 
Bintrafusp Alpha- M7824                    
 
 15 June 2020 
 
 
 
                                                             2.0 GI Toxicities 
 
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 
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 


72 
Clinical Study Protocol 9.0                                                      
MDA Cancer Center 
Bintrafusp Alpha- M7824                    
 
 15 June 2020 
 
 
 
                                                             2.0 GI Toxicities 
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 
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-


73 
Clinical Study Protocol 9.0                                                      
MDA Cancer Center 
Bintrafusp Alpha- M7824                    
 
 15 June 2020 
 
 
 
                                                             2.0 GI Toxicities 
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 


74 
Clinical Study Protocol 9.0                                                      
MDA Cancer Center 
Bintrafusp Alpha- M7824                    
 
 15 June 2020 
 
 
 
                                                         2.0 GI Toxicities 
 
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) 
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 


75 
Clinical Study Protocol 9.0                                                      
MDA Cancer Center 
Bintrafusp Alpha- M7824                    
 
 15 June 2020 
 
 
 
                                                           2.0 GI Toxicities 
 
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. 


76 
Clinical Study Protocol 9.0                                                      
MDA Cancer Center 
Bintrafusp Alpha- M7824                    
 
 15 June 2020 
 
 
 
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 


77 
Clinical Study Protocol 9.0                                                      
MDA Cancer Center 
Bintrafusp Alpha- M7824                    
 
 15 June 2020 
 
 
 
  3.0 Lung Toxicities 
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. 


78 
Clinical Study Protocol 9.0                                                      
MDA Cancer Center 
Bintrafusp Alpha- M7824                    
 
 15 June 2020 
 
 
 
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) 


79 
Clinical Study Protocol 9.0                                                      
MDA Cancer Center 
Bintrafusp Alpha- M7824                    
 
 15 June 2020 
 
 
 
                                                      4.0 Endocrine Toxicity 
 
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 
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 


80 
Clinical Study Protocol 9.0                                                      
MDA Cancer Center 
Bintrafusp Alpha- M7824                    
 
 15 June 2020 
 
 
 
                                                         4.0 Endocrine Toxicity 
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 
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 
 


81 
Clinical Study Protocol 9.0                                                      
MDA Cancer Center 
Bintrafusp Alpha- M7824                    
 
 15 June 2020 
 
 
 
                                                       4.0 Endocrine Toxicity 
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. 


82 
Clinical Study Protocol 9.0                                                      
MDA Cancer Center 
Bintrafusp Alpha- M7824                    
 
 15 June 2020 
 
 
 
                                                      4.0 Endocrine Toxicity 
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). 
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 


83 
Clinical Study Protocol 9.0                                                      
MDA Cancer Center 
Bintrafusp Alpha- M7824                    
 
 15 June 2020 
 
 
 
                                                       4.0 Endocrine Toxicity 
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. 
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 


84 
Clinical Study Protocol 9.0                                                      
MDA Cancer Center 
Bintrafusp Alpha- M7824                    
 
 15 June 2020 
 
 
 
                                                        4.0 Endocrine Toxicity 
 
Admit for inpatient management: 
Concerns for developing DKA, 
Symptomatic patients regardless of 
diabetes type, New-onset T1DM unable to 
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 of normal. 


85 
Clinical Study Protocol 9.0                                                      
MDA Cancer Center 
Bintrafusp Alpha- M7824                    
 
 15 June 2020 
 
 
 
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 


86 
Clinical Study Protocol 9.0                                                      
MDA Cancer Center 
Bintrafusp Alpha- M7824                    
 
 15 June 2020 
 
 
 
                                                   5.0 Musculoskeletal Toxicities 
 
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 
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 


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Clinical Study Protocol 9.0                                                      
MDA Cancer Center 
Bintrafusp Alpha- M7824                    
 
 15 June 2020 
 
 
 
                                              5.0 Musculoskeletal Toxicities 
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 (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 


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Clinical Study Protocol 9.0                                                      
MDA Cancer Center 
Bintrafusp Alpha- M7824                    
 
 15 June 2020 
 
 
 
                                                    5.0 Musculoskeletal Toxicities 
 
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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Clinical Study Protocol 9.0                                                      
MDA Cancer Center 
Bintrafusp Alpha- M7824                    
 
 15 June 2020 
 
 
 
                                                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. 


90 
Clinical Study Protocol 9.0                                                      
MDA Cancer Center 
Bintrafusp Alpha- M7824                    
 
 15 June 2020 
 
 
 
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 


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Clinical Study Protocol 9.0                                                      
MDA Cancer Center 
Bintrafusp Alpha- M7824                    
 
 15 June 2020 
 
 
 
                                                      6.0 Renal Toxicities 
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) 
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. 


92 
Clinical Study Protocol 9.0                                                      
MDA Cancer Center 
Bintrafusp Alpha- M7824                    
 
 15 June 2020 
 
 
 
Table 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 


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Clinical Study Protocol 9.0                                                      
MDA Cancer Center 
Bintrafusp Alpha- M7824                    
 
 15 June 2020 
 
 
 
                                               7.0 Nervous System Toxicities 
 
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 (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 


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Clinical Study Protocol 9.0                                                      
MDA Cancer Center 
Bintrafusp Alpha- M7824                    
 
 15 June 2020 
 
 
 
                                                7.0 Nervous System Toxicities 
 
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 
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 


95 
Clinical Study Protocol 9.0                                                      
MDA Cancer Center 
Bintrafusp Alpha- M7824                    
 
 15 June 2020 
 
 
 
                                                        7.0 Nervous System Toxicities 
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 


96 
Clinical Study Protocol 9.0                                                      
MDA Cancer Center 
Bintrafusp Alpha- M7824                    
 
 15 June 2020 
 
 
 
                                                 7.0 Nervous System Toxicities 
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 


97 
Clinical Study Protocol 9.0                                                      
MDA Cancer Center 
Bintrafusp Alpha- M7824                    
 
 15 June 2020 
 
 
 
                                                7.0 Nervous System Toxicities 
 
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. 
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 
Permanently discontinue 
ICPi Methylprednisolone 2 
mg/kg 
Strongly consider higher doses of 1 g/d for 
3- 5 days Strongly consider IVIG 
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. 


98 
Clinical Study Protocol 9.0                                                      
MDA Cancer Center 
Bintrafusp Alpha- M7824                    
 
 15 June 2020 
 
 
 
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 


99 
Clinical Study Protocol 9.0                                                      
MDA Cancer Center 
Bintrafusp Alpha- M7824                    
 
 15 June 2020 
 
 
 
                                                   8.0 Hematologic Toxicities 
 
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 
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 
 


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Clinical Study Protocol 9.0                                                      
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Bintrafusp Alpha- M7824                    
 
 15 June 2020 
 
 
 
                                                    8.0 Hematologic Toxicities 
                           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 
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 


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Clinical Study Protocol 9.0                                                      
MDA Cancer Center 
Bintrafusp Alpha- M7824                    
 
 15 June 2020 
 
 
 
                                                  8.0 Hematologic Toxicities 
 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 
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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Clinical Study Protocol 9.0                                                      
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Bintrafusp Alpha- M7824                    
 
 15 June 2020 
 
 
 
                                                    8.0 Hematologic Toxicities 
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 


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Clinical Study Protocol 9.0                                                      
MDA Cancer Center 
Bintrafusp Alpha- M7824                    
 
 15 June 2020 
 
 
 
                                                  8.0 Hematologic Toxicities 
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 
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 


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Clinical Study Protocol 9.0                                                      
MDA Cancer Center 
Bintrafusp Alpha- M7824                    
 
 15 June 2020 
 
 
 
                                                        8.0 Hematologic Toxicities 
 
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 (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 


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Clinical Study Protocol 9.0                                                      
MDA Cancer Center 
Bintrafusp Alpha- M7824                    
 
 15 June 2020 
 
 
 
                                                  8.0 Hematologic Toxicities 
 
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. 


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Clinical Study Protocol 9.0                                                      
MDA Cancer Center 
Bintrafusp Alpha- M7824                    
 
 15 June 2020 
 
 
 
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 
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. 


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Clinical Study Protocol 9.0                                                      
MDA Cancer Center 
Bintrafusp Alpha- M7824                    
 
 15 June 2020 
 
 
 
                                              9.0 Cardiovascular Toxicities 
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 
Grading 
Management 
G1: Venous thrombosis (eg, superﬁcial 
thrombosis) 
Continue ICPi 
Warm compress 
Clinical 
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 


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Clinical Study Protocol 9.0                                                      
MDA Cancer Center 
Bintrafusp Alpha- M7824                    
 
 15 June 2020 
 
 
 
                                                9.0 Cardiovascular Toxicities 
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. 


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Clinical Study Protocol 9.0                                                      
MDA Cancer Center 
Bintrafusp Alpha- M7824                    
 
 15 June 2020 
 
 
 
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 


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Clinical Study Protocol 9.0                                                      
MDA Cancer Center 
Bintrafusp Alpha- M7824                    
 
 15 June 2020 
 
 
 
                                                     10.0 Ocular Toxicities 
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 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 
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 


111 
Clinical Study Protocol 9.0                                                      
MDA Cancer Center 
Bintrafusp Alpha- M7824                    
 
 15 June 2020 
 
 
 
10.0 Ocular Toxicities 
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. 


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Clinical Study Protocol 9.0                                                      
MDA Cancer Center 
Bintrafusp Alpha- M7824                    
 
 15 June 2020 
 
 
 
Appendix 2 Adverse Events: Definitions and Procedures for Recording, Evaluating, 
Follow-up, and Reporting 
Definitions Adverse 
Event 
An adverse event is the appearance or worsening of any undesirable sign, symptom, or medical 
condition occurring after the first protocol intervention, even if the event is not considered to be 
related to study treatment. Medical conditions/diseases present before starting study therapy are 
only considered adverse events if they worsen after starting study treatment. Abnormal laboratory 
values or test results constitute adverse events only if they induce clinical signs or symptoms, are 
considered clinically significant, or require therapy. 
 
For surgical or diagnostic procedures, the condition/illness leading to such a procedure is 
considered as the AE rather than the procedure itself. 
Compared to baseline (Screening or the Week 1, Day 1 visit), medical conditions that do not 
worsen in severity or frequency during the study are defined as baseline medical conditions, and 
are NOT to be considered as AEs. 
All newly diagnosed or worsening pre-existing conditions (clinically significant changes in 
frequency, and/or intensity), signs, and symptoms observed from baseline (Screening or the Week 
1, Day 1 visit), whether related to study intervention or not, are to be reported as AEs. 
Progression of the cancer under study is not considered an AE. 
The Investigator is required to grade the severity or toxicity of each AE. 
Investigators will reference the National Cancer Institute - Common Terminology Criteria for AEs 
(CTCAE), version 5.0 (publication date: 27 Nov 2017), a descriptive terminology that can be used 
for AE toxicity grade reporting. 
A general grading (severity/intensity; hereafter referred to as severity) scale is provided at the 
beginning of the above referenced document, and specific event grades are also provided. 
If the severity for an AE is not specifically graded by NCI-CTCAE, the Investigator is to use the 
general NCI-CTCAE definitions of Grade 1 through Grade 5, using his or her best medical 
judgment. 
The 5 general grades are: 
Grade 1 or Mild 
Grade 2 or Moderate Grade 3 
or Severe 
Grade 4 or Life-threatening Grade 5 
or Death 
Any clinical AE with severity of Grade 4 or 5 must also be reported as an SAE. However, a 
laboratory abnormality of Grade 4, such as anemia or neutropenia, is considered serious only if the 
condition meets one of the serious criteria specified below. 
If death occurs, the primary cause of death or event leading to death should be recorded and 
reported as an SAE. “Fatal” will be recorded as the outcome of this specific event and  death 


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Clinical Study Protocol 9.0                                                      
MDA Cancer Center 
Bintrafusp Alpha- M7824                    
 
 15 June 2020 
 
 
 
will not be recorded as separate event. Only, if no cause of death can be reported (eg, sudden 
death, unexplained death), the death per se might then be reported as an SAE. 
Investigators must also systematically assess the causal relationship of AEs to study intervention 
(including any other nonstudy interventions, radiation therapy, etc.) using the following 
definitions. Decisive factors for the assessment of causal relationship of an AE to the study 
intervention include, but may not be limited to, temporal relationship between the AE and the study 
intervention, known side effects of study intervention, medical history, concomitant medication, 
course of the underlying disease, and study procedures. 
Unrelated: Not reasonably related to the study intervention. AE could not medically 
(pharmacologically/clinically) be attributed to the study intervention under study in this clinical study 
protocol. A reasonable alternative explanation must be available. 
Related: 
Reasonably 
related 
to 
the 
study 
intervention. 
AE 
could 
medically 
(pharmacologically/clinically) be attributed to the study intervention under study in this clinical study 
protocol. 
Abnormal Laboratory Findings and Other Abnormal Investigational Findings 
Abnormal laboratory findings and other abnormal investigational findings (eg, on an ECG trace) 
should not be reported as AEs unless they are associated with clinical signs and symptoms, lead 
to study intervention discontinuation or are considered otherwise medically important by the 
Investigator. If a laboratory abnormality fulfills these criteria, the identified medical condition (eg, 
anemia or increased ALT) must be reported as the AE rather than the abnormal value itself. 
 
Any important medical event can and should be reported as an SAE if deemed appropriate by 
the Principal Investigator or the IND Sponsor, IND Office. 
 
Serious Adverse Events 
An SAE is any untoward medical occurrence that at any dose: 
• Results in death 
• Is life-threatening. Life-threatening refers to an event in which the participant is at risk of 
death at the time of the event, not an event that hypothetically might have caused death if 
it was more severe. 
• Requires inpatient hospitalization or prolongs an existing hospitalization 
• Results in persistent or significant disability or incapacity 
• Is a congenital anomaly or birth defect 
• Is otherwise considered to be medically important. Important medical events that may not 
result in death, be life-threatening, or require hospitalization may be considered as SAEs 
when, based upon appropriate medical judgment, they may jeopardize the participant or 
may require medical or surgical intervention to prevent one of the outcomes listed above. 
Examples of such events include allergic bronchospasm requiring intensive treatment in an 
emergency room or at home, blood dyscrasias or convulsions that do not result in inpatient 
hospitalization, or the development of drug dependency or drug abuse. 


114 
Clinical Study Protocol 9.0                                                      
MDA Cancer Center 
Bintrafusp Alpha- M7824                    
 
 15 June 2020 
 
 
 
For the purposes of reporting, any suspected transmission of an infectious agent via a study 
intervention is also considered an SAE, as specified below for reporting SAEs, AESIs and DLTs. 
Events that Do Not Meet the Definition of an SAE 
Elective hospitalizations to administer, or to simplify study intervention or procedures (eg, an 
overnight stay to facilitate chemotherapy and related hydration therapy application) are not 
considered SAEs. The following hospitalizations are also not considered SAEs: 
• 
a visit to the emergency room or other hospital department < 72 hours, that does not 
result in admission (unless considered an important medical or life-threatening event) 
 
• 
elective surgery, planned prior to signing consent 
 
• 
admissions as per protocol for a planned medical/surgical procedure 
 
• 
routine health assessment requiring admission for baseline/trending of health status (eg, 
routine colonoscopy) 
 
• 
Medical/surgical admission other than to remedy ill health and planned prior to entry into the 
study. Appropriate documentation is required in these cases 
 
• 
Admission encountered for another life circumstance that carries no bearing on health 
status and requires no medical/surgical intervention (eg, lack of housing, economic 
inadequacy, caregiver respite, family circumstances, administrative reason). 
Events Not to Be Considered as AEs/SAEs 
Medical conditions present at the initial study visit that do not worsen in severity or frequency 
during the study are defined as baseline medical conditions, and are not to be considered AEs. 
AE/SAEs Observed in Association with Disease Progression 
Progression of the disease/disorder being studied assessed by measurement of lesions on 
radiographs or other methods as well as associated clinical signs or symptoms (including 
laboratory abnormalities) should not be reported as an (S)AE, unless the patient’s general 
condition is more severe than expected for the participant’s condition and/or unless the outcome is 
fatal within the adverse event reporting period. 
Adverse Events of Special Interest 
Adverse events of special interest can be serious or nonserious events; however, must always 
be reported on the SAE/AESI Report Form, and will follow the procedure described below for 
reporting SAEs and AESIs. 
Categories of AESIs related to M7824 include: 
• Infusion-related reactions including immediate hypersensitivity 
• Immune-related adverse events 
• Potential TGFβ-mediated skin adverse events 
• Treatment-related anemia adverse events 


115 
Clinical Study Protocol 9.0                                                      
MDA Cancer Center 
Bintrafusp Alpha- M7824                    
 
 15 June 2020 
 
 
 
Recording and Follow-Up of AE and/or SAE 
It is important that each AE report include a description of the event, its duration (onset and 
resolution dates and also onset and resolution times, when it is important to assess the time of AE 
onset relative to the recorded study intervention administration time), its severity, its causal 
relationship with the study intervention, any other potential causal factors, any treatment given or 
other action taken, including dose modification or discontinuation of the study intervention, and its 
outcome. In addition, serious cases should be identified and the appropriate seriousness criteria 
documented. 
Reporting Serious Adverse Events and Adverse Events of Special Interest Serious 
Adverse Events 
All events occurring during the conduct of a protocol and meeting the definition of a SAE must be 
reported to the IRB in accordance with the timeframes and procedures outlined in “The 
University of Texas M. D. Anderson Cancer Center Institutional Review Board Policy for 
Investigators on Reporting Serious Unanticipated Adverse Events for Drugs and Devices”. 
Unless stated otherwise in the protocol, all SAEs, expected or unexpected, must be reported to 
the IND Office, regardless of attribution (within 5 working days of knowledge of the event). 
 
SAEs, whether related or not related to study drug as detailed below, must be reported to EMD 
Serono within 5 working days from the time of knowledge of the event to: Pavithra Prasad, Fax: 
+49 6151 72 6914; E-mail: ICSR_CT_GPS@merckgroup.com 
. 
 
 
 
If only limited information is initially available, follow-up reports are required. (Note: Follow-up 
SAE reports should include the same investigator term(s) initially reported.) 
 
If an ongoing SAE changes in its intensity or relationship to study drug or if new information 
becomes available, a follow-up SAE report should be sent within 5 working days to the EMD 
Serono (or designee) using the same procedure used for transmitting the initial SAE report. 
 
All SAEs should be followed to resolution or stabilization. 
 
The principal investigator will ensure that all SAEs in the clinical database are reported to EMD 
Serono and any applicable health authority during the conduct of the study. 
 
SAEs will be reported on the EMD Serono approved form for prompt reporting (full form): “Internal 
SAE Report Form for Prompt Reporting” Institutional Review Board. 
SAEs will be submitted to both the Office of Protocol Research, Unit 1437 at The University of 
Texas MD Anderson Cancer Center and also sent to: 
 
MEDWATCH 
5600 Fishers Lane 
Rockville, MD 20852-9787 
Fax: 1-800-FDA-0178 (1-800-332-0178) 
http://www.accessdata.fda.gov/scripts/medwatch/ 


116 
Clinical Study Protocol 9.0                                                      
MDA Cancer Center 
Bintrafusp Alpha- M7824                    
 
 15 June 2020 
 
 
 
All SAEs should simultaneously be faxed or e-mailed to EMD  Serono to: 
Pavithra Prasad, Fax: +49 6151 72 6914; E-mail: ICSR_CT_GPS@merckgroup.com 
 
An SAE report should be completed for any event where doubt exists regarding its seriousness. 
 
If the investigator believes that an SAE is not related to study drug, but is potentially related to 
the conditions of the study (such as withdrawal of previous therapy or a complication of a study 
procedure), the relationship should be specified in the narrative section of the SAE Report Form. 
 
If only limited information is initially available, follow-up reports are required. (Note: Follow-up 
SAE reports should include the same investigator term(s) initially reported.) 
 
If an ongoing SAE changes in its intensity or relationship to study drug or if new information 
becomes available, a follow-up SAE report should be sent within 5 working days to EMD Serono 
using the same procedure used for transmitting the initial SAE report. All SAEs should be 
followed to resolution or stabilization. All SAEs should be followed to resolution or stabilization. 
 
• 
All life-threatening or fatal events, that are unexpected, and related to the study drug, must 
have a written report submitted within 24 hours (next working day) of knowledge of the event 
to the Safety Project Manager in the IND Office. 
• 
Unless otherwise noted, the electronic SAE application (eSAE) will be utilized for safety 
reporting to the IND Office and MDACC IRB. 
• 
Serious adverse events will be captured from the time of the first protocol-specific 
intervention, until 100 days after the last dose of drug, unless the participant 
withdraws consent. Serious adverse events must be followed until clinical recovery is 
complete and laboratory tests have returned to baseline, progression of the event has 
stabilized, or there has been acceptable resolution of the event. 
• 
Additionally, any serious adverse events that occur after the 100 day time period that 
are related to the study treatment must be reported to the IND Office. This may 
include the development of a secondary malignancy. 
 
Reporting to FDA: 
Serious adverse events will be forwarded to FDA by the IND Sponsor (Safety Project Manager 
IND Office) according to 21 CFR 312.32. 
 
It is the responsibility of the PI and the research team to ensure serious adverse events are 
reported according to the Code of Federal Regulations, Good Clinical Practices, the protocol 
guidelines, the sponsor’s guidelines, and Institutional Review Board policy. 
 
Pregnancy and Reporting 
 
If, following initiation of the investigational product, it is subsequently discovered that a study 
subject is pregnant or may have been pregnant at the time of investigational product exposure, 
including during at least 6 half-lives after product administration, the investigational product will be 
permanently discontinued in an appropriate manner (eg, dose tapering if necessary for subject 
safety). The investigator must immediately notify EMD Serono of this event via the Pregnancy 
Surveillance Form in accordance with SAE reporting procedures within 24 hours. 


117 
Clinical Study Protocol 9.0                                                      
MDA Cancer Center 
Bintrafusp Alpha- M7824                    
 
 15 June 2020 
 
 
 
 
Follow-up information regarding the course of the pregnancy, including perinatal and neonatal 
outcome and, where applicable, offspring information must be reported on the Pregnancy 
Surveillance Form [provided upon request from EMD Serono]. 
 
Any pregnancy that occurs in a female partner of a male study participant should be reported to 
EMd Serono. Information on this pregnancy will be collected on the Pregnancy Surveillance 
Form. 
 
Adverse Events of Special Interest 
In the event of a nonserious AESI, the Investigator will notify EMD Serono by completing the AESI 
Report Form within 24 hours. Serious AESIs must be reported in an expedited manner as SAEs 
as outlined above. 
Reporting of nonserious AESIs via paper report form is required as a back-up method only in the 
case of EDC failure. Names, addresses, and telephone and fax numbers will be included on the 
paper report form. 
 
The investigator (or physician designee) is responsible for verifying and providing source 
documentation for all adverse events and assigning the attribution for all adverse events for 
subjects enrolled. 
 
 
 
 
 
 
 
 
 
 
 
 
Recommended Adverse Event Recording Guidelines 
Attribution 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Grade 5 
Unrelated 
Phase I 
Phase I 
Phase I 
Phase II 
Phase 
I 
Phase 
II 
Phase       III 
Phase 
I 
Phase 
II 
Phase       III 
Unlikely 
Phase I 
Phase I 
Phase I 
Phase II 
Phase 
I 
Phase 
II 
Phase       III 
Phase 
I 
Phase 
II 
Phase       III 
Possible 
Phase I 
Phase II 
Phase 
I 
Phase 
II 
Phase        III 
Phase 
I 
Phase 
II 
Phase       III 
Phase 
I 
Phase 
II 
Phase       III 
Phase 
I 
Phase 
II 
Phase       III 
Probable 
Phase I 
Phase II 
Phase 
I 
Phase 
II 
Phase       III 
Phase 
I 
Phase 
II 
Phase       III 
Phase 
I 
Phase 
II 
Phase       III 
Phase 
I 
Phase 
II 
Phase       III 
Definitive 
Phase I 
Phase II 
Phase 
I 
Phase 
II 
Phase        III 
Phase 
I 
Phase 
II 
Phase       III 
Phase 
I 
Phase 
II 
Phase       III 
Phase 
I 
Phase 
II 
Phase       III 


118 
Clinical Study Protocol 9.0                                                      
MDA Cancer Center 
Bintrafusp Alpha- M7824                    
 
 15 June 2020 
 
 
 
Serious Adverse Event (SAE) Reporting 
 
An adverse event or suspected adverse reaction is considered “serious” if, in the view of either the 
investigator or the sponsor, it results in any of the following outcomes: 
 
• Death 
• A life-threatening adverse drug experience – any adverse experience that places the patient, in 
the view of the initial reporter, at immediate risk of death from the adverse experience as it 
occurred. It does not include an adverse experience that, had it occurred in a more severe form, 
might have caused death. 
• Inpatient hospitalization or prolongation of existing hospitalization 
• A persistent or significant incapacity or substantial disruption of the ability to conduct normal life 
functions. 
• A congenital anomaly/birth defect. 
 
Important medical events that may not result in death, be life-threatening, or require hospitalization 
may be considered a serious adverse drug experience when, based upon appropriate medical 
judgment, they may jeopardize the patient or subject and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition. Examples of such medical events 
include allergic bronchospasm requiring intensive treatment in an emergency room or at home, 
blood dyscrasias or convulsions that do not result in inpatient hospitalization, or the development of 
drug dependency or drug abuse (21 CFR 312.32). 
 
• Important medical events as defined above, may also be considered serious adverse events. Any 
important medical event can and should be reported as an SAE if deemed appropriate by the 
Principal Investigator or the IND Sponsor, IND Office. 
• All events occurring during the conduct of a protocol and meeting the definition of a SAE must be 
reported to the IRB in accordance with the timeframes and procedures outlined in “The University 
of Texas M. D. Anderson Cancer Center Institutional Review Board Policy for Investigators on 
Reporting Serious Unanticipated Adverse Events for Drugs and Devices”. Unless stated 
otherwise in the protocol, all SAEs, expected or unexpected, must be reported to the IND Office, 
regardless of attribution (within 5 working days of knowledge of the event). 
• All life-threatening or fatal events, that are unexpected, and related to the study drug, must 
have a written report submitted within 24 hours (next working day) of knowledge of the event to 
the Safety Project Manager in the IND Office. 
• Unless otherwise noted, the electronic SAE application (eSAE) will be utilized for safety reporting 
to the IND Office and MDACC IRB. 
• Serious adverse events will be captured from the time of the first protocol-specific intervention, 
until 100 days after the last dose of drug, unless the participant withdraws consent. Serious 
adverse events must be followed until clinical recovery is complete and laboratory tests have 
returned to baseline, progression of the event has stabilized, or there has been acceptable 
resolution of the event. 
• Additionally, any serious adverse events that occur after the 30 day time period that are related to 
the study treatment must be reported to the IND Office. This may include the development of a 
secondary malignancy. 
 
Reporting to FDA: 
• Serious adverse events will be forwarded to FDA by the IND Sponsor (Safety Project Manager 
IND Office) according to 21 CFR 312.32. 


119 
Clinical Study Protocol 9.0                                                      
MDA Cancer Center 
Bintrafusp Alpha- M7824                    
 
 15 June 2020 
 
 
 
It is the responsibility of the PI and the research team to ensure serious adverse events are 
reported according to the Code of Federal Regulations, Good Clinical Practices, the 
protocol guidelines, the sponsor’s guidelines, and Institutional Review Board policy.