Phase II Prospective Study of Bintrafusp Alfa in Previously Treated Patients With Recurrent and Metastatic (R/M) Non-keratinizing Nasopharyngeal Carcinoma (NPC)
Phase: PHASE2
Conditions: Nasopharyngeal Carcinoma, Recurrent Carcinoma, Metastatic Cancer, Non-keratinizing Carinoma
Sponsor: The University of Hong Kong

M7824 Clinical Protocol v2.0 dated 01-Dec-2021 
Page 1 of 116 
 
 
 
Phase II Prospective Study of Bintrafusp Alfa in 
Previously Treated Patients with Recurrent and 
Metastatic (R/M) Non-keratinizing Nasopharyngeal 
Carcinoma (NPC) 
 
Sponsor:  
 
 
 
The University of Hong Kong, Hong Kong 
Funder:  
 
 
 
Merck Healthcare KGaA, Darmstadt, Germany 
ClinicalTrials.gov Identifier: 
NCT04396886 
Local Institutional Review Boards: UW 19-675 
 
 

M7824 Clinical Protocol v2.0 dated 01-Dec-2021 
Page 2 of 116 
 
 
Study Summary 
Protocol Title: 
Phase II prospective study of bintrafusp alfa in previously treated 
patients with recurrent and metastatic (R/M) non-keratinizing 
nasopharyngeal carcinoma (NPC) 
Protocol Version and 
Date 
Version 2.0 dated 01 Dec 2021 
Principal Investigator: 
Dr. CHIANG Chi Leung 
Department of Clinical Oncology 
The University of Hong Kong 
E-mail: chiangcl@hku.hk 
Telephone: +852-2255-4352 
Co-Investigators: 
Dr. LAM Tai Chung 
Department of Clinical Oncology 
The University of Hong Kong 
E-mail: lamtc@hku.hk  
Telephone: +852-2255-4352 
 
Dr. LI Chun Bong James 
Department of Paediatrics and Adolescent Medicine 
The University of Hong Kong 
E-mail: jamesli@hku.hk  
Telephone: +852-2819-9863 
Consulting Statistician: 
Dr. Horace CHOI Cheuk Wai 
Department of Clinical Oncology 
The University of Hong Kong 
E-mail: hcchoi@hku.hk 
Telephone: +852-2255-4352 
Sponsor: 
The University of Hong Kong 
Funder:  
Merck Healthcare KGaA, Darmstadt, Germany (monetary and 
drug support)  
Laboratory: 
Hospital Pathology Service, 
Queen Mary Hospital, 
Pokfulam, Hong Kong 

M7824 Clinical Protocol v2.0 dated 01-Dec-2021 
Page 3 of 116 
 
 
Protocol-specific Sponsor contact information can be found in the Investigator(s) Study File. 
Laboratory-related information can be found in the Investigator(s) Study File, Section 
named ‘Laboratory Documents’. 
 
 
 
Investigator Signatory 
I agree to conduct this Clinical Study in accordance with the designed outlined in this protocol 
and to abide by all provisions of this protocol. 
 
 
 
 
Name 
 
 
 
 
Signature 
 
 
 
 
Date 

M7824 Clinical Protocol v2.0 dated 01-Dec-2021 
Page 4 of 116 
 
 
TABLE OF CONTENT 
1 
BACKGROUND ................................................................................................................... 8 
2 
STUDY OBJECTIVES ...................................................................................................... 15 
2.1 
Primary Objective .......................................................................................................... 15 
2.2 
Secondary Objectives .................................................................................................... 15 
2.3 
Exploratory Objectives .................................................................................................. 15 
2.4 
Study Design .................................................................................................................. 15 
2.5 
Study Participants .......................................................................................................... 16 
3 
ELIGIBILITY CRITERIA ................................................................................................ 16 
3.1 
Inclusion Criteria ........................................................................................................... 16 
3.2 
Exclusion Criteria .......................................................................................................... 16 
4 
STUDY SCHEMA .............................................................................................................. 18 
4.1 
Informed Consent .......................................................................................................... 18 
4.2 
Registration Guidelines .................................................................................................. 19 
5 
STUDY INTERVENTION ................................................................................................ 19 
5.1 
General Information of Study Intervention Bintrafusp alfa ........................................... 19 
5.2 
Pharmaceutical Properties and Description of the Formulation .................................... 19 
5.3 
Handling of the Dosage Form ........................................................................................ 19 
5.4 
Instructions for Storage .................................................................................................. 20 
5.5 
Bintrafusp Alfa Administration ..................................................................................... 20 
5.6 
Bintrafusp Alfa Adverse Event Management ................................................................ 21 
5.6.1 
Bintrafusp Alfa Adverse Events ............................................................ 21 
5.6.2 
Dose Modifications for Bintrafusp Alfa as Single Agent...................... 22 

M7824 Clinical Protocol v2.0 dated 01-Dec-2021 
Page 5 of 116 
 
 
5.6.3 
Adverse Drug Reaction Requiring Bintrafusp Alfa Discontinuation or 
Delays 22 
5.6.4 
Management of Infusion Related Reaction (IRR) ................................. 23 
5.6.5 
Management of Immune-Related Adverse Events (IrAEs) ................... 25 
Management of Skin irAEs in Patients Treated With ICPis ..................................................... 27 
Management of Bleeding irAEs in Patients Treated With ICPis .............................................. 35 
Management of GI irAEs in Patients Treated With ICPis ........................................................ 38 
Management of Lung irAEs in Patients Treated With ICPis .................................................... 45 
Management of Endocrine irAEs in Patients Treated With ICPis ........................................... 46 
Management of Musculoskeletal irAEs in Patients Treated With ICPis ................................. 56 
Management of Renal irAEs in Patients Treated With ICPis ................................................... 63 
Management of Nervous System irAEs in Patients Treated With ICPis .................................. 65 
Management of Hematologic irAEs in Patients Treated With ICPis ....................................... 74 
Management of Cardiovascular irAEs in Patients Treated With ICPis ................................... 87 
Management of Ocular irAEs in Patients Treated With ICPis ................................................. 90 
5.6.6 
Management of Adverse Skin Reaction ................................................ 93 
5.6.7 
Management of Treatment-Related Anemia ......................................... 93 
5.6.8 
Management of Bleeding Adverse Events ............................................ 94 
5.6.9 
Alterations in Wound Healing or Repair of Tissue Damages ............... 96 
5.6.10 
Embryo-Fetal Toxicities ........................................................................ 96 
5.6.11 
Mild to Moderate Bleeding of the Mucous Membranes (Mucosal Bleeding 
Events)  ............................................................................................................... 96 
6 
FOLLOW UP AND OUTCOME EVALUATION .......................................................... 96 
6.1 
Follow-Up Schedule ...................................................................................................... 96 

M7824 Clinical Protocol v2.0 dated 01-Dec-2021 
Page 6 of 116 
 
 
6.2 
Outcome Measures ........................................................................................................ 97 
6.3 
Follow-Up and Record of Events .................................................................................. 98 
6.4 
Criteria for Removal from Protocol Treatment ............................................................. 98 
6.5 
Exploratory Biomarkers ................................................................................................. 98 
6.6 
Safety Reporting ............................................................................................................ 99 
6.6.1 
Adverse Events ...................................................................................... 99 
6.6.2 
Serious Adverse Events (SAE) ............................................................ 100 
6.6.3 
Adverse Events of Special Interest (AESI) ......................................... 100 
6.6.4 
Pregnancy Reports ............................................................................... 101 
6.6.5 
Assessment of Causality of Adverse Events ....................................... 101 
6.6.6 
Methods of Recording Adverse Events ............................................... 101 
6.6.7 
Procedure of Reporting Serious Adverse Events ................................ 102 
6.6.8 
Monitoring of Subjects with Adverse Events ...................................... 103 
7 
STATISTICS ..................................................................................................................... 104 
7.1 
Statistical Analysis ....................................................................................................... 104 
7.2 
Sample Size Calculation .............................................................................................. 104 
7.3 
Early Stopping Rule ..................................................................................................... 105 
8 
ETHICAL, REGULATORY & STUDY OVERSIGHT CONSIDERATIONS.......... 105 
8.1 
Responsibilities of the Investigator(s) ......................................................................... 105 
8.2 
Subject Information ..................................................................................................... 105 
8.3 
Informed Consent ........................................................................................................ 105 
8.4 
Compensation to Subjects ............................................................................................ 106 
8.5 
Ethics Committee or Institutional Review Board ........................................................ 106 

M7824 Clinical Protocol v2.0 dated 01-Dec-2021 
Page 7 of 116 
 
 
8.6 
Role of Funding Source ............................................................................................... 106 
8.7 
Publication Policy ........................................................................................................ 106 
9 
STUDY MANAGEMENT ............................................................................................... 108 
9.1 
Data Quality Assurance ............................................................................................ 108 
9.2 
Direct Access to Source Data/Documents ............................................................... 108 
9.3 
Study File and Archiving ......................................................................................... 109 
10 REFERENCES ................................................................................................................. 110 
11 APPENDIX ........................................................................................................................ 115 
 
 

M7824 Clinical Protocol v2.0 dated 01-Dec-2021 
Page 8 of 116 
 
 
1 
BACKGROUND 
Background of the Study Population   
 
Nasopharyngeal cancer (NPC) represents a unique malignancy with skewed geographical 
distribution and greater tendency among head and neck cancer for metastases. (1) Worldwide, NPC 
is an uncommon cancer with approximately 87,000 incident cases and 50,000 deaths reported in 
2012. Over 80% of new cases occurred in Asia and its incidence peaks at Southern China, which 
is 20-50 times higher than that in Western Countries. (2)  
 
Even the best available treatment in modern practice, retrospective reports of patients treated with 
intensity-modulated radiotherapy (IMRT) over the past decade revealed that 5% to 15% of patients 
would develop local failure, and 15% to 30% will experience distant failure. Also, around 5% of 
patients present with de novo metastases. (3) Despite the varying success of aggressive local 
therapy for metastatic lesion(s) in highly selected population, a vast majority of R/M cases are 
only amendable to systemic therapy.  
 
Platinum-containing doublet chemotherapy regimens are generally considered the standard first-
line systemic therapy. Evidence suggests that the combination of Cisplatin plus Gemcitabine is the 
preferred regime. In the randomized study, this combination was associated with better median 
progression-free survival (7.0 months vs. 5.6 months, hazard ratio [HR] 0.55, 95% CI 0.44-0.68) 
and overall survival (29.1 versus 20.9 months, HR 0.62, 95% CI 0.45-0.84) compared to Cisplatin 
plus 5-fluorouracil (5-FU). (4)  
 
Second-line systemic therapy may be considered for patients with a good performance status who 
become refractory to Cisplatin-based regimens. Multiple single-arm phase II trials have 
demonstrated several mono-therapies were associated with overall response rates ranging from 
3% to 50%, and in approximately time to progression (TTP) of 4 months. (5-10) However, we 
lack randomized data to recommend single regime over the others. Among the most commonly 
used salvage chemotherapy regimens are Gemcitabine, Capecitabine, and Docetaxel as follows:  
 
Regime 
Line Phase N 
ORR 
PFS/TTP 
OS 
Gemcitabine 
2/3 
II 
27 
48.1% 5.1 months 
10.5 months 
Gemcitabine 
1+ 
II 
32 
43.8% 5.1 months 
16 months 
Capecitabine 
2-4 
II 
17 
23.5% 4.9 months 
7.6 months 
Docetaxel  
2-4 
II 
30 
36.7% 5.3 months 
12.8 months 
Table 1. Mono Chemotherapy Regimens Overview 
 
Attempts have been made to increase the overall response rate (ORR) by using combination 
regime. Despite the increased ORR, there were minimal improvement of durability of response 
with progression-free survival (PFS) and TTP of 5-6 months but more toxic. (11-12) Also, several 
exploratory phase II studies of targeted therapy have been conducted, for example using epidermal 
growth factor receptor inhibitors (e.g., Gefitinib and Cetuximab) or angiogenesis inhibitors (e.g. 
Pazopanib and Sunitinib). (13-16) However these studies were failed to meet their primary 
endpoints. For instance, in the studies of pazopanib and sunitinib, the median TTP was only around 
4 months. 
 
 

M7824 Clinical Protocol v2.0 dated 01-Dec-2021 
Page 9 of 116 
 
 
In brief, despite the advancement of treatment and the fact that NPC was historically described as 
chemo-sensitive and radio-sensitive disease, over half of those diagnosed with NPC will 
eventually succumbed of their disease. Patients who failed the first line Platinum based therapy, 
multiple options exist, but the responses are usually modest, and none have gained the regulatory 
approval.  
 
Pre-clinical Evidence for the Role of PD-1/PD-L1 in NPC 
 
NPC is distinguished from other head and neck cancers as being an Epstein-Barr virus (EBV)-
driven malignancy. The chronic EBV infection leads to increased viral EBV load. This chronically 
increased virus load results in and correlates with increased expression of PD-1 on cytotoxic 
memory T-cells, leading to T-cell exhaustion with resultant decreased function and number of 
these cells. (17) This up-regulation is specific for PD-1 as CTLA-4 levels were unaffected. (18-
19) Increased PD-1 expression also occurs in the virally affected host cells. The relative 
quantitative and qualitative CD 8+ T-cell decrease leads to altered T-cell immunity, which 
prevents clearance of the EBV infection and allows further increase of viremia. EBV-latent 
infection is associated with expression of LMP-1 protein, which induces PD-L1 expression. (20) 
Increased PD-1 and PD-L1 work together to suppress the immune system, leading to decreased 
EBV cellular immunity. In vitro, anti-PD-L1 blockade was demonstrated to restore exhausted 
CD8+ T-cell function and decrease viral load. (18) Therefore, anti-PD-L1 blockade holds the 
promising potential in restoring anti-EBV tumor CD-8 positive T-cells, decrease viral load and 
target NPC.  
 
Clinical Evidence for anti-PD1 / anti-PD L1 Therapy in NPC  
 
KEYNOTE-028 (NCT02054806) is a non-randomized, multi-cohort, phase Ib trial of 
Pembrolizumab in patients with PD-L1–positive advanced solid tumors. PD-L1 positivity, defined 
as PD-L1 expression by immunohistochemistry (IHC) (≥ 1% PD-L1 membrane staining of tumor 
cells or tumor-infiltrating lymphocytes), was required for the study entry. The key eligibility 
criteria of NPC cohort was unresectable or metastatic NPC patients who are not amendable to 
curative treatment whose disease progressed on at least one line of prior therapies. (21)  
 
Enrolled subjects were predominantly of Asian ethnicity (67%), male (77.8%), with an Eastern 
Cooperative Oncology Group (ECOG) performance status of 1 (74%). Of note, approximately 
two-thirds had received 3 or more prior treatments for metastatic disease. All patients had received 
prior platinum-based therapy. 98% of screened and 100% of evaluable subjects were PD-L1 
positive. In this heavily pre-treated cohort, evidence of clinical activity was demonstrated, as 
22.2% had a confirmed ORR, 25.9% had unconfirmed response, and 51.9% had stable disease 
(SD). With a median follow-up of 7.8 months, the 6-month and 12-month progression free survival 
(PFS) rate was 49.7% and 30.1% respectively. Notably, a 6-month and 12-month overall survival 
(OS) rate was 85.2% and 66.7% demonstrated respectively. Grade 3 ≥ drug-related adverse events 
occurred in 29.6% of patients, and there was one drug-related death due to sepsis.   
 
NCI-9742 is an international, multi-center study of Nivolumab in recurrent or metastatic NPC. 
(22) Similar population of advanced or metastatic NPC patients who are not amendable to curative 
treatment whose disease progressed on at least one line of platinum therapies was enrolled. 
However, PD-L1 positivity is not the mandatory eligibility requirement.   

M7824 Clinical Protocol v2.0 dated 01-Dec-2021 
Page 10 of 116 
 
 
Enrolled subjects were predominantly of Asian ethnicity (82%), male (77.8%), with an Eastern 
Cooperative Oncology Group (ECOG) performance status of 1-2 (62%). Again, the enrolled 
subjects are heavily pre-treated with approximately 60% had received 3 or more prior treatments 
for metastatic disease. A total of 44 patients were evaluated and the overall ORR was 20.5% (CR 
= 1; PR= 8). Nine patients received nivolumab for ≥12 months (20%). The 1-year OS rate was 
59% and 1-year PFS rate was 19.3%. Treatment was well tolerated and 22.2% of subjects 
experienced ≥ grade 3 drug-related adverse events.  
 
Collectively, anti-PD1 therapy has promising activity in R/M NPC and manageable toxicity 
profile. The overall survival rate was compared favorably with historical data in similar 
populations. PD-L1 is a potential predictive biomarker of efficacy.    
 
Rationale of Blocking TGF-B Pathway  
 
Despite the promising clinical activity, only 20% of NPC patients respond to anti–PD-1/PD-L1 
therapies. Thus, there is an urgent need to improve objective response rates. One strategy is to 
combine anti–PD-L1/PD-1 with other immunotherapies, (23) as exemplified by the combination 
of anti–PD-1 and anti–CTLA-4, which has been approved for advanced melanoma. (24)  
 
In normal physiology, the regulatory cytokine transforming growth factor-β (TGF-β) functions to 
maintain immunological self-tolerance. (25-27) However, TGF-β can promote tumor progression 
and facilitate tumor immune evasion through its effects on the innate and adaptive immune 
systems. The three TGF-β isoforms, TGF-β1, TGF-β2, and TGF-β3 (25, 27), are highly expressed 
in many tumor types, and their serum concentrations correlate with poor clinical outcome. (27-29) 
TGF-β functions as an autocrine or paracrine signal within the tumor microenvironment, where it 
promotes tumor progression via stromal modification, angiogenesis, and induction of epithelial-
mesenchymal transition (EMT). (30-32) TGF-β signaling in myeloid cells is also critical in driving 
metastasis. (33) In addition, TGF-β1 can directly inhibit T cell division and acquisition of effector 
function and natural killer (NK) cell function. (34-38) Furthermore, because the up-regulation of 
TGF-β signaling–associated genes has been linked to anti–PD-1 resistance, blockade of TGF-β 
signaling may target mechanisms of resistance and sensitize tumors to anti–PD-1/PD-L1 therapies. 
(39)  
 
In NPC patients, high levels of TGF-β1 are positively correlated with disease stage. (40) Up-
regulation of TGF-β pathway is associated with aggressive phenotype of NPC by inducing EMT, 
that ZEB1/2 genes, Flot1/2, human high mobility group A2 (HMGA2) are the possible mediators. 
(41-44) Furthermore, a recent report found that miR-449b, a miRNA strongly associated with NPC 
distant metastasis, activates of the TGF-β pathway, which subsequently induces Cisplatin 
resistance in NPC through the PTEN/AKT pathway. (45)   
All these provide rationale for dual blockage of PD-1/PD-L1 axis and TGF-b pathway. Merck 
Healthcare KgGA, Darmstadt, Germany developed M7824 (MSB0011359C) – International 
Nonproprietary Name (INN) known as bintrafusp alfa, a bi-functional fusion protein designed to 
simultaneously block the TGF-β and PD-L1 pathways. Bintrafusp alfa (M7824) is an 
investigational bifunctional immunotherapy designed to simultaneously block 2 pro-tumorigenic 
immunosuppressive pathways, TGF-β and PD-L1, to inhibit tumor growth by potentially restoring 
and enhancing antitumor responses.  
 
 

M7824 Clinical Protocol v2.0 dated 01-Dec-2021 
Page 11 of 116 
 
 
Pre-Clinical Evidence for Bintrafusp Alfa 
 
Bintrafusp alfa induces superior tumor regression compared with equimolar dose of anti-PD-L1 
therapy in the EMT-6 orthotopic breast tumor model and MC38 colorectal cancer model. 
Bintrafusp alfa has been shown to reduce the incidence of lung metastases than anti-PD L1 therapy 
in vitro. In addition, bintrafusp alfa provides long-term antitumor immunity in tumor re-challenge 
mouse models. When bintrafusp alfa-cured mice were re-challenged subcutaneously with EMT-6 
cells without additional bintrafusp alfa treatment, they did not develop tumors, whereas treatment-
naive mice rapidly developed tumors. (46)   
 
Clinical Evidence for Bintrafusp Alfa in Other Cancers 
 
In the first-in-human phase I trial of bintrafusp alfa to determine its safety, pharmacokinetics, and 
efficacy in 19 patients with heavily pretreated advanced solid tumors using a 3+3 dose-escalation 
design (NCT02517398), eligible patients received bintrafusp alfa at 1, 3, 10, or 20 mg/kg once 
every 2 weeks until confirmed progression, unacceptable toxicity, or trial withdrawal. Grade ≥3 
treatment-related adverse events (TRAE) occurred in four patients (skin infection secondary to 
localized bullous pemphigoid, asymptomatic lipase increase, colitis with associated anemia, and 
gastroparesis with hypokalemia). (47) The maximally tolerated dose (MTD) was not reached. 
Bintrafusp alfa saturated peripheral PD-L1 and sequestered any released plasma TGF-β1, -β2, and 
-β3 throughout the dosing period at >1 mg/kg. There were signs of efficacy across all dose levels, 
including one ongoing confirmed complete response (cervical cancer), two durable confirmed 
partial responses (PR; pancreatic cancer; anal cancer), one near-PR (cervical cancer), and two 
cases of prolonged stable disease in patients with growing disease at study entry (pancreatic 
cancer; carcinoid). 
 
In the phase I trial by J Strauss et al. to evaluate the efficacy and safety of bintrafusp alfa in human 
papilloma virus (HPV) associated cancers (NCT03427411), (48) 16 patients (9 cervical, 4 anal, 
and 3 head and neck squamous cell cancer) were enrolled, objective response rate (ORR) of 35.3% 
and 41.7% in HPV-associated cancer and HPV-positive patients were observed respectively. 
Grade 3 or above treatment-related toxicities were seen in 18.8% (3/16) of patients (colitis, cystitis, 
and gastroparesis).  
 
In the expansion cohort of ongoing phase I trial NCT02517398, patients with advanced non-small 
cell lung cancer (NSCLC) unselected for PD-L1 who progressed following first line standard 
treatment were randomized to receive bintrafusp alfa 500 mg (n = 40) or 1200 mg (n = 40) every 
2 weeks. At the recommended phase II dose 1200mg, clinical activity was seen across PD-L1 sub-
group. The ORR was 27.5%, 40.7%, and 71.4% in the entire group, PD-L1 + (≥1%), and PD-L1 
high (≥80%) respectively. Treatment was well tolerated with Grade ≥3 TRAEs occurred in 25% 
of patients; the commonest TRAEs were pruritus (18.8%), maculo-papular rash (17.5%), and 
decreased appetite (12.5%). 7.5% patients discontinued treatment due to TRAEs. No treatment 
related death reported. (49)  
 
In another phase I study in Asian patients pretreated recurrent or refractory gastric cancer (NCT 
02699515), 31 heavily pretreated patients received bintrafusp alfa for a median duration of 6.1 
(range: 2-30) weeks; 8 patients remained on treatment. Four patients (12.9%) experienced grade 3 
TRAE (anemia and diarrhea 1 each and 2 rash). No treatment-related grade 4 AEs occurred. One 

M7824 Clinical Protocol v2.0 dated 01-Dec-2021 
Page 12 of 116 
 
 
grade 5 event was suspected due to rupture of pre-existing thoracic aortic aneurysm. The ORR of 
16.1% based on investigator assessment was reported. (50)  
 
Taken together, bintrafusp alfa has encouraging anti-tumor activity and compared favorably to 
anti-PD-1 or anti-PD-L1 antibodies. The treatment is well tolerated and has manageable toxicity 
profile.  
 
Three clinical studies in two types of cancers (a type of lung cancer called NSCLC and biliary 
tract cancer) have been recently discontinued as improved efficacy versus other available therapies 
could not be shown.  In some patients in these studies, the patients’ tumors continued to grow 
resulting in fatal outcome in some cases. It is therefore possible that the symptoms of patients’ 
condition will not improve during the study or may even worsen and have a fatal outcome. 
 
Rationale for Dose Selection of Bintrafusp Alfa 
 
The selection of 1200 mg q2w RP2D for bintrafusp alfa is based on the available clinical data from 
Phase I Study EMR200647-001 and Study MS200647 0008, including safety/tolerability, PK, and 
PD (PD-L1 TO in PBMCs and TGFβ plasma concentrations), PK-PD correlation analysis, as well 
as efficacy of bintrafusp alfa following 500 and 1200 mg q2w in 2L NSCLC cohorts from Study 
EMR200647-001. The selection of RP2D for bintrafusp alfa is also supported by popPK and 
exposure-response modeling and simulation. 
 
Specifically: 
 Clinical PK-PD profiles from dose escalation cohorts of Phase I studies were used to establish 
a target serum concentration (50 μg/mL) that inhibits all 4 targets of bintrafusp alfa in blood. 
Based on popPK modeling, > 95% of participants dosed with 1200 mg q2w of bintrafusp alfa 
are expected to achieve trough concentration at steady-state (Ctrough,ss) above the target 
concentration of 50 μg/mL. Following a single IV infusion, approximately dose-proportional 
increase in all exposure metrics and constant terminal t1/2 was observed at doses higher than 3 
mg/kg, suggesting that target-mediated clearance mechanism is saturated at 1200 mg q2w dose. 
 Exposure-response and dose-response for efficacy were assessed in participants with the 2L 
NSCLC randomized into 2 dose levels: 500 mg q2w and 1200 mg q2w. There was a trend 
towards an association between exposure variables and efficacy variables, but the effect size 
was relatively small. Overall, dose-efficacy and exposure-efficacy evaluations supported 
selection of 1200 mg q2w as the RP2D for NSCLC participants. Based on the mechanism of 
action of bintrafusp alfa, clinical experience with other checkpoint inhibitors, and the fact that 
there were no clinically relevant differences in bintrafusp alfa exposures among tumor types, 
there is no evidence to suggest that the pharmacologically active/efficacious dose would differ 
substantially among tumor types. 
 Overall safety/tolerability data from Phase I studies and exposure-safety analysis conducted on 
an integrated data-set with > 670 participants supported the selection of 1200 mg q2w as the 
RP2D. The highest dose for bintrafusp alfa tested was 30 mg/kg (2100 mg for a 70 kg 
participant) and the MTD was not reached. At 1200 mg q2w the overall emerging safety profile 
of bintrafusp alfa is considered manageable. Although apparent exposure-safety associations 
were observed for some AE, bintrafusp alfa exposure metrics were generally weakly correlated 

M7824 Clinical Protocol v2.0 dated 01-Dec-2021 
Page 13 of 116 
 
 
with probability of AEs and effect size were relatively small. 
 The selection of flat dose versus mg/kg dosing approach is supported by modeling and 
simulations, which showed that variability in exposure was indeed lower for flat dosing 
compared with weight-based dosing. 
In summary, integration of all available Phase I data and modeling and simulations support the 
selection of 1200 mg as the RP2D for q2w dosing of bintrafusp alfa. In addition, none of the 
examined intrinsic factors were considered clinically meaningful and no dose adjustments related 
to these intrinsic factors are warranted. 
 
Study Hypothesis 
 
Based on the above findings, we hypothesize that bintrafusp alfa offers better response rate than 
historical results by anti-PD-1/ anti-PD L1 therapy in previously platinum treated recurrent or 
metastatic NPC patients. 
 
Rationale for biomarkers and exploratory analysis  
 
(a) PD-L1 status  
 
NPC often exhibits a dense lymphocytic infiltrate and increased PD-L1 expression. (51) The 
prognostic role of PD-L1 expression in NPC remains inconclusive, but it probably because of 
different assays and scoring methods used across studies; (52-54) and the predictive utility of PD-
L1 expression is affected by the differential expression in immune cells versus tumor cells. (55) 
Studies that had made such a distinction found that PD-L1 was expressed in 24% to 33% of tumor 
cells and 40% to 75% of immune cells. (53-54) In the NCI-9742 study, a non-significant higher 
ORR rate was observed in PD-L1 positive tumor among R/M NPC patients who receiving 
Nivolumab;(22) similar findings were reported in another study using Pembrolizumab. (21) The 
findings are consistent with other disease sites that checkpoint inhibitor is more efficacious in PD-
L1+ tumors. (56-57)  
 
(b) Plasma EBV-DNA Level  
 
Circulating fragments of EBV-derived deoxyribonucleic acid (DNA) can be detected in 95% of 
patients with advanced NPC and have been shown to carry prognostic and predictive value. (58) 
High plasma EBV-DNA levels are a poor prognostic factor (59), and the dynamic change of 
plasma EBV-DNA level after chemotherapy or chemo-radiotherapy correlate with the efficacy. 
(60-61) Similar findings were seen in patients receiving Pembrolizumab, but the sample size is 
small. (62) 
 
(c) HLA Protein Expression  
 
Loss of human leukocyte antigen (HLA) class I expression in solid tumor associated with poor 
prognosis and more immunosuppressive environment. (63) Around 30% of primary NPC tumors 
harbor major histocompatibility complex (MHC) class I gene aberrations, with inactivating 
mutations and rearrangements in the human leukocyte antigen (HLA)–A and HLA-B genes being 

M7824 Clinical Protocol v2.0 dated 01-Dec-2021 
Page 14 of 116 
 
 
the most common and account for 50% of cases, which invariably results in the loss of HLA-A 
and HLA-B protein expression. (64) Even a higher percentage of MHC down-regulation is 
expected in metastatic tumor in allowing the MHC-class I negative tumors to escape from T-cell 
killing. (65) Although the intact MHC-antigen presenting machinery is thought to be the perquisite 
of the actions of PD1 inhibitors; it is intriguing to find that in R/M NPC patients receiving 
Nivolumab, those with loss of HLA protein expression had better prognosis. (22) Similarly, over 
half of patients with Hodgkin’s lymphoma who responded to PD-1 inhibitors have total loss of 
MHC class I expression. (66) However, in melanoma, an association between response to PD-L1 
inhibitor and intact MHC-I gene expression has been reported. (67-68) The role of MHC class I 
down-regulation in NPC patients receiving immunotherapy thus remains to be evaluated, and this 
will shed light on the mechanism of action of bintrafusp alfa in R/M NPC patients.  
 
(d) Immune Markers 
 
Flow cytometry analyses revealed that, bintrafusp alfa increased the density of CD8+ tumor-
infiltrating lymphocytes (TIL), tumor-infiltrating NK cells (TINKs), tumor-associated dendritic 
cells (TADCs), tumor-associated monocytes, but significantly decreased the density of tumor-
associated neutrophils (TANs) and PD-1+ tumor-associated macrophage (TAM). Further analysis 
by immune cell depletion studies shown that the anti-tumor activity of bintrafusp alfa was mainly 
mediated by CD8+ T-cells and NK cells. Also, RNA sequencing has demonstrated that bintrafusp 
alfa promotes the expression of immune cell signature genes (69).  
 
There are also recent findings suggest that exosomal PD-L1 plays an important role by causing 
immuno-suppression in melanoma and breast cancer. (70-71) High level of circulating exosomal 
PD-L1 pre-anti-PD-1 treatment may reflect the “exhaustion” of T-cells, while an increase in the 
level of circulating exosomal PD-L1 after anti-PD-1 treatment may reflect re-invigoration of T-
cell activity against melanoma. So exosomal PD-L1 may be a sensitive marker to predict response 
check-point inhibitor immunotherapy. 
 
(e) Immune-related RECIST (ir-RECIST)  
 
Immunotherapeutic agents may produce anti-tumor effects by potentiating endogenous cancer-
specific immune responses. The response patterns seen with such an approach may extend beyond 
the typical time course of responses seen with cytotoxic agents and can manifest a clinical response 
after an initial increase in tumor burden or even the appearance of new lesions. Standard RECIST 
1.1 may, thus, not provide an accurate response assessment of bintrafusp alfa. Based on an analysis 
of patients with melanoma enrolled with KEYNOTE-001, 7% of evaluable patients experienced 
delayed or early tumor pseudo-progression. Of note, patients who had progressive disease by 
RECIST 1.1, but not immune-related response criteria, has longer OS than patients with PD by 
both criteria. Additionally, the data suggest that RECIST 1.1 may underestimate the benefit of 
anti-PD1 therapy in approximately 15% of patients. (72) These findings support the need to apply 
a modification to RECIST 1.1 that takes into account the unique patterns of atypical response in 
immunotherapy and enable treatment beyond initial radiographic progression. Immune-related 
RECIST is RECIST 1.1 adapted to account for the unique tumor response seen with 
immunotherapy as described in Nishino et al. (73)  

M7824 Clinical Protocol v2.0 dated 01-Dec-2021 
Page 15 of 116 
 
 
2 
STUDY OBJECTIVES 
2.1 
Primary Objective 
 
1. To evaluate the tumor objective response rate (ORR) to bintrafusp alfa in previously treated 
R/M NPC patients per response evaluation criteria of solid tumor (RECIST) version 1.1  
 
2.2 
Secondary Objectives  
 
1. To assess the progression-free survival (PFS) per RECIST version 1.1 
2. To assess the time-to-progression (TTP) per RECIST version 1.1 
3. To assess the median survival, overall survival (OS) and survival rate in 12 months and 24 
months  
4. To evaluate the disease control rate (DCR), duration of response (DOR), and time to 
response (TTR) in previously treated R/M NPC patients receiving bintrafusp alfa 
5. To measure the toxicities and tolerability in previously treated R/M NPC patients receiving 
bintrafusp alfa 
6. To investigate the relationship between the response to bintrafusp alfa and plasma Epstein-
Barr virus (EBV) deoxyribonucleic acid (DNA) level  
7. To evaluate ORR, PFS and TTP, OS, and DCR per immune-related RECIST (irRECIST) 
8. To evaluate the patient-reported quality of life (QoL) during treatment 
 
2.3 
Exploratory Objectives 
 
1. To investigate the association between treatment outcome and expression of programmed 
cell death-ligand (PD-L1) in archived NPC tissues 
2. To explore the relationship between response to treatment (ORR, PFS, and overall survival 
OS) and TGF-β1 
3. To explore the relationship between response to treatment (ORR, PFS, and overall survival 
OS) and the profile of exosomal PD-L1 
 
 
2.4 
Study Design  
 
This is a prospective phase II, single arm clinical trial conducted in Queen Mary Hospital (Hong 
Kong) assessing the efficacy and safety of bintrafusp alfa in previously treated recurrent / 
metastatic nasopharyngeal cancer patients. 
 
 

M7824 Clinical Protocol v2.0 dated 01-Dec-2021 
Page 16 of 116 
 
 
2.5 
Study Participants  
 
A total of 38 patients will be accrued to assess the potential benefit of bintrafusp alfa. 
 
3 
ELIGIBILITY CRITERIA  
3.1 
Inclusion Criteria  
 
1. Histologically or cytologically confirmed non-keratinizing differentiated (World Health 
Organization WHO Type II) or undifferentiated (WHO Type III) nasopharyngeal 
carcinoma (NPC) that has recurred at regional or / and distant sites 
2. Measurable disease according to the RECIST criteria (version 1.1) for the evaluation of 
measurable disease 
3. Received one or more lines of chemotherapy, which must include prior treatment with a 
platinum agent either  
a. For the treatment of metastatic or recurrent disease 
b. Experienced progression of disease within 6 months following completion of a 
platinum-based combination therapy as part of (neo)-adjuvant therapy  
4. Male or female subjects with age: 18-79 years old 
5. Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2 
6. No prior immunotherapy  
7. Written informed consent obtained for clinical trial participation and providing archival 
tumor tissue, if available 
8. Females of childbearing potential or non-sterilized male who are sexually active must use 
a highly effective method of contraception 
9. Females of childbearing potential must have negative serum or urine pregnancy test 
10. Have life expectancy ≥ 3 months 
11. Adequate organ function as defined as: 
a. Absolute neutrophil count ≥ 1.5 x 10^9/L 
b. Platelet count ≥ 100 x 10^9/L 
c. Hemoglobin >= 8.0 g/dL 
d. Serum alanine aminotransferase ([ALT]; serum glutamate-pyruvate transferase 
[SGPT]), or serum aspartate aminotransferase [AST] where available at the center) 
< 2.5 x upper limit of normal (ULN), OR < 5 x ULN in the presence of liver 
metastases 
e. Serum total bilirubin < 2 x ULN 
f. Serum creatinine < 1.5 x ULN 
 
3.2 
Exclusion Criteria  
 
1. Prior invasive malignancy within 2 years except for non-invasive malignancies such as 
cervical carcinoma in situ, in situ prostate cancer, non-melanomatous carcinoma of the 
skin, lobular or ductal carcinoma in situ of the breast that has been surgically cured 
2. Isolated local recurrence or persistent disease  
3. Has disease that is suitable for local therapy administrated with curative intent  

M7824 Clinical Protocol v2.0 dated 01-Dec-2021 
Page 17 of 116 
 
 
4. Severe, active co-morbidity 
5. Currently participating in and receiving clinical trial treatment or has participated in a trial 
of an investigational agent and received study treatment or used an investigational device 
within 4 weeks of the first dose of treatment 
6. Has prior chemotherapy, targeted therapy, or radiation therapy within 2 weeks prior to 
study Day 1 or who has not recovered (≤ grade 1 or at baseline) from adverse events due 
to previous administered agent 
7. Untreated active central nervous system (CNS) metastatic disease, lepto-meningeal 
disease, or cord compression 
8. Clinically significant (active) cardiovascular disease: cerebral vascular accident/stroke (<6 
months prior to enrollment), myocardial infarction (<6 months prior to enrollment), 
unstable angina, congestive heart failure (≥New York Heart Association Classification 
Class II), or serious cardiac arrhythmia requiring medication. 
9. Prior treatment with any other anti-programmed cell death protein-1 (anti-PD-1), or PD 
Ligand-1 (PD-L1) or PD Ligand-2 (PD-L2) agent or an antibody targeting other immuno-
regulatory receptors or mechanisms 
10. Irritable bowel syndrome or other serious gastrointestinal chronic conditions associated 
with diarrhea within the past 3 years prior to the start of treatment 
11. Known history of testing positive for HIV or known acquired immunodeficiency 
syndrome. 
12. On chronic systemic steroid or any other forms of immunosuppressive medication within 
14 days prior to the treatment. Except: 
a. Intra-nasal, inhaled, topical steroids, or local steroid injection (e.g., intraarticular 
injection); 
b. Systemic corticosteroids at physiologic doses ≤10 mg/day of prednisone or 
equivalent; 
c. Steroids as premedication for hypersensitivity reactions due to bintrafusp alfa  
13. Active or prior documented autoimmune or inflammatory disorders in the past 2 years, 
except diabetes type I, vitiligo, psoriasis, or hypo- or hyperthyroid diseases not requiring 
immunosuppressive treatment 
14. Known active hepatitis B or known hepatitis C is detected; subjects who have been treated 
and now have an undetectable viral load are eligible  
15. History of primary immunodeficiency or solid organ transplantation 
16. Receipt of live, attenuated vaccine within 28 days prior to the study treatment 
17. Active infection requiring systemic therapy 
18. Severe hypersensitivity reaction to treatment with another monoclonal antibody (mAb) 
19. Females who are pregnant, lactating, or intend to become pregnant during their 
participation in the study 
20. Psychiatric disorders and substance (drug/alcohol) abuse 
 
 
 

M7824 Clinical Protocol v2.0 dated 01-Dec-2021 
Page 18 of 116 
 
 
4 
STUDY SCHEMA 
 
 
 
 
 
 
Study Treatment: Bintrafusp alfa 1200mg IV Every 2 weeks until progression or unacceptable 
toxicity or maximum of 2 years. 
 
4.1 
Informed Consent   
 
The Investigator(s) (according to applicable regulatory requirements), or a person designated by 
the Investigator(s), and under the Investigator(s)’s responsibility, should fully inform the patient 
of all pertinent aspects of the clinical study including the written information giving 
approval/favorable opinion by the Ethics Committee (IRB/EC). All participants shall be informed 
to the fullest extent possible about the study, in language and terms they are able to understand. 
 
Prior to a patients’ participation in the clinical study, the written Informed Consent Form (Form 
B) and any other local applicable documents in accordance with local laws and regulations, should 
be signed, name filled in and personally dated by the patient or by the patient’s legally acceptable 
representative, and by the person who conducted the informed consent discussion. A copy of the 
signed and dated written Informed Consent Form will be provided to the patient. 
 
The Informed Consent From used by the Investigator(s) for obtaining the patient’s informed 
consent must be reviewed and approved by the appropriate Ethics Committee (IRB/EC) for 
approval/favorable opinion. 
 
During a patient’s participation in the trial, any updates to the consent form any updates to the 
written information will be provided to the patient. 
 
Further information about the informed consent is available in Section 8.2 and Section 8.3. 
 
 
Eligible  
 R/M NPC 
patients failed 
Platinum-based 
chemotherapy 
Bintrafusp alfa 
1200mg IV  
Every 2 weeks 
Treatment end until 
 
1. Progression 
2. Unacceptable 
toxicity 
3. Maximum of 2 
years 
Survival  
Follow-up 
up to 2 years 

M7824 Clinical Protocol v2.0 dated 01-Dec-2021 
Page 19 of 116 
 
 
4.2 
Registration Guidelines 
 
 All the patients must be registered with the Investigator(s) prior to initiation of treatment 
 Forms A (registration) and B (consent) will be submitted 
 The registration desk will confirm all eligibility criteria and obtain essential information 
(including patient number) 
 
5 
STUDY INTERVENTION  
5.1 
General Information of Study Intervention Bintrafusp alfa 
 
Bintrafusp alfa is a first-in-class, bifunctional fusion protein comprised of the ECD of the human 
TGF-βRII or TGF-β Trap covalently linked to the C terminus of the heavy chain of the fully human 
IgG1, anti-PD L1 antibody via a flexible (Gly4Ser)4G linker.  
 
5.2 
Pharmaceutical Properties and Description of the Formulation 
 
Bintrafusp alfa drug product is primarily provided as a sterile liquid formulation. 
 
The Powder for Concentrate for Solution for Infusion (freeze-dried formulation) is packaged in 
United States Pharmacopeia (USP) and European Pharmacopeia (Ph. Eur.) type I glass vials. Each 
vial is filled with 45 mg of bintrafusp alfa (45 mg/vial) as a preservative-free powder containing 
histidine, trehalose dihydrate, sodium chloride, L-methionine, and polysorbate 20 (Tween 20). The 
vials are closed with a rubber stopper in lyophilization format complying with USP and Ph. Eur. 
and sealed with an aluminum plastic crimping cap. Only excipients that conform to the current 
USP and/or Ph. Eur. are used for bintrafusp alfa drug product. 
 
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 liquid formulation, compared with the freeze-dried formulation, has the same composition in 
terms of excipients, qualitatively and quantitatively, except for the addition of water. Of note, there 
is no change to the drug substance process. 
 
The excipients are viewed as standard, and therefore, not a safety risk. The estimated volumes of 
delivery are anticipated to be either 250 or 500 mL, which are clinically acceptable.  
 
5.3 
Handling of the Dosage Form  
 
For applications in clinical studies, the freeze-dried drug product must be reconstituted with 4.5 
mL of water for injection and further diluted with 0.9% saline solution (sodium chloride injection) 

M7824 Clinical Protocol v2.0 dated 01-Dec-2021 
Page 20 of 116 
 
 
supplied in an infusion bag. The liquid formulation is diluted directly with 0.9% saline solution. 
The estimated volumes of delivery are anticipated to be either 250 mL or 500 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, and assigned dose levels and 
concrete volumes to be replaced to prepare the target doses are described in the Pharmacy Manual. 
 
Bintrafusp alfa 1200mg will be administered intravenously on Day 1 of each 2-week study cycle. 
Bintrafusp alfa may be administered up to 3 days before or after the scheduled day of 
administration of each cycle due to administrative reasons. 
 
5.4 
Instructions for Storage  
 
Bintrafusp alfa 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 bintrafusp alfa. 
 
Bintrafusp alfa drug product stored at room (23°C to 27°C) or higher temperatures for extended 
periods of time might be subject to degradation. 
 
The liquid formulation is diluted directly with 0.9% saline solution. The chemical and physical in-
use stability for the infusion solution of bintrafusp alfa 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 bintrafusp alfa. 
 
5.5 
Bintrafusp Alfa Administration  
 
Pre-medication: Flat dose of 1200 mg administered over 60 minutes (± 10-20 minutes) 
intravenous infusion once every 2 weeks. In order to mitigate infusion-related reactions, a 
premedication regimen of diphenhydramine 25 to 50 mg IV or oral equivalent and paracetamol 
500 mg IV or oral equivalent is mandatory approximately 30 to 60 minutes prior to each dose of 
bintrafusp alfa. 
 
Setting: bintrafusp alfa should be administered in a setting that allows for immediate access to an 
intensive care unit or equivalent environment and administration of therapy for anaphylaxis, such 
as the ability to implement immediate resuscitation measures. Steroids (dexamethasone 10 mg), 
epinephrine (1:1,000 dilution), allergy medications (IV antihistamines), bronchodilators, or 
equivalents, and oxygen should be available for immediate access. 
 
Observation period: Following infusions, patients must be observed for 30 minutes post-infusion 
for potential infusion-related reactions. 
 

M7824 Clinical Protocol v2.0 dated 01-Dec-2021 
Page 21 of 116 
 
 
Drug accountability and return, or local discard and destruction, if appropriate, must be completed 
with appropriate documentation for all study sites. Lot number, and expiry date for bintrafusp alfa 
is recorded in the study site as per local guidelines unless otherwise instructed by the Sponsor. 
 
The Investigator is responsible for taking steps to maintain appropriate records and ensure 
appropriate supply, storage, handling, distribution and usage of study treatments in accordance 
with the protocol and any applicable laws and regulations. 
 
5.6 
Bintrafusp Alfa Adverse Event Management 
 
5.6.1 Bintrafusp Alfa Adverse Events 
Based on the available preclinical data, pharmacological class effect, and periodic safety reviews, 
the following were considered as adverse events upon Bintrafusp Alfa infusion and classified as:  
 
 Important identified risks  
o Infusion-related reaction (IRR) 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 
o 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 micro-vasculitis, myositis, skin reactions like rash 
(generalized, maculopapular, erythematous, pemphigoid) 
o Skin lesions with hyperkeratosis, keratoacanthoma, cutaneous squamous cell 
carcinoma possibly due to TGF-β inhibition. 
 
 Important potential risks  
o Treatment related anemia 
o Alterations in wound healing, repair of tissue damage, or mucosal bleeding events  
o Embryofetal toxicities 
 
 
Non-important potential risk:  
o 
Mucosal bleeding 
 
Mucosal bleeding events are a potential risk for M7824. Respective risk mitigation measures have 
been implemented in the protocol.  
 
The following side effects have been observed in ≥10% of patients among 630 patients treated 
with bintrafusp alfa according to the results from two oncology clinical studies in patients with 
advanced solid tumors. Common side effects (reported in more than to 1 in 10 people) include: 
 
 Anemia (low number of red blood cells) 
 Decreased appetite 
 Fatigue 
 Pruritis (itching) 

M7824 Clinical Protocol v2.0 dated 01-Dec-2021 
Page 22 of 116 
 
 
 Dyspnea (shortness of breath) 
 Constipation (difficulty passing stools) 
 Nausea (feeling sick to the stomach) 
 Pyrexia (raised body temperature) 
 Asthenia (decreased muscle strength) 
 Diarrhea (frequent loose, watery stools) 
 Abdominal pain 
 Vomiting 
 Cough 
 Headache 
 Epistaxis (bleeding from the nose) 
 Rash (maculo-papular rash) 
 Aspartate aminotransferase increased (elevation of liver enzyme) 
 Oedema peripheral (buildup of fluid in the body causing swelling) 
 
5.6.2 Dose Modifications for Bintrafusp Alfa as Single Agent 
 
No dose reductions are permitted in this study, but doses may be omitted based on persisting 
toxicity. Any adverse event suspected to be immune-related should be managed according to the 
guidance for management of irAEs 
 
5.6.3 Adverse Drug Reaction Requiring Bintrafusp Alfa Discontinuation or Delays  
 
The following adverse reactions (ADRs) require permanent treatment discontinuation of 
bintrafusp alfa: 
 
Any Grade 4 ADRs require bintrafusp alfa treatment discontinuation except for single 
laboratory values out of normal range that are unlikely related to trial treatment as assessed by 
the Investigator(s), do not have any clinical correlate, and resolve within 7 days with adequate 
medical management. 
 
Any Grade 3 ADRs require bintrafusp alfa treatment discontinuation except for any of the 
following: 
 
 Transient (≤6 hours) Grade 3 flu-like symptoms or fever, which is controlled with medical 
management 
 Transient (≤24 hours) Grade 3 fatigue, local reactions, headache, nausea, or emesis that 
resolves to Grade ≤1 
 Single laboratory values out of normal range (excluding Grade ≥3 liver function test 
increase) that are unlikely related to trial treatment according to the Investigator(s), do not 
have any clinical correlate, and resolve to Grade ≤1 within 7 days with adequate medical 
management 
 Tumor flare phenomenon defined as local pain, irritation, or rash localized at sites of 
known or suspected tumor 
 Change in Eastern Cooperative Oncology Group Performance Status (ECOG PS) to 3 that 

M7824 Clinical Protocol v2.0 dated 01-Dec-2021 
Page 23 of 116 
 
 
resolve to ≤2 within 14 days (infusions should not be given on the following cycle, if the 
ECOG PS is 3 on the day of trial drug administration) 
 
Any Grade 2 ADR should be managed as follows: 
 
 If a Grade 2 ADR resolves to Grade ≤1 within 2 weeks treatment may continue 
 If a Grade 2 ADR does not resolve to Grade ≤1 within 2 weeks, bintrafusp alfa should be 
held. If after another 2 weeks the event has not resolved to Grade 1, the patient should 
permanently discontinue treatment with bintrafusp alfa (except for hormone 
insufficiencies, that can be managed by replacement therapy; for these hormone 
insufficiencies, up to 2 subsequent doses may be omitted) 
 Upon the second occurrence of the same Grade 2 ADR (except for hormone insufficiencies 
that can be managed by replacement therapy) in the same patient, treatment with bintrafusp 
alfa has to be permanently discontinued 
 
5.6.4 Management of Infusion Related Reaction (IRR) 
 
IRRs including hypersensitivity (immediate) were listed as an important identified risk of 
bintrafusp alfa. IRR are divided into reactions versus signs and symptoms.  
 
 Reactions are 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 infusion related reaction, 
drug hypersensitivity, anaphylactic reaction, hypersensitivity and Type 1 hypersensitivity 
 Signs and symptoms are considered when onset is on the day of infusion (during or after 
the infusion) and resolved with the end date within 2 days after onset for pyrexia, chills, 
flushing, hypotension, dyspnea, wheezing, back pain, abdominal pain and urticaria 
 
Pre-medication with an anti-histamine and with paracetamol (acetaminophen) was mandatory in 
order to mitigate potential infusion related reactions during the first 2 infusions in Study 
EMR200647-001 and Study MS200647-0008. 
 
 

M7824 Clinical Protocol v2.0 dated 01-Dec-2021 
Page 24 of 116 
 
 
Treatment Modification for Symptoms of Infusion-Related Reactions 
NCI-CTCAE Grade  
Treatment Modification 
Grade 1 - mild 
Mild transient reaction; in general, infusion 
interruption not indicated; intervention not 
indicated 
 
Increase monitoring of vital signs as medically 
indicated as participants are deemed medically 
stable by the attending Investigator. 
 
Hold infusion if deemed necessary by the 
investigator. 
Grade 2 – moderate 
Therapy or infusion interruption indicated but 
responds promptly to symptomatic treatment 
(for example, antihistamines, nonsteroidal 
anti-inflammatory drugs, narcotics, IV fluids); 
prophylactic medications indicated for  24 h. 
 
Stop the infusion of the study intervention.  
 
Increase monitoring of vital signs as medically 
indicated as participants are deemed medically 
stable by the attending Investigator. 
 
If symptoms resolve quickly, resume infusion at 
50% of original rate with close monitoring of 
any worsening signs and symptoms, otherwise 
dosing held until resolution of symptoms with 
mandated premedication for the next scheduled 
visit. 
 
If not improving, consider administration of 
glucocorticoids and stop the infusion for that 
day. 
 
If the participant has a second IRR Grade ≥ 2 
on the slower infusion rate despite 
premedication, the infusion should be stopped, 
and the investigator may consider withdrawal of 
this participant from the study. 
Grade 3 or Grade 4 – severe or 
life-threatening 
o Grade 3: Prolonged (for example, not 
rapidly responsive to symptomatic 
medication and/or brief interruption of 
infusion); recurrence of symptoms 
following initial improvement; 
hospitalization indicated for clinical 
sequelae. 
o Grade 4: Life-threatening consequences; 
urgent intervention indicated. 
 
Stop the infusion of study intervention 
immediately and disconnect infusion tubing 
from the participant with additional appropriate 
medical measures and closely monitor until 
deemed medically stable by the attending 
Investigator. Hospitalization and/or close 
monitoring is recommended 
  Administration of glucocorticoids may be 
required 
 
For Grade 3 or 4 IRRs, permanent 
discontinuation of study intervention is 
mandated. 
Once the infusion is interrupted or rate reduced to 50% of previous infusion rate, it must remain 
decreased for all subsequent infusions.  
For all types and grades of infusion reactions, details about drug physical constitution, method of 
preparation, and infusion must be recorded. 
Participants should be instructed to report any delayed reaction immediately. 
IRR=infusion-related reactions, IV=intravenous, NCI-CTCAE=National Cancer Institute-Common 
Terminology Criteria for Adverse Event, NSAIDs=nonsteroidal anti-inflammatory drugs.  
 
 

M7824 Clinical Protocol v2.0 dated 01-Dec-2021 
Page 25 of 116 
 
 
Immediate Hypersensitivity Reaction 
Hypersensitivity reactions may require immediate intensive care. Bintrafusp alfa should be 
administered in a setting that allows immediate access to an intensive care unit or equivalent 
environment and administration of therapy for anaphylaxis, such as the ability to implement 
immediate resuscitation measures. Potent steroids (e.g. dexamethasone), catecholamines 
(e.g. epinephrine), allergy medications (IV antihistamines), bronchodilators, or equivalents 
and oxygen should be available for immediate access. 
A complete guideline for the emergency treatment of anaphylactic reactions according to the 
Working Group of the Resuscitation Council United Kingdom and can be found at 
https://www.resus.org.uk/pages/reaction.pdf. 
Flu-Like Symptoms 
Treatment is based on clinical assessment and at the discretion of the Investigator. For 
prophylaxis of flu like symptoms, a nonsteroidal anti-inflammatory drug (NSAID), e.g., 
ibuprofen 400 mg or comparable NSAID dose, may be administered 2 hours before and 8 
hours after the start of each IV infusion. 
 
Additional Modifications for Patients with Grade 2 Infusion-Related Reactions  
If in the event of a Grade 2 infusion-related reaction that does not improve or worsens after 
implementation of the modifications indicated in Table 6 (including reducing the infusion rate by 
50%), the Investigators may consider treatment with corticosteroids, and the infusion should not 
be resumed. At the next dose, the Investigators may consider the addition of H2 blocker 
antihistamines (e.g., famotidine or ranitidine), meperidine, or ibuprofen to the mandatory 
premedication. Prophylactic steroids are NOT permitted. 
 
Severe Hypersensitivity Reactions  
If hypersensitivity reaction occurs, the patient 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) can be found at 
https://www.resus.org.uk/pages/reaction.pdf. Patients should be instructed to report any delayed 
reactions to the Investigators immediately. 
 
Symptoms include impaired airway, decreased oxygen saturation (<92%), confusion, lethargy, 
hypotension, pale or clammy skin, and cyanosis. These symptoms can be managed with 
epinephrine injection and dexamethasone. Patients should be placed on monitor immediately, and 
the intensive care unit (ICU) should be alerted for possible transfer if required. 
 
5.6.5 Management of Immune-Related Adverse Events (IrAEs)  
 
Because inhibition of PD-L1 by anti-PD-L1 component stimulates the immune system, bintrafusp 
alfa may cause toxicity by increasing the immune response, leading to inflammatory reactions 
collectively referred to as immune-related adverse events (irAEs). 
 
Immune-related AEs are specific to immunotherapies and vary by organ system.  
Following immune-related AEs are important identified risks for bintrafusp alfa:  
 Immune-related pneumonitis 
 Immune-related hepatitis 

M7824 Clinical Protocol v2.0 dated 01-Dec-2021 
Page 26 of 116 
 
 
 Immune-related colitis 
 Immune-related nephritis and renal dysfunction 
 Immune-related endocrinopathies  
 (thyroid disorders, adrenal insufficiency, type 1 diabetes mellitus, pituitary disorders) 
 Immune related rash 
 Other immune-related events (myositis, myocarditis, encephalitis) 
 
Following immune-related AEs are important potential risks for bintrafusp alfa: 
 Guillain-Barré syndrome 
 Uveitis 
 Pancreatitis 
 Myasthenia gravis/myasthenic syndrome 
 
Recommended guidance and management for specific irAEs are provided in the current NCCN 
guideline available at http://www.nccn.org. 
 
Requirements in addition to NCCN guidelines: 
 
 Permanent treatment discontinuation is required in case of immune-related Grade 4 
rash/inflammatory dermatitis, nephritis, autoimmune hemolytic anemia, hemolytic uremic 
syndrome, 
aplastic 
anemia, 
immune 
thrombocytopenia, 
acquired 
thrombotic 
thrombocytopenic purpura inflammatory arthritis, myositis and polymyalgia-like 
syndrome. 
 
 For Grade 4 immune-related lymphopenia, permanent treatment discontinuation will be 
required, if lymphopenia is considered immune-related in nature, no clear alternative 
explanation exists for the event, and it does not resolve within 14 days. Permanent 
treatment discontinuation is not required when the AE is manifested by a single laboratory 
value out of normal range without any clinical correlates. In this case, treatment should be 
held until the etiology is determined. If the event is not considered immune-related and 
resolves to Grade ≤ 1, restarting treatment may be considered. 
 
 For Grade 1 immune-related pneumonitis: continue treatment. If clinically indicated, 
monitor participants weekly or more frequently as needed with history, physical 
examination and pulse oximetry. If symptoms appear and/or changes in the physical exam 
are noted, treat as Grade 2. 
 
 For myositis: in case of management with rituximab, treatment should be discontinued. 
 
The side effects listed below may be temporary, long term, permanent, life-threatening or result in 
death. However, most of these side effects are reversible. 
 
General Principle of Treatment of irAEs (NCI CTCAE grade): 
 Grades 1 to 2: treat symptomatically or with moderate dose steroids, more frequent 
monitoring. 

M7824 Clinical Protocol v2.0 dated 01-Dec-2021 
Page 27 of 116 
 
 
 Grades 1 to 2 (persistent): manage similar to high grade AE (Grades 3 to 4). 
Grades 3 to 4: treat with high dose corticosteroids or equivalent and/or other 
immunosuppressant as needed  
 
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 work-up 
Pertinent history and physical examination 
Rule out any other etiology of the skin problem, such as an infection, an effect of another drug, or a
skin condition linked to another systemic disease or unrelated primary skin disorder 
If needed, a biologic checkup, including a blood cell count and liver and kidney tests 
Directed serologic studies if an autoimmune condition is suspected, such as lupus or
dermatomyositis: a screening antinuclear antibody test, SS-A/Anti-Ro, SS-B/Anti-La if
predominantly photodistributed/photosensitivity, antihistone, double-stranded DNA, and other 
relevant serologies. Consider expanding serologic studies or diagnostic work-up if other
autoimmune conditions are considered based on signs, symptoms Skin biopsy 
Consider clinical monitoring with use of serial clinical photography 
Review full list of patient medications to rule out other drug-induced cause for photosensitivity 
Grading 
Management 
Grading according to CTCAE is a challenge 
for skin. Instead, severity may be based on 
BSA, tolerability, morbidity, and duration. 
G1: Symptoms do not affect the quality of life 
or controlled with topical regimen and/or oral 
antipruritic 
Continue ICPi 
Treat with topical emollients and/or mild-
moderate potency topical corticosteroids 
Counsel patients to avoid skin irritants 
and sun exposure 

M7824 Clinical Protocol v2.0 dated 01-Dec-2021 
Page 28 of 116 
 
 
G2: Inﬂammatory reaction that affects quality of
life and requires intervention based on diagnosis
Consider holding ICPi and monitor weekly 
for improvement. If not resolved, interrupt 
treatment until skin AE has reverted to Grade 
1 
Consider initiating prednisone (or equivalent) 
at dosing 1 mg/kg, tapering over at least 4 
weeks 
In addition, treat with topical emollients, oral 
antihistamines, and medium- to high-potency 
topical corticosteroids 
G3: As G2 but with failure to respond to 
indicated interventions for a G 2 dermatitis 
Hold ICPi therapy and consult with 
dermatology to determine appropriateness 
of resuming 
Treat 
with 
topical 
emollients, 
oral 
antihistamines, and high-potency topical 
corticosteroids 
Initiate (methyl)prednisolone (or equivalent) 1-2
mg/kg, tapering over at least 4 weeks 
G4: All severe rashes unmanageable 
with prior interventions and intolerable 
Permanently discontinue ICPi 
Systemic 
corticosteroids: 
IV 
(methyl)prednisolone (or equivalent) dosed at 
1-2 mg/kg with slow tapering when the toxicity 
resolves 

M7824 Clinical Protocol v2.0 dated 01-Dec-2021 
Page 29 of 116 
 
 
1.0 Skin Toxicities 
Monitor closely for progression to severe 
cutaneous adverse reaction 
Should admit patient immediately with direct 
oncology involvement and with an urgent
consult by dermatology 
1.2 Bullous dermatoses 
Deﬁnition: Including bullous pemphigoid or other autoimmune bullous dermatoses, bullous drug 
reaction Diagnostic work-up 
Physical examination 
Rule out any other etiology of the skin problem, such as an infection, an effect of another drug, or a
skin condition linked to another systemic disease 
If needed, a biologic checkup, including a blood cell count, liver, and kidney tests; consider serum
antibody tests to rule out bullous pemphigoid or, under the guidance of dermatology, sending 
patient serum for indirect immunoﬂuorescent testing to rule out other autoimmune blistering
diseases 
Referral to dermatology for blisters that are not explained by infectious or transient other causes 
(eg, herpes simplex, herpes zoster, bullous impetigo, bullous insect bite, friction or pressure 
blister) 
Consider skin biopsy (both hematoxylin and eosin evaluation of lesional skin and direct
immunoﬂuorescence evaluation of perilesional skin) 
Grading 
Management 
G1: Asymptomatic, blisters covering < 10% 
BSA and no associated erythema 
If blisters are < 10% BSA, asymptomatic, and 
noninﬂammatory (such as the case with friction 
blisters or pressure blisters), cessation of ICPi is 
not necessary, and only observation and/or 
local wound care is warranted. 
When symptomatic bullae or erosions, which are
deroofed vesicles or bullae, are observed on the
skin or mucosal surfaces, the cutaneous irAE is 
by deﬁnition considered at least G2 
See G2 management recommendations 

M7824 Clinical Protocol v2.0 dated 01-Dec-2021 
Page 30 of 116 
 
 
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: 

M7824 Clinical Protocol v2.0 dated 01-Dec-2021 
Page 31 of 116 
 
 
 
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. 

M7824 Clinical Protocol v2.0 dated 01-Dec-2021 
Page 32 of 116 
 
 
G4: Blisters covering > 30% BSA with 
associated ﬂuid or electrolyte abnormalities 
Permanently discontinue ICPi 
Admit patient immediately and place under 
supervision of a dermatologist 
Administer 
IV 
(methyl)prednisolone 
(or
equivalent) 1-2 mg/kg with tapering over at least 
4 weeks when the toxicity resolves 
If bullous pemphigoid is diagnosed, it may be 
possible to avoid long-term use of systemic 
corticosteroids and treat with rituximab as an 
alternative approach to treating the irAE 
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 

M7824 Clinical Protocol v2.0 dated 01-Dec-2021 
Page 33 of 116 
 
 
1.0 Skin Toxicities 
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 pustulosis 
Consider following patients closely using serial clinical photography 
If mucous membrane involvement or blistering is observed on the skin, consider early admission 
to a burn center for further monitoring and management Primer on monitoring for complicated 
cutaneous adverse drug reactions: 
Review of systems: Skin pain (like a sunburn), fevers, malaise, myalgias, arthralgias, abdominal 
pain, ocular discomfort or photophobia, sores or discomfort in the nares, sores or discomfort in the 
oropharynx, odynophagia, hoarseness, dysuria, sores or discomfort in the vaginal area for women 
or involving the meatus of the penis for men, sores in the perianal area, or pain with bowel 
movements 
Physical examination: Include vital signs and a full skin examination speciﬁcally evaluating all 
skin surfaces and mucous membranes (eyes, nares, oropharynx, genitals, and perianal area). Assess
for lymphadenopathy, facial or distal extremity swelling (may be signs of DIHS/DRESS). Assess
for pustules or blisters or erosions in addition to areas of “dusky erythema,” which may feel painful 
to palpation. To assess for a positive Nikolsky sign, place a gloved ﬁnger tangentially over 
erythematous skin and apply friction parallel to the skin surface. Nikolsky sign is positive if this 
results in detached or sloughing epidermis demonstrating poor attachment of the epidermis to the 
dermis, which is the case in some autoimmune disorders (eg, pemphigus) and SJS/TEN 
Grading 
Management 
All Grades 
In cases of suspected SJS or any mucous 
membrane involvement, discontinue ICPi 
treatment 
and 
monitor 
closely 
for 
improvement, regardless of grade 
G1: NA 
For SCARs, there is no G1 category; if lower 
BSA is involved with bullae or erosions, there 
should remain a high concern that this reaction 
will progress to G3 or G4 
G2: 
Morbilliform 
(“maculopapular”) 
exanthem covering 10%-30% BSA with 
systemic symptoms, lymphadenopathy, or 
facial swelling 
Hold ICPi and monitor patients closely every 3 
days with G2 irAEs for progression to 
involvement of greater BSA and/or mucous 
membrane involvement 
Consider following patients closely 
using serial photography 
Initiate therapy with topical emollients, oral 
antihistamines, and medium- to high-strength 
topical corticosteroids 
Consider 
initiation 
of 
prednisone 
(or 
equivalent) 0.5-1 mg/kg tapered over at least 
4 weeks 

M7824 Clinical Protocol v2.0 dated 01-Dec-2021 
Page 34 of 116 
 
 
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 

M7824 Clinical Protocol v2.0 dated 01-Dec-2021 
Page 35 of 116 
 
 
1.0 Skin Toxicities 
For mucous membrane involvement of SJS 
or TEN, appropriate consulting services 
should be offered to guide management in 
preventing sequelae from scarring (eg, 
ophthalmology; ear, nose, and throat; 
urology; gynecology; etc, as appropriate) 
G4: Skin erythema and blistering/sloughing 
covering 
≥ 10% to > 30% BSA with associated signs (eg, 
erythema, purpura, epidermal detachment, 
mucous membrane detachment) and/or systemic 
symptoms and concerning associated blood 
work abnormalities (eg, liver function test 
elevations in the setting of DRESS/DIHS) 
Permanently discontinue ICPi 
Admit patient immediately to a burn unit or 
ICU with consulted dermatology and wound 
care services 
Consider further consultations based on 
management of mucosal surfaces 
(eg, ophthalmology; urology; gynecology; ear, 
nose, and throat surgery; etc) Initiate IV 
(methyl)prednisolone 
(or 
equivalent) 
1-2 
mg/kg, tapering when toxicity resolves to 
normal 
IVIG or cyclosporine may also be considered in 
severe or corticosteroid-unresponsive cases 
Consider pain/palliative consultation and/or 
admission in patients presenting with DRESS 
manifestations 
Additional considerations: The usual prohibition of corticosteroids for SJS is not relevant here, as
the underlying mechanism is a T-cell immunodirected toxicity 
Adequate suppression is necessary with corticosteroids or other agents and may be prolonged in
cases of DRESS/DIHS 
All recommendations are expert consensus based, with beneﬁts outweighing harms, and strength of
recommendations are moderate 
Abbreviations: ADL, activities of daily living; AE, adverse event; BSA, body surface area; CBC, complete blood 
count; CTCAE, Common Terminology Criteria for Adverse Events; DIHS, drug-induced hypersensitivity 
syndrome; DRESS, drug reaction with eosinophilia and systemic symptoms; G, Grade; ICPi, immune 
checkpoint inhibitor; ICU, intensive care unit; irAE, immune-related adverse event; IV, intravenous; IVIG, 
intravenous immunoglobulin; NA, not applicable; SCAR, severe cutaneous adverse reactions; SJS, Stevens-
Johnson syndrome; TENS, toxic epidermal necrolysis. 
 
 

M7824 Clinical Protocol v2.0 dated 01-Dec-2021 
Page 36 of 116 
 
 
MANAGEMENT OF BLEEDING irAES IN PATIENTS TREATED WITH ICPis 
2.0 Bleeding Adverse Events 
Bleeding adverse events are considered important identified risk for bintrafusp alfa. 
In general, mild and moderate mucosal bleedings resolve without discontinuation of 
treatment. 
These events may include, but are not limited to the following: 
Epistaxis 
Hemoptysis  
Gingival bleeding 
Hematuria 
Mucosal/Non-tumor Bleeding 
Grading 
Management 
Grade 2 
If resolves to Grade ≤ 1 by the day before 
the next infusion, study intervention may 
be continued 
If not resolved to Grade ≤ 1 by the day 
before the next infusion, but is manageable 
and /or not clinically relevant, consult 
Medical Monitor to assess if clinically 
reasonable to administer the following 
infusion. 
Grade ≥3 
 
Permanently discontinue treatment unless 
an 
alternative 
explanation 
can 
be 
identified (such as concomitant use of 
antithrombotic agents, traumatic events, 
etc.)  
In case of alternative explanations, hold 
study treatment until the event recovers to 
Grade ≤ 1 
If Grade ≥3 bleeding event is observed, 
regardless of causality with the study 
intervention, upon resumption of study 
intervention bintrafusp alfa dose should be 
reduced by 50% (600 mg Q2W for 
participants dosed with 1200 mg, 1200 mg 
for participants dosed with 2400 mg). 
Once there is stable resolution and no 
recurrence of bleeding on reduced dose, 
Investigator 
is 
encouraged 
to 
communicate with Medical Monitor on 
potential dose re-escalation after careful 
benefit-risk assessment. 
Grade 4 
Treatment 
must 
be 
permanently 
discontinued if no alternative explanation 
is identified. 
In case of rapid decrease of hemoglobin (Hgb), such as a decrease greater than 2.0 g/dL 
across a 2 weeks period, withhold the subsequent cycles of study intervention until Hgb is 

M7824 Clinical Protocol v2.0 dated 01-Dec-2021 
Page 37 of 116 
 
 
stabilized and do a thorough assessment of bleeding (for example, upper and lower GI 
endoscopy, enhancement CT etc.); if Grade 1 or greater bleeding is observed or suspected, 
withhold the bintrafusp alfa until the bleeding is resolved/controlled and resume the dose of 
bintrafusp alfa reduced by 50%. Once Hgb decrease is recovered to ≤ Grade 1 or baseline 
and stably controlled, the Investigator is encouraged to communicate with Medical Monitor 
to re-escalate the dose. The dose of bintrafusp alfa may be re-escalated to full dose once 
Hgb is stabilized without further need for blood transfusion in the subsequent cycles. The 
timing of re escalation may need a case-by-case decision. See Section Table 5 regarding 
stabilization of anemia. 
Tumor Bleeding 
Grade ≥ 2 
Study treatment must be held till the event 
recovers to Grade ≤ 1 
Permanently discontinue treatment if the 
Investigator considers the participant to be 
at risk for additional severe bleeding. 
Grade ≥ 3 
If Grade ≥ 3 bleeding event had been 
observed, regardless of causality with the 
study intervention, upon resumption of the 
study intervention bintrafusp alfa dose 
should be reduced by 50%. Once there is 
stable resolution and no recurrence of 
bleeding on reduced dose, Investigator is 
encouraged to communicate with Medical 
Monitor potential dose re-escalation after 
careful benefit-risk assessment. Treatment 
should be permanently discontinued if the 
Investigator considers the participant to be 
at risk for additional severe bleeding. 
In case of rapid decrease of hemoglobin 
(Hgb), see Section Mucosal/Non-Tumor 
bleeding. 
 

M7824 Clinical Protocol v2.0 dated 01-Dec-2021 
Page 38 of 116 
 
 
MANAGEMENT OF GI irAES IN PATIENTS TREATED WITH ICPis 
 
3.0 GI Toxicities 
3.1 Colitis 
Deﬁnition: A disorder characterized by inﬂammation of the 
colon Diagnostic work-up 
G2 
Work-up of blood (CBC, comprehensive metabolic panel, TSH, ESR, CRP), stool (culture, 
Clostridium difficile, parasite, CMV or other viral etiology, ova and parasite) should be 
performed 
Consider testing for lactoferrin (for patient stratiﬁcation to determine who needs more urgent 
endoscopy) and calprotectin (to follow-up on disease activity) 
Screening laboratories (HIV, hepatitis A and B, and blood quantiferon for TB) to prepare patients 
to start inﬂiximab should be routinely done in patients at high risk for those infections and 
appropriately selected patients based on infectious disease expert’s evaluation 
Imaging (eg, CT scan of abdomen and pelvis and GI endoscopy with biopsy) should be 
considered as there is evidence showing that the presence of ulceration in the colon can predict a 
corticosteroid-refractory course, which may require early inﬂiximab 
Consider repeating endoscopy for patients who do not respond to immunosuppressive agents; 
repeating endoscopy for disease monitoring can be considered when clinically indicated and 
when planning to resume therapy 
G3-4 
All the work-up listed for G2 (blood, stool, imaging, and scope with biopsy) should be 
completed immediately 
Consider repeating endoscopy for patients who do not respond to immunosuppressive agents; 
repeating endoscopy for disease monitoring should only be considered when clinically indicated 
and when planning to resume ICPi 
Grading (based on CTCAE for diarrhea, 
as most often used clinically) 
Management 
All patients 
Counsel all patients to be aware of and 
inform their health care provider 
immediately if they experience: 
Abdominal pain, nausea, cramping, blood or 
mucus in stool or changes in bowel habits, 
fever, abdominal distention, obstipation, 
constipation 
For G2 or higher, consider permanently 
discontinuing CTLA-4 agents and may restart 
PD-1, PD-L1 agents if patient can recover to 
G1 or less; concurrent immunosuppressant 
maintenance therapy should be considered 
only if clinically indicated in individual cases 

M7824 Clinical Protocol v2.0 dated 01-Dec-2021 
Page 39 of 116 
 
 
G1: Increase of fewer than four stools per day 
over baseline; mild increase in ostomy output 
compared with baseline 
Continue ICPi; alternatively, ICPi may be 
held temporarily and resumed if toxicity 
does not exceed 
G1 
Monitor for dehydration and recommend 
dietary changes Facilitate expedited phone 
contact with patient/caregiver May obtain 
gastroenterology consult for prolonged G1 
cases 
G2: Increase of four to six stools per day over 
baseline; moderate increase in ostomy output 
compared with baseline 
Should hold ICPi temporarily until patient’s 
symptoms recover to G1; can consider 
permanently 
discontinuing CTLA-4 agents and may 
restart PD-1, PD-L1 agents if patient can 
recover to G1 or less 
Concurrent immunosuppressant maintenance 
therapy (10 mg prednisone equivalent dose) 
may be offered only if clinically indicated in 
individual cases 
May also include supportive care with 
medications such as Imodium if infection has 
been ruled out 
Should consult with gastroenterology for G2 or 
higher 

M7824 Clinical Protocol v2.0 dated 01-Dec-2021 
Page 40 of 116 
 
 
3.0 GI Toxicities 
Administer corticosteroids, unless diarrhea is 
transient, starting with initial dose of 1 
mg/kg/day prednisone or equivalent 
When symptoms improve to G1 or less, taper 
corticosteroids over at least 4-6 weeks before 
resuming treatment, although resuming 
treatment while on low- dose corticosteroid 
may also be an option after an evaluation of 
the risks and beneﬁts 
EGD/colonoscopy, endoscopy evaluation 
should be highly recommended for cases 
Grade ≥ 2 to stratify patients for early 
treatment with inﬂiximab based on the 
endoscopic ﬁndings and to determine the 
safety of resuming PD-1, PD-L1 therapy 
Stool inﬂammatory markers can be 
considered (lactoferrin and calprotectin) in 
cases of G2 or higher to differentiate 
functional versus inﬂammatory diarrhea, and 
use calprotectin to monitor treatment 
response if provider prefers 
Repeat colonoscopy is optional for cases 
of G2 or higher for disease activity 
monitoring to achieve complete remission, 
especially if there is a plan to resume ICPi 
G3: Increase of seven or more stools per day 
over baseline, incontinence, hospitalization 
indicated, severe increase in ostomy output 
compared with baseline, limiting self-care ADL 
Should consider permanently discontinuing 
CTLA-4 agents and may restart PD-1, PD-L1 
agents if patient can recover to G1 or less. 
Administer corticosteroids (initial dose of 1-
2 mg/kg/d prednisone or equivalent) 
Consider hospitalization or outpatient facility for 
patients with dehydration or electrolyte 
imbalance 
If symptoms persist ≥ 3-5 days or recur after 
improvement, consider administering IV 
corticosteroid or noncorticosteroid (eg, 
inﬂiximab) 
Consider colonoscopy in cases where 
patients have been on immunosuppression 
and may be at risk for opportunistic 
infections as an independent cause for 
diarrhea (ie, CMV colitis) and for those who 
are anti- TNF or corticosteroid refractory 

M7824 Clinical Protocol v2.0 dated 01-Dec-2021 
Page 41 of 116 
 
 
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 (not approved in Japan) 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 

M7824 Clinical Protocol v2.0 dated 01-Dec-2021 
Page 42 of 116 
 
 
3.0 GI Toxicities 
3.2 Hepatitis 
Deﬁnition: A disorder characterized by a viral pathologic process involving the liver 
parenchyma Diagnostic work-up 
Monitor patient for abnormal liver blood tests: AST, ALT, and bilirubin prior to each infusion 
and/or weekly if G1 liver function test elevations. No treatment is recommended for G1 liver 
function test abnormality 
For G2 or higher: 
Work-up for other causes of elevated liver enzymes should be tested, viral hepatitis, alcohol 
history, iron study, thromboembolic event, liver ultrasound, cross-sectional imaging for potential 
liver metastasis from primary malignancy. If suspicion for primary autoimmune hepatitis is high, 
can consider ANAs, antismooth muscle antibodies, antineutrophil cytoplasmic antibodies. If 
patients with elevated alkaline phosphatase alone, g-glutamyl transferase should be tested. For 
isolated elevation of transaminases, consider checking CK for other etiologies 
Grading 
Management 
All patients 
Counsel all patients to be aware of and 
inform 
their 
health 
care 
provider 
immediately if they experience: 
Yellowing of skin or whites of the eyes Severe 
nausea or vomiting 
Pain on the right side of the abdomen 
Drowsiness Dark urine (tea colored) 
Bleeding or bruising more easily than normal 
Feeling less hungry than usual 
G1: Asymptomatic (AST or ALT > ULN to 
3.0 x ULN and/or total bilirubin > ULN to 
1.5 x ULN) 
Continue ICPi with close monitoring; consider 
alternate etiologies 
Monitor laboratories one to two times 
weekly Manage with supportive care for 
symptom control 
G2: Asymptomatic (AST or ALT > 3.0 to ≤ 
5 x ULN and/or total bilirubin > 1.5 to ≤ 3 
x ULN) 
Hold ICPi temporarily and resume if recover 
to G1 or less on prednisone ≤ 10 mg/d 
For Grade 2 hepatic toxicity with symptoms, 
may administer corticosteroid 0.5-1 mg/kg/d 
prednisone or equivalent if the abnormal 
elevation persists with signiﬁcant clinical 
symptoms in 3-5 days Increase frequency of 
monitoring to every 3 days 
Inﬂiximab might not be the most appropriate 
treatment option in the situation of immune-
mediated hepatitis given the potential risk of 
idiosyncratic liver failure (Note: No clear 
evidence shows the liver toxicity from 
inﬂiximab from other studies) 
In follow-up, may resume ICPi treatment 
followed by taper only when symptoms 
improve to G1 or less and corticosteroid ≤ 10 

M7824 Clinical Protocol v2.0 dated 01-Dec-2021 
Page 43 of 116 
 
 
mg/d; taper over at least 1 month 
Patients should be advised to stop 
unnecessary medications and any known 
hepatotoxic drugs 
G3: Symptomatic liver dysfunction, ﬁbrosis 
by biopsy, compensated cirrhosis, reactivation 
of chronic hepatitis (AST or ALT 5-20 x ULN 
and/or total bilirubin 3-10x3 ULN) 
Permanently discontinue ICPi 
Immediately start corticosteroid 1-2 
mg/kg 
methylprednisolone 
or 
equivalent 
If corticosteroid refractory or no improvement 
after 3 days, consider mycophenolate mofetil or 
azathioprine (if using azathioprine should test 
for thiopurine methyltransferase deﬁciency) 
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 

M7824 Clinical Protocol v2.0 dated 01-Dec-2021 
Page 44 of 116 
 
 
3.0 GI Toxicities 
Inﬂiximab might not be the most appropriate 
treatment option in the situation of immune-
mediated hepatitis given the potential risk of 
liver failure (Note: No clear evidence shows 
that the liver toxicity from inﬂiximab from 
other studies); alternatives include non–TNF-a 
agents as systemic immunosuppressants If no 
improvement is achieved with corticosteroids 
or for patients on combination therapy with a 
novel agent, with standard chemotherapy, or 
with targeted therapy, refer to hepatologist for 
further pathologic evaluation of hepatitis 
Corticosteroid taper can be attempted around 
4-6 weeks; re-escalate if needed; optimal 
duration unclear 
G4: Decompensated liver function (eg, ascites, 
coagulopathy, encephalopathy, coma; AST or 
ALT > 20 x ULN and/or total bilirubin > 10 x 
ULN) 
Permanently discontinue ICPi 
Administer 2 mg/kg/d methylprednisolone 
equivalents 
If 
corticosteroid 
refractory 
or 
no 
improvement 
after 
3 
days, 
consider 
mycophenolate mofetil 
Monitor laboratories daily; consider inpatient 
monitoring 
Avoid the use of inﬂiximab in the situation of 
immune- mediated hepatitis 
Hepatology consult if no improvement was 
achieved with corticosteroid 
Corticosteroid taper can be attempted 
around 4-6 weeks when symptoms 
improve to G1 or less; re- escalate if 
needed; optimal duration unclear 
Consider transfer to tertiary care facility if 
necessary 
All recommendations are expert consensus based, with beneﬁts outweighing harms, and strength of 
recommendations is moderate. 
 
*not approved in Japan. 
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. 
 

M7824 Clinical Protocol v2.0 dated 01-Dec-2021 
Page 45 of 116 
 
 
MANAGEMENT OF LUNG irAES IN PATIENTS TREATED WITH ICPis 
 
4.0 Lung Toxicities 
4.1 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 
Continue ICPi 
If clinically indicated. Monitor participants 
weekly or more frequently as needed with 
history, physical examination and pulse 
oximetry; may also offer CXR. May offer one 
repeat CT scan in 3-4 weeks; in patients who 
have had baseline testing, may offer a repeat 
spirometry/DLCO in 3-4 weeks 
If symptoms appear and/or changes in the 
physical exam are noted, treat as G2 
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 
± 
transbronchial biopsy Patients should be 
hospitalized for further management 

M7824 Clinical Protocol v2.0 dated 01-Dec-2021 
Page 46 of 116 
 
 
Additional considerations 
GI and Pneumocystis prophylaxis with PPI and Bactrim may be offered to patients on prolonged 
corticosteroid use (> 12 weeks), according to institutional guidelines 
Consider calcium and vitamin D supplementation with prolonged corticosteroid use 
The role of prophylactic ﬂuconazole with prolonged corticosteroid use (> 12 weeks) remains 
unclear, and physicians should proceed according to institutional guidelines 
Bronchoscopy + biopsy; if clinical picture is consistent with pneumonitis, no need for biopsy 
All recommendations are expert consensus based, with beneﬁts outweighing harms, and strength of 
recommendations are moderate. 
Abbreviations: ADL, activities of daily living; BAL, bronchoalveolar lavage; CT, computed tomography; CXR, 
chest x- ray; DLCO, diffusing capacity of lung for carbon monoxide; G, Grade; GI, gastrointestinal; ICPi, 
immune checkpoint inhibitor; irAE, immune-related adverse event; IV, intravenous; IVIG, intravenous 
immunoglobulin; PPI, proton pump inhibitor. 
 

M7824 Clinical Protocol v2.0 dated 01-Dec-2021 
Page 47 of 116 
 
 
MANAGEMENT OF ENDOCRINE irAES IN PATIENTS TREATED WITH ICPis 
 
5.0 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 
5.1 Thyroid 
5.1.1 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 

M7824 Clinical Protocol v2.0 dated 01-Dec-2021 
Page 48 of 116 
 
 
G1: TSH < 10 mIU/L and asymptomatic 
G2: Moderate symptoms; able to perform 
ADL; TSH persistently > 10 mIU/L 
Should continue ICPi with close follow-up and 
monitoring of TSH, FT4 May hold ICPi until 
symptoms resolve to baseline 
Consider endocrine consultation 
Prescribe thyroid hormone supplementation in 
symptomatic patients with any degree of TSH 
elevation or in asymptomatic patients with TSH 
levels that persist 
> 10 mIU/L (measured 4 weeks apart) 
Monitor TSH every 6-8 weeks while titrating 
hormone replacement to normal TSH FT4 can 
be used in the short term (2 weeks) to ensure 
adequacy of therapy in those with frank 
hypothyroidism where the FT4 was initially 
low 
Once adequately treated, should monitor 
thyroid function (at least TSH) every 6 weeks 
while on active ICPi therapy or as needed for 
symptoms to ensure appropriate replacement; 
repeat testing annually or as indicated by 
symptoms once stable 
G3-4: 
Severe 
symptoms, 
medically 
signiﬁcant or life- threatening consequences, 
unable to perform ADL 
Hold ICPi until symptoms resolve to 
baseline with appropriate supplementation 
Endocrine consultation 

M7824 Clinical Protocol v2.0 dated 01-Dec-2021 
Page 49 of 116 
 
 
5.0 Endocrine Toxicity 
May admit for IV therapy if signs of 
myxedema 
(bradycardia, 
hypothermia) 
Thyroid supplementation and reassessment 
as in G2 
Additional considerations 
For patients without risk factors, full replacement can be estimated with an ideal body weight–based
dose of approximately 1.6 µg/kg/d 
For elderly or fragile patients with multiple comorbidities, consider titrating up from low dose, 
starting at 25-50 mg 
Extreme elevations of TSH can be seen in the recovery phase of thyroiditis and can be watched in
asymptomatic patients to determine whether there is recovery to normal within 3-4 weeks 
Under guidance of endocrinology, consider tapering hormone replacement and retesting in 
patients with a history of thyroiditis (initial thyrotoxic phase) 
Adrenal dysfunction, if present, must always be replaced before thyroid hormone therapy is 
initiated 
5.1.2 Hyperthyroidism 
Deﬁnition: Suppressed TSH and high normal or elevated FT4 and/or 
triiodothyronine Diagnostic work-up 
Monitor TSH, FT4 every 4-6 weeks from the start of therapy or as needed for case detection in 
symptomatic patients 
Consider TSH receptor antibodies if there are clinical features and suspicion of Grave disease (eg, 
ophthalmopathy) 
Close monitoring of thyroid function every 2-3 weeks after diagnosis to catch transition to 
hypothyroidism in patients with thyroiditis and hyperthyroidism 
Grading 
Management 
G1: Asymptomatic or mild symptoms 
Can continue ICPi with close follow-up and 
monitoring of TSH, FT4 every 2-3 weeks until 
it is clear whether there will be persistent 
hyperthyroidism 
(see 
below) 
or 
hypothyroidism (see 4.1.1) 
Consider holding ICPi until symptoms return to
baseline Consider endocrine consultation 
b-Blocker (eg, atenolol, propranolol) for 
symptomatic relief 
Hydration and supportive care 
Corticosteroids are not usually required to 
shorten duration 
For persistent hyperthyroidism (> 6 weeks) or 
clinical suspicion, work-up for Graves 
disease (TSI or TRAb) 
and consider 
thionamide (methimazole or PTU) Refer to 
endocrinology for Graves disease 

M7824 Clinical Protocol v2.0 dated 01-Dec-2021 
Page 50 of 116 
 
 
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 

M7824 Clinical Protocol v2.0 dated 01-Dec-2021 
Page 51 of 116 
 
 
 
5.0 Endocrine Toxicity 
Deﬁnition: Adrenal gland failure leading to low morning cortisol, high morning ACTH, as well as
hyponatremia and hyperkalemia with orthostasis and volume depletion due to loss of aldosterone 
Diagnostic work-up for patients in whom 
adrenal insufﬁciency is suspected: 
Evaluate ACTH (AM), cortisol level 
(AM) Basic metabolic panel (Na, K, 
CO2, glucose) 
Consider ACTH stimulation test for 
indeterminate results 
If primary adrenal insufﬁciency (high 
ACTH, 
low 
cortisol) 
is 
found 
biochemically: 
Evaluate for precipitating cause of crisis 
such as infection Perform an adrenal CT 
for metastasis/hemorrhage 
Grading 
Management 
G1: Asymptomatic or mild symptoms 
Consider holding ICPi until patient is 
stabilized on replacement hormone 
Endocrine consultation 
Replacement therapy with prednisone (5-10 mg 
daily) or hydrocortisone (10-20 mg orally every 
morning, 5-10 mg orally in early afternoon) 
May require ﬂudrocortisone (0.1 mg/d) for 
mineralocorticoid replacement in primary 
adrenal insufﬁciency 
Titrate dose up or down as symptoms dictate 
G2: Moderate symptoms, able to perform ADL Consider holding ICPi until patient is 
stabilized on replacement hormone 
Endocrine consultation 
Initiate outpatient treatment at two to 
three times maintenance 
(if prednisone, 20 mg daily; if hydrocortisone, 
20-30 mg in the morning, and 10-20 mg in the 
afternoon) to manage acute symptoms. 
Taper stress-dose corticosteroids down to 
maintenance doses over 5-10 days 
Maintenance therapy as in G1. 

M7824 Clinical Protocol v2.0 dated 01-Dec-2021 
Page 52 of 116 
 
 
G3-4: 
Severe 
symptoms, 
medically 
signiﬁcant or life- threatening consequences, 
unable to perform ADL 
Hold ICPi until patient is stabilized on 
replacement hormone 
Endocrine consultation 
See in clinic or, for after hours, make an 
emergency department referral for normal 
saline (at least 2 L) and IV stress-dose 
corticosteroids 
on 
presentation 
hydrocortisone 100 mg or dexamethasone 4 
mg (if the diagnosis is not clear and 
stimulation testing will be needed) 
Taper stress-dose corticosteroids down to 
maintenance doses over 7-14 days after 
discharge 
Maintenance therapy as in G1 
Additional considerations 
Primary and secondary adrenal insufﬁciency can be distinguished by the relationship between 
ACTH and cortisol. If the ACTH is low with low cortisol, then management is as per 4.3. 
Patients on corticosteroids for management of other conditions will have low morning 
cortisol as a result of iatrogenic, secondary adrenal insufﬁciency. ACTH will also be low in 
these patients. A diagnosis of adrenal insufﬁciency is challenging to make in these 
situations (see next section on hypophysitis). 

M7824 Clinical Protocol v2.0 dated 01-Dec-2021 
Page 53 of 116 
 
 
5.0 Endocrine Toxicity 
Emergent therapy for someone with suspected adrenal insufﬁciency is best done with
dexamethasone as a stimulation test can still be performed. If the diagnosis is already conﬁrmed,
can use hydrocortisone 100 mg. 
All patients need education on stress dosing and a medical alert bracelet for adrenal insufﬁciency to
trigger stress- dose corticosteroids by EMS. 
Endocrine consultation prior to surgery or any procedure for stress-dose planning. 
5.3 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 ± new severe
headaches or complaints of vision changes 
Grading 
Management 
G1: Asymptomatic or mild symptoms 
Consider holding ICPi until patient is 
stabilized on replacement hormones 
Endocrine consultation 
Hormonal supplementation as in G1 
G3-4: 
Severe 
symptoms, 
medically 
signiﬁcant or life- threatening consequences, 
unable to perform ADL 
Hold ICPi until patient is stabilized on 
replacement hormones 
Endocrine consultation 
Hormonal supplementation as in G1 
Consider initial pulse dose therapy with 
prednisone 1-2 mg/kg oral daily (or equivalent) 
tapered over at least 1- 2 weeks 
Additional considerations 
Be aware of the need to start corticosteroids ﬁrst when planning hormone replacement therapy for
multiple deﬁciencies 
All patients need instruction on doubling doses for illness (stress dosing) and a medical alert bracelet
for adrenal insufﬁciency to trigger stress-dose corticosteroids by EMS 
Corticosteroid use can cause isolated central adrenal insufﬁciency 
Work-up cannot be done with a simple AM cortisol in a patient on corticosteroids for other 
conditions Laboratory conﬁrmation of adrenal insufﬁciency should not be attempted until 
treatment with corticosteroids for other disease is ready to be discontinued. For long-term 
exposure, consult endocrinology for recovery and 
weaning protocol using hydrocortisone. 
5.4 Diabetes 

M7824 Clinical Protocol v2.0 dated 01-Dec-2021 
Page 54 of 116 
 
 
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 
5.0 Endocrine Toxicity 
G1: Asymptomatic or mild symptoms; fasting 
glucose value > ULN (160 mg/dL); fasting 
glucose value > ULN (8.9 mmol/L); no 
evidence of ketosis or laboratory evidence of 
T1DM 
Can continue ICPi with close clinical 
follow-up and laboratory evaluation 
May initiate oral therapy for those with new-
onset T2DM 
Screen for T1DM if appropriate, for 
example, acute onset with prior normal 
values or clinical concern for ketosis 
G2: Moderate symptoms, able to perform 
ADL, fasting glucose value > 160-250 mg/dL; 
fasting glucose value> 8.9-13.9 mmol/L, 
ketosis or evidence of T1DM at any glucose 
level 
May hold ICPi until glucose control is obtained 
Titrate oral therapy or add insulin for worsening 
control in T2DM Should administer insulin for 
T1DM (or as default therapy if there is 
confusion about type) 
Urgent endocrine consultation for any 
patient with T1DM; in the absence of 
endocrinology, internal medicine may 
sufﬁce 
Consider admission for T1DM if early 
outpatient evaluation is not available or signs 
of ketoacidosis are present 
G3-4: 
Severe 
symptoms, 
medically 
signiﬁcant or life- threatening consequences, 
unable to perform ADL 
G3: > 250-500 mg/dL (> 13.9-27.8 mmol/L) 
G4: > 500 mg/dL (> 27.8 mmol/L) 
Hold ICPi until glucose control is obtained on 
therapy with reduction of toxicity to G1 or 
less 
Urgent endocrine consultation for all 
patients Initiate insulin therapy for all 
patients 
Admit for inpatient management: Concerns 
for developing DKA, Symptomatic patients 
regardless of diabetes type, New-onset T1DM 
unable to see endocrinology 

M7824 Clinical Protocol v2.0 dated 01-Dec-2021 
Page 55 of 116 
 
 
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. 
 

M7824 Clinical Protocol v2.0 dated 01-Dec-2021 
Page 56 of 116 
 
 
MANAGEMENT OF MUSCULOSKELETAL irAES IN PATIENTS TREATED WITH ICPis 
 
6.0 Musculoskeletal Toxicities 
6.1 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 ± 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 

M7824 Clinical Protocol v2.0 dated 01-Dec-2021 
Page 57 of 116 
 
 
G2: Moderate pain associated with signs 
of inﬂammation, erythema, or joint 
swelling, limiting instrumental ADL 
Hold ICPi and resume upon symptom control 
and on prednisone ≤ 10 mg/d 
Escalate analgesia and consider higher 
doses of NSAIDS as needed 
If inadequately controlled, initiate prednisone 
or prednisolone 10-20 mg/d or equivalent for 
4-6 weeks 
If improvement, slow taper according to 
response during the next 4-6 weeks; if no 
improvement after initial 4-6 weeks, treat as G3 
If unable to lower corticosteroid dose to < 10 
mg/d after 3 months, consider DMARD 
Consider intra-articular corticosteroid injections
for large joints 
Referral to rheumatology 
G3-4: Severe pain associated with signs of 
inﬂammation, erythema, or joint swelling; 
irreversible joint damage; disabling; limiting 
self-care ADL 
For G3: Hold ICPi temporarily and may resume 
in consultation with rheumatology, if recover to
G1 or less For G4: permanently discontinue
ICPi 
Initiate oral prednisone 0.5-1 mg/kg 
If failure of improvement after 4 weeks or
worsening in meantime, consider synthetic or
biologic DMARD 

M7824 Clinical Protocol v2.0 dated 01-Dec-2021 
Page 58 of 116 
 
 
6.0 Musculoskeletal Toxicities 
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. 
6.2 Myositis 
Deﬁnition: A disorder characterized by muscle inﬂammation with weakness and elevated 
muscle enzymes (CK). Muscle pain can be present in severe cases. Can be life threatening if 
respiratory muscles or myocardium are involved 
Diagnostic work-up 
Complete rheumatologic and neurologic history regarding differential diagnosis; rheumatologic
and neurologic examination, including muscle strength; and examination of the skin for ﬁndings
suggestive of dermatomyositis. Muscle weakness is more typical of myositis than pain. Consider
preexisting conditions that can cause similar symptoms. 
Blood testing to evaluate muscle inﬂammation 
CK, transaminases (AST, ALT), LDH, and aldolase can also be elevated 
Troponin to evaluate myocardial involvement and other cardiac testing, such as echocardiogram, as
needed Inﬂammatory markers (ESR and CRP) 
Consider EMG, imaging (MRI), and/or biopsy on an individual basis when diagnosis is uncertain
and overlap with neurologic syndromes, such as myasthenia gravis, is suspected 
Consider paraneoplastic autoantibody testing for myositis and neurologic conditions, such as
myasthenia gravis Monitoring: CK, ESR, CRP 
G1: Complete examination and laboratory work-up as above 
G2: Complete history and examination as above; autoimmune myositis blood panel; EMG, MRI of
affected joints Early referral to a rheumatologist or neurologist 
G3-4: As for G2 
Urgent referral to a rheumatologist or neurologist 
Grading 
Management 
G1: Mild weakness with or without pain 
Continue ICPi 
If CK is elevated and patient has muscle 
weakness, may offer oral corticosteroids, 
and treat as G2 

M7824 Clinical Protocol v2.0 dated 01-Dec-2021 
Page 59 of 116 
 
 
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 

M7824 Clinical Protocol v2.0 dated 01-Dec-2021 
Page 60 of 116 
 
 
6.0 Musculoskeletal Toxicities 
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 
For G3: Hold ICPi until G1 or less and 
permanently discontinue if any evidence of 
myocardial 
involvement 
For 
G4: 
permanently discontinue ICPi 
Consider hospitalization for severe 
weakness Referral to rheumatologist 
or neurologist 
Initiate prednisone 1 mg/kg or equivalent. 
Consider 1-2 mg/kg of methylprednisolone IV or 
higher-dose 
bolus if 
severe 
compromise 
(weakness severely limiting mobility, cardiac, 
respiratory, dysphagia) 
Consider 
plasmapheresis 
Consider IVIG therapy 
Consider other immunosuppressant therapy, 
such 
as 
methotrexate, 
azathioprine, 
or 
mycophenolate mofetil, if symptoms and CK 
levels do not improve or worsen after 4-6 
weeks; rituximab is used in primary myositis 
but caution is advised given its long biologic 
duration 
In 
case 
of 
management 
with 
rituximab, ICPi treatment should be 
discontinued 
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 

M7824 Clinical Protocol v2.0 dated 01-Dec-2021 
Page 61 of 116 
 
 
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 

M7824 Clinical Protocol v2.0 dated 01-Dec-2021 
Page 62 of 116 
 
 
6.0 Musculoskeletal Toxicities 
G3-4: Severe stiffness and pain, limiting self-
care ADL 
For G3: Hold ICPi and may resume, in 
consultation with rheumatology, if recover to G1 
or less; however, note that cases of toxicity 
returning upon rechallenge have been reported. 
ICPi should be permanently discontinued in 
such cases 
For G4: permanently discontinue ICPi 
Referral to rheumatology 
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. 
 

M7824 Clinical Protocol v2.0 dated 01-Dec-2021 
Page 63 of 116 
 
 
MANAGEMENT OF RENAL irAES IN PATIENTS TREATED WITH ICPis 
 
7.0 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 
7.1 Nephritis 
Deﬁnition: Inﬂammation of the kidney affecting the structure 
Grading 
Management 
G1: Creatinine level increase 
> ULN - 1.5 x ULN 
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 
> 1.5 - 3.0 x baseline; > 1.5 - 3.0 x ULN 
Hold ICPi 
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 
> 3.0 x baseline; > 3.0 - 6.0 x ULN 
Permanently discontinue ICPi 
G4: Life-threatening consequences; 
dialysis indicated; 
> 6.0 x ULN 
Permanently discontinue ICPi 
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) 

M7824 Clinical Protocol v2.0 dated 01-Dec-2021 
Page 64 of 116 
 
 
Additional 
considerations  
Monitor creatinine 
weekly 
Reﬂex kidney biopsy should be discouraged until corticosteroid treatment has been attempted 
7.2 Symptomatic nephritis: follow-up 
Grading 
Management 
G1 
Improved to baseline, resume routine 
creatinine monitoring 
G2 
If improved to G1, taper corticosteroids over at 
least 3 weeks before resuming treatment with 
routine creatinine monitoring If elevations 
persist > 7 days or worsen and no other cause 
found, treat as G3 
G3 
If improved to G1, taper corticosteroids over at 
least 4 weeks 
7.0 Renal Toxicities 
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. 

M7824 Clinical Protocol v2.0 dated 01-Dec-2021 
Page 65 of 116 
 
 
MANAGEMENT OF NERVOUS SYSTEM irAES IN PATIENTS TREATED WITH ICPis 
 
8.0 Nervous System Toxicities 
8.1 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 
Gradi
ng 
Managem
ent 
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 

M7824 Clinical Protocol v2.0 dated 01-Dec-2021 
Page 66 of 116 
 
 
G3-4: Limiting self-care and aids warranted, 
weakness limiting walking, ANY dysphagia, 
facial weakness, respiratory muscle weakness, 
or rapidly progressive symptoms, or MGFA 
severity 
class 
3-4 
moderate 
to 
severe 
generalized weakness to myasthenic crisis 
Permanently discontinue ICPi 
Admit patient, may need ICU-level 
monitoring Neurology consult 
Continue corticosteroids and initiate IVIG 2 
g/kg IV over 5 days (0.4 g/kg/d) or 
plasmapheresis for 5 days Frequent pulmonary 
function assessment 
Daily neurologic review 
Additional considerations 
Avoid medications that can worsen myasthenia: β-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 
8.2 Guillain-Barré syndrome 

M7824 Clinical Protocol v2.0 dated 01-Dec-2021 
Page 67 of 116 
 
 
8.0 Nervous System Toxicities 
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 
Permanently discontinue ICPi. 
Admission to inpatient unit with capability of 
rapid transfer to ICU-level monitoring Start 
IVIG (0.4 g/kg/d for 5 days for a total dose of 2 
g/kg) or plasmapheresis. Corticosteroids are 
usually not recommended for idiopathic 
Guillain-Barré syndrome; however, in ICPi- 
related 
forms, 
a 
trial 
is 
reasonable 
(methylprednisolone 2-4 mg/kg/d), followed 
by slow corticosteroid taper 
Pulse 
corticosteroid 
dosing 
(methylprednisolone 1 g/d for 5 days) may also 
be considered for G3-4 along with IVIG or 
plasmapheresis 
Frequent neurochecks and pulmonary 
function monitoring 
Monitor for concurrent autonomic 
dysfunction Nonopioid management of 
neuropathic 
pain 
Treatment 
of 
constipation/ileus 

M7824 Clinical Protocol v2.0 dated 01-Dec-2021 
Page 68 of 116 
 
 
Additional considerations 
Slow prednisone taper after corticosteroid pulse plus IVIG or plasmapheresis May require repeat
IVIG courses Caution with rechallenging for severe cases 
8.3 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 

M7824 Clinical Protocol v2.0 dated 01-Dec-2021 
Page 69 of 116 
 
 
8.0 Nervous System Toxicities 
MRI spine advised/MRI of brain if cranial nerve Consider 
EMG/NCS Consider neurology consultation 
G3-4: go to Guillain-Barré syndrome algorithm 
Gradi
ng 
Managem
ent 
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 
8.4 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 

M7824 Clinical Protocol v2.0 dated 01-Dec-2021 
Page 70 of 116 
 
 
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 
8.5 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

M7824 Clinical Protocol v2.0 dated 01-Dec-2021 
Page 71 of 116 
 
 
8.0 Nervous System Toxicities 
May see elevated WBC count with normal glucose, normal culture, and Gram stain; may see 
reactive lymphocytes or histiocytes on cytology 
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 
8.6 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 
Neurologic consultation 
MRI of brain with or without contrast may reveal T2/ﬂuid-attenuated inversion recovery changes
typical of what is seen in autoimmune encephalopathies or limbic encephalitis or may be normal 
Lumbar puncture: check cell count and protein glucose and perform Gram stain, culture, PCR for 
HSV and other viral PCRs depending on suspicion, cytology, oligoclonal bands, autoimmune 
encephalopathy, and paraneoplastic panels. 
May see elevated WBC count with lymphocytic predominance and/or 
elevated protein EEG to evaluate for subclinical seizures 
Blood: metabolic, CBC, ESR, CRP, ANCA (if suspect vasculitic process), thyroid panel including
TPO and thyroglobulin Rule out concurrent anemia/thrombocytopenia, which can present with
severe headaches and confusion 
Grading 
Management 
G1: Mild, no interference with function and 
symptoms not concerning to patient. Note: 
Any cranial nerve problem should be 
managed as moderate. 
G2: Moderate, some interference with ADL, 
symptoms concerning to patient (ie, pain but 
no weakness or gait limitation) 
G3-4: Severe, limiting self-care and aids
warranted 
Hold ICPi and discuss resumption with patient 
only after taking into account the risks and 
beneﬁts 
As above for aseptic meningitis suggest 
concurrent IV acyclovir until PCR results 
obtained and negative 
Trial of methylprednisolone 1-2 mg/kg 
If 
severe 
or 
progressing 
symptoms 
or 
oligoclonal bands present, consider pulse 
corticosteroids methylprednisolone 1 g IV daily 
for 3-5 days plus IVIG 2 g/kg over 5 days If 
positive 
for 
autoimmune 
encephalopathy 
antibody and limited or no improvement, 
consider rituximab or plasmapheresis in 
consultation with neurology. 

M7824 Clinical Protocol v2.0 dated 01-Dec-2021 
Page 72 of 116 
 
 
8.7 Transverse myelitis 
Deﬁnition: Acute or subacute weakness or sensory changes bilateral, often with increased deep 
tendon reﬂexes 
Diagnostic 
work-up 
Neurologic consultation 
MRI of spine (with thin axial cuts through the region of suspected abnormality) and MRI of brain
Lumbar puncture: cell count, protein, glucose, oligoclonal bands, viral PCRs, cytology, 
onconeural antibodies Blood: B12, HIV, RPR, ANA, Ro/La, TSH, aquaporin-4 IgG 
Evaluation for urinary retention, constipation 
Grading 
Management 
G1: Mild, no interference with function and 
symptoms not concerning to patient. Note: 
Any cranial nerve problem should be 
managed as moderate. 
Permanently discontinue 
ICPi Methylprednisolone 
2 mg/kg 

M7824 Clinical Protocol v2.0 dated 01-Dec-2021 
Page 73 of 116 
 
 
8.0 Nervous System Toxicities 
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 
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. 
 

M7824 Clinical Protocol v2.0 dated 01-Dec-2021 
Page 74 of 116 
 
 
MANAGEMENT OF HEMATOLOGIC irAES IN PATIENTS TREATED WITH ICPis 
 
9.0 Hematologic Toxicities 
9.1 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 

M7824 Clinical Protocol v2.0 dated 01-Dec-2021 
Page 75 of 116 
 
 
G3: Hgb < 8.0 g/dL; < 4.9 mmol/L; < 80 g/L;
transfusion indicated 
Permanently discontinue ICPi 
Should use clinical judgment and consider 
admitting the patient 
Hematology consult 
Prednisone 1-2 mg/kg/d (oral or IV 
depending 
on 
symptoms/speed 
of 
development) 
If worsening or no improvement, 1-2 mg/kg/d 
prednisone equivalents and permanently 
discontinue ICPi treatment 
Consider RBC transfusion per existing 
guidelines; do not transfuse more than the 
minimum number of RBC units necessary to 
relieve symptoms of anemia or to return a 
patient to a safe Hgb range (7-8 g/dL in stable, 
noncardiac inpatients) 
Should offer patients supplementation with 
folic acid 1 mg once daily 
G4: Life-threatening consequences, urgent 
intervention indicated 
Permanently discontinue 
ICPi Admit patient 
Hematology consult 
IV prednisone corticosteroids 1-2 mg/kg/d 

M7824 Clinical Protocol v2.0 dated 01-Dec-2021 
Page 76 of 116 
 
 
9.0 Hematologic Toxicities 
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 
9.2 Acquired TTP 
Deﬁnition: A disorder characterized by the presence of microangiopathic hemolytic anemia,
thrombocytopenic purpura, fever, renal abnormalities, and neurologic abnormalities, such as 
seizures, hemiplegia, and visual disturbances. It is an acute or subacute condition. 
Diagnostic work-up 
History with speciﬁc questions related to drug exposure (eg, chemotherapy, sirolimus, tacrolimus,
opana ER antibiotics, quinine) Physical examination, peripheral smear 
ADAMTS13 activity level and inhibitor titer 
LDH, haptoglobin, reticulocyte count, bilirubin, urinalysis to rule out 
other causes PT, activated PTT, ﬁbrinogen 
Blood group and antibody screen, direct antiglobulin test, CMV 
serology Consider CT/MRI brain, echocardiogram, ECG 
Viral studies 
Note: This disorder is usually associated with a severe drop in platelets and hemolysis/anemia 
precipitously 
Grading 
Management 
All grades 
The ﬁrst step in the management of TTP is a 
high index of suspicion for the diagnosis and 
timely recognition; hematology consult should 
immediately be called, as delay in identiﬁcation 
is 
associated 
with 
increased 
mortality/morbidity. 
Initially, the patient should be stabilized and any 
critical organ dysfunction stabilized 
G1: 
Evidence 
of 
RBC 
destruction 
(schistocytosis) without anemia, renal 
insufﬁciency, 
or 
thrombocytopenia 
clinically 
G2: 
Evidence 
of 
RBC 
destruction 
(schistocytosis) 
without 
clinical 
consequence 
with 
G2 
anemia 
and 
thrombocytopenia 
Hold ICPi and discuss resumption with patient 
only after taking into account the risks and 
beneﬁts, noting that there are currently no data 
to 
recommend 
restarting 
ICPi 
therapy 
Hematology consult 
Administer 0.5-1 mg/kg/d prednisone 

M7824 Clinical Protocol v2.0 dated 01-Dec-2021 
Page 77 of 116 
 
 
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) 
For G3: 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 
For G4: permanently discontinue ICPi 
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 
In 
case 
of 
management 
with 
rituximab, ICPi treatment will be 
discontinued 

M7824 Clinical Protocol v2.0 dated 01-Dec-2021 
Page 78 of 116 
 
 
9.0 Hematologic Toxicities 
9.3 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 
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) 
For G1 and G2: Continue ICPi with close 
clinical follow- up and laboratory evaluation 
Supportive care 
For G3 and G4: 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 

M7824 Clinical Protocol v2.0 dated 01-Dec-2021 
Page 79 of 116 
 
 
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 

M7824 Clinical Protocol v2.0 dated 01-Dec-2021 
Page 80 of 116 
 
 
9.0 Hematologic Toxicities 
Type and screen patient for transfusions and notify blood bank that all transfusions need to be 
irradiated and ﬁltered 
Grading 
Management 
G1: Nonsevere, < 0.5 polymorphonuclear cells 
x 109/L hypocellular marrow, with marrow 
cellularity < 25%, peripheral platelet count > 
20,000, reticulocyte count 
< 20,000 
Hold ICPi and provide growth factor support 
and close clinical follow-up, and laboratory 
evaluation 
Supportive transfusions as per local guidelines 
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% 
For G3: Hold ICPi and monitor weekly for 
improvement; if not resolved, discontinue 
treatment until AE has reverted to G1 
For G4: permanently discontinue 
ICPi 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 
9.5 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) 
 
 

M7824 Clinical Protocol v2.0 dated 01-Dec-2021 
Page 81 of 116 
 
 
Grading 
Management 
G1-2: 500-1,000 PB lymphocyte 
count 
G3: 
250-499 
PB 
lymphocyte count G4: < 250 PB 
lymphocyte count 
Continue ICPi for G1 to G2 
For G3 single laboratory values out of normal 
range without any clinical correlates, hold 
treatment until resolution to G1 
For G4, for single laboratory values out of 
normal range without any clinical correlates, 
permanent treatment discontinuation is not 
required. 
Treatment should be held until the etiology is 
determined. 
Permanent 
treatment 
discontinuation will only be required, if 
lymphopenia is considered of immune related in 
nature, no clear alternative explanation exists 
for the event, and grade 4 lymphopenia does not 
resolve within 14 days. If the event is not 
considered immune related and resolves to G ≤1 
restarting treatment may be considered. 

M7824 Clinical Protocol v2.0 dated 01-Dec-2021 
Page 82 of 116 
 
 
9.0 Hematologic Toxicities 
Check 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. 
9.6 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 
Gradi
ng 
Managem
ent 
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 

M7824 Clinical Protocol v2.0 dated 01-Dec-2021 
Page 83 of 116 
 
 
G4: Platelet count < 25/µL 
Permanently discontinue ICPi 
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 

M7824 Clinical Protocol v2.0 dated 01-Dec-2021 
Page 84 of 116 
 
 
9.0 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) 
9.7 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 ± 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 

M7824 Clinical Protocol v2.0 dated 01-Dec-2021 
Page 85 of 116 
 
 
G3-4: Severe, < 1% of normal factor activity in 
blood, < 
0.01 IU/mL of whole blood 
Permanently discontinue 
ICPi Admit patient 
Hematology consult 
Administration of factor replacement, choice 
based on Bethesda unit level of inhibitor 
Bypassing agents may be used (factor VII, 
factor VIII inhibitor bypass activity); caution 
should be taken in the elderly and those with 
coronary artery disease 
Prednisone 1-2 mg/kg/d (oral or IV depending 
on symptoms) ± 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. 

M7824 Clinical Protocol v2.0 dated 01-Dec-2021 
Page 86 of 116 
 
 
9.0 Hematologic Toxicities 
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. 
 

M7824 Clinical Protocol v2.0 dated 01-Dec-2021 
Page 87 of 116 
 
 
MANAGEMENT OF CARDIOVASCULAR irAES IN PATIENTS TREATED WITH ICPis 
 
10.0 Cardiovascular Toxicities 
10.1 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: 
For G1: Hold ICPi 
For 
G2, 
G3, 
and 
G4: 
Permanently 
discontinue ICPi For G1-G4: High-dose 
corticosteroids (1-2 mg/kg of prednisone) 
initiated rapidly (oral or IV depending on 
symptoms) 
Admit patient, cardiology consultation 
Immediate transfer to a coronary care unit for
patients with elevated troponin or conduction
abnormalities 
In patients without an immediate response to
high-dose 
corticosteroids, 
consider 
early 
institution of cardiac transplant rejection doses 
of corticosteroids (methylprednisolone 1 g every
day) and the addition of either mycophenolate, 
inﬂiximab, or antithymocyte globulin 
Qualifying statement: Treatment recommendations are based on anecdotal evidence and the life-
threatening nature of cardiovascular complications. 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. 
10.2 Venous thromboembolism 

M7824 Clinical Protocol v2.0 dated 01-Dec-2021 
Page 88 of 116 
 
 
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 

M7824 Clinical Protocol v2.0 dated 01-Dec-2021 
Page 89 of 116 
 
 
10.0 Cardiovascular Toxicities 
Grading 
Management 
G1: 
Venous 
thrombosis 
(eg, 
superﬁcial 
thrombosis) 
Continue 
ICPi 
Warm compress 
Clinical 
surveillance 
G2: 
Venous 
thrombosis 
(eg, 
uncomplicated DVT), medical intervention 
indicated 
G3: Thrombosis (eg, uncomplicated PE 
[venous], nonembolic cardiac mural [arterial] 
thrombus), medical intervention indicated 
Hold ICPi until AE reverts back to G1 or less. 
If reverts to G2, use benefit-risk assessment for 
ICPi continuation 
Consider consult from cardiology or other 
relevant specialties 
LMWH is suggested over VKA, dabigatran, 
rivaroxaban apixaban, or edoxaban for initial 
and long-term treatment 
IV heparin is an acceptable alternative for 
initial 
use, 
and oral anticoagulants are 
acceptable for the long term 
G4: 
Life-threatening 
(eg, 
PE, 
cerebrovascular event, arterial insufﬁciency), 
hemodynamic or neurologic instability, 
urgent intervention indicated 
Permanently discontinue ICPi 
Admit patient and management according to 
CHEST, ACC, and/or AHA guidelines and 
with guidance from cardiology 
Respiratory and hemodynamic support 
LMWH is suggested over VKA, dabigatran, 
rivaroxaban, apixaban, or edoxaban for initial 
and long-term treatment 
IV heparin is an acceptable alternative for 
initial 
use, 
and oral anticoagulants are 
acceptable for the long term 
Further clinical management as indicated 
based on symptoms 
Additional considerations 
While it may be impossible to determine the etiology of thromboembolic disease in patients with
advanced cancer and the role, if any, that ICPi treatment plays, it is reasonable to remove the 
potential inciting agents given the severity and life-threatening potential of G4 complications. 
Clinicians are to use clinical judgment and take into account the risks and beneﬁts when deciding
whether to discontinue ICPi treatment. 
Anticoagulant therapy duration should continue for a minimum of 9-12 months to indeﬁnitely in the
setting of active cancer unless patient is asymptomatic, doing well, or in remission. 
All recommendations are expert consensus based, with beneﬁts outweighing harms, and strength of
recommendations are moderate. 
Abbreviations: 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. 

M7824 Clinical Protocol v2.0 dated 01-Dec-2021 
Page 90 of 116 
 
 
MANAGEMENT OF OCULAR irAES IN PATIENTS TREATED WITH ICPis 
 
11.0 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 
11.1 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 

M7824 Clinical Protocol v2.0 dated 01-Dec-2021 
Page 91 of 116 
 
 
reduced to ≤ 10 mg; continued topical/ocular 
corticosteroids are permitted when resuming 
therapy to manage and minimize local toxicity 
Re-treat after return to G1 or less 
G3: Posterior or panuveitis 
Permanently discontinue 
ICPi 
Urgent 
ophthalmology referral. 
Systemic 
corticosteroids 
and 
intravitreal/periocular/topical corticosteroids 
G4: 20/200 or worse 
Permanently 
discontinue 
ICPi 
Emergent 
ophthalmology referral 

 
Page 92 of 116 
 
 
11.0 Ocular Toxicities 
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-α blockers in cases that are 
severe and refractory to standard treatment 
11.2 Episcleritis 
Deﬁnition: Inﬂammatory condition affecting the episcleral tissue between the conjunctiva and the 
sclera that occurs in the absence of an infection Diagnostic work-up: As per 10.0 
Grading 
Management 
G1: Asymptomatic 
Continue ICPi 
Refer to ophthalmology within 
1 week Artiﬁcial tears 
G2: Vision 20/40 or better 
Hold ICPi therapy temporarily until after 
ophthalmology consult 
Urgent ophthalmology referral 
Topical corticosteroids, cycloplegic agents, 
systemic corticosteroids 
G3: Symptomatic and vision worse than 2/40 
Permanently discontinue 
ICPi 
Urgent 
ophthalmology referral. 
Systemic 
corticosteroids 
and 
topical 
corticosteroids with cycloplegic agents 
G4: 20/200 or worse 
Permanently 
discontinue 
ICPi 
Emergent 
ophthalmology referral. 
Systemic 
corticosteroids 
and 
topical 
corticosteroids with cycloplegic agents 
Additional considerations: Consider use of inﬂiximab or other TNF-α blockers in cases that are 
severe and refractory to standard treatment 
11.3 Blepharitis 
Deﬁnition: Inﬂammation of the eyelid that affects the eyelashes or tear production Diagnostic work-
up: As per 10.0 
Grading 
Management 
No formal grading system 
Warm compresses and lubrication drops 
Continue therapy unless persistent and 
serious 
All recommendations are expert consensus based, with beneﬁts outweighing harms, and strength of 
recommendations are moderate. 
Abbreviations: ICPi, immune checkpoint inhibitor; G, Grade; irAE, immune-related adverse 
event; IV, intravenous, TNF, tumor necrosis factor. 
 
 

 
Page 93 of 116 
 
 
5.6.6 Management of Adverse Skin Reaction  
 
TGF-β inhibition mediated skin reactions are considered important identified risk for 
bintrafusp alfa.             Skin assessment must be performed at baseline and at least every 6 
weeks during treatment and at the end of treatment or 28 (±5 days) days post-treatment 
safety follow-up (if not performed in the previous 6 weeks). 
 
Hyperkeratosis 
 
Keratoacanthoma 
 
Cutaneous squamous cell carcinoma (cSCC) 
 
Basal cell carcinoma 
 
Actinic keratosis 
Management 
 
Baseline skin assessment with detailed medical history 
 
Discontinuation or termination not required in most cases. Continuation of treatment 
should be evaluated by the Investigator. 
 
Emollients may be used 
 
Develop diagnostic and treatment plan in collaboration with Investigator and 
dermatologist 
 
Treatment follow-up will depend on number and localization of lesions. 
o Single lesion: full excision may be recommended 
o Multiple lesion or location not suitable for full excision: Mohrs surgery, 
cryotherapy or other standard treatment options depending on pathology. 
Retinoids may be used after discussion with Investigator. 
 
Close clinical follow-up for re-evaluation, resolution and potential recurrence should 
be implemented 
 
In general, treatment of TGF-β mediated skin lesions should be based on local 
guidelines/standard of care. 
Additional consideration: Keratoacanthoma lesions may resolve spontaneously without 
surgical intervention within weeks after discontinuing bintrafusp alfa. 
Consult with Medical Monitor as needed for management of TGF-β mediated skin lesions. 
 
5.6.7 Management of Treatment-Related Anemia  
 
 
Anemia is considered an important identified risk for bintrafusp alfa. 
 
Hematology assessment must be performed at baseline, prior to each bintrafusp alfa 
dose, at the end of treatment visit and at 28 (±5 days) days post-treatment safety 
follow-up. 
 
Participants must enter the study with Hgb values at least 9g/dl 
 
All relevant hematological testing for treatment-related anemias should be done prior 
to a blood transfusion, if clinically feasible 
Basic Anemia Evaluation 
 
CBC with emphasis on red cell indices 
 
If indicated and at clinical discretion, the following should be considered: 
o Iron studies 
o Serum Folate and Vit B12 values 
o Coagulation factors 
o Fecal occult blood 
o Urinalysis 
o Hormone panel: TSH, Erythropoietin 

 
Page 94 of 116 
 
 
o Peripheral blood smear 
Further Recommendation Based on Suspected Etiology (in Addition to Basic Anemia 
Testing) 
 
 
Suspected Hemolysis 
o bilirubin, LDH, Coombs test, haptoglobin 
 
Suspected bleeding:  
o Consider imaging/interventional radiology consultation as indicated 
o Consider imaging and/or endoscopy as clinically indicated 
 
Suspected aplastic anemia: 
o Hematology consultation 
o Consider bone marrow aspiration/morphologic evaluation 
 
Additional consideration:  
In general, blood transfusions and erythroid growth factors are permitted as clinically 
indicated. 
Abbreviation: CBC: complete blood count, TSH: thyroid stimulating hormone, LDH: lactate 
dehydrogenase 
 
5.6.8 Management of Bleeding Adverse Events 
Bleeding Adverse Events 
 
Bleeding adverse events are considered important identified risk for bintrafusp alfa. 
 
In general, mild and moderate mucosal bleedings resolve without discontinuation of 
treatment. 
 
These events may include, but are not limited to the following: 
o Epistaxis 
o Hemoptysis  
o Gingival bleeding 
o Hematuria 
Mucosal/Non-tumor Bleeding 
Grading 
Management 
Grade 2 
 
If resolves to Grade ≤ 1 by the day 
before the next infusion, study 
intervention may be continued 
 
If not resolved to Grade ≤ 1 by the day 
before the next infusion, but is 
manageable and /or not clinically 
relevant, consult Medical Monitor to 
assess if clinically reasonable to 
administer the following infusion. 
Grade ≥3 
 
 
Permanently discontinue treatment 
unless an alternative explanation can be 
identified (such as concomitant use of 
antithrombotic agents, traumatic events, 
etc.)  
 
In case of alternative explanations, hold 
study treatment until the event recovers 
to Grade ≤ 1 

 
Page 95 of 116 
 
 
 
If Grade ≥3 bleeding event is observed, 
regardless of causality with the study 
intervention, upon resumption of study 
intervention bintrafusp alfa dose should 
be reduced by 50% (600 mg Q2W for 
participants dosed with 1200 mg, 1200 
mg for participants dosed with 2400 
mg). Once there is stable resolution and 
no recurrence of bleeding on reduced 
dose, Investigator is encouraged to 
communicate with Medical Monitor on 
potential dose re-escalation after careful 
benefit-risk assessment. 
Grade 4 
 
Treatment must be permanently 
discontinued if no alternative 
explanation is identified. 
In case of rapid decrease of hemoglobin (Hgb), such as a decrease greater than 2.0 g/dL 
across a 2 weeks period, withhold the subsequent cycles of study intervention until Hgb is 
stabilized and do a thorough assessment of bleeding (for example, upper and lower GI 
endoscopy, enhancement CT etc.); if Grade 1 or greater bleeding is observed or suspected, 
withhold the bintrafusp alfa until the bleeding is resolved/controlled and resume the dose of 
bintrafusp alfa reduced by 50%. Once Hgb decrease is recovered to ≤ Grade 1 or baseline 
and stably controlled, the Investigator is encouraged to communicate with Medical Monitor 
to re-escalate the dose. The dose of bintrafusp alfa may be re-escalated to full dose once 
Hgb is stabilized without further need for blood transfusion in the subsequent cycles. The 
timing of re escalation may need a case-by-case decision. See Section Table 5 regarding 
stabilization of anemia. 
Tumor Bleeding 
Grade ≥ 2 
 
Study treatment must be held till the 
event recovers to Grade ≤ 1 
 
Permanently discontinue treatment if the 
Investigator considers the participant to 
be at risk for additional severe bleeding. 
Grade ≥ 3 
 
If Grade ≥ 3 bleeding event had been 
observed, regardless of causality with 
the study intervention, upon resumption 
of the study intervention bintrafusp alfa 
dose should be reduced by 50%. Once 
there is stable resolution and no 
recurrence of bleeding on reduced dose, 
Investigator is encouraged to 
communicate with Medical Monitor 
potential dose re-escalation after careful 
benefit-risk assessment. Treatment 
should be permanently discontinued if 
the Investigator considers the participant 
to be at risk for additional severe 
bleeding. 
 
In case of rapid decrease of hemoglobin 
(Hgb), see Section Mucosal/Non-Tumor 
bleeding. 
 
 

 
Page 96 of 116 
 
 
5.6.9 Alterations in Wound Healing or Repair of Tissue Damages 
 
 Impaired wound healing is considered important potential risk for bintrafusp 
alfa 
 Management should be discussed with Medical Monitor for participants 
requiring surgery on study. 
It is recommended to hold study intervention for approximately 4 weeks post 
major surgery for observation. Post-operative wound healing should be closely 
monitored 
 
5.6.10 Embryo-Fetal Toxicities 
 
Embryofetal toxicities are known risk of the PD 1/PD L1 targeting class and are 
considered important potential risks for bintrafusp alfa. Animal models link the PD 
1/PD L1 signaling pathway with maintenance of pregnancy through induction of 
maternal immune tolerance to fetal tissue. Embryofetal toxicity is an important 
potential risk of bintrafusp alfa. An appropriate contraception warning is provided as 
part of the inclusion criteria. Pregnant and breastfeeding women are not allowed in the 
bintrafusp alfa study, and adequate contraceptive measures are recommended during 
the study to minimize or eliminate the potential risk to the developing fetus 
 
5.6.11 Mild to Moderate Bleeding of the Mucous Membranes (Mucosal Bleeding 
Events)  
 
Mucosal bleeding of mild to moderate severity has been observed in patients treated 
with bintrafusp alfa in ongoing studies and is a potential risk of bintrafusp alfa. This 
type of bleeding may include nosebleeds, cough with blood in the phlegm (sputum), 
bleeding of the gums (gingival bleeding), or blood in the urine, among others. In 
general, this bleeding resolves without stopping treatment. 
 
6 
FOLLOW UP AND OUTCOME EVALUATION 
6.1 
Follow-Up Schedule  
 
All participants will be followed every 2 weeks during the intervention. At each visit, 
patient’s performance status and toxicity of treatment will be monitored, and blood test 
will be checked for complete blood count, liver function, and renal function. Thyroid 
function test and early morning cortisol (9am) will be performed at least every 4 weeks 
while on bintrafusp alfa therapy. For female patients in reproductive age, urine or serum 
pregnancy test needs to be performed at least every month while the subject is on 
bintrafusp alfa therapy. All adverse events and laboratory abnormalities will be graded 
per the National Cancer Institute Common Terminology Criteria for Adverse Events, 
version 4.0. 
 
For blood-borne immune markers and exploratory biomarkers, plasma EBV DNA will 
be determined before treatment and every 2 weeks until disease progression; plasma 
TGFβ1 measurement will be performed every 8 weeks until disease progression; exo-
PD-L1 concentration will be measured every 2 weeks until disease progression. 

 
Page 97 of 116 
 
 
 
Tumor imaging by CT head, neck, chest, abdomen, and pelvis will be done at baseline, 
every 8 weeks for the first 12 months, then every 12 weeks thereafter. Response will 
be assessed per RECIST version 1.1. Treatment decisions will be based on 
Investigator(s) review.  
 
 
6.2 
Outcome Measures 
 
Primary outcome:  
 
 Objective response rate (ORR): The percentage of patients with radiologically 
complete or partial response as determined by the Investigator according to 
RECIST version 1.1. 
 
Secondary outcomes:  
 
 Progression-free Survival (PFS): PFS is measured from the date of informed 
consent to radiographically documented progression according to RECIST 1.1 
or death from any cause (whichever occurs first). Participants alive and without 
disease progression or lost to follow-up will be censored at the date of their last 
radiographic assessment 
 
 Time to progression (TTP): TTP is measured from the date of informed consent 
to radiographically documented progression according to RECIST 1.1. 
Participants death and without disease progression, alive without disease 
progression, or lost to follow-up will be censored at the date of their last 
radiographic assessment 
 
 Overall survival (OS): OS is measured from date of informed consent to the 
date of death from any cause. Participants alive or lost to follow-up will be 
censored at the date of their last radiographic assessment 
 
Survival rate at 12 months and 24 months: The percentage of study population 
who are still alive for 12 months and 24 months from the date of study 
enrollment. Participants alive or lost to follow-up will be censored at the date 
of their last radiographic assessment 
 
Duration of response (DOR): DOR is the time from documentation of tumor 
response to radiographically documented disease progression 
 
 ORR, TTP, and PFS of the same definitions as above are measured against 
immune-related RECIST (irRECIST) criteria as one of the secondary endpoints.   
 
 Safety outcome measures: Incidence, nature, and severity of adverse events 
graded according to the National Cancer Institute Common Terminology 
Criteria for Adverse Events (NCI-CTCAE v.4) 
 
 Pre-treatment, serial post-treatment plasma EBV-DNA levels, and dynamics of 

 
Page 98 of 116 
 
 
EBV DNA levels will be measured 
 
 Disease control rate (DCR): The percentage of patients with a CR, PR, or SD ≥ 
6 months per RECIST 1.1 
 
 Time to response (TTR): TTR is measured from the date of informed consent 
to first radiographically documented tumor response per RECIST 1.1 
 
 Quality of life (QoL): as assessed by the European Organization for Research 
and Treatment of Cancer Core Quality of Life Questionnaire (EORTC-QLQ-
C30) and the head and neck cancer-specific H&N-35 questionnaires 
 
 
6.3 
Follow-Up and Record of Events 
 
 The patients should be followed-up for up to 2 years. 
 
 The incidence of late toxicities > grade 3 by Common Toxicity Criteria for 
Adverse Events version 4.0 (NCI-CTCAE v.4) should be recorded. 
 
 All causes of death (if occur) will be recorded. Deaths due to unknown cause 
are counted as deaths due to NPC if disease is still present at last assessment. 
 
 
6.4 
Criteria for Removal from Protocol Treatment 
 
 Disease progression 
 Inter-current disease that would affect assessments of clinical status to a 
significant degree, require discontinuation of drug, or both. 
 Unacceptable toxicity. 
 The patient may withdraw from treatment at any time for any reason. The reason 
should be recorded. Follow-up will be continued for all consenting patients for 
up to 2 years. 
 
6.5 
Exploratory Biomarkers 
 
 Archived NPC tissues will be retrieved from various pathology laboratory in 
Hong Kong in FFPE slides 
 
 For blood-based biomarkers, the logistics will be as follows, 
 Peripheral blood will be collected in lithium heparin tubes every 2 weeks 
for 8 weeks. 
 Extracellular Vesicle (EV) Isolation 
 Plasma will be extracted using low-speed centrifugation and 
cryopreserved for further analysis using standard protocols. 
Extracellular vesicles will be isolated and purified from 
cryopreserved plasma using ExoQuick® ULTRA EV Isolation Kit 
for Serum and Plasma or other commercially available kits. Purified 
EV will be obtained according to the kit manufacturer’s instructions. 

 
Page 99 of 116 
 
 
 
Nanoparticle Tracking Analysis (NTA) and Total Protein Isolation of 
EV 
 EV characterisation will be performed by NTA provided by 
NanoSight NS300 or other commercially available tools. Total 
protein will be isolated from purified EV using Total Exosome RNA 
& Protein Isolation Kit (Invitrogen™) or other commercially 
available kits and obtained according to the kit manufacturer’s 
instructions. Protein qualitative detection will be performed by 
western blot. 
 Flow Cytometry of Total Protein from EV 
 Total protein will be labelled with antibodies directed against CD4, 
CD8, CD3, CD16, CD25, CD45RA, CD56, CD62L, CD-83, 
CD127, ICOS, PD-1, PD-L1, CTLA-4, FoxP3, TIM-3, Ki67 and 
other proteins of interest. Antibodies will be purchased from BD 
Bioscience, BioLegend, eBioscience, or Beckman Coulter. 
Permeabilization 
will 
be 
performed 
using 
FOXP3 
Fixation/Permeabilization 
Concentrate 
and 
Diluent 
kit 
(eBioscience™) or other commercially available kits. Proteins will 
be interrogated by LSR II flow cytometer (BD) and results will be 
analysed using FlowJo software (Tree Star). 
 
 Prognostic and predictive power of exploratory bio-markers will be explored 
 Expression level of PD-L1 levels in archived NPC tissues 
 Pre-treatment and post-treatment levels of TGFβ1 
 Pre-treatment and post-treatment plasma exosomal PD-L1 levels 
 
6.6 
Safety Reporting 
 
6.6.1 Adverse Events 
 
 According to the ICH guideline for Good Clinical Practice, an adverse event is 
any untoward medical occurrence in a clinical investigation subject 
administered a pharmaceutical product, regardless of causal attribution. An 
adverse event can therefore be any of the following: 
 
 Any unfavorable and unintended sign (including an abnormal laboratory 
finding), symptom, or disease temporally associated with the use of a medicinal 
product, whether or not considered related to the medicinal product 
 
 Any new disease or exacerbation of an existing disease (a worsening in the 
character, frequency, or severity of a known condition) 
 
 Recurrence of an intermittent medical condition (e.g., headache) not present at 
baseline 
 
 Any deterioration in a laboratory value or other clinical test (e.g., ECG, X-ray) 
that is associated with symptoms or leads to a change in study treatment or 
concomitant treatment or discontinuation from study drug 
 

 
Page 100 of 116 
 
 
 Adverse events that are related to a protocol-mandated intervention, including 
those that occur prior to assignment of study treatment (e.g., screening invasive 
procedures such as biopsies) 
 
6.6.2 Serious Adverse Events (SAE) 
 
 A serious adverse event is any adverse event that meets any of the following 
criteria: 
 Is fatal (i.e., the adverse event actually causes or leads to death) 
 Is life threatening (i.e., the adverse event, in the view of the 
Investigator(s), places the patient at immediate risk of death) 
 This does not include any adverse event that, had it occurred in a more 
severe form or was allowed to continue, might have caused death. 
 Requires or prolongs inpatient hospitalization 
 Results in persistent or significant disability/incapacity (i.e., the adverse 
event results in substantial disruption of the patient’s ability to conduct 
normal life functions) 
 Is a congenital anomaly/birth defect in a neonate/infant born to a mother 
exposed to study drug 
 Is a significant medical event in the Investigator(s)'s judgment (e.g., may 
jeopardize the patient or may require medical/surgical intervention to 
prevent one of the outcomes listed above) 
 
 The terms “severe” and “serious” are not synonymous. Severity refers to the 
intensity of an adverse event (e.g., rated as mild, moderate, or severe, or 
according to National Cancer Institute Common Terminology Criteria for 
Adverse Events [NCI-CTCAE]; the event itself may be of relatively minor 
medical significance (such as severe headache without any further findings). 
 
 Severity and seriousness need to be independently assessed for each adverse 
event recorded in the clinical database. 
 
6.6.3 Adverse Events of Special Interest (AESI) 
 
 AESIs are a subset of Events to Monitor of scientific and medical interest 
specific to the Merck Drugs in this protocol. Such an event might require further 
investigation in order to characterize and understand it. 
 
 AESIs include following: 
• 
Infusion-related reactions including immediate hypersensitivity. 
• 
Immune-related adverse events. 
• 
TGF-β inhibition mediated skin reactions. 
• 
Anemia. 
• 
Bleeding AEs. 
 
 Any AE that is suspicious to be an AESI do not require expedited reporting 
unless they are serious. Should the AESI be serious, a SAE form should be filled 
instead and the reporting process for SAEs should be followed. 
 

 
Page 101 of 116 
 
 
6.6.4 Pregnancy Reports 
 
 Female patients of childbearing potential will be instructed to immediately 
inform the Investigator(s) if they become pregnant during the study. 
 
6.6.5 Assessment of Causality of Adverse Events 
 
Investigator(s) should use their knowledge of the patient, the circumstances 
surrounding the event, and an evaluation of any potential alternative causes to 
determine whether an adverse event is considered to be related to the study drug, 
indicating “Yes” or “No” accordingly. The following guidance should be taken into 
consideration: 
 
 Temporal relationship of event onset to the initiation of study drug 
 Course of the event, with special consideration of the effects of dose reduction, 
 discontinuation of study drug, or reintroduction of study drug (as applicable) 
 Known association of the event with the study drug or with similar treatments 
 Known association of the event with the disease under study 
 Presence of risk factors in the patient or use of concomitant medications known 
to increase the occurrence of the event 
 Presence of non-treatment-related factors that are known to be associated with 
the occurrence of the event 
 
6.6.6 Methods of Recording Adverse Events 
 
 All AEs must be documented in the appropriate section of the CRF. An SAE 
report form (initial or follow up) must be completed in case of any of the 
seriousness criteria is met. 
 
 The following aspects must be recorded for each event in the CRF: 
 A description of the AE in medical terms, not as reported by the subject; 
 The date of onset (start date) 
 The time of onset (start time) 
 The date of recovery (stop date) 
 The time of recovery (stop time) 
 The severity of the sign and/or symptom or clinically significant 
abnormal laboratory 
 Value according to NCI-CTCAE v.4. If no toxicity grade is described 
for a given sign, symptom or abnormal laboratory value, the 
Investigator(s) will grade the severity as mid (grade 1), moderate (grade 
2), severe (grade 3), or life-threatening or disabling (grade 4). 
 Death (grade 5) as defined by NCI-CTCAE v.4 is mainly regarded as an 
outcome and will be documented accordingly (see below). 
 
 The causal relationship to bintrafusp alfa as assessed by the Investigator(s); the 
decisive factor in the documentation is the temporal relation between the AE 
and the study drug. The following judgments of the causality to study drug or 
study procedures are to be used: 
 Not Related = not suspected to be reasonably related to the 

 
Page 102 of 116 
 
 
investigational product. AE could not medically (pharmacologically/ 
clinically) be attributed to the investigational product under study in this 
protocol 
 Related = suspected to be reasonably related to the investigational 
product. AE could medically (pharmacologically/ clinically) be 
attributed to the investigational product under study in this protocol 
 Action taken on bintrafusp alfa (none, medication discontinued, dose 
reduction, medication delayed, reduction of infusion rate). 
 Other action (none, concomitant medication given, new or prolonged 
hospitalization, procedural surgery). 
 The outcome according to the following definitions: 
 Recovered without sequelae (AE disappeared) 
 Recovered 
with 
sequelae 
(AE 
has 
resulted 
in 
permanent 
disability/incapacity) 
 Not yet recovered 
 Not recovered at death 
 Change in toxicity grade/severity or seriousness (e.g., an AE with no 
change of toxicity grade but newly classified as an SAE due to 
hospitalization. 
 Fatal (AE resulted in death) 
 
 Concomitant medication given: Yes or No (Note: If this question is answered 
“Yes” the corresponding serious criteria must be ticked) § Subject died 
 Life-threatening 
 New or prolonged hospitalization 
 Persistent/significant disability § Congenital abnormality 
 Important medical event 
 Seriousness: Yes or No 
 
 If in any one patient the same AE occurs on several occasions, then the AE in 
question must be documented and assessed anew each time. 
 
6.6.7 Procedure of Reporting Serious Adverse Events 
 
 The Sponsor-Investigator primary responsibilities for safety reporting are to 
identify and follow-up on Serious Adverse Events (SAEs) experienced by 
participants in the study and to: 
 
o Evaluate and forward the information to the local regulatory authorities 
as required by local regulations  
 
o Forward to Merck/EMD Serono as required within the applicable 
contract executed between Merck/EMD Serono & the Sponsor-
Investigator 
 
 The following reportable events must be submitted to Merck within 2 business 
days or 3 calendar days (whichever comes first) using the applicable safety 
report form provided. The Principal Investigator(s) will assume responsibility 
for submitting the reportable event(s) to Merck as well as ensuring that any local 

 
Page 103 of 116 
 
 
reporting requirements are completed in parallel. 
 
 Serious Adverse Events (see section 6.6.2) 
 Exposure during Pregnancy or Breastfeeding (even if not associated 
with an adverse event) 
 Occupational exposure (even if not associated with an adverse event) 
 
 Contact information for submission of reportable events to Merck: 
o Fax: +49 6151 72 6914 or 
o E-mail: ICSR_CT_GPS @merckgroup.com  
o Specifying: 
 PROTOCOL Number and/or Title 
 Funder’s Study Identifier 
 SUBJECT Number 
 Principal Investigator Name 
 Sponsor Name 
 SAE/ONSET DATE 
 
6.6.8 Monitoring of Subjects with Adverse Events 
 
 Any AE that occurs in the course of a clinical study must be monitored and 
followed up until the last study visit. It is the responsibility of the Investigator(s) 
that any necessary additional therapeutic measures and follow-up procedures 
are performed. 
 
 

 
Page 104 of 116 
 
 
7 
STATISTICS  
7.1 
Statistical Analysis  
Objective response rate (ORR) will be expressed based on exact binomial distribution. 
Survival outcomes, including TTP, PFS, OS, and survival rate their corresponding 95% 
confidence interval, will be estimated using Kaplan-Meier method. The Fisher exact 
test will be used to correlate the binary clinical and biomarker data. The cut-off values 
of baseline and changes in the exo-PD-L1 and TGF-β1 levels will be calculated by the 
Receiver Operating Characteristic (ROC) curve analyses. 
All of the reported P values will be 2-tailed, and P<0.05 will be considered statistically 
significant. No multiplicity will be considered. The analyses will be performed using 
statistical software packages SPSS and R.  
Procedures for Handling Missing, Unused, and Spurious Data: All available data 
will be included in the data listings and tabulations. Where appropriate, imputations of 
values for missing data for primary and secondary efficacy analyses will be performed 
as specified in the Statistical Analysis Plan. All data recorded on the CRF will be 
included in the data listings that will accompany the clinical study report. 
If, after the study has begun, but prior to the conduct of any analysis, changes made to 
primary and / or key secondary endpoints, or the statistical methods related to those 
hypotheses, then the protocol will be amended. Changes to exploratory analyses made 
after the protocol finalized will be documented and referenced in the final report. Post 
hoc exploratory analyses will also be identified in the final report.  
7.2 
Sample Size Calculation 
H0: The null hypothesis is that the overall response rate (ORR) is similar to historical 
result of immunotherapy, i.e. 20% 
H1: The alternative hypothesis of treatment efficacy: experimental treatment with 
bintrafusp alfa would result in 40% ORR. 
To detect 20% of differences from 20% to 40% in the number of patients proceeding 
to surgery, with Type I error of 0.05 and 80% power, the target sample size is 33 
patients.  
Modified Simon’s two-stage optimal design will be used. In the first stage, 18 patients 
will be enrolled. If there are 4 or fewer responses in these 18 patients, the study will be 
stopped. Otherwise, 15 additional patients will be accrued for a total of 33 valid cases. 
The null hypothesis will be rejected if 11 or more responses are observed in 33 patients 
and the treatment will be considered worthy of further investigation. Patients may drop 
out before their objective response can be assessed. Such patients will be excluded for 
the ORR assessment and will be replaced by other patients that the objective response 
can be assessed. The study will be continued until the first or the second stage 
evaluation is achieved. Assuming 10% drop out rate, 38 patients will be accrued 
initially. We assume 50% of screened population will be eligible for the study, thus we 
plan to screen for 76 patients.  

 
Page 105 of 116 
 
 
7.3 
Early Stopping Rule 
Excessive toxicity will also be monitored. Assuming no more than a 10% SAE rate on 
historical treatment, the increase of treatment-related SAE to a rate of 30% or greater 
in the studied treatment will be considered unacceptable, and the study will be then 
stopped prematurely and will early stop the trial if treatment related SAE >30%. Upon 
the recruitment of these 38 patients, if 10 or more patients had treatment-related SAE, 
the study will be stopped. The corresponding lower bound of exact one-sided 90% 
confidence interval is 30.5%. 
 
8 
ETHICAL, REGULATORY & STUDY OVERSIGHT CONSIDERATIONS 
8.1 
Responsibilities of the Investigator(s) 
The Investigator(s) undertake(s) to perform the clinical study in accordance with this 
clinical study protocol, ICH guideline for Good Clinical Practice (GCP) (ICH E6 R2 
Step 4) approved on November 9, 2016) and applicable regulatory requirements in 
Hong Kong. These documents state that the informed consent of the subjects is an 
essential precondition for participation in the clinical study. 
8.2 
Subject Information 
An unconditional prerequisite for a patient participating in the study is his/her written 
informed consent. Adequate information must therefore be given to the subject by the 
Investigator(s) before informed consent is obtained. A person designated by the 
Investigator(s) may give the information, if permitted by local regulations. A subject 
information sheet in the local language and prepared in accordance with Good Clinical 
Practice will be provided by the Investigator(s) for the purpose of obtaining informed 
consent. In addition to this written information, the Investigator(s) or his/her/their 
designate will inform the subject verbally. In doing so, the wording used will be chosen 
so that the information can be fully and readily understood by laypersons. 
The patient information sheet will be revised whenever important new information 
becomes available that may be relevant to the consent of patients. 
8.3 
Informed Consent  
The consent of the patient to participate in the clinical study has to be given in writing 
before any study-related activities are carried out. It must be signed and personally 
dated by the patient and by the Investigator(s)/person designated by the Investigator(s) 
to conduct the informed consent discussion. 
Provision of consent will be confirmed in the case report form (CRF) by the 
Investigator(s). The signed and dated declaration of informed consent will remain at 
the Investigator(s)'s site and must be safely archived by the Investigator(s) so that the 
forms can be retrieved at any time for monitoring, auditing and inspection purposes. A 
copy of the signed and dated information and consent should be provided to the patient 
prior to participation. 

 
Page 106 of 116 
 
 
If the patient or legally acceptable representative is unable to read, a reliable, impartial, 
and independent witness should be present during the entire informed consent 
discussion. The choice of the witness must not breach the subject’s right to 
confidentiality. A reliable independent witness is defined as one not affiliated with the 
institution or engaged in the investigation. A family member or acquaintance is an 
appropriate independent witness. After the subject or legally acceptable representative 
verbally consents and has signed, if capable, the witness should sign and personally 
date the consent form attesting that the information is accurate and that the subject or 
legally acceptable representative has fully understood the content of the informed 
consent agreement and is giving true informed consent. 
Also, patient will be informed in a timely manner whenever new information becomes 
available that may be relevant to the patient’s willingness to continue participation in 
the study; the revised informed consent form containing such information is to be 
provided to the patient, and communication of this information will be documented.  
8.4 
Compensation to Subjects 
The patients will not receive payment for taking part in the study. Patients who are 
entitled to discounted or free health care, e.g. civil servants, will receive their entitled 
free treatment as normal. The study is covered by an insurance policy managed by the 
Clinical Trial Centre of The University of Hong Kong, in which to cover claim by, or 
compensation for, patients treated in study. 
8.5 
Ethics Committee or Institutional Review Board 
Prior to commencement of the study, the study protocol will be submitted together with 
its associated documents (patient information, consent form, IB) to the IRB/EC for their 
favourable opinion. The favourable opinion/approval of the IRB/EC will be filed in the 
study file. The study will only commence following provision of a written favourable 
opinion. 
Any amendments to the protocol will be submitted to the IRB/EC and they will be 
informed about SAEs in accordance with national and/or local requirements. 
8.6 
Role of Funding Source 
The study drug and partial funding will be provided by Merck Healthcare KGaA, 
Darmstadt, Germany. The Funder otherwise has no role in study design, data collection, 
data analysis, data interpretation, or in the writing of the study report. The Funder will 
review the manuscript before submission for publication. 
8.7 
Publication Policy 
The results of this study may be published or presented at scientific meetings. The 
Sponsor will comply with the requirements for publication of study results in 
accordance with standard editorial and ethical practice. 

 
Page 107 of 116 
 
 
The Sponsor agrees to submit all manuscripts or abstracts to the Funder for review 
before submission for publication. This allows the Funder to protect proprietary 
information and to provide comments. 
Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements. 
 
 

 
Page 108 of 116 
 
 
9 
STUDY MANAGEMENT  
9.1 
Data Quality Assurance 
The main objective is to obtain those data required by the study protocol in a complete, 
accurate, legible and timely fashion. The data in the CRF should be consistent with the 
relevant source documents. 
The CRFs must be filled in completely and legibly (with either black or blue ballpoint 
pen, acceptable for use on official documents). Any amendments and corrections 
necessary must be undertaken and countersigned by the Investigator(s), stating the date 
of the amendment/correction. Errors must remain legible and may not be deleted with 
correction aids (e.g., Tipp-Ex®). The Investigator(s) must state his/her reasons for the 
correction of important data. In the case of missing data/remarks, the entry spaces 
provided in the case report form should be cancelled out so as to avoid unnecessary 
follow-up inquiries. 
CRF entries will be done by the study team and checked against source documents, 
except for the pre-identified source data directly recorded in the CRF. The Informed 
Consent Form will include a statement by which the patient allows the Sponsor’s duly 
authorized personnel, the Ethics Committee (IRB/EC), and the regulatory authorities to 
have direct access to source data which support the data on the CRF. Such personnel, 
bound by professional secrecy, must keep confidential all personal identity or personal 
medical information (according to confidentiality rules). 
9.2 
Direct Access to Source Data/Documents 
For the purpose of ensuring compliance with the clinical study protocol, Good Clinical 
Practice and applicable regulatory requirements, the Investigator(s) shall permit 
auditing by the Sponsor, the Funder, and inspection by applicable regulatory authority.  
The Investigator(s) agree(s) to allow the auditors/inspectors to have direct access to the 
study records for review, being understood that these personnel is bound by 
professional secrecy, and as such will not disclose personal identity or personal medical 
information. 
The Investigator(s) will make every effort to help with the performance of the audits 
and inspections, giving access to all necessary facilities, data, and documents. 
As soon as the Investigator(s) is/are notified of a future inspection by the authority, he 
will inform the Sponsor and the Funder. 
The confidentiality of the data verified, and the protection of the patients should be 
respected during these inspections. 
Any result and information arising from the inspections by the regulatory authority will 
be immediately communicated by the Investigator(s) to the Sponsor and the Funder as 
per timeframe stipulated in the ISS agreement. 

 
Page 109 of 116 
 
 
The Investigator(s) shall take appropriate measures required by the Sponsor to take 
corrective actions for all problems found during the audit or inspections. 
9.3 
Study File and Archiving 
The Investigator(s) shall maintain a Study File for the study purpose. This file contains 
all relevant documents necessary for the conduct of the study. This file must be safely 
archived after termination of the study in accordance with the local relevant regulations. 
 
 

 
Page 110 of 116 
 
 
10 REFERENCES 
 
1. Ferlay J, Soerjomataram I, Dikshit R, et al. Cancer incidence and mortality 
worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J 
Cancer. 2015 Mar 1;136(5): E359-86 
2. Neda Mahdavifar, Mahshid Ghoncheh, Abdollah Mohammadian-Hafshejani et 
al. Epidemiology and Inequality in the Incidence and Mortality of Nasopharynx 
Cancer in Asia. Osong Public Health Res Perspect. 2016 Dec; 7(6): 360–372. 
3. Lee AW, Ma BB, Ng WT, et al. Management of Nasopharyngeal Carcinoma: 
Current Practice and Future Perspective. J Clin Oncol. 2015 Oct 
10;33(29):3356-64 
4. Zhang L, Huang Y, Hong S, et al. Gemcitabine plus cisplatin versus fluorouracil 
plus cisplatin in recurrent or metastatic nasopharyngeal carcinoma: a 
multicentre, 
randomised, 
open-label, 
phase 
3 
trial. 
Lancet. 
2016;388(10054):1883. Epub 2016 Aug 23. 
5. Chua DT, Sham JS, Au GK. A phase II study of capecitabine in patients with 
recurrent and metastatic nasopharyngeal carcinoma pretreated with platinum-
based chemotherapy. Oral Oncol. 2003;39(4):361.  
6. Ciuleanu E, Irimie A, Ciuleanu TE, et al. Capecitabine as salvage treatment in 
relapsed nasopharyngeal carcinoma: a phase II study. J BUON. 2008;13(1):37. 
7. Poon D, Chowbay B, Cheung YB, et al. Phase II study of irinotecan (CPT-11) 
as salvage therapy for advanced nasopharyngeal carcinoma. Cancer. 
2005;103(3):576. 
8. Ngeow J, Lim WT, Leong SS, et al. Docetaxel is effective in heavily pretreated 
patients 
with 
disseminated 
nasopharyngeal 
carcinoma. 
Ann 
Oncol. 
2011;22(3):718. Epub 2010 Aug 17.  
9. Au E, Tan EH, Ang PT. Activity of paclitaxel by three-hour infusion in Asian 
patients with metastatic undifferentiated nasopharyngeal cancer. Ann Oncol. 
1998;9(3):327.  
10. Foo KF, Tan EH, Leong SS, et al. Gemcitabine in metastatic nasopharyngeal 
carcinoma of the undifferentiated type. Ann Oncol. 2002;13(1):150. 
11. Chen CS, Wang FH, Wang ZQ, et al. alvage gemcitabine-vinorelbine 
chemotherapy in patients with metastatic nasopharyngeal carcinoma pretreated 
with platinum-based chemotherapy. Oral Oncol. 2012 Nov;48(11):1146-51. 
12. Chua DT, Kwong DL, Sham JS, et al. A phase II study of ifosfamide, 5-
fluorouracil and leucovorin in patients with recurrent nasopharyngeal 
carcinoma previously treated with platinum chemotherapy. Eur J Cancer. 
2000;36(6):736.  
13. Lim WT, Ng QS, Ivy P, et al: A phase II study of pazopanib in Asian patients 
with recurrent/metastatic nasopharyngeal carcinoma. Clin Cancer Res 17:5481-
5489, 2011 
14. Hui EP, Ma BB, King AD, et al: Hemorrhagic complications in a phase II study 
of sunitinib in patients of nasopharyngeal carcinoma who has previously 
received high-dose radiation. Ann Oncol 22:1280-1287, 2011 
15. Chan AT, Hsu MM, Goh BC, et al. Multicenter, phase II study of cetuximab in 
combination with carboplatin in patients with recurrent or metastatic 
nasopharyngeal carcinoma. J Clin Oncol. 2005;23(15):3568. Epub 2005 Apr 4.  
 

 
Page 111 of 116 
 
 
16. Chua DT, Wei WI, Wong MP, et al. Phase II study of gefitinib for the treatment 
of recurrent and metastatic nasopharyngeal carcinoma. Head Neck. 
2008;30(7):863.  
17. Wherry EJ, Barbar DL, Kaech SM, et al. Antigen-independent memory CD8 T 
cells do not develop during chronic viral infection. Proc Natl Acad Sci U S A. 
2004 Nov 9;101(45):16004-9. 
18. Barber DL, Wherry EJ, Masopust D, et al. Restoring function in exhausted CD8 
T cells during chronic viral infection. Nature. 2006 Feb 9;439(7077):682-7. 
19. Day CL, Kaufmann DE, Kiepiela P, et al. PD-1 expression on HIV-specific T 
cells is associated with T-cell exhaustion and disease progression. Nature. 2006 
Sep 21;443(7109):350-4. 
20. Green MR, Rodig S, Juszczynski P, et al. Constitutive AP-1 activity and EBV 
infection induce PD-L1 in Hodgkin lymphomas and posttransplant 
lymphoproliferative disorders: implications for targeted therapy. Clin Cancer 
Res. 2012 Mar 15;18(6):1611-8. 
21. Hsu C, Lee SH, Ejadi S, et al. Safety and Antitumor Activity of Pembrolizumab 
in Patients With Programmed Death-Ligand 1-Positive Nasopharyngeal 
Carcinoma: Results of the KEYNOTE-028 Study. J Clin Oncol. 
2017;35(36):4050. 
22. Ma BBY, Lim WT, Goh BC, et al. Antitumor Activity of Nivolumab in 
Recurrent and Metastatic Nasopharyngeal Carcinoma: An International, 
Multicenter Study of the Mayo Clinic Phase 2 Consortium (NCI-9742). J Clin 
Oncol. 2018;36(14):1412. 
23. I Melero, DM Berman, MA Aznar, et al. Evolving synergistic combinations of 
targeted immunotherapies to combat cancer. Nat. Rev. Cancer 2015; 15, 457–
472. 
24. J Larkin, V Chiarion-Sileni, R Gonzalez, et al. Combined nivolumab and 
ipilimumab or monotherapy in untreated melanoma. N. Engl. J. Med. 2015;373, 
23–34. 
25. RJ Akhurst, A Hata, Targeting the TGF-β signalling pathway in disease. Nat. 
Rev. Drug Discov. 2012; 11, 790–811 
26. MO Li, RA Flavell. Contextual regulation of inflammation: A duet by 
transforming growth factor-β and interleukin-10. Immunity 2008; 28, 468–476  
27. SH Wrzesinski, YY Wan, RA Flavell. Transforming growth factor-β and the 
immune response: Implications for anticancer therapy. Clin. Cancer Res. 
2007;13, 5262–5270 
28. LJAC Hawinkels, HW Verspaget, W van Duijn, et al. Tissue level, activation 
and cellular localisation of TGF-β1 and association with survival in gastric 
cancer patients. Br. J. Cancer 2007; 97, 398–404 
29. DR Principe, JA Doll, J Bauer, et al. TGF-β: Duality of function between tumor 
prevention and carcinogenesis. J. Natl. Cancer Inst. 2014;106, djt369  
30. JJ Lebrun. The dual role of TGF-β in human cancer: From tumor suppression 
to cancer metastasis. ISRN Mol. Biol. 2012; 381428  
31. C Neuzillet, A Tijeras-Raballand, R Cohen, et al.Targeting the TGF-β pathway 
for cancer therapy. Pharmacol. Ther. 2015; 147, 22–31  
32. JM Yingling, KL Blanchard, JS Sawyer. Development of TGF-β signalling 
inhibitors for cancer therapy. Nat. Rev. Drug Discov. 2004; 33, 1011–1022  
33. Y Pang, SK Gara, BR Achyut, et al. TGF-β signaling in myeloid cells is required 
for tumor metastasis. Cancer Discov. 2013; 3, 936–951. 

 
Page 112 of 116 
 
 
34. D Gate, M Danielpour, J Rodriguez Jr. et al. T-cell TGF-β signaling abrogation 
restricts medulloblastoma progression. Proc. Natl. Acad. Sci. U.S.A. 2014; 111, 
E3458–E3466 
35. MO Li, S Sanjabi, RA Flavell. Transforming growth factor-β controls 
development, homeostasis, and tolerance of T cells by regulatory T cell-
dependent and –independent mechanisms. Immunity 2006; 25, 455–471  
36. MO Li, YY Wan, RA Flavell. T cell-produced transforming growth factor-β1 
controls T cell tolerance and regulates Th1- and Th17-cell differentiation. 
Immunity 2007; 26, 579–591 
37. DA Thomas, J Massague. TGF-β directly targets cytotoxic T cell functions 
during tumor evasion of immune surveillance. Cancer Cell 2005; 8, 369–380  
38. S Viel, A Marcais, FS Guimaraes, et al. TGF-β inhibits the activation and 
functions of NK cells by repressing the mTOR pathway. Sci. Signal. 2016; 9, 
ra19  
39. W Hugo, JM Zaretsky, L Sun, et al.  Genomic and transcriptomic features of 
response to anti-PD-1 therapy in metastatic melanoma. Cell 2017; 168, 542  
40. YY Xia, L Yin, N Jiang et al. Downregulating HMGA2 attenuates epithelial-
mesenchymal transition-induced invasion and migration in nasopharyngeal 
cancer cells. Biochem. Biophys. Res. Commun. 2015; 463, 357–363. 
41. Wang  L, Tian WD, Xu X et al.Epstein-Barr virus nuclear antigen (EBNA1) 
protein induction of epithelial-mesenchymal transition in nasopharyngeal 
carcinoma cells. Cancer 2014, 120,363–372. 
42. Cao S, Cui Y, Xiao H, et al. Up-regulation of flotillin-1 promotes invasion and 
metastasis by activating TGF-beta signaling in nasopharyngeal carcinoma. 
Oncotarget 2016; 7, 4252–4264. 
43. Zhao L, Lin L, Pan C, et al. Flotillin-2 promotes nasopharyngeal carcinoma 
metastasis and is necessary for the epithelial-mesenchymal transition induced 
by transforming growth factor-β. Oncotarget 2015, 6, 9781–9793. 
44. Xia YY, Yin L, Jiang N, et al.Downregulating HMGA2 attenuates epithelial-
mesenchymal transition-induced invasion and migration in nasopharyngeal 
cancer cells. Biochem. Biophys. Res. Commun. 2015; 463, 357–363. 
45. Bissey PA, Law JH, Bruce JP, et al. Dysregulationof the MiR-449b target 
TGFBI alters the TGFbeta pathway to induce cisplatin resistance in 
nasopharyngeal carcinoma. Oncogenesisl 2018, 7, 40 
46. Lan Y, Zhang D, Xu C, et al. Enhanced preclinical antitumor activity of M7824, 
a bifunctional fusion protein simultaneously targeting PD-L1 and TGF-β. Sci 
Transl Med. 2018 Jan 17;10(424) 
47. Strauss J, Heery CR, Schlom J, et al. Phase I Trial of M7824 (MSB0011359C), 
a Bifunctional Fusion Protein Targeting PDL1 and TGFβ, in Advanced Solid 
Tumors. Clin Cancer Res. 2018 Mar 15;24(6):1287-1295. 
48. Julius Strauss, Margaret Elena Gatti-Mays, Jason Redman, et al. Safety and 
activity of M7824, a bifunctional fusion protein targeting PD-L1 and TGF-β, in 
patients with HPV associated cancers. ASCO 2018 
49. Luis G. Paz-Ares, TM Kim, David Vicente Baz, et al. Results from a second-
line (2L) NSCLC cohort treated with M7824 (MSB0011359C), a bifunctional 
fusion protein targeting TGF-β and PD-L1. ASCO 2018 
50. YK Kang, T Doi, S Kondo, et al. M7824 (MSB0011359C), a bifunctional fusion 
protein targeting PD-L1 and TGF-β, in Asian patients with pretreated recurrent 
or refractory gastric cancer: Preliminary results from a phase I trial. ASCO GI 
2018 

 
Page 113 of 116 
 
 
51. Chen BJ, Chapuy B, Ouyang J, et al: PD-L1 expression is characteristic of a 
subset of aggressive B-cell lymphomas and virus-associated malignancies. Clin 
Cancer Res 19:3462-3473, 2013 
52. Fang W, Zhang J, Hong S, et al: EBV-driven LMP1 and IFN-g up-regulate PD-
L1 in nasopharyngeal carcinoma: Implications for oncotargeted therapy. 
Oncotarget 5:12189-12202, 2014 
53. Chan OS, Kowanetz M, Ng WT, et al: Characterization of PD-L1 expression 
and immune cell infiltration in nasopharyngeal cancer. Oral Oncol 67:52-60, 
2017 
54. Zhu Q, Cai MY, Chen CL, et al: Tumor cells PDL1 expression as a favorable 
prognosis factor in nasopharyngeal carcinoma patients with pre-existing 
intratumor-infiltrating lymphocytes. OncoImmunology 6:e1312240, 2017 
55. Kluger HM, Zito CR, Turcu G, et al: PD-L1 studies across tumor types, its 
differential expression and predictive value in patients treated with immune 
checkpoint inhibitors. Clin Cancer Res 23:4270-4279, 2017 
56. Ferris RL, Blumenschein G, Jr., Fayette J, et al: Nivolumab for recurrent 
squamous-cell carcinoma of the head and neck.N Engl J Med 375:1856-1867, 
2016 
57. Chow LQM, Haddad R, Gupta S, et al: Antitumor activity of pembrolizumab in 
biomarker-unselected patients with recurrent and/or metastatic head and neck 
squamous cell carcinoma: Results from the phase Ib KEYNOTE-012 expansion 
cohort. J Clin Oncol 34:3838-3845, 2016 
58. Lo YM, Leung SF, Chan LY, et al: Kinetics of plasma Epstein-Barr virus DNA 
during radiation therapy for nasopharyngeal carcinoma. Cancer Res 60:2351-
2355, 2000 
59. Lin JC, Wang WY, Chen KY, et al: Quantification of plasma Epstein-Barr virus 
DNA in patients with advanced nasopharyngeal carcinoma. N Engl J Med 
350:2461-2470, 2004 
60. An X, Wang FH, Ding PR, et al: Plasma Epstein-Barr virus DNA level strongly 
predicts survival in metastatic/recurrent nasopharyngeal carcinoma treated with 
palliative chemotherapy. Cancer 117:3750-3757, 2011 
61. Wang WY, Twu CW, Chen HH, et al: Plasma EBV DNA clearance rate as a 
novel prognostic marker for metastatic/recurrent nasopharyngeal carcinoma. 
Clin Cancer Res 16:1016-1024, 2010 
62. Kao HF, Hsu C, Huang HC, et al: Correlation between plasma Epstein-Barr 
virus DNA and clinical response to pembrolizumab in patients with advanced 
or metastatic nasopharyngeal carcinoma. Eur J Cancer 51:S576, 2016 (abstr 
2860)  
63. Garrido F, Ruiz-Cabello F, Aptsiauri N: Rejection versus escape: The tumor 
MHC dilemma. Cancer Immunol Immunother 2017; 66:259-271 
64. Li YY, Chung GT, Lui VW, et al: Exome and genome sequencing of 
nasopharynx cancer identifies NF-kB pathway activating mutations. Nat 
Commun 8:14121, 2017 
65. Lo´ pez-NevotMA, Esteban F, Ferro´n A, et al. HLA class I gene expression on 
human primary tumours and autologous metastases: Demonstration of selective 
losses of HLA antigens on colorectal, gastric and laryngeal carcinomas. Br J 
Cancer 59:221-226, 1989 
66. Roemer MG, Advani RH, Redd RA, et al. Classical Hodgkin lymphoma with 
reduced b2M/ MHC class I expression is associated with inferior outcome 
independent of 9p24.1 status. Cancer Immunol Res 4:910-916, 2016 

 
Page 114 of 116 
 
 
67. Hugo W, Zaretsky JM, Sun L, et al. Genomic and transcriptomic features of 
response to anti-PD-1 therapy in metastatic melanoma. Cell 165:35-44, 2016 
68. Zaretsky JM, Garcia-Diaz A, Shin DS, et al. Mutations associated with acquired 
resistance to PD-1 blockade in melanoma. N Engl J Med 375:819-829,2016 
69. Yang Y, Li CW, Chan LC, et al. Exosomal PD-L1 harbors active defense 
function to suppress T cell killing of breast cancer cells and promote tumor 
growth. Cell Res. 2018 Aug;28(8):862-864. 
70. MS Farina, KT Lundgren, J Bellmunt. Immunotherapy in urothelial cancer: 
Recent results and future perspectives. Drugs 2017; 77, 1077–1089 
71. Chen G, Huang AC, Zhang W, et al. Exosomal PD-L1 Contributes to 
Immunosuppression and is Associated with anti-PD-1 Response. Nature. 2018 
Aug;560(7718):382-386. 
72. Hodi FS, Hwu WJ, Kefford R, et al. Evaluation of Immune-Related Response 
Criteria and RECIST v1.1 in Patients With Advanced Melanoma Treated With 
Pembrolizumab. J Clin Oncol. 2016 May 1;34(13):1510-7. 
73. Nishino M, Giobbie-Hurder A, Gargano M, et al. Developing a common 
language for tumor response to immunotherapy: immune-related response 
criteria using unidimensional measurements. Clin Cancer Res. 2013 Jul 
15;19(14):3936-43. 
74. M7824 (MSB0011359C) Investigator’s Brochure Version No. 7.0, Release 
Date: 05 Apr 2021 
75. NCI-CTCAE v.4: 
https://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03/Archive/CTCAE_4.0_2009
-05-29_QuickReference_8.5x11.pdf 
 

 
Page 115 of 116 
 
 
11 APPENDIX 
Schedule of Assessments 
 
 
 
 
 
 
 
Procedures 
 
 
 
 Screening  
Treatment Period 
 
 
 
Disease Progression 
(bintrafusp alfa until PD; unacceptable toxicity; death or withdrawal; maximum of 2 years) 
 
Cycle 1 m 
Cycle = 14 Days ± 7 Days 
Cycle 2 
Cycle 3 
Cycle 4 
Cycle 5   
Cycle 6 
Cycle 7  
Cycle 8 
Cycle 9 and 
thereafter 
Day -28 – 0 
Day 1 
Day 1 
Day 1 
Day 1 
Day 1 
Day 1 
Day 1 
Day 1 
Day 1 
Tests and Observations 
 
Informed Consent d 
× 
 
 
 
 
 
 
 
 
 
 
Medical History 
× 
 
 
 
 
 
 
 
 
 
 
Physical 
Examination 
(including skin 
examination) e 
× 
× 
× 
× 
× 
× 
× 
× 
× 
×a 
× 
Vital Signs  
× 
× 
× 
× 
× 
× 
× 
× 
× 
×a 
× 
ECOG Performance 
Status  
× 
× 
× 
× 
× 
× 
× 
× 
× 
×a 
× 
ECG 
× 
× 
 
 
 
× 
 
 
 
×b 
× 
Adverse Event 
Evaluation  
× 
× 
× 
× 
× 
× 
× 
× 
× 
×a 
× 
Concomitant 
Medication Review  
× 
× 
× 
× 
× 
× 
× 
× 
× 
×a 
× 
Laboratory Tests 
 
CBC f 
× 
× 
× 
× 
× 
× 
× 
× 
× 
×a 
× 
Coagulation Test h 
× 
× 
 
 
 
× 
 
 
 
×b 
× 
Comprehensive 
Serum Chemistry 
Panel g 
× 
× 
× 
× 
× 
× 
× 
× 
× 
×a 
× 
Exploratory blood-
based biomarkers i 
× 
×i 
× 
×i 
× 
×i 
× 
×i 
× 
×i 
× 
Urinalysis  
× 
× 
× 
× 
× 
× 
× 
× 
× 
×a 
× 
Pregnancy Test j 
× 
Repeat only if necessary 
 
Thyroid Function 
Test  
 
× 
 
× 
 
× 
 
× 
 
×c 
× 
Cortisol 9AM 
 
× 
 
× 
 
× 
 
× 
 
×c 
× 
Disease Assessment 
 
CT Scan (Head, 
Neck, Chest, 
Abdomen, Pelvis) k 
× 
× 
 
 
 
× 
 
 
 
×k 
× 
MRI Scan (Brain) 
 
Check if suspected brain metastasis  
 
Survival follow-up 
 
 
× 
Quality of life 
assessment l 
× 
× 
 
 
 
 
 
× 
 
 
× 

 
Page 116 of 116 
 
 
a. Assessments/procedures are to be performed on Day 1 every cycle and prior to treatment unless otherwise specified. 
b. Assessments and procedures are to be performed on Day 1 every 4 cycles and prior to treatment unless otherwise specified. 
c. Assessments and procedures are to be performed on Day 1 every 2 cycles and prior to treatment unless otherwise specified. 
d. Informed Consent must be obtained ≤ 28 days prior to the initiation of trial treatment. 
e. Physical examinations will include measurements of weight and vital signs (resting heart rate, blood pressure, respiratory rate, temperature). 
f. Hematology parameters include the following laboratory tests: complete blood count with 3-part differential (i.e. total neutrophil count 
including bands, lymphocytes, and monocytes), hemoglobin, hematocrit and platelets. 
g. Blood chemistry must include glucose, BUN, creatinine (eGFR), sodium, potassium, magnesium, chloride, calcium, CO2, alkaline phosphate, 
AST (SGOT), total bilirubin, total protein, albumin, phosphorus, uric acid. 
h. Coagulation test include PT, PTT and INR. 
i. Plasma EBV DNA will be determined before treatment and every 2 weeks until disease progression; plasma TGFβ1 measurement will be 
performed every 8 weeks until disease progression; PD-L1 concentration in the exosome will be measured every 2 weeks until disease 
progression. 
j. Pregnancy test will be performed within 1 week prior to treatment, if a cycle is missed during treatment or pregnancy and at the end of 
treatment visit only for women of childbearing potential.   
k. Patients will have CT scan at Screening/Baseline (≤ 28 days prior to initiation of trial treatment), every 8 weeks for the first 12 months, and 
every 12 weeks thereafter. Patients will also have CT scan whenever disease progression is suspected. For patients who discontinue treatment 
without radiographic progression per RECIST 1.1 (e.g. in patients who discontinue treatment for clinical progression or adverse reactions), 
disease assessment should continue as stated in schedule until radiographic disease progression or alternate therapy is given. 
l. Quality of life (QoL) will be assessed by patient-reported EORTC QLQ-C30 and H&N-35 questionnaires every 12 weeks in the first year. 
m. If screening assessments were completed within 28 days, they do not need to be repeated on Day 1 of Cycle 1 if patient’s condition has not 
changed.