Clinical trial NCT02592551
Conditions: Mesothelioma
Sponsor: Baylor College of Medicine
Start date: 2016-05-11; Completion date: 2022-09-01
Enrollment: 24 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The objective of this study is to determine whether MEDI4736 or combination therapy with MEDI4736 + tremelimumab are associated with favorable alterations of the intratumoral immunologic environment in subjects undergoing resectional surgery for Malignant Pleural Mesothelioma MPM.

Detailed description:
Subjects with MPM will undergo surgical mediastinal lymph node biopsy (cervical mediastinoscopy) and simultaneous surgical biopsy of the pleural tumor by thoracoscopy, at which time tumor tissue (at least 2 g) and peripheral blood will be collected for the study. These procedures are performed as standard of care in the treatment of these subjects. The subject will be randomized. Three days to three weeks after the biopsy, subjects will be randomly treated with either MEDI-4736 (15 mg/kg once intravenously) or MEDI-4736 (1500 mg once intravenously) plus tremelimumab (75 mg once intravenously) or a control group in a randomized controlled study design. There will be two treatment arms (MEDI4736 only and combination MEDI4736+tremelimumab) and one untreated arm (control). Randomization, stratified by receiving previous chemotherapy or not, will be performed and will help to minimize patient selection biases between three arms. Subjects under 30 kg will be treated with weight-based dosing for both MEDI4736 and Tremelimumab combination therapy. These patients are excluded from fixed based dosing to limit endotoxin exposure from the drug preparations. One to six weeks after the infusion, subjects will undergo resectional surgery, including extrapleural pneumonectomy (EPP) or pleurectomy/decortication (P/D), at which time the tumor will be removed (typically 200-1000 g) and obtained for study. Four patients that do not undergo treatment with MEDI-4736 or tremelimumab will be included as controls. Blood will be obtained after the induction of general anesthesia for both the thoracoscopy procedure and the EPP or P/D resectional procedure, as is routinely done in these procedures. The sixth rib will be obtained at the time of the resection. After the removal of the tumor, standard protocol includes intraoperative heated chemotherapy using a lavage of intracavitary cisplatin in the presence of conserved renal function (Sugarbaker et al., 2013, 2014; Richards et al., 2006).

Arms: arm 1: 8 patients will receive an infusion of MEDI4736 (15 mg/kg intravenously, once), one to six weeks prior to surgical resection. arm 2: 8 patients will receive an infusion of MEDI4736 (1500 mg intravenously, once) + tremelimumab (75mg intravenously, once), one to six weeks prior to surgical resection. arm 3: 4 patients will not receive MEDI4736 or Tremelimumab.
Interventions: intervention 1: MEDI4736 intervention 2: Tremelimumab intervention 3: no other name
Intervention descriptions: intervention 1: MEDI4736 is formulated at 50 mg/mL in 26 mM histidine/histidine-HCl, 275 mM trehalose dihydrate, 0.02% (w/v) polysorbate 80, pH 6.0. intervention 2: Tremelimumab Drug Product is formulated at a nominal concentration of 20 mg/mL in 20 mM histidine/histidine hydrochloride, 222 mM trehalose dihydrate, 0.02% (weight/volume \[w/v\]) polysorbate 80, 0.27 mM disodium edetate dihydrate (EDTA), pH 5.5. intervention 3: Neither MEDI4736 nor Tremelimumab will be used.

Protocol documents:
Prot_SAP_000.pdf: 
Clinical Study Protocol 
Drug Substance MEDI4736 
Study Number ESR-14-10744 
Edition Number 8 
Date 17 April 2019 
 
Page 1 of 134 
 
Investigational Drug 
Substance(s) 
MEDI4736 
Tremelimumab 
Study Number 
ESR-14-10744 
Version Number 
8 
Date 
17 April 2019 
WINDOW OF OPPORTUNITY PHASE II STUDY OF MEDI4736 OR 
MEDI4736 + TREMELIMUMAB IN SURGICALLY RESECTABLE 
MALIGNANT PLEURAL MESOTHELIOMA 
Sponsor: Baylor College of Medicine 
 
 
 
 
 


Clinical Study Protocol 
Drug Substance Tremelimumab 
Study Number ESR-14-10744 
Edition Number 8 
Date 17 April 2019 
 
Page 2 of 134 
 
 
PERSONNEL 
Principal Investigator                                               Co-Investigator 
Bryan Burt, MD                                                          Hyun-Sung Lee, MD 
Baylor College of Medicine                                        Baylor College of Medicine                                                   
Michael E. DeBakey Department of Surgery             Michael E. DeBakey Department of Surgery  
Division of General Thoracic Surgery                        Division of General Thoracic Surgery 
Office: 713-798-8266                                                  Office: 713-798-8010 
Email: Bryan.Burt@bcm.edu                                      Email: hyunsunl@bcm.tmc.edu 
 
Co Investigator 
Robert Taylor Ripley, MD 
Baylor College of Medicine 
Michael E. DeBakey Department of Surgery 
Division of General Thoracic Surgery 
Office: 713-798-2881 
Email: Rober.Ripley@bcm.edu                            
 
Co-Investigator 
 
 
 
 
 
Shawn S. Groth, MD, MS 
 
 
 
 
Baylor College of Medicine  
 
 
 
Michael E. DeBakey Department of Surgery  
  
Division of General Thoracic Surgery 
 
 
Office: 713-798-6281  
 
 
 
 
Email: Shawn.Groth@bcm.edu 
 
 
  
 
Co-Investigator 
 
 
 
 
Co-Investigator 
Hazem El Osta, MD  
 
 
 
Anita Sabichi, MD 
Baylor College of Medicine  
 
 
Baylor College of Medicine 
Department of Oncology 
 
 
 
Hematology and Oncology 
 
 
Office: 713-798-3750  
 
 
 
Office: 713-798-3750 
Email: Hazem.Elosta@bcm.edu 
 
 
Email: sabichi@bcm.edu  
 
Co-Investigator 
 
 
 
 
Co-Investigator 
Susan Hilsenbeck, PhD 
 
 
 
Daniel Ying Wang, MD 
Baylor College of Medicine  
 
 
Baylor College of Medicine 
Lester and Sue Smith Breast Center  
 
Hematology and Oncology 
Dan Duncan Cancer Center  
 
 
Office: 713-798-3750 
Office: 713-798-1627  
 
 
 
Email: Daniel.Wang2@bcm.edu 
Email: sgh@bcm.edu 
 


Clinical Study Protocol 
Drug Substance Tremelimumab 
Study Number ESR-14-10744 
Edition Number 8 
Date 17 April 2019 
 
Page 3 of 134 
 
 
 
PROTOCOL SYNOPSIS 
Clinical Protocol ESR-14-10744 
Study Title: WINDOW OF OPPORTUNITY PHASE II STUDY OF MEDI4736 OR MEDI4736 + 
TREMELIMUMAB IN SURGICALLY RESECTABLE MALIGNANT PLEURAL 
MESOTHELIOMA 
Protocol Number:  ESR-14-10744 
 
Clinical Phase: II 
 
Study Duration: 24 months 
 
Investigational Product(s) and Reference Therapy: 
MEDI4736 will be supplied in glass vials containing 500 mg of liquid solution at a concentration of 50 
mg/mL for intravenous (IV) administration. 
 
Tremelimumab is supplied as a sterile IV solution in 20 mL clear glass vials with a rubber stopper and 
aluminum seal.  
Research Hypothesis: 
Our hypothesis is that neoadjuvant therapy with anti-PD-L1 monoclonal antibody MEDI4736 in 
combination with anti-CTLA-4 monoclonal antibody tremelimumab will result in favorable alterations 
of the intratumoral immunologic environment in subjects undergoing resectional surgery for malignant 
pleural mesothelioma (MPM). 
Objectives: 
 
Primary Objectives:  
The primary objective of this study will be comparison of the ratio of intratumoral cytotoxic T cells to 
regulatory T cells (CD8/Treg) before and after treatment with combination MEDI-4736 and 
Tremelimumab checkpoint inhibitor therapy.  
 
Secondary Objective(s): 
The secondary objectives of this study are: 
1) Comparison of the percentage of inducible T-cell co-stimulator (ICOS) positive intratumoral 
CD4 T cells before and after treatment with combination MEDI-4736 and Tremelimumab 
checkpoint inhibitor therapy. 
2) Comparison of tumor tissue expression (Ventana assay) of programmed death-ligand 1 (PD-L1) 
before and after treatment with combination MEDI-4736 and Tremelimumab checkpoint 
inhibitor therapy. 


Clinical Study Protocol 
Drug Substance Tremelimumab 
Study Number ESR-14-10744 
Edition Number 8 
Date 17 April 2019 
 
Page 4 of 134 
 
3) Comparison of the ratio of the intratumoral CD8/Treg ratio in patients treated with 
combination therapy (MEDI-4736 and Tremelimumab) compared to either patients treated 
with MEDI-4736 alone , and separately compare to untreated patients. 
4) Comparison of the percentage of inducible T-cell co-stimulator (ICOS) positive intratumoral 
CD4 T cells in patients treated with combination therapy (MEDI-4736 and Tremelimumab) 
compared to either patients treated with MEDI-4736 alone, and separately compare to 
untreated patients. 
5) Comparison of tumor tissue expression (Ventana assay) of programmed death-ligand 1 (PD-
L1) in patients treated with combination therapy (MEDI-4736 and Tremelimumab) compared 
to either patients treated with MEDI-4736 alone, and separately compare to untreated patients. 
6) Comparison of overall survival in patients treated with either MEDI-4736 alone or MEDI-4736 
plus Tremelimumab with historical untreated controls. These analysis will be post-protocol 
analysis based upon data obtained from the standard of care follow up in our post-surgical 
patients.  
7) Comparison of recurrence-free survival in patients treated with either MEDI-4736 alone or 
MEDI-4736 plus Tremelimumab with historical untreated controls. These analysis will be 
post-protocol analysis based upon data obtained from the standard of care follow up in our 
post-surgical patients. 
 
Study Design: 
Subjects with MPM will undergo surgical mediastinal lymph node biopsy (cervical mediastinoscopy) 
and simultaneous surgical biopsy of the pleural tumor by thoracoscopy, at which time tumor tissue (at 
least 2 g) and peripheral blood will be collected for the study. These procedures are performed as our 
standard of care in the treatment of these subjects. The subject will be randomized. Three days to three 
weeks after the biopsy, 20 evaluable subjects (if tissue obtained) will be randomly treated with either 
MEDI-4736 alone (15 mg/kg once intravenously) (n=8) or MEDI-4736 (1500 mg once intravenously) 
plus tremelimumab (75 mg once intravenously) (n=8), or a control group (n=4)  in a randomized 
controlled study design. There will be two treatment arms (MEDI4736 only and combination 
MEDI4736+tremelimumab) and one untreated arm (control). Randomization, stratified by receiving 
previous chemotherapy or not, will be performed and will help to minimize patient selection biases 
between three arms. Subjects under 30 kg will be treated with weight-based dosing for both MEDI4736 
and Tremelimumab combination therapy. These patients are excluded from fixed based dosing to limit 
endotoxin exposure from the drug preparations. One to six weeks after the infusion, subjects will undergo 
resectional surgery, including extrapleural pneumonectomy (EPP) or pleurectomy/decortication (P/D), 
at which time the tumor will be removed (typically 200-1000 g) and obtained for study. Four patients 
that do not undergo treatment with MEDI-4736 or tremelimumab will be included as controls. Blood 
will be obtained after the induction of general anesthesia for both the thoracoscopy procedure and the 
EPP or P/D resectional procedure, as is routinely done in these procedures. The sixth rib will be obtained 
at the time of the resection. After the removal of the tumor, our standard protocol includes intraoperative 
heated chemotherapy using a lavage of intracavitary cisplatin in the presence of conserved renal function 
(Sugarbaker et al., 2013, 2014; Richards et al., 2006).  


Clinical Study Protocol 
Drug Substance Tremelimumab 
Study Number ESR-14-10744 
Edition Number 8 
Date 17 April 2019 
 
Page 5 of 134 
 
 
Tumor tissues obtained either by thorasoscopic biopsy or by resectional surgery will be evaluated by 
time-of-flight mass spectrometry (CyTOF) to determine intratumoral CD8/Treg ratios and percentage of 
ICOS positive CD4 T cells, and by immunohistochemistry (Ventana assay) to determine the tissue 
expression of PD-L1. These variables will be compared before and after treatment (changes within the 
same patient tumor), or between treatment groups (MEDI-4736 alone, MEDI-4736+tremelimumab, 
untreated) following treatment. Additional hypothesis-generating analyses will include a comprehensive 
systems based evaluation of the intratumoral immune cell population composition and phenotype 
phenotype [e.g., dendritic cells, macrophages, myeloid derived suppressor cells (MDSC), neutrophils, 
T-cell subsets, natural killer (NK) cells, and B cells], and  immune-related gene expression using the 
nanostring system within the tumors, blood, and bone marrow of patients in all treatment groups.  
 
Number of Centers: 1 
Number of Subjects: 20 
Study Population: 
Subjects aged 18 years or older with resectable MPM 
Inclusion Criteria: 
1. 
Written informed consent obtained from the subject prior to performing any protocol-
related procedures, including screening evaluations  
2. 
Age > 18 years at time of study entry 
3. 
 Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1  
4. 
Adequate normal organ and marrow function as defined below:   
− 
Hemoglobin ≥ 9.0 g/dL 
− 
Absolute neutrophil count (ANC) ≥ 1.5 × 109/L (> 1500 per mm3) 
− 
Platelet count ≥ 100 × 109/L (>100,000 per mm3) 
− 
Serum bilirubin ≤ 1.5× institutional upper limit of normal (ULN)AST <3.0 
− 
Creatinine clearance >50mL/miN 
− 
Aspartate transaminase (AST) and alanine transaminase (ALT) ≤ 2.5 × ULN (≤ 
5 × ULN if documented liver metastasis are present); 
− 
 Serum creatinine ≤ 2.0 mg/dL or calculated creatinine clearance ≥ 50 mL/min 
as determined by the Cockcroft-Gault equation; 


Clinical Study Protocol 
Drug Substance Tremelimumab 
Study Number ESR-14-10744 
Edition Number 8 
Date 17 April 2019 
 
Page 6 of 134 
 
Males: 
 
 
Creatinine CL 
(mL/min) 
= 
Weight (kg) × (140 – Age)        
72 × serum creatinine (mg/dL) 
 
 
 
Females: 
 
 
Creatinine CL 
(mL/min) 
= 
Weight (kg) × (140 – Age)           × 0.85 
72 × serum creatinine (mg/dL) 
 
5. 
Female subjects must either be of non-reproductive potential (i.e., post-menopausal by 
history: ≥60 years old and no menses for 1 year without an alternative medical cause; OR 
history of hysterectomy, OR history of bilateral tubal ligation, OR history of bilateral 
oophorectomy) or must have a negative serum pregnancy test upon study entry.   
6. 
Subject is willing and able to comply with the protocol for the duration of the study 
including undergoing treatment and scheduled visits and examinations including follow up. 
7. 
Surgically resectable MPM with no disease extension beyond the ipsilateral hemithorax 
8. 
Planned resectional surgery for MPM [extrapleural pneumonectomy (EPP) or pleurectomy 
and decortication (P/D)] 
9. 
Any MPM histology (epithelial, mixed, sarcomatoid) 
a. N0 or N1 nodal disease, as present on preoperative chest CT and/or PET/CT 
b. N2 nodal disease if no progression after 2 cycles of standard chemotherapy. Progression 
will be considered if additional N1 or N2 disease develop during chemotherapy.  
 
Exclusion Criteria: 
1. 
Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff 
and/or staff at the study site) or previous enrollment or randomization in the present study 
2. 
Participation in another clinical study with an investigational product during the last 3 
months 
3. 
Any previous treatment with a PD1 or PD-L1 inhibitor, including MEDI4736  
4. 
Receipt of the last dose of anti-cancer therapy (chemotherapy, immunotherapy, endocrine 
therapy, targeted therapy, biologic therapy, tumor embolization, monoclonal antibodies, 
other investigational agent) 30 days prior to the first dose of study drug, and 30 days prior 


Clinical Study Protocol 
Drug Substance Tremelimumab 
Study Number ESR-14-10744 
Edition Number 8 
Date 17 April 2019 
 
Page 7 of 134 
 
to the first dose of study drug for subjects who have received prior TKIs [e.g., erlotinib, 
gefitinib and crizotinib] and within 6 weeks for nitrosourea or mitomycin C).  
5. 
Current or prior use of immunosuppressive medication within 28 days before the infusion 
with MEDI4736 or MEDI4736 + tremelimumab and through 90 days post infusion, with 
the exceptions of intranasal and inhaled corticosteroids or systemic corticosteroids at 
physiological doses, which are not to exceed 10 mg/day of prednisone, or an equivalent 
corticosteroid.  
6. 
Any unresolved toxicity (>CTCAE grade 2) from previous anti-cancer therapy.   
7. 
Any prior Grade ≥3 immune-related adverse event (irAE) while receiving any previous 
immunotherapy agent, or any unresolved irAE >Grade 1  
8. 
Active or prior documented autoimmune disease within the past 2 years NOTE: Subjects 
with vitiligo, Grave’s disease, or psoriasis not requiring systemic treatment (within the past 
2 years) are not excluded. 
9. 
Active or prior documented inflammatory bowel disease (e.g., Crohn’s disease, ulcerative 
colitis) 
10. 
History of primary immunodeficiency 
11. 
History of allogeneic organ transplant  
12. 
History of hypersensitivity to MEDI4736 or any excipient  
13. 
History of hypersensitivity to tremelimumab or the combination of MEDI4736 + 
tremelimumab  
14. 
Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, 
symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, 
cardiac arrhythmia, active peptic ulcer disease or gastritis, active bleeding diatheses 
including any subject known to have evidence of acute or chronic hepatitis B, hepatitis C or 
human immunodeficiency virus (HIV), or psychiatric illness/social situations that would 
limit compliance with study requirements or compromise the ability of the subject to give 
written informed consent 
15. 
Known history of previous clinical diagnosis of tuberculosis 
16. 
History of leptomeningeal carcinomatosis 
17. 
Receipt of live attenuated vaccination within 30 days prior to study entry or within 6 
months of receiving MEDI4736 or MEDI + tremelimumab 


Clinical Study Protocol 
Drug Substance Tremelimumab 
Study Number ESR-14-10744 
Edition Number 8 
Date 17 April 2019 
 
Page 8 of 134 
 
18. 
Receipt of drugs with laxative properties and herbal or natural remedies for constipation 
within 90 days of receiving MEDI4736 or MEDI + tremelimumab 
19. 
Receipt of sunitinib within 3 months of receiving tremelimumab 
20. 
Female subjects who are pregnant, breastfeeding, or male or female subjects of 
reproductive potential who are not employing an effective method of birth control 
21. 
Any condition that, in the opinion of the investigator, would interfere with the evaluation of 
the study treatment or interpretation of subject safety or study results 
22. 
Symptomatic or uncontrolled brain metastases requiring concurrent treatment, inclusive of 
but not limited to surgery, radiation, and/or corticosteroids.  
23. 
Subjects with uncontrolled seizures 
24. 
N3 nodal disease 
 
25. 
History of interstitial lung disease/pneumonitis  
 
26. 
No tissue is obtainable at the time of thoracoscopy. 
 
27. 
Intraabdominal malignancy discovered at laparoscopy and proven pathologically, or nodal 
disease discovered at mediastinoscopy (N2 or N3 disease) and proven pathologically 
 
Investigational Product(s), Dose and Mode of Administration: 
MEDI4736, 15 mg, IV infusion once prior to resection 
 
 
Or: Subjects will be administered MEDI4736 (1500 mg intravenously) + tremelimumab (75 mg 
intravenously) once during the study.  
Subjects under 30 kg will be treated with weight-based dosing for both MEDI4736 and Tremelimumab 
combination therapy. These patients are excluded from fixed based dosing to limit endotoxin exposure 
from the drug preparations. 
 
Study Assessments and Criteria for Evaluation: 
 
Safety Assessments: 
On the infusion day with MEDI4736 or MEDI4736 + tremelimumab, we will conduct clinical 
chemistry, hematology, and vitals. Subjects will be followed for 90 days after the last dose for safety to 
monitor any AEs, SAEs, etc.   


Clinical Study Protocol 
Drug Substance Tremelimumab 
Study Number ESR-14-10744 
Edition Number 8 
Date 17 April 2019 
 
Page 9 of 134 
 
 
Efficacy Assessments: 
PRIMARY ENDPOINTS 
1) 
Intratumoral CD8/Treg ratio determined by CyTOF.  
 
SECONDARY ENDPOINTS 
1) 
Percentage of ICOS+ CD4 T cells will be determined by CyTOF in blood, tumor, and bone 
marrow 
2) 
PD-L1 expression will be determined in tumor tissue by IHC (Ventana assay); PD-L1 will also 
be determined on immune cell subsets by CyTOF in blood, tumor, and bone marrow. 
3) 
NanoString gene expression arrays will be used to compare the gene expression of 300 
immune-related genes in frozen tumor tissue obtained preoperatively and postoperatively. 
4) 
Overall and recurrence-free survival  survival will be measured according to our usual routine 
follow-up protocol and compared with historical controls. These analysis will be post-protocol 
analysis based upon data obtained from the standard of care follow up in our post-surgical 
patients.  
5) 
 A comprehensive evaluation of immune cell composition and phenotype will performed in 
preoperative and postoperative tumor tissue and peripheral blood, as well as bone marrow. 
Appendix C outlines the complete CyTOF panel that will be used for each individual 
specimen. Substudies will include:  
a. Changes in T-cell subset (i.e., CD4, CD8, FoxP3) frequency and memory and activation 
phenotype (i.e., CD25, CD127, CD45RA,    
CD62L, CCR4, CCR6, Tim1). 
b. Changes in the T-cell polarization state (intracellular interferon-gamma, TNF-alpha, IL-17, 
IL-2). 
c. Changes in myeloid cell composition: dendritic cell, macrophage, MDSC, neutrophil (i.e., 
HLA-DR, CD11c, BDCA-1, BDCA-2, BDCA-3, BDCA-4, CD68, CD163, CD206, 
CD66b, CD15). 
d. Changes in NK cell and NK T-cell composition (i.e., CD56, CD3, V224, Vbeta1) 
 
For all experiments requiring  tissue, whereas relatively large tissue samples are generally 
obtainable from both pre-resection biopsies performed by thoracoscopy, and at the time of 
tumor resection, our experiments will be prioritized as follows: 
1) CyTOF 
2) IHC  
3) Gene expression  
 
 
 
 
 


Clinical Study Protocol 
Drug Substance Tremelimumab 
Study Number ESR-14-10744 
Edition Number 8 
Date 17 April 2019 
 
Page 10 of 134 
 
Statistical Methods and Data Analysis: 
 
There will be two treatment arms (MEDI4736 only and combination MEDI4736+tremelimumab) and 
one untreated arm (control). Randomization, stratified by receiving previous chemotherapy or not, will 
help to minimize patient selection biases between three arms. Preliminary tests will be performed to 
assess whether our data is normally or non-normally distributed. Patient characteristics will be 
summarized descriptively. Baseline characteristics will be compared by treatment assignment. For our 
primary objective that compares outcome variable in tissues before and after treatment with combination 
MEDI4736 and tremelimumab, we will use a paired t-test in log-transformed ratio of intratumoral 
cytotoxic T cells to regulatory T cells (CD8/Treg) before and after the treatment. In our secondary 
objective numerous variable comparisons are made between tumor tissues from untreated patients with 
from patients undergoing treatment with either MEDI4736 or MEDI4736 + tremelimumab, and between 
tumor tissues from patients undergoing treatment with MEDI4736 and tumor tissues from patients 
undergoing treatment with MEDI4736+tremelimumab. In these comparisons, a paired t-test or Student 
t-tests will be performed. Because approximately 20 comparisons of immune cell populations will be 
performed, a Bonferroni correction will be applied to correct for multiple comparisons. For the 
comparison of overall survival and recurrence-free survival between treatment groups, log-rank test will 
be used. These analysis will be post-protocol analysis based upon data obtained from the standard of 
care follow up in our post-surgical patients. SAS software will be used for all other statistical analyses. 


Clinical Study Protocol 
Drug Substance Tremelimumab 
Study Number ESR-14-10744 
Edition Number 8 
Date 17 April 2019 
 
Page 11 of 134 
 
Sample Size Determination: 
 
The primary objective is comparison of the ratio of CD8/Treg before and after treatment with 
combination MEDI4736+Tremelimumab. A total of 20 evaluable subjects will be enrolled in this study 
for 24 months and 8 subjects will be assigned to combination MEDI4736+Tremelimumab (8 subjects 
to MEDI4736 only and 4 subjects to control). The outcome of interest in this study is a change in ratio 
of CD8/Treg before and after treatment with combination MEDI4736+Tremelimumab within subjects. 
Our sample size was therefore calculated based upon the change in CD8/Treg ratio in tumor tissues 
before and after treatment with combination MEDI4736+Tremelimumab therapy. This sample size 
calculation is also applicable to our secondary objectives including the change in CD8/Treg ratio in 
tumor tissues before and after treatment with MEDI4736 monotherapy. 
 
Because there are no data available to estimate a change of ratio of CD8/Treg before and after the 
treatment in MPM, we utilized data from preclinical reports, and clinical data in melanoma patients. 
The ratio of CD8 T cells to regulatory T cells (CD8/Treg) is increased by the blockade of CTLA-4 and 
PD-1 within B16 mouse melanoma tumors (CD8/Treg ratio 2 in untreated, 11 in CTLA-4 treated, and 
8 in PD-1 treated)  (Curran et al., 2010), and this ratio is predictive of therapeutic efficacy in this 
model (Quezada et al., 2006). In a recent report of melanoma patients undergoing PD-1 blockade, 
subjects who had a significant clinical response were found to have an increase in the number of 
intratumoral CD8 T cells following drug delivery (15.1 ± 6.6 to 36.0 ± 8.4 CD8 T cells/mm2) (Tumeh 
et al., 2014). Further, ourour pilot data from 6 subjects with MPM the log transformed ratio of 
CD8/Treg was approximately normally distributed with a mean of 1.94(6.96 in raw scale) and standard 
deviation of 0.808(2.24 in raw scale). Assuming that repeat values are moderately correlated(r=0.5), 
then the difference between before and after the combination treatment will also have a standard 
deviation of 0.808(2.24 in raw scale). We estimate that we will have 80% power (alpha=5%, a paired t-
test) to detect an increased log ratio CD8/Treg of 2.87(17.71 in raw scale) after the combination 
treatment with 8 subjects. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Clinical Study Protocol 
Drug Substance Tremelimumab 
Study Number ESR-14-10744 
Edition Number 8 
Date 17 April 2019 
 
Page 12 of 134 
 
SCHEDULE OF STUDY ASSESSMENTS 
 
 
 
Schedule of study assessments: Screening and Treatment Period (24 
months: maximum of 1 dose) 
Visit  
(Assessments to be 
performed at the 
times stipulated in 
the table and as 
clinically required 
in the management 
of the subject.) 
 
Screening 
(Up to 28 
days before 
or on Day 1) 
 
 
 
All assessments to be performed pre-
infusion unless stated otherwise 
Baseline 
 
 
Mediastinoscopy 
& Thoracoscopy 
 
 
Oncology 
Visit 
Infusion 
(3 days-3 weeks 
after 
mediastinoscopy 
& thoracoscopy) 
 
 
Clinic 
Visit 
Surgical 
Resection 
1-6 weeks 
after 
infusioni 
Follow-
up 
(after 
expected 
average 2 
week 
hospital 
stay) 
 
Day 
 
-28 to 1 
1 
 
 
 
 
Week 
 
-4 to 1 
0 
 
 
 
 
 
0-1 
 
 
 
 
 
0-3 
 
0-3 
 
 
 
 
1-6 
1-6 
After 
dis-
charge 
from 
hospital 
1 week 
later, then 
2 weeks 
later, then 
4 weeks 
later. 
 
 
 
 
 
(±7 days) 
Written informed 
consent/assignme
nt of  subject 
identification 
number 
 
X 
 
 
 
 
 
 
 
 
Preliminary 
eligibility 
fulfillment 
(investigator’s 
opinion) 
 
X 
 
 
 
 
 
 
 
 
Demography and 
history of 
tobacco and 
alcohol use 
 
X 
 
 
 
 
 
 
 
 
 
Previous 
treatments for 
malignant pleural 
mesothelioma  
 
X 
 
 
 
 
 
 
 
 
 
Archival FFPE 
tumor tissue 
sample for PD-
L1 assay, if 
applicable  
 
 
 
 
 
 
 
 
 
 


Clinical Study Protocol 
Drug Substance Tremelimumab 
Study Number ESR-14-10744 
Edition Number 8 
Date 17 April 2019 
 
Page 13 of 134 
 
 
 
 
Schedule of study assessments: Screening and Treatment Period (24 
months: maximum of 1 dose) 
Visit  
(Assessments to be 
performed at the 
times stipulated in 
the table and as 
clinically required 
in the management 
of the subject.) 
 
Screening 
(Up to 28 
days before 
or on Day 1) 
 
 
 
All assessments to be performed pre-
infusion unless stated otherwise 
Baseline 
 
 
Mediastinoscopy 
& Thoracoscopy 
 
 
Oncology 
Visit 
Infusion 
(3 days-3 weeks 
after 
mediastinoscopy 
& thoracoscopy) 
 
 
Clinic 
Visit 
Surgical 
Resection 
1-6 weeks 
after 
infusioni 
Follow-
up 
(after 
expected 
average 2 
week 
hospital 
stay) 
 
Day 
 
-28 to 1 
1 
 
 
 
 
Week 
 
-4 to 1 
0 
 
 
 
 
 
0-1 
 
 
 
 
 
0-3 
 
0-3 
 
 
 
 
1-6 
1-6 
After 
dis-
charge 
from 
hospital 
1 week 
later, then 
2 weeks 
later, then 
4 weeks 
later. 
 
 
 
 
 
(±7 days) 
Recent formalin-
fixed tumor 
biopsy for PD-L1 
assay, if 
applicable 
 
 
 
 
 
 
 
 
 
 
Formal 
verification of 
eligibility criteria 
 
 
 
 
Xh 
 
 
 
 
 
 
Medical and 
surgical history 
 
X 
 
 
 
 
 
 
 
 
Hepatitis B and 
C; HIV 
 
X 
 
 
 
 
 
 
 
 
Urine hCG or 
serum βhCGa 
 
X 
 
 
 
As clinically indicated 
MEDI4736 
administration  
 
 
 
 
 
X (or MEDI473 + 
tremelimumab) 
 
 
 
 
 MEDI4736 + 
tremelimumab 
 
 
 
 
 
X (or MEDI4736) 
 
 
 
 
Physical 
examinationb 
 
X 
X 
 
 
 
X 
 
X 
 
Vital signs (pre- 
during and post-
infusion vital 
signs 
assessments)c 
 
X 
X 
 
 
X 
 
 
 
 


Clinical Study Protocol 
Drug Substance Tremelimumab 
Study Number ESR-14-10744 
Edition Number 8 
Date 17 April 2019 
 
Page 14 of 134 
 
 
 
 
Schedule of study assessments: Screening and Treatment Period (24 
months: maximum of 1 dose) 
Visit  
(Assessments to be 
performed at the 
times stipulated in 
the table and as 
clinically required 
in the management 
of the subject.) 
 
Screening 
(Up to 28 
days before 
or on Day 1) 
 
 
 
All assessments to be performed pre-
infusion unless stated otherwise 
Baseline 
 
 
Mediastinoscopy 
& Thoracoscopy 
 
 
Oncology 
Visit 
Infusion 
(3 days-3 weeks 
after 
mediastinoscopy 
& thoracoscopy) 
 
 
Clinic 
Visit 
Surgical 
Resection 
1-6 weeks 
after 
infusioni 
Follow-
up 
(after 
expected 
average 2 
week 
hospital 
stay) 
 
Day 
 
-28 to 1 
1 
 
 
 
 
Week 
 
-4 to 1 
0 
 
 
 
 
 
0-1 
 
 
 
 
 
0-3 
 
0-3 
 
 
 
 
1-6 
1-6 
After 
dis-
charge 
from 
hospital 
1 week 
later, then 
2 weeks 
later, then 
4 weeks 
later. 
 
 
 
 
 
(±7 days) 
Weight 
 
X 
X 
 
 
 
X 
 
 
 
Electrocardiogra
md 
 
 
X 
 
 
X 
 
 
X (week 
16 only)  
Adverse 
event/serious 
adverse event 
assessment 
 
X 
X 
 
 
 
 
All visits 
Concomitant 
medications 
 
X 
X 
 
 
 
All visits 
Palliative 
radiotherapy 
 
 
 
 
As clinically indicated 
ECOG 
performance 
status 
 
X 
X 
 
 
 
X 
 
 
 
Liver enzyme 
panelf 
 
 
 
 
 
X 
 
 
 
 
Serum Chemistry 
(Complete clin 
chem. panel 
including Liver 
Enzymes, 
Amylase, 
Lipase)e 
 
X 
X 
 
 
 
X  
 
 
 
Thyroid function 
tests (TSH and 
fT3 and fT4)f 
 
X 
X 
 
 
 
X 
 
 
 


Clinical Study Protocol 
Drug Substance Tremelimumab 
Study Number ESR-14-10744 
Edition Number 8 
Date 17 April 2019 
 
Page 15 of 134 
 
 
 
 
Schedule of study assessments: Screening and Treatment Period (24 
months: maximum of 1 dose) 
Visit  
(Assessments to be 
performed at the 
times stipulated in 
the table and as 
clinically required 
in the management 
of the subject.) 
 
Screening 
(Up to 28 
days before 
or on Day 1) 
 
 
 
All assessments to be performed pre-
infusion unless stated otherwise 
Baseline 
 
 
Mediastinoscopy 
& Thoracoscopy 
 
 
Oncology 
Visit 
Infusion 
(3 days-3 weeks 
after 
mediastinoscopy 
& thoracoscopy) 
 
 
Clinic 
Visit 
Surgical 
Resection 
1-6 weeks 
after 
infusioni 
Follow-
up 
(after 
expected 
average 2 
week 
hospital 
stay) 
 
Day 
 
-28 to 1 
1 
 
 
 
 
Week 
 
-4 to 1 
0 
 
 
 
 
 
0-1 
 
 
 
 
 
0-3 
 
0-3 
 
 
 
 
1-6 
1-6 
After 
dis-
charge 
from 
hospital 
1 week 
later, then 
2 weeks 
later, then 
4 weeks 
later. 
 
 
 
 
 
(±7 days) 
Hematologye 
 
X 
X 
 
 
 
X 
 
 
 
Urinalysisg 
 
X 
 
 
 
 
X 
 
 
 
 
Coagulation 
parametersh 
 
X 
 
 
 
As clinically indicted 
Tumor tissue 
collection for 
Cytof, IHC, gene 
analysis 
 
 
 
X 
 
 
 
X 
 
 
Blood collection 
for Cytof 
 
 
 
X 
 
 
 
X 
 
 
Oncology visit 
discuss treatment 
 
 
 
 
X 
 
 
 
 
 
Clinic visit discuss 
surgery 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Clinical Study Protocol 
Drug Substance Tremelimumab 
Study Number ESR-14-10744 
Edition Number 8 
Date 17 April 2019 
 
Page 16 of 134 
 
 
 
a Pre-menopausal female subjects of childbearing potential only 
b Full physical examination at baseline; targeted physical examination at other timepoints 
c Subjects will have their blood pressure and pulse measured before, during and after the infusion at the following times (based on 
a 60-minute infusion): 
• 
At the beginning of the infusion (at 0 minutes) 
• 
At 30 minutes during the infusion (±5 minutes) 
• 
At the end of the infusion (at 60 minutes ±5 minutes) 
• 
In the 1 hour observation period post-infusion: 30 and 60 minutes after the infusion (i.e., 90 and 120 minutes from the 
start of the infusion) (±5 minutes) – for the first infusion only and then for subsequent infusions as clinically indicated 
If the infusion takes longer than 60 minutes then blood pressure and pulse measurements should follow the principles 
as described above or more frequently if clinically indicated. 
d 
On Day 1 and as clinically indicated. ECGs should be taken within an hour prior to the start of the infusion and at least 
one time point 0 to 3 hours after the infusion.   
e 
If screening laboratory assessments are performed within 3 days prior to Day 1 they do not need to be repeated at Day 
1. Results for safety bloods must be available and reviewed before commencing an infusion.  
f 
Free T3 and free T4 will only be measured if TSH is abnormal. They should also be measured if there is clinical 
suspicion of an adverse event related to the endocrine system. 
g 
Urinalysis performed at Screening, Day 1, and as clinically indicated. 
h 
Coagulation tests: prothrombin time, APTT and INR – only performed at Screening and as clinically indicated. 
i 
Patients  in control arm can proceed from mediastinoscopy and thoracoscopy directly to resectional surgery.  
j 
This eligibility will be checked after the laparoscopy/mediastinoscopy procedure when the path report becomes available. 
 
 
 


Clinical Study Protocol 
Investigational Drug Substance: MEDI4736, tremelimumab 
Study Number ESR-14-10744 
Edition Number  8 
 
 
Date: 17 April 2019 
 
Page 17 of 134 
 
TABLE OF CONTENTS 
PAGE 
SYNOPSIS ............................................................................................................... 3 
SCHEDULE OF ASSESSMENTS .......................................................................... 5 
TABLE OF CONTENTS ....................................................................................... 18 
LIST OF TABLES IN TEXT................................................................................. 22 
LIST OF FIGURES IN TEXT ............................................................................... 22 
ABBREVIATIONS AND DEFINITION OF TERMS .......................................... 22 
1. 
INTRODUCTION ................................................................................................. 27 
1.1 
Disease Background ............................................................................................... 27 
1.2 
MEDI-4736 Background ....................................................................................... 29 
1.2.1 
Summary of non-clinical experience ..................................................................... 29 
1.2.2 
Summary of clinical experience ............................................................................. 30 
1.3 
Research hypothesis ............................................................................................... 35 
1.4 
Rationale for conducting this study ....................................................................... 36 
1.5 
Benefit/risk and ethical assessment........................................................................ 39 
2. 
STUDY OBJECTIVES .......................................................................................... 42 
2.1 
Primary objective(s) ............................................................................................... 42 
2.2 
Secondary objective(s) ........................................................................................... 42 
3. 
STUDY DESIGN ................................................................................................... 43 
3.1 
Overview of study design ...................................................................................... 43 
3.2 
Study schema ......................................................................................................... 43 
3.3 
Study Oversight for Safety Evaluation .................................................................. 46 
4. 
SUBJECT SELECTION ........................................................................................ 46 
4.1 
Inclusion criteria .................................................................................................... 46 
4.2 
Exclusion criteria ................................................................................................... 48 
4.3 
Withdrawal of Subjects from Study Treatment and/or Study ................................ 50 
4.4 
Replacement of subjects ........................................................................................ 51 
5. 
INVESTIGATIONAL PRODUCT(S) ................................................................... 51 
5.1 
MEDI4736 ............................................................................................................. 51 
5.1.1 
Formulation/packaging/storage .............................................................................. 51 
5.1.2 
Doses and treatment regimens ............................................................................... 52 
5.1.3 
Study drug preparation ........................................................................................... 52 
5.1.4 
Dose administration ............................................................................................... 52 
5.1.5 
Monitoring of dose administration ......................................................................... 53 
5.1.6 
Accountability and dispensation ............................................................................ 53 
5.1.7 
Disposition of unused investigational study drug .................................................. 54 


Clinical Study Protocol 
Investigational Drug Substance: MEDI4736, tremelimumab 
Study Number ESR-14-10744 
Edition Number  8 
 
 
Date: 17 April 2019 
 
Page 18 of 134 
 
5.2 
Tremelimumab ....................................................................................................... 58 
5.2.1 
Formulation/packaging/storage .............................................................................. 54 
5.2.2 
Doses and treatment regimens ............................................................................... 54 
5.2.3 
Product preparation ................................................................................................ 55 
5.2.4 
Dose administration ............................................................................................... 55 
5.2.5 
Monitoring of dose administration ......................................................................... 55 
5.2.6 
Accountability and dispensation ............................................................................ 55 
5.2.7 
Disposition of unused investigational study drug .................................................. 55 
6. 
TREATMENT PLAN ............................................................................................ 55 
6.1 
Subject enrollment and randomization .................................................................. 55 
6.1.1 
Procedures for randomization ................................................................................ 55 
6.1.2 
Procedures for handling subjects incorrectly enrolledor randomized .................... 56 
6.2 
Blinding and procedures for unblinding the study ................................................. 56 
6.2.1 
Methods for ensuring blinding ............................................................................... 56 
6.2.2 
Methods for unblinding the study .......................................................................... 56 
6.3 
Dosage and Administration .................................................................................... 56 
6.4 
Dose Escalation Decision Rules ............................................................................ 56 
6.5 
Definition of DLT .................................................................................................. 56 
6.6 
Toxicity Management ............................................................................................ 57 
6.6.1 
MEDI4736 ............................................................................................................. 57 
7. 
RESTRICTIONS DURING THE STUDY AND CONCOMITANT 
TREATMENT(S) .................................................................................................. 88 
7.1 
Restrictions during the study ................................................................................. 88 
7.2 
Concomitant treatment(s) ....................................................................................... 89 
7.2.1 
Permitted concomitant medications ....................................................................... 89 
7.2.2 
Excluded Concomitant Medications ...................................................................... 89 
8. 
STUDY PROCEDURES ....................................................................................... 90 
8.1 
Schedule of study procedures ................................................................................ 91 
8.1.1 
Screening Phase ..................................................................................................... 91 
8.1.2 
Treatment Phase ..................................................................................................... 92 
8.1.3 
End of Treatment ................................................................................................... 93 
8.2 
Description of study procedures ............................................................................ 93 
8.2.1 
Medical history and physical examination, electrocardiogram, weight and 
vital signs ............................................................................................................... 93 
8.2.2 
Clinical laboratory tests ......................................................................................... 94 
 
8.3 
Biological sampling procedures ............................................................................. 96 
 
8.3.1 
Biomarker/Pharmacodynamic sampling and evaluation methods ......................... 96 
8.3.2 
Estimate of volume of blood to be collected.......................................................... 97 
8.3.3 
Fresh tumor biopsies .............................................................................................. 97 
8.3.4 
Withdrawal of informed consent for donated biological samples ......................... 97 


Clinical Study Protocol 
Investigational Drug Substance: MEDI4736, tremelimumab 
Study Number ESR-14-10744 
Edition Number  8 
 
 
Date: 17 April 2019 
 
Page 19 of 134 
 
9. 
DISEASE EVALUATION AND METHODS ...................................................... 98 
9.1.1 
Primary efficacy variables ..................................................................................... 98 
9.1.2 
Secondary efficacy variables ................................................................................. 89 
10. 
ASSESSMENT OF SAFETY .............................................................................. 100 
10.1.1 
Safety Parameters ................................................................................................. 100 
10.1.1.1 Definition of adverse events ................................................................................ 100 
10.1.2 
Definition of serious adverse events .................................................................... 101 
10.1.3 
Definition of adverse events of special interest (AESI) ....................................... 101 
10.1.3.1 Pneumonitis .......................................................................................................... 102 
10.1.3.2 Hypersensitivity reactions ...................................................................................... 93 
10.1.3.3 Hepatic function abnormalities (hepatotoxicity) ................................................. 104 
10.2 
Assessment of safety parameters ......................................................................... 111 
10.2.1 
Assessment of severity ......................................................................................... 111 
10.2.2 
Assessment of relationship .................................................................................. 112 
10.3 
Recording of adverse events and serious adverse events ..................................... 112 
10.3.1 
Study recording period and follow-up for adverse events amd serious 
adverse events ...................................................................................................... 113 
10.3.2 
Reporting of serious adverse events..................................................................... 114 
10.3.2.1 Reporting of deaths .............................................................................................. 116 
10.3.3 
Other events requiring reporting .......................................................................... 117 
10.3.3.1 Overdose .............................................................................................................. 117 
10.3.3.2 Hepatic function abnormality .............................................................................. 117 
10.3.3.3 Pregnancy ............................................................................................................. 118 
11. 
STATISTICAL METHODS AND SAMPLE SIZE DETERMINATION .......... 119 
11.1 
Description of analysis sets .................................................................................. 116 
11.1.1 
Safety analysis set ................................................................................................ 116 
11.1.2 
Efficacy analysis set ............................................................................................. 116 
11.2 
Methods of statistical analyses ............................................................................. 116 
11.2.2 
Efficacy Analyses ................................................................................................ 116 
11.3 
Determination of sample size ............................................................................... 116 
12. 
ETHICAL AND REGULATORY REQUIREMENTS ....................................... 120 
12.1 
Ethical conduct of the study ................................................................................. 120 
12.2 
Ethics and regulatory review................................................................................ 120 
12.3 
Informed consent ................................................................................................. 120 
12.4 
Changes to the protocol and informed consent form ........................................... 121 
12.5 
Audits and inspections ......................................................................................... 121 
13. 
STUDY MANAGEMENT .................................................................................. 121 
13.1 
Training of study site personnel ........................................................................... 121 
13.2 
Monitoring of the study ....................................................................................... 121 
13.2.1 
Source data ........................................................................................................... 121 
13.3 
Study timetable and end of study ......................................................................... 122 


Clinical Study Protocol 
Investigational Drug Substance: MEDI4736, tremelimumab 
Study Number ESR-14-10744 
Edition Number  8 
 
 
Date: 17 April 2019 
 
Page 20 of 134 
 
14. 
DATA MANAGEMENT ..................................................................................... 122 
15. 
LIST OF REFERENCES ..................................................................................... 123 
 
 
 


Clinical Study Protocol 
Investigational Drug Substance: MEDI4736, tremelimumab 
Study Number ESR-14-10744 
Edition Number  8 
 
 
Date: 17 April 2019 
 
Page 21 of 134 
 
LIST OF TABLES 
 
Table 1 
Dosing modification and toxicity management guidelines for 
immune-mediated reactions associated with MEDI4736 ......................... 53 
 Table 2 
Dosing modification and toxicity management guidelines for 
infusion-related reactions associated with MEDI4736 ............................. 72 
Table 3 
Dosing modification and toxicity management guidelines for non-
immune-mediated reactions associated with MEDI4736 ......................... 73 
 
Table 4 
Toxicity management for MEDI4736 and combination drug .................. 75 
Table 5 
Effective methods of contraception (two methods must be used) ............ 76 
Table 6 
Hematology laboratory tests ..................................................................... 83 
Table 7 
Clinical chemistry laboratory tests ........................................................... 84 
Table 8 
Urinalysis tests .......................................................................................... 84 
Table 9 
Estimate of volume of blood to be collected ............................................ 87 
 
 
LIST OF FIGURES 
Figure 1 
Study flow chart ....................................................................................... 30 
 
LIST OF APPENDICES 
Appendix A 
MEDI4736 Dose Calculations 
Appendix B 
Schedule of study procedures: follow-up for subjects who have completed 
MEDI4736 treatment or MEDI4736 treatment plus tremelimumab  
Appendix C 
CyTOF antibody panel including cell definitions 


Clinical Study Protocol 
Investigational Drug Substance: MEDI4736, tremelimumab 
Study Number ESR-14-10744 
Edition Number  8 
 
 
Date: 17 April 2019 
 
Page 22 of 134 
 
ABBREVIATIONS AND DEFINITION OF TERMS 
The following abbreviations and special terms are used in this study Clinical Study Protocol. 
Abbreviation or 
special term 
Explanation 
ADA 
anti-drug antibody 
ADCC 
antibody-dependent cell-mediated cytotoxicity 
AE 
adverse event 
AESI 
adverse event of special interest 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
APC 
antigen-presenting cells 
AST 
aspartate aminotransferase 
AUC 
area under the concentration-time curve 
B7 H1 
B7 homolog 1  
CD 
cluster of differentiation  
CDC 
Complement dependent cytotoxicity 
CI 
confidence interval 
CL 
clearance 
Cmax 
peak concentration 
Cmax,ss 
peak concentration at steady state 
Cmin 
trough concentration 
Cmin,ss 
trough concentration at steady state 
CNS 
central nervous system 
CR 
complete response 
CT 
computed tomography 
CTLA-4 
cytotoxic T-lymphocyte-associated antigen-4 
CyTOF 
time-of-flight mass cytometry 
DC 
disease control 
DCR 
disease control rate 


Clinical Study Protocol 
Investigational Drug Substance: MEDI4736, tremelimumab 
Study Number ESR-14-10744 
Edition Number  8 
 
 
Date: 17 April 2019 
 
Page 23 of 134 
 
Abbreviation or 
special term 
Explanation 
DLT 
dose-limiting toxicity 
DNA 
deoxyribonucleic acid 
DoR 
duration of response 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
EDTA 
disodium edetate dihydrate 
EPP 
extrapleural pneumonectomy 
Fc 
fragment crystallizable 
FDA 
Food and Drug Administration 
FFPE 
formalin fixed paraffin embedded 
FSH 
follicle-stimulating hormone 
FTIH 
first-time-in-human 
GCP 
Good Clinical Practice 
GMP 
Good Manufacturing Practice 
GLP 
Good Laboratory Practice 
HCC 
hepatocellular carcinoma  
HCl 
hydrochloride 
HIV 
human immunodeficiency virus 
ICF 
informed consent form 
ICH 
International Conference on Harmonization 
ICOS 
inducible T-cell co-stimulator 
IEC 
Independent Ethics Committee 
IFN 
interferon 
IGF 
insulin-like growth factor 
IgG1 
immunoglobulin G1 
IgG2 
immunoglobulin G2 
IGSF 
immunoglobulin superfamily 
IHC 
immunohistochemistry  


Clinical Study Protocol 
Investigational Drug Substance: MEDI4736, tremelimumab 
Study Number ESR-14-10744 
Edition Number  8 
 
 
Date: 17 April 2019 
 
Page 24 of 134 
 
Abbreviation or 
special term 
Explanation 
IL 
interleukin 
irAE 
immune-related adverse event 
IRB 
Institutional Review Board 
IV 
intravenous(ly) 
MAb 
monoclonal antibody 
MDSC 
Myeloid derived suppressor cells 
MedDRA 
Medical Dictionary for Regulatory Activities 
miRNA 
micro ribonucleic acid 
MPM 
malignant pleural mesothelioma 
MRI 
magnetic resonance imaging 
mRNA 
messenger ribonucleic acid 
MTD 
maximum tolerated dose 
NCI CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse 
Events  
NK 
natural killer 
NOAEL 
no-observed-adverse-effect level 
NSCLC 
non-small cell lung cancer 
OR 
objective response 
ORR 
objective response rate 
OS 
overall survival 
PBMC 
peripheral blood mononuclear cell 
P/D 
pleurectomy/decortication  
PD 
progressive disease 
PD-1 
programmed cell death 1 
PD-L1 
programmed cell death ligand 1 
PD-L2 
programmed cell death ligand 2 
PFS 
progression-free survival 
PK 
pharmacokinetic(s) 


Clinical Study Protocol 
Investigational Drug Substance: MEDI4736, tremelimumab 
Study Number ESR-14-10744 
Edition Number  8 
 
 
Date: 17 April 2019 
 
Page 25 of 134 
 
Abbreviation or 
special term 
Explanation 
PR 
partial response 
PRO 
patient-reported outcome 
PVC 
polyvinyl chloride 
Q2W 
every 2 weeks 
Q3M 
every 3 months 
Q3W 
every 3 weeks 
Q4W 
every 4 weeks 
Q12W 
every 12 weeks 
QoL 
quality of life 
QTc 
the time between the start of the Q wave and the end of the T wave 
corrected for heart rate 
QTcF 
QT interval on ECG corrected using the Frederica’s formula 
RCC 
renal cell carcinoma 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RNA 
ribonucleic acid 
SAE 
serious adverse event 
SCCHN 
squamous cell carcinoma of the head and neck  
SD 
stable disease 
SID 
subject identification 
sPD-L1 
soluble programmed cell death ligand 1 
SOCS3 
suppressor of cytokine signaling 3 
SUSAR 
suspected unexpected serious adverse reaction 
t½ 
half-life 
TEAE 
treatment-emergent adverse event 
TIL 
tumor infiltrating lymphocyte 
Tmax 
time to peak concentration 
Tmax,ss 
time to peak concentration at steady state 
TNF-α 
tumor necrosis factor alpha 


Clinical Study Protocol 
Investigational Drug Substance: MEDI4736, tremelimumab 
Study Number ESR-14-10744 
Edition Number  8 
 
 
Date: 17 April 2019 
 
Page 26 of 134 
 
Abbreviation or 
special term 
Explanation 
Treg 
regulatory T-cells 
TSH 
thyroid stimulating hormone 
ULN 
upper limit of normal 
USA 
United States of America 
WFI 
water for injection 
WHO 
World Health Organization 
(w/v) 
weight/volume 
 


Clinical Study Protocol 
Investigational Drug Substance: MEDI4736, tremelimumab 
Study Number ESR-14-10744 
Edition Number  8 
 
 
Date: 17 April 2019 
 
Page 27 of 134 
 
1. 
INTRODUCTION 
Malignant pleural mesothelioma (MPM) is an aggressive malignancy of the pleura that is 
associated with prior exposure to asbestos and is fatal in most cases. The tumor most commonly 
arises within the parietal pleura and spreads locally to the ipsilateral visceral pleura, lung, chest 
wall, diaphragm, pericardium, and mediastinum. Treatment with standard cytotoxic 
chemotherapy regimens, including cisplatin and pemetrexed, results in an extension of the 
median survival time to 12 months, compared with cisplatin alone (Vogelzang et al, 2003). For 
patients with disease confined to the ipsilateral hemithorax, surgical resection combined with 
systemic or intracavitary chemotherapy, radiation therapy, and/or other local modalities, has 
been offered with reports of more optimistic outcomes. The operative procedures most 
commonly used in these multimodal approaches include the following: extrapleural 
pneumonectomy (EPP), which involves en bloc resection of the lung, pericardium, diaphragm, 
visceral, and parietal pleura; and pleurectomy/decortication (P/D), which involves resection of 
the visceral and parietal pleura with or without resection of the pericardium and/or diaphragm. 
Nonetheless, the majority of these patients will suffer from recurrence and ultimately succumb 
to the disease (Rusch et al., 2012; Sugarbaker et al., 2014). There is a clear need for better 
systemic therapies for MPM.  
1.1 
Disease Background 
Immune responses directed against tumors are one of the body’s natural defenses against the 
growth and proliferation of cancer cells. However, over time and under pressure from immune 
attack, cancers develop strategies to evade immune-mediated killing, which allows them to 
develop unchecked. One such mechanism involves the upregulation of surface proteins that 
deliver inhibitory signals to cytotoxic T cells. Programmed cell death ligand 1 (PD-L1) is one 
such protein, and is upregulated in a broad range of cancers with a high frequency, with up to 
88% expression in some tumor types. In a number of these cancers, including lung (Mu et al., 
2011), renal (Thompson et al., 2005; Thompson et al., 2006; Krambeck et al., 2007), 
pancreatic (Nomi et al., 2007; Loos et al., 2008; Wang et al., 2010), ovarian cancer 
(Hamanishi et al., 2007), and hematologic malignancies (Andorsky et al., 2011; Brusa et al., 
2013), tumor cell expression of PD-L1 is associated with reduced survival and an unfavorable 
prognosis. 
The blockade of negative regulatory signals to T-cells, such as PD-L1 and cytotoxic T-
lymphocyte antigen 4 (CTLA-4), has shown promising clinical activity. Ipilimumab is a 
monoclonal antibody that binds to CTLA-4 and prevents the interaction of CTLA-4 with cluster 
of differentiation (CD) 80 and CD86, which results in enhanced T-cell activation and 
proliferation (Lipson et al., 2011). Ipilimumab was shown to extend survival in patients with 


Clinical Study Protocol 
Investigational Drug Substance: MEDI4736, tremelimumab 
Study Number ESR-14-10744 
Edition Number  8 
 
 
Date: 17 April 2019 
 
Page 28 of 134 
 
advanced melanoma (Hodi et al., 2010), and was granted United States Food and Drug 
Administration (FDA) approval in 2011 for the treatment of metastatic melanoma.  
PD-L1 (B7 homolog 1 [B7 H1], CD274) is part of a complex system of receptors and ligands 
that are involved in controlling T-cell activation. In normal tissue, PD-L1 is expressed on T 
cells, B cells, dendritic cells (DC), macrophages, mesenchymal stem cells, bone marrow-
derived mast cells, and in various non-hematopoietic cells (Keir et al., 2008). The normal 
function of PD-L1 is to regulate the balance between T-cell activation and tolerance through the 
interaction with two receptors, programmed death 1 (PD-1, CD279) and CD80 (B7-1). In the 
tumor microenvironment, PD-L1 expressed on tumor cells binds to PD-1 on activated T cells, 
which delivers an inhibitory signal to those T cells, preventing them from killing target tumor 
cells and thus protecting the tumor from immune elimination (Zou et al., 2008). In the clinic, 
antibody-mediated blockade of PD-L1 induced durable tumor regression (objective response 
rate of 6 to 17%) and prolonged stabilization of the disease (rates of 12 to 41% at 24 weeks) in 
patients with advanced cancers, including non-small-cell lung cancer, melanoma, and renal-cell 
cancer (Brahmer et al., 2012). Similarly, treatment with anti-PD-1 antibodies produced 
objective responses in approximately one in four to one in five patients with non-small-cell lung 
cancer, melanoma, or renal-cell cancer (Topalian et al., 2012). 
Pre-clinical data and clinical research suggests that the concurrent targeting of immunologic 
checkpoints may generate superior anti-tumor activity when compared with a single-agent 
checkpoint blockade, which may translate into higher and more durable rates of response. 
Mouse data indicate that the mechanisms of activation of sites known to be involved in the 
activity of CTLA-4 and PD-1 are non-redundant, and therefore targeting both pathways may 
have additive or synergistic activity (Pardoll, 2012). For example, in mouse tumor models, the 
combination of PD-1 and CTLA-4 blockade achieved more pronounced anti-tumor activity than 
the blockade of either pathway alone (Curran et al., 2010; Duraiswamy et al., 2013). Notably, 
in models of murine melanoma, anti-PD-1 blockade increased the expression of CTLA-4 on 
intratumoral T cells, and reciprocally, CTLA-4 blockade increased PD-1 expression on 
intratumoral T cells, suggesting one potential mechanism for the increased efficacy of dual 
checkpoint therapy (Curran et al., 2010). The concurrent administration of monoclonal 
antibodies to CTLA-4 (ipilimumab) and PD-1 (nivolumab) was recently evaluated in a Phase I 
trial that showed impressive preliminary evidence of improved benefit in advanced melanoma 
patients. The overall response rate was 53% at the maximum tolerated dose. Three patients 
presented with a complete response (CR), and all responding patients experienced a ≥80% 
decline in tumor burden at 12 weeks (Wolchok et al., 2013). 
MPM has recently been recognized as an immunogenic tumor, and durable clinical responses 
to immunotherapy have been obtained in the laboratory setting (Tan et al., 2014; Adusumilli 


Clinical Study Protocol 
Investigational Drug Substance: MEDI4736, tremelimumab 
Study Number ESR-14-10744 
Edition Number  8 
 
 
Date: 17 April 2019 
 
Page 29 of 134 
 
2014; Adusumilli et al., 2014; Fridlender et al., 2009; Anraku et al., 2008; Wu et al., 2012). In 
murine models of MPM, for example, CTLA-4 blockade results in significant anti-tumor 
responses (Wu et al., 2012). In the clinic, tremelimumab has shown encouraging clinical activity 
and an acceptable safety and tolerability profile in patients with advanced MPM who have been 
previously treated with cytotoxic chemotherapy (Calabro et al., 2013). 
 
1.2 
MEDI-4736 Background 
Investigators should be familiar with the current MEDI4736 Investigator Brochure (IB). 
MEDI4736 is being developed as a potential anticancer therapy for patients with advanced 
solid tumors. MEDI4736 is a human monoclonal antibody (MAb) of the immunoglobulin G1 
kappa (IgG1κ) subclass that inhibits binding of programmed cell death ligand 1 (PD-L1) (B7 
homolog 1 [B7-H1], cluster of differentiation [CD]274) to programmed cell death 1 (PD-1; 
CD279) and CD80 (B7-1). MEDI4736 is composed of 2 identical heavy chains and 2 identical 
light chains, with an overall molecular weight of approximately 149 kDa. MEDI4736 contains 
a triple mutation in the constant domain of the immunoglobulin (Ig) G1 heavy chain that 
reduces binding to complement protein C1q and the fragment crystallizable gamma (Fcγ) 
receptors involved in triggering effector function. 
1.2.1 
Summary of non-clinical experience 
The non-clinical experience is fully described in the current version of the MEDI4736 
Investigator’s Brochure (IB).    
MEDI4736 binds with high affinity and specificity to human PD-L1 and blocks its interaction 
with PD-1 and CD80. In vitro studies demonstrate that MEDI4736 antagonizes the inhibitory 
effect of PD-L1 on primary human T cells, resulting in their restored proliferation and release 
of interferon gamma (IFN-γ). Additionally, MEDI4736 demonstrated a lack of antibody-
dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) 
in cell-based functional assays. In vivo studies show that MEDI4736 inhibits tumor growth in 
a xenograft model via a T lymphocyte (T-cell) dependent mechanism. Moreover, an anti-
mouse PD-L1 antibody demonstrated improved survival in a syngeneic tumor model when 
given as monotherapy and resulted in complete tumor regression in > 50% of treated mice 
when given in combination with chemotherapy. Combination therapy (dual targeting of PD-
L1 and cytotoxic T-lymphocyte-associated antigen 4 [CTLA-4]) resulted in tumor regression 
in a mouse model of colorectal cancer.  


Clinical Study Protocol 
Investigational Drug Substance: MEDI4736, tremelimumab 
Study Number ESR-14-10744 
Edition Number  8 
 
 
Date: 17 April 2019 
 
Page 30 of 134 
 
Cynomolgus monkeys were selected as the only relevant species for evaluation of the 
pharmacokinetics (PK)/pharmacodynamics and potential toxicity of MEDI4736. Following 
intravenous (IV) administration, the PK of MEDI4736 in cynomolgus monkeys was nonlinear. 
Systemic clearance (CL) decreased and concentration half-life (t1/2) increased with increasing 
doses, suggesting saturable target binding-mediated clearance of MEDI4736. No apparent 
gender differences in PK profiles were observed for MEDI4736.  
In general, treatment of cynomolgus monkeys with MEDI4736 was not associated with any 
MEDI4736-related adverse effects that were considered to be of relevance to humans. 
Adverse findings in the non-Good Laboratory Practice (GLP) PK/pharmacodynamics and 
dose range-finding study, and a GLP 4-week repeat-dose toxicity study were consistent with 
antidrug antibody (ADA)-associated morbidity and mortality in individual animals. The death 
of a single animal in the non-GLP, PK/pharmacodynamics, and dose range-finding study was 
consistent with an ADA-associated acute anaphylactic reaction. The spectrum of findings, 
especially the clinical signs and microscopic pathology, in a single animal in the GLP, 4-
week, repeat-dose study was also consistent with ADA immune complex deposition, and 
ADA:MEDI4736 immune complexes were identified in a subsequent non-GLP, investigative 
immunohistochemistry study. Similar observations were reported in cynomolgus monkeys 
administered human mAbs unrelated to MEDI4736. Given that immunogenicity of human 
mAbs in nonclinical species is generally not predictive of responses in humans, the ADA-
associated morbidity and mortality were not considered for the determination of the no-
observed-adverse-effect level (NOAEL) of MEDI4736.  
Finally, data from the pivotal 3-month GLP toxicity study with MEDI4736 in cynomolgus 
monkeys showed that subchronic dosing of MEDI4736 was not associated with any adverse 
effects. Therefore, the NOAEL of MEDI4736 in all the general toxicity studies was 
considered to be 100 mg/kg, the highest dose tested in these studies. In addition to the in vivo 
toxicology data, no unexpected membrane binding of MEDI4736 to human or cynomolgus 
monkey tissues was observed in GLP tissue cross-reactivity studies using normal human and 
cynomolgus monkey tissues. 
1.2.2 
Summary of clinical experience 
Clinical experience with MEDI4736 is fully described in the current version of the MEDI4736 
Investigator’s Brochure. 
As of the DCO dates (15Apr2015 to 12Jul2015), a total of 1,883 subjects have been enrolled 
and treated in 30 ongoing MEDI4736 clinical studies, including 20 sponsored and 10 


Clinical Study Protocol 
Investigational Drug Substance: MEDI4736, tremelimumab 
Study Number ESR-14-10744 
Edition Number  8 
 
 
Date: 17 April 2019 
 
Page 31 of 134 
 
collaborative studies (Table 1.2-1). Of the 1,883 subjects, 1,279 received MEDI4736 
monotherapy, 440 received MEDI4736 in combination with tremelimumab or other anticancer 
agents, 14 received other agents (1 gefitinib, 13 MEDI6383), and 150 have been treated with 
blinded investigational product. No studies have been completed or terminated prematurely 
due to toxicity. 
 
Pharmacokinetics and Product Metabolism  
The PK and immunogenicity profiles of MEDI4736 as monotherapy and combined with 
tremelimumab are described below based on data from key studies. 
 
Pharmacokinetics and Immunogenicity Profile of MEDI4736 Monotherapy 
 
Study CD-ON-MEDI4736-1108: As of 09Feb2015, PK data were available for 378 subjects 
in the dose-escalation and dose-expansion phases of Study CD-ON-MEDI4736-1108 
following treatment with MEDI4736 0.1 to 10 mg/kg every 2 weeks (Q2W) or 15 mg/kg 
every 3 weeks (Q3W). The maximum observed concentration (Cmax) increased in an 
approximately dose-proportional manner over the dose range of 0.1 to 15 mg/kg. The area 
under the concentration-time curve from 0 to 14 days (AUC0-14) increased in a greater than 
dose-proportional manner over the dose range of 0.1 to 3 mg/kg and increased dose 
proportionally at ≥ 3 mg/kg. These results suggest MEDI4736 exhibits nonlinear PK likely 
due to saturable target-mediated CL at doses < 3 mg/kg and approaches linearity at doses ≥ 3 
mg/kg. Near complete target saturation (soluble programmed cell death ligand 1 
[sPD-L1] and membrane bound) is expected with MEDI4736 ≥ 3 mg/kg Q2W. Exposures 
after multiple doses showed accumulation consistent with PK parameters estimated from the 
first dose. In addition, PK simulations indicate that following MEDI4736 10 mg/kg Q2W 
dosing, > 90% of subjects are expected to maintain PK exposure ≥ 40 μg/mL throughout the 
dosing interval. 
 
As of 09Feb2015, a total of 388 subjects provided samples for ADA analysis. Only 8 of 388 
subjects (1 subject each in 0.1, 1, 3, and 15 mg/kg cohorts, and 4 subjects in 10 mg/kg cohort) 
were ADA positive with an impact on PK/pharmacodynamics in 1 subject in the 3 mg/kg 
cohort. 
Pharmacokinetics and Immunogenicity Profile of MEDI4736 Combination Therapy 
 
Study D4190C00006: As of 20Feb2015, MEDI4736 PK (n = 55) and tremelimumab PK (n = 
26) data were available from 10 cohorts (1a, 2a, 3a, 3b, 4, 4a, 5, 5a, 8, and 9) following 
MEDI4736 every 4 weeks (Q4W) or Q2W dosing in combination with tremelimumab Q4W 
regimens. An approximately dose-proportional increase in PK exposure (Cmax and area under 
the concentration-time curve from 0 to 28 days [AUC0-28]) of both MEDI4736 and 
tremelimumab was observed over the dose range of 3 to 15 mg/kg MEDI4736 Q4W and 1 to 
10 mg/kg tremelimumab Q4W. Exposures following multiple doses demonstrated 


Clinical Study Protocol 
Investigational Drug Substance: MEDI4736, tremelimumab 
Study Number ESR-14-10744 
Edition Number  8 
 
 
Date: 17 April 2019 
 
Page 32 of 134 
 
accumulation consistent with PK parameters estimated from the first dose. It is to be noted 
that steady state PK parameters are based on limited numbers of subjects. The observed PK 
exposures of MEDI4736 and tremelimumab following combination were consistent with 
respective monotherapy data, indicating no PK interaction between these 2 agents. 
 
As of 20Feb2015, ADA data were available from 60 subjects for MEDI4736 and 53 subjects 
for tremelimumab in Study D4190C00006. Four of 60 subjects were ADA positive for anti-
MEDI4736 antibodies post treatment. One of 53 subjects was ADA positive for anti-
tremelimumab antibodies post treatment. There was no clear relationship between ADA and 
the dose of either MEDI4736 or tremelimumab, and no obvious association between ADA and 
safety or efficacy. MEDI4736 has also been combined with other anticancer agents, including 
gefitinib, dabrafenib, and trametinib. To date, no PK interaction has been observed between 
MEDI4736 and these agents. 
Safety  
The safety profile of MEDI4736 as monotherapy and combined with other anticancer agents 
was consistent with the pharmacology of the target and other agents in the immune checkpoint 
inhibitor class. No tumor types appeared to be associated with unique AEs. 
Immune-related AEs (irAEs), which are important risks of immune checkpoint inhibitors, 
have been observed with MEDI4736 and include colitis, pneumonitis, hepatitis/hepatotoxicity, 
neuropathy/neuromuscular toxicity, endocrinopathy, dermatitis, and nephritis. In addition, 
pancreatitis is an important potential risk particularly with MEDI4736 and tremelimumab 
combination therapy. These events are manageable by available/established treatment 
guidelines as described in the study protocols. 
AEs reported with MEDI4736 monotherapy and MEDI4736 and tremelimumab combination 
therapy in key clinical studies are described below. 
 
 
Adverse Event Profile of MEDI4736 Monotherapy 
 
Study CD-ON-MEDI4736-1108: The safety profile of MEDI4736 monotherapy in the 694 
subjects with advanced solid tumors treated at 10 mg/kg Q2W in Study CD-ON-MEDI4736-
1108 has been broadly consistent with that of the overall 1,279 subjects who have received 
MEDI4736 monotherapy (not including subjects treated with blinded investigational product) 
across the clinical development program. The majority of treatment related AEs were 
manageable with dose delays, symptomatic treatment, and in the case of events suspected to 
have an immune basis, the use of established treatment guidelines for immune-mediated 
toxicity. As of 07May2015, among the 694 subjects treated with MEDI4736 10 mg/kg Q2W in 
Study CD-ON-MEDI4736-1108, a total of 378 subjects (54.5%) experienced a treatment-
related AE, with the most frequent (occurring in ≥ 5% of subjects) being fatigue (17.7%), nausea 


Clinical Study Protocol 
Investigational Drug Substance: MEDI4736, tremelimumab 
Study Number ESR-14-10744 
Edition Number  8 
 
 
Date: 17 April 2019 
 
Page 33 of 134 
 
(8.6%), diarrhea (7.3%), decreased appetite (6.8%), pruritus (6.3%), rash (6.1%), and vomiting 
(5.0%). A majority of the treatment-related AEs were Grade 1 or Grade 2 in severity with ≥ 
Grade 3 events occurring in 65 subjects (9.4%). Treatment-related ≥ Grade 3 events reported in 
3 or more subjects (≥ 0.4%) were fatigue (12 subjects, 1.7%); increased aspartate 
aminotransferase (AST; 7 subjects, 1.0%); increased gamma-glutamyltransferase (GGT; 6 
subjects, 0.9%); increased alanine aminotransferase (ALT; 5 subjects, 0.7%); and colitis, 
vomiting, decreased appetite, and hyponatremia (3 subjects, 0.4% each). Six subjects had 
treatment-related Grade 4 AEs (upper gastrointestinal hemorrhage, increased AST, dyspnea, 
neutropenia, colitis, diarrhea, and pneumonitis) and 1 subject had a treatment-related Grade 5 
event (pneumonia). Treatment related serious adverse events (SAEs) that occurred in ≥ 2 
subjects were colitis and pneumonitis (3 subjects each). A majority of the treatment-related 
SAEs were ≥ Grade 3 in severity and resolved with or without sequelae. AEs that resulted in 
permanent discontinuation of MEDI4736 were considered as treatment related in 18 subjects 
(2.6%), with colitis being the most frequent treatment-related AE resulting in discontinuation 
(3 subjects). A majority of the treatment-related AEs resulting in discontinuation of MEDI4736 
were ≥ Grade 3 in severity and resolved with or without sequelae. 
 
 
Study D4191C00003/ATLANTIC: The safety profile of MEDI4736 monotherapy in Study 
CD-ON-MEDI4736-1108 is generally consistent with that of Study D4191C00003/ATLANTIC 
in subjects with locally advanced or metastatic non-small cell lung cancer (NSCLC) treated with 
MEDI4736 10 mg/kg Q2W. As of 05May2015, 264 of 303 subjects (87.1%) reported any AE 
in Study D4191C00003/ATLANTIC. Overall, events reported in ≥ 10% of subjects were 
dyspnea (18.8%), fatigue (17.8%), decreased appetite (17.5%), cough (14.2%), pyrexia 
(12.2%), asthenia (11.9%), and nausea (11.2%). Nearly two-thirds of the subjects experienced 
AEs that were Grade 1 or 2 in severity and manageable by general treatment guidelines as 
described in the current MEDI4736 study protocols. Grade 3 or higher AEs were reported in 
107 of 303 subjects (35.3%). A total of 
128 subjects (42.2%) reported AEs that were considered by the investigator as related to 
investigational product. Treatment-related AEs (all grades) reported in ≥ 2% of subjects were 
decreased appetite (6.6%); fatigue (5.9%); asthenia (5.0%); nausea (4.6%); pruritus (4.3%); 
diarrhea, hyperthyroidism, hypothyroidism, and pyrexia (3.3% each); rash (2.6%); weight 
decreased (2.3%); and vomiting (2.0%). Treatment-related Grade 3 AEs reported in ≥ 2 subjects 
were pneumonitis (3 subjects) and increased GGT (2 subjects). There was no treatment-related 
Grade 4 or 5 AEs. Ninety-four of 303 subjects (31.0%) reported any SAE. SAEs that occurred 
in ≥ 1.0% of subjects were dyspnea (6.6%); pleural effusion, general physical health 
deterioration (2.3% each); pneumonia (2.0%); hemoptysis, pulmonary embolism (1.3% each); 
and pneumonitis, respiratory failure, disease progression (1.0% each). Nine subjects had an SAE 
considered by the investigator as related to MEDI4736. Each treatment-related SAE occurred 
in 1 subject each with the exception of pneumonitis, which occurred in 3 subjects. Fifteen of 
303 subjects (5.0%) have died due to an AE (pneumonia [3 subjects]; general physical health 
deterioration, disease progression, hemoptysis, dyspnea [2 subjects each]; pulmonary sepsis, 
respiratory distress, cardiopulmonary arrest [verbatim term (VT)], hepatic failure, and sepsis [1 
subject each]). None of these events was considered related to MEDI4736. Twenty-three of 303 


Clinical Study Protocol 
Investigational Drug Substance: MEDI4736, tremelimumab 
Study Number ESR-14-10744 
Edition Number  8 
 
 
Date: 17 April 2019 
 
Page 34 of 134 
 
subjects= (7.6%) permanently discontinued MEDI4736 treatment due to AEs. Events that led 
to discontinuation of MEDI4736 in ≥ 2 subjects were dyspnea, general physical health 
deterioration, and pneumonia. Treatment-related AEs that led to discontinuation were increased 
ALT and increased hepatic enzyme, which occurred in 1 subject each. 
 
Adverse Event Profile of MEDI4736 and Tremelimumab Combination Therapy 
Study D4190C00006: The safety profile of MEDI4736 and tremelimumab combination 
therapy in the 102 subjects with advanced NSCLC in Study D4190C00006 is generally 
consistent with that observed across 177 subjects treated with MEDI4736 and tremelimumab 
combination therapy (not including subjects treated with blinded investigational product). As 
of 15Apr2015, 95 of 102 subjects (93.1%) reported at least 1 AE. All subjects in the 
tremelimumab 3 and 10 mg/kg dose cohorts experienced AEs; subjects in the MEDI4736 20 
mg/kg and tremelimumab 1 mg/kg Q4W cohort experienced the lowest AE rate (77.8%). 
Treatment-related AEs were reported in 74 of 102 subjects (72.6%), with events occurring in > 
10% of subjects being diarrhea (27.5%), fatigue (22.5%), increased amylase and pruritus 
(14.7% each), rash (12.7%), colitis (11.8%), and increased lipase (10.8%). Treatment-related ≥ 
Grade 3 AEs reported in ≥ 5% of subjects were colitis (8.8%), diarrhea (7.8%), and increased 
lipase (5.9%). Five subjects reported treatment-related Grade 4 events (sepsis, increased ALT, 
and increased AST in 1 subject; increased amylase in 2 subjects; myasthenia gravis in 1 subject; 
and pericardial effusion in 1 subject) and 2 subjects had treatment-related Grade 5 events 
(polymyositis and an uncoded event of neuromuscular disorder [VT]); the Grade 4 event of 
myasthenia gravis and Grade 5 polymyositis occurred in 1 subject. There were 2 subjects (both 
in the MEDI4736 20 mg/kg + tremelimumab 3 mg/kg Q4W cohort) with dose-limiting toxicities 
(DLTs): 1 subject with Grade 3 increased AST, and 1 subject with Grade 3 increased amylase 
and Grade 4 increased lipase. Fifty-six subjects (54.9%) reported SAEs, with events occurring 
in > 5% of subjects being colitis (9.8%) and diarrhea (7.8%). Thirty-six subjects (35.3%) 
experienced treatment-related SAEs. Twenty-seven subjects (26.5%) permanently discontinued 
treatment due to AEs. Treatment-related AEs resulting in discontinuation in ≥ 2 subjects were 
colitis (7 subjects), pneumonitis (5 subjects), diarrhea (3 subjects), and increased AST (2 
subjects). 
 
Efficacy  
Partial efficacy data are available for 2 monotherapy studies (CD-ON-MEDI4736-1108 
andD4190C00007) and 2 combination therapy studies (CD-ON-MEDI4736-1161 and 
D4190C00006). Clinical activity has been observed across the 4 studies. 
 
Study CD-ON-MEDI4736-1108: Overall, 456 of 694 subjects treated with MEDI4736 10 
mg/kg Q2W were evaluable for response (defined as having ≥ 24 weeks follow-up, 
measurable disease at baseline, and ≥ 1 follow-up scan, or discontinued due to disease 
progression or death without any follow-up scan). In PD-L1 unselected patients, the objective 
response rate (ORR), based on investigator assessment per Response Evaluation Criteria in 
Solid Tumors (RECIST) v1.1, ranged from 0% in uveal melanoma (n = 23) to 20.0% in 


Clinical Study Protocol 
Investigational Drug Substance: MEDI4736, tremelimumab 
Study Number ESR-14-10744 
Edition Number  8 
 
 
Date: 17 April 2019 
 
Page 35 of 134 
 
bladder cancer (n = 15), and disease control rate at 24 weeks (DCR-24w) ranged from 4.2% in 
triple-negative breast cancer (TNBC; n = 24) to 39.1% in advanced cutaneous melanoma (n = 
23). PD-L1 status was known for 383 of the 456 response evaluable subjects. Across the PD-
L1-positive tumors, ORR was highest for bladder cancer, advanced cutaneous melanoma, 
hepatocellular carcinoma (HCC; n = 3 each, 33.3% each), NSCLC (n = 86, 26.7%), and 
squamous cell carcinoma of the head and neck (SCCHN; n = 22, 18.2%). In the PD-L1-
positive subset, DCR-24w was highest in advanced cutaneous melanoma (n = 3, 66.7%), 
NSCLC (n = 86, 36.0%), HCC and bladder cancer (n = 3 each, 33.3% each), and SCCHN (n = 
22, 18.2%). 
 
Study D4190C00007: Of the 32 subjects with myelodysplastic syndrome (MDS) treated in 
Study D4190C00007, 21 subjects had at least 1 post-baseline disease assessment. Among 
these subjects, the best overall responses were marrow complete remission (mCR) in 4 
subjects (19.0%); stable disease (SD) in 4 subjects (19.0%); and progressive disease (PD) in 5 
subjects (23.8%). The remaining 8 subjects (38.1%) did not meet the criteria for complete 
remission (CR), mCR, partial remission (PR), SD, or PD at the date of assessment. 
 
Study CD-ON-MEDI4736-1161: Of the 65 subjects with metastatic or unresectable 
melanoma treated with the combination of MEDI4736 and BRAF inhibitor (BRAFi; 
dabrafenib)/MEK inhibitor (MEKi; trametinib), 63 subjects were evaluable for response. A 
total of 35 subjects (55.6%) had a best overall response of confirmed or unconfirmed PR. The 
disease control rate (DCR; CR + PR [regardless of confirmation] + SD ≥ 12 weeks) was 
79.4%. 
 
Study D4190C00006: Of the 102 subjects with advanced NSCLC treated with MEDI4736 in 
combination with tremelimumab in Study D4190C00006, 63 subjects with at least 16 weeks 
of follow-up were evaluable for response (defined as measurable disease at baseline and at 
least 1 follow-up scan; this included discontinuations due to disease progression or death 
without follow-up scan). Of the 63 evaluable subjects, 17 (27%) had a best overall response of 
PR, 14 (22%) had SD, 22 (35%) had PD, and 10 (16%) were not evaluable. The ORR 
(confirmed and unconfirmed CR or PR) was 27% and the DCR (CR, PR, or SD) was 49% as 
assessed by RECIST v1.1. 
 
 
1.3 
Research hypothesis 
Our hypothesis is that neoadjuvant therapy with anti-PD-L1 monoclonal antibody MEDI4736 
in combination with anti-CTLA-4 monoclonal antibody tremelimumab will result in favorable 
alterations of the intratumoral immunologic environment in subjects undergoing resectional 
surgery for malignant pleural mesothelioma (MPM). 


Clinical Study Protocol 
Investigational Drug Substance: MEDI4736, tremelimumab 
Study Number ESR-14-10744 
Edition Number  8 
 
 
Date: 17 April 2019 
 
Page 36 of 134 
 
1.4 
Rationale for conducting this study 
Malignant pleural mesothelioma (MPM) is an aggressive malignancy of the pleura that is 
associated with prior exposure to asbestos and is fatal in most cases. The tumor most 
commonly arises within the parietal pleura and spreads locally to the ipsilateral visceral 
pleura, lung, chest wall, diaphragm, pericardium, and mediastinum. Treatment with standard 
cytotoxic chemotherapy regimens, including cisplatin and pemetrexed, results in an extension 
of the median survival time to 12 months, compared with cisplatin alone (Vogelzang, 2003). 
For patients with disease confined to the ipsilateral hemithorax, surgical resection combined 
with systemic or intracavitary chemotherapy, radiation therapy, and/or other local modalities, 
has been offered with reports of more optimistic outcomes. The operative procedures most 
commonly used in these multimodal approaches include the following: extrapleural 
pneumonectomy (EPP), which involves en bloc resection of the lung, pericardium, diaphragm, 
visceral, and parietal pleura; and pleurectomy/decortication (P/D), which involves resection of 
the visceral and parietal pleura with or without resection of the pericardium and/or diaphragm 
(Rice et al., 2011). Nonetheless, the majority of these patients will suffer from recurrence and 
ultimately succumb to the disease (Rusch et al., 2012; Sugarbaker et al., 2014). There is a 
clear need for better systemic therapies for MPM. 
The blockade of negative regulatory signals to T-cells, such as PD-L1 and cytotoxic T-
lymphocyte antigen 4 (CTLA-4), has shown promising clinical activity. Ipilimumab is a 
monoclonal antibody that binds to CTLA-4 and prevents the interaction of CTLA-4 with cluster 
of differentiation (CD) 80 and CD86, which results in enhanced T-cell activation and 
proliferation (Lipson et al., 2011). Ipilimumab was shown to extend survival in patients with 
advanced melanoma (Hodi et al., 2010), and was granted United States Food and Drug 
Administration (FDA) approval in 2011 for the treatment of metastatic melanoma.  
PD-L1 (B7 homolog 1 [B7 H1], CD274) is part of a complex system of receptors and ligands 
that are involved in controlling T-cell activation. In normal tissue, PD-L1 is expressed on T 
cells, B cells, dendritic cells (DC), macrophages, mesenchymal stem cells, bone marrow-
derived mast cells, and in various non-hematopoietic cells (Keir et al., 2008). The normal 
function of PD-L1 is to regulate the balance between T-cell activation and tolerance through the 
interaction with two receptors, programmed death 1 (PD-1, CD279) and CD80 (B7-1). In the 
tumor microenvironment, PD-L1 expressed on tumor cells binds to PD-1 on activated T cells, 
which delivers an inhibitory signal to those T cells, preventing them from killing target tumor 
cells and thus protecting the tumor from immune elimination (Zou et al., 2008). In the clinic, 
antibody-mediated blockade of PD-L1 induced durable tumor regression (objective response 
rate of 6 to 17%) and prolonged stabilization of the disease (rates of 12 to 41% at 24 weeks) in 
patients with advanced cancers, including non-small-cell lung cancer, melanoma, and renal-cell 


Clinical Study Protocol 
Investigational Drug Substance: MEDI4736, tremelimumab 
Study Number ESR-14-10744 
Edition Number  8 
 
 
Date: 17 April 2019 
 
Page 37 of 134 
 
cancer (Brahmer et al., 2012). Similarly, treatment with anti-PD-1 antibodies produced 
objective responses in approximately one in four to one in five patients with non-small-cell lung 
cancer, melanoma, or renal-cell cancer (Topalian et al., 2012). 
Pre-clinical data and clinical research suggests that the concurrent targeting of immunologic 
checkpoints may generate superior anti-tumor activity when compared with a single-agent 
checkpoint blockade, which may translate into higher and more durable rates of response. 
Mouse data indicate that the mechanisms of activation of sites known to be involved in the 
activity of CTLA-4 and PD-1 are non-redundant, and therefore targeting both pathways may 
have additive or synergistic activity (Pardoll, 2012). For example, in mouse tumor models, the 
combination of PD-1 and CTLA-4 blockade achieved more pronounced anti-tumor activity than 
the blockade of either pathway alone (Curran et al., 2010; Duraiswamy et al., 2013). Notably, 
in models of murine melanoma, anti-PD-1 blockade increased the expression of CTLA-4 on 
intratumoral T cells, and reciprocally, CTLA-4 blockade increased PD-1 expression on 
intratumoral T cells, suggesting one potential mechanism for the increased efficacy of dual 
checkpoint therapy (Curran et al., 2010). The concurrent administration of monoclonal 
antibodies to CTLA-4 (ipilimumab) and PD-1 (nivolumab) was recently evaluated in a Phase I 
trial that showed impressive preliminary evidence of improved benefit in advanced melanoma 
patients. The overall response rate was 53% at the maximum tolerated dose. Three patients 
presented with a complete response (CR), and all responding patients experienced a ≥80% 
decline in tumor burden at 12 weeks (Wolchok et al., 2013). 
MPM has recently been recognized as an immunogenic tumor, and durable clinical responses 
to immunotherapy have been obtained in the laboratory setting (Tan et al., 2014; Adusumilli 
2014; Adusumilli et al., 2014; Fridlender et al., 2009; Anraku et al., 2008; Wu et al., 2012). In 
murine models of MPM, for example, CTLA-4 blockade results in significant anti-tumor 
responses (Wu et al., 2012). In the clinic, tremelimumab has shown encouraging clinical activity 
and an acceptable safety and tolerability profile in patients with advanced MPM who have been 
previously treated with cytotoxic chemotherapy (Calabro et al., 2013). 
The effects of PD-L1 or CTLA-4 blockade on the tumor microenvironment in humans are 
largely unknown. At Baylor College of Medicine, we surgically treat 2-4 patients with MPM 
per week, and are therefore uniquely positioned to study this disease. This phase II, window of 
opportunity, neoadjuvant trial in patients with surgically resectable MPM will 
comprehensively characterize the influence of MEDI4736 and the combination therapy of 
MEDI4736 + tremelimumab on the local immunologic environment of the tumor, as well as 
the systemic blood and bone marrow compartments. Our primary objective will be a 
comparison of the CD8/Treg ratio, the percentage of ICOS+ CD4 T cells, and the tissue 


Clinical Study Protocol 
Investigational Drug Substance: MEDI4736, tremelimumab 
Study Number ESR-14-10744 
Edition Number  8 
 
 
Date: 17 April 2019 
 
Page 38 of 134 
 
expression of PD-1, PD-L1, and CTLA-4 before and after the delivery of the 
immunotherapeutic agent(s). 
Our hypothesis is that neoadjuvant therapy with anti-PD-L1 monoclonal antibody MEDI4736 
in combination with anti-CTLA-4 monoclonal antibody tremelimumab will result in favorable 
alterations of the intratumoral immunologic environment in subjects undergoing resectional 
surgery for malignant pleural mesothelioma (MPM). The primary objective of this study will 
be comparison of the ratio of intratumoral cytotoxic T cells to regulatory T cells (CD8/Treg) 
before and after treatment with combination MEDI-4736 and Tremelimumab checkpoint 
inhibitor therapy. In vitro, an antibody that blocks the interaction between PD-L1 and its 
receptors can relieve PD-L1-dependent immunosuppressive effects and enhance the cytotoxic 
activity of anti-tumor T-cells (Blank et al., 2006). The ratio of CD8 T cells to regulatory T 
cells (CD8/Treg) is increased by the blockade of CTLA-4, PD-1, or PD-L1 within B16 mouse 
melanoma tumors (Curran et al., 2010), and this ratio is predictive of therapeutic efficacy in 
this model (Quezada et al., 2006). Importantly, combination therapy with CTLA-4 and PD-1 
increases the CD8/Treg ratio more significantly than monotherapy (Curran et al., 2010). In a 
recent report of melanoma patients undergoing PD-1 blockade, subjects who had a significant 
clinical response were found to have an increase in the number of intratumoral CD8 T cells 
following drug delivery (Tumeh et al., 2014), suggesting that PD-1 blockade favorably 
influences the tumor microenvironment. The levels of tumor-infiltrating CD8 T-cells have 
been correlated with improved prognosis in MPM (Anraku et al., 2008) and a number of other 
malignancies, including colorectal, melanoma, and lung cancer (Pagès et al., 2010), which 
further suggests that an intratumoral CD8 T-cell response is beneficial to patients.  
Based on these findings, we expect that the addition of tremelimumab to MEDI4736 in 
patients with MPM will result in an increased percentage of intratumoral CD4 T cells that 
express ICOS. Treatment with anti-CTLA-4 antibodies in patients with melanoma or bladder 
cancer has resulted in a significant increase of blood ICOS+ CD4 T cells ( Ng Tang et al., 
2013; Liakou et al., 2008; Chen et al., 2009; Vonderheide et al., 2010). Notably, this 
statistically significant increase in ICOS+ CD4 blood T cells was seen after one dose of the 
drug (Ng Tang et al., 2013). In addition, it has been reported that a sustained increase in the 
frequency of ICOS+ CD4 T cells was correlated with a clinical benefit in patients with 
melanoma undergoing anti-CTLA-4 therapy (Carthon et al., 2010). Moreover, in patients 
undergoing radical cystectomy for bladder cancer who received 2 doses of the anti-CTLA-4 
antibody ipilimumab, a significant increase in the percentage of ICOS+ CD4 T cells was seen 
in the tumor tissues (Liakou et al., 2008). 
We additionally hypothesize that the addition of tremelimumab to MEDI4736 will increase 
the tumor expression of PD-L1, which provides a potential mechanism for the improved 


Clinical Study Protocol 
Investigational Drug Substance: MEDI4736, tremelimumab 
Study Number ESR-14-10744 
Edition Number  8 
 
 
Date: 17 April 2019 
 
Page 39 of 134 
 
efficacy of combination PD-L1 and CTLA-4 blockade compared with a single-agent therapy. 
PD-L1 is expressed with a relatively high frequency in a broad range of human malignancies, 
up to 88% in some cancers. In a number of these cancers, including lung (Mu et al., 2011), 
renal (Krambeck et al., 2007), pancreatic (Nomi et al., 2007), and ovarian cancer (Hamanishi 
et al., 2007), the expression of PD-L1 is associated with reduced survival and an unfavorable 
prognosis. PD-LI is expressed in a substantial proportion of MPM tumors (21% of epithelial 
MPM tumors and 74% of non-epithelial MPM tumors), and its expression is associated with a 
decreased overall survival (Mansfield et al., 2014). Although it appears that the selection of 
patients based on PD-L1 expression within the tumor microenvironment may improve the 
probability and/or quality of responses to PD-1 pathway -targeting agents, there remain a 
number of patients with PD-L1-negative tumors that respond to the blockade with the PD-LI 
inhibitor MEDI4736 (Brahmer et al., 2014). Furthermore, the expression of PD-L1 may not 
have as much of an impact when a combination of checkpoint inhibitors is utilized. For 
example, a study investigating the combination of a PD-1 inhibitor (nivolumab) and a CTLA-
4 inhibitor (ipilimumab) in patients with melanoma suggested that the combination of CTLA-
4 and PD-1 blockade may have an effect independent from tumoral PD-L1 expression 
(Wolchok et al., 2013). Interestingly, in mouse models of melanoma, PD-1 blockade increased 
the expression of CTLA-4 on intratumoral T cells, and reciprocally, CTLA-4 blockade 
increased PD-1 expression on intratumoral T cells. This finding may provide an explanation 
for the synergistic activities of these two drugs, and we expect to uncover similar findings in 
human MPM tumors after treating patients with these drugs.  
1.5 
Benefit/risk and ethical assessment 
Benefits/risk associated with MEDI4736 
 
Clinical activity has been observed across the 2 monotherapy studies (CD-ON-MEDI4736-
1108 and D4190C00007) and 2 combination therapy studies (CD-ON-MEDI4736-1161 and 
D4190C00006) for which partial efficacy data are available. 
 
• Study CD-ON-MEDI4736-1108: Overall, 456 of 694 subjects treated with MEDI4736 10 
mg/kg Q2W were evaluable for response (defined as having ≥ 24 weeks follow-up, 
measurable disease at baseline, and ≥ 1 follow-up scan, or discontinued due to disease 
progression or death without any follow-up scan). In PD-L1 unselected subjects, the ORR, 
based on investigator assessment per RECIST v1.1, ranged from 0% in uveal melanoma (n = 
23) to 20.0% in bladder cancer (n = 15), and DCR-24w ranged from 4.2% in TNBC (n = 24) 
to 39.1% in advanced cutaneous melanoma (n = 23). PD-L1 status was known for 383 of the 
456 response evaluable subjects. Across the PD-L1-positive tumors, ORR was highest for 
bladder cancer, advanced cutaneous melanoma, HCC (n = 3 each, 33.3% each), NSCLC (n = 
86; 26.7%), and SCCHN (n = 22; 18.2%). In the PD-L1-positive subset, DCR-24w was 


Clinical Study Protocol 
Investigational Drug Substance: MEDI4736, tremelimumab 
Study Number ESR-14-10744 
Edition Number  8 
 
 
Date: 17 April 2019 
 
Page 40 of 134 
 
highest in advanced cutaneous melanoma (n = 3; 66.7%), NSCLC (n = 86; 36.0%), HCC and 
bladder cancer (n = 3 each; 33.3% each), and SCCHN (n = 22; 18.2%). 
 
• Study D4190C00007: Of the 32 subjects with MDS treated in this study, 21 subjects had at 
least 1 post-baseline disease assessment. Among these subjects, the best overall responses 
were mCR in 4 subjects (19.0%); SD in 4 subjects (19.0%); and PD in 5 subjects (23.8%). The 
remaining 8 subjects (38.1%) did not meet the criteria for CR, mCR, PR, SD, or PD at the date 
of assessment. 
 
• Study CD-ON-MEDI4736-1161: Of the 65 subjects with metastatic or unresectable 
melanoma treated with the combination of MEDI4736 and BRAFi/MEKi, 63 subjects were 
evaluable for response. A total of 35 subjects (55.6%) had a best overall response of 
confirmed or unconfirmed PR. The confirmed and unconfirmed DCR (CR + PR + SD) for ≥ 
12 weeks was 79.4%. 
 
• Study D4190C00006: Of the 102 subjects with advanced NSCLC treated with MEDI4736 
in combination with tremelimumab, 63 subjects with at least 16 weeks of follow-up were 
evaluable for response (defined as 
measurable disease at baseline and at least 1 follow-up scan; this included discontinuations 
due to disease progression or death without follow-up scan). Of the 63 evaluable subjects, 17 
(27%) had a best overall response of PR, 14 (22%) had SD, 22 (35%) had PD, and 10 (16%) 
were not evaluable. The ORR (confirmed and unconfirmed CR or PR) was 27% and the DCR 
(CR, PR, or SD) was 49% as assessed by RECIST v1.1. 
 
Benefit/risk associated with tremelimumab: 
In the clinical development program of tremelimumab and that of the related anti-CTLA-4 
mAb, ipilimumab, a pattern of efficacy has emerged that appears to be consistent across tumor 
types. Response rates are generally low (~10%); however, in those subjects who respond, the 
responses are generally durable, lasting several months even in subjects with aggressive 
tumors (e.g., refractory metastatic melanoma). In a large Phase 3 study of tremelimumab 
versus DTIC/temozolomide in subjects with advanced melanoma, the median OS was 12.6 
months for tremelimumab versus 10.7 months for DTIC/temozolomide (HR = 1.1416, p = 
0.1272). 
The safety profile across the tremelimumab nonclinical and clinical programs is dominated by 
immune-mediated reactions that can result in an inflammatory response. The important 
potential risks for tremelimumab that require further evaluation in clinical studies are 
immune-mediated gastrointestinal events such as colitis, endocrinopathies, dermatitis, 
pancreatitis, hepatitis, pneumonitis, neurotoxicities, cytopenias, and nonimmune-mediated 
infusion-related reactions, anaphylaxis and serious allergic reactions. Adverse events similar 
to those reported with ipilimumab were observed during clinical development of 
tremelimumab in melanoma, with diarrhea (40%), pruritus (23%), rash (22%), nausea (22%), 
and fatigue (17%) being the most common (Kirkwood et al, 2010). Grade 3 or higher AEs 


Clinical Study Protocol 
Investigational Drug Substance: MEDI4736, tremelimumab 
Study Number ESR-14-10744 
Edition Number  8 
 
 
Date: 17 April 2019 
 
Page 41 of 134 
 
observed were diarrhea (11%), fatigue (2%), rash (1%), nausea (1%), vomiting (1%), and 
anorexia (1%).  
Potential risks associated with tremelimumab include immune-mediated gastrointestinal 
events including colitis, intestinal perforation, abdominal pain, dehydration, nausea and 
vomiting, and decreased appetite (anorexia); immune-mediated dermatitis including urticaria, 
skin exfoliation, and dry skin; immune-mediated endocrinopathies including hypophysitis, 
adrenal insufficiency, and hyper- and hypothyroidism; immune-mediated hepatitis including 
autoimmune hepatitis, and increased serum alanine aminotransferase and aspartate 
aminotransferase; immune-mediated pancreatitis including autoimmune pancreatitis, and 
lipase and amylase elevation; immune-mediated respiratory tract events including pneumonitis 
and interstitial lung disease; immune-mediated nervous system events including encephalitis, 
peripheral motor and sensory neuropathies, Guillain-Barre and myasthenia gravis (the latter 
reported with combination of tremelimumab and MEDI4736); immune-mediated cytopenias 
including thrombocytopenia, anemia and neutropenia; infusion-related reactions, anaphylaxis, 
and serious allergic reactions; and headache, fatigue, and pyrexia. 
 
Benefits/risks associated with combination treatment: 
A total of 18 subjects have been treated, with 3 subjects each receiving 1 mg/kg 
tremelimumab and 3 mg/kg MEDI4736 Q4W, 1 mg/kg tremelimumab and 10 mg/kg 
MEDI4736 Q4W, 1 mg/kg tremelimumab and 15 mg/kg MEDI4736 Q4W, 3 mg/kg 
tremelimumab and 10 mg/kg MEDI4736 Q4W, 3 mg/kg tremelimumab and 15 mg/kg 
MEDI4736 Q4W, and 10 mg/kg tremelimumab and 15 mg/kg MEDI4736 Q4W. Overall, 
subjects have received between 0 and 7 doses of investigational products. 
Across all dose cohorts, 17 of 18 subjects (94.4%) reported at least 1 AE (regardless of 
causality). The most frequently reported (> 3 subjects) AEs (all grades) were fatigue, pruritus, 
increased amylase, and arthralgia. Treatment-related AEs were reported in 13 of 18 subjects 
(72.2%). Of the 13 subjects, 4 had Grade 1, 3 had Grade 2, and 6 had ≥ Grade 3 events as 
maximum severity. Treatment-related Grade 3 events that occurred in 2 or more subjects were 
fatigue (6 subjects), increased amylase (4 subjects); diarrhea, nausea, and increased alanine 
aminotransferase (3 subjects each); and abdominal pain, colitis, epigastric discomfort, 
vomiting, increased aspartate aminotransferase, decreased appetite, and arthralgia (2 subjects 
each). No consistent pattern in the nature, dose-relationship, frequency, or severity of AEs has 
been noted with escalating doses of the combination.  
 
Nine subjects have reported 15 SAEs (Table 5.3.1.6-2). None of the preferred terms were 
reported in more than 1 subject. The majority of the SAEs were Grade 3 or higher in severity. 
Half of the SAEs were considered related to investigational products. Three subjects with 
SAEs of disease progression, colitis, and malignant neoplasm progression, respectively, 
permanently discontinued investigational products due to these events. The event of malignant 
neoplasm progression, considered not related to investigational products, resulted in death. In 


Clinical Study Protocol 
Investigational Drug Substance: MEDI4736, tremelimumab 
Study Number ESR-14-10744 
Edition Number  8 
 
 
Date: 17 April 2019 
 
Page 42 of 134 
 
addition, 1 subject died due to the SAE of polymyositis that was considered related to both 
MEDI4736 and tremelimumab.  
 
Benefits/risks associated with the study procedures 
Both MEDI4736 and tremelimumab are administered intravenously. Possible risks associated 
with IV administration of the study drug(s) are infection, redness, swelling, and pain at the 
administration site. 
 
 
2. 
STUDY OBJECTIVES 
The objective of this study is to determine whether MEDI4736 or combination therapy with 
MEDI4736 + tremelimumab are associated with favorable alterations of the intratumoral 
immunologic environment in subjects undergoing resectional surgery for MPM. 
 
2.1 
Primary objective(s) 
The primary objective of this study will be comparison of the ratio of intratumoral cytotoxic T 
cells to regulatory T cells (CD8/Treg) before and after treatment with combination MEDI-4736 
and Tremelimumab checkpoint inhibitor therapy.  
2.2 
Secondary objective(s) 
The secondary objectives of this study are: 
1) Comparison of the percentage of inducible T-cell co-stimulator (ICOS) positive 
intratumoral CD4 T cells before and after treatment with combination MEDI-4736 and 
Tremelimumab checkpoint inhibitor therapy. 
2) Comparison of tumor tissue expression (Ventana assay) of programmed death-ligand 1 
(PD-L1) before and after treatment with combination MEDI-4736 and Tremelimumab 
checkpoint inhibitor therapy. 
3) Comparison of the ratio of the intratumoral CD8/Treg ratio in patients treated with 
combination therapy (MEDI-4736 and Tremelimumab) compared to either patients 
treated with MEDI-4736 alone , and separately compare to untreated patients. 
4) Comparison of the percentage of inducible T-cell co-stimulator (ICOS) positive 
intratumoral CD4 T cells in patients treated with combination therapy (MEDI-4736 
and Tremelimumab) compared to either patients treated with MEDI-4736 alone, and 
separately compare to untreated patients. 


Clinical Study Protocol 
Investigational Drug Substance: MEDI4736, tremelimumab 
Study Number ESR-14-10744 
Edition Number  8 
 
 
Date: 17 April 2019 
 
Page 43 of 134 
 
5) Comparison of tumor tissue expression (Ventana assay) of programmed death-ligand 1 
(PD-L1) in patients treated with combination therapy (MEDI-4736 and 
Tremelimumab) compared to either patients treated with MEDI-4736 alone, and 
separately compare to untreated patients. These analysis will be post-protocol analysis 
based upon data obtained from the standard of care follow up in our post-surgical 
patients.  
6) Comparison of overall survival in patients treated with either MEDI-4736 alone or 
MEDI-4736 plus Tremelimumab with historical untreated controls. These analysis will 
be post-protocol analysis based upon data obtained from the standard of care follow up 
in our post-surgical patients. 
7) Comparison of recurrence-free survival in patients treated with either MEDI-4736 
alone or MEDI-4736 plus Tremelimumab with historical untreated controls. These 
analysis will be post-protocol analysis based upon data obtained from the standard of 
care follow up in our post-surgical patients. 
3. 
STUDY DESIGN 
3.1 
Overview of study design 
Subjects with MPM will undergo surgical mediastinal lymph node biopsy (cervical 
mediastinoscopy) and simultaneous surgical biopsy of the pleural tumor by thoracoscopy, at 
which time tumor tissue (at least 2 g) and peripheral blood will be collected for the study. These 
procedures are performed as our standard of care in the treatment of these subjects. The subject 
will be randomized. Three days to three weeks after the biopsy, 20 evaluable  subjects (if tissue 
obtained) will be randomly treated with either MEDI-4736 alone (15 mg/kg once intravenously) 
(n=8) or MEDI-4736 (1500 mg once intravenously) plus tremelimumab (75 mg once 
intravenously) (n=8), or a control group (n=4)  in a randomized controlled study design. There 
will be two treatment arms (MEDI4736 only and combination MEDI4736+tremelimumab) and 
one untreated arm (control). Randomization, stratified by receiving previous chemotherapy or 
not, will be performed and will help to minimize patient selection biases between three arms. 
Subjects under 30 kg will be treated with weight-based dosing for both MEDI4736 and 
Tremelimumab combination therapy. These patients are excluded from fixed based dosing to 
limit endotoxin exposure from the drug preparations. One to six weeks after the infusion, 
subjects will undergo resectional surgery, including extrapleural pneumonectomy (EPP) or 
pleurectomy/decortication (P/D), at which time the tumor will be removed (typically 200-1000 
g) and obtained for study. Four patients that do not undergo treatment with MEDI-4736 or 
tremelimumab will be included as controls. Blood will be obtained after the induction of general 
anesthesia for both the thoracoscopy procedure and the EPP or P/D resectional procedure, as is 
routinely done in these procedures. The sixth rib will be obtained at the time of the resection. 


Clinical Study Protocol 
Investigational Drug Substance: MEDI4736, tremelimumab 
Study Number ESR-14-10744 
Edition Number  8 
 
 
Date: 17 April 2019 
 
Page 44 of 134 
 
After the removal of the tumor, our standard protocol includes intraoperative heated 
chemotherapy using a lavage of intracavitary cisplatin in the presence of conserved renal 
function (Sugarbaker et al., 2013, 2014; Richards et al., 2006).  
 
Tumor tissues obtained either by thorasoscopic biopsy or by resectional surgery will be 
evaluated by time-of-flight mass spectrometry (CyTOF) to determine intratumoral CD8/Treg 
ratios and percentage of ICOS positive CD4 T cells, and by immunohistochemistry (Ventana 
assay) to determine the tissue expression of PD-L1. These variables will be compared before 
and after treatment (changes within the same patient tumor), or between treatment groups 
(MEDI-4736 alone, MEDI-4736+tremelimumab, untreated) following treatment. Additional 
hypothesis-generating analyses will include a comprehensive systems based evaluation of the 
intratumoral immune cell population composition and phenotype phenotype [e.g., dendritic 
cells, macrophages, myeloid derived suppressor cells (MDSC), neutrophils, T-cell subsets, 
natural killer (NK) cells, and B cells], and  immune-related gene expression using the nanostring 
system within the tumors, blood, and bone marrow of patients in all treatment groups.  
 
 
 
 
 
 
 
 
 
 
 
 
 


Clinical Study Protocol 
Investigational Drug Substance: MEDI4736, tremelimumab 
Study Number ESR-14-10744 
Edition Number  8 
 
 
Date: 17 April 2019 
 
Page 45 of 134 
 
3.2 
Study schema 
 
Figure 1 
Study flow chart 
 
 
 
Control (n=4) 
Screening/ 
enrolment 
Cervical 
mediastinoscopy 
+ thoracoscopy 
MEDI4736 
(n=8) 
MEDI4736 + 
tremelimumab 
(n=8) 
Resectional 
surgery 
Follow-up 


Clinical Study Protocol 
Drug Substance Tremelimumab 
Study Number ESR-14-10744 
Edition Number 8 
 
Date 17 April 2019 
 
Page 46 of 134 
 
Study Oversight for Safety Evaluation 
 
There are no stopping criteria for this study except for the following: 
a. Investigators decide to stop recruitment; 
b. Sponsor decides to discontinue the study; 
c. Subject withdraws consent at any time, for any reason.  
Treatment may be put on hold, and pending full review of the data, the study may be stopped 
if any of the following criteria are met, and no further dosing or dose decisions will be taken 
pending a full safety review:  
a. 1 study drug-related serious adverse event is reported 
b. At least 4 subjects experience a similar unanticipated adverse event that is assessed 
4. 
AS EITHER MODERATE OR SEVERE IN INTENSITY AND IS 
POTENTIALLY RELATED TO THE STUDY DRUG. SUBJECT 
SELECTION  
Potential subjects will be evaluated from our clinical population of patients with MPM who 
are eligible for surgical resection and meet all inclusion/exclusion criteria. Study investigators 
will determine eligibility from clinical chemistry, hematology, physical examination, and a 
review of medical history during screening prior to enrollment in the study.  
4.1 
Inclusion criteria 
For inclusion in the study subjects must fulfill all of the following criteria: 
1.  
Written informed consent and any locally-required authorization (e.g., HIPAA in the 
 
USA, EU Data Privacy Directive in the EU) obtained from the subject prior to  
 
performing any protocol-related procedures, including screening evaluations  
2. 
Age > 18 years at time of study entry 
3. 
Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 
4. 
Adequate normal organ and marrow function as defined below:   
− 
Hemoglobin ≥ 9.0 g/dL 
− 
Absolute neutrophil count (ANC) ≥ 1.5 x 109/L (> 1500 per mm3) 
− 
Platelet count ≥ 100 x 109/L (>100,000 per mm3) 


Clinical Study Protocol 
Drug Substance Tremelimumab 
Study Number ESR-14-10744 
Edition Number 8 
 
Date 17 April 2019 
 
Page 47 of 134 
 
− 
Serum bilirubin ≤ 1.5 x institutional upper limit of normal (ULN).   
− 
AST (SGOT)/ALT (SGPT) ≤ 2.5 x institutional upper limit of normal unless 
liver metastases are present, in which case it must be ≤ 5x ULN 
− 
Serum creatinine CL>50 mL/min by the Cockcroft-Gault formula (Cockcroft 
and Gault 1976) or by 24-hour urine collection for determination of creatinine 
clearance: 
Males: 
 
 
Creatinine CL 
(mL/min) 
= Weight (kg) x (140 – Age)        
72 x serum creatinine (mg/dL) 
 
 
 
Females: 
 
 
Creatinine CL 
(mL/min) 
= Weight (kg) x (140 – Age)        
x 0.85 
72 x serum creatinine (mg/dL) 
 
5. 
Female subjects must either be of non-reproductive potential (i.e., post-menopausal 
by history: ≥60 years old and no menses for 1 year without an alternative medical 
cause; OR history of hysterectomy, OR history of bilateral tubal ligation, OR 
history of bilateral oophorectomy) or must have a negative serum pregnancy test 
upon study entry.   
6. 
Subject is willing and able to comply with the protocol for the duration of the study 
including undergoing treatment and scheduled visits and examinations including 
follow up. 
7.  
    Surgically resectable MPM with no disease extension beyond the ipsilateral  
   
 
    hemithorax 
8. 
Planned resectional surgery for MPM [extrapleural pneumonectomy (EPP) or 
pleurectomy and decortication (P/D)] 
9. 
Any MPM histology (epithelial, mixed, sarcomatoid) 
a. N0 or N1 nodal disease as present on preoperative chest CT and/or PET-CT 
b. N2 nodule disease if no progression after 2 cycles of standard chemotherapy. 
Progression will be considered if additional N1 or N2 disease develop during 
chemotherapy.  


Clinical Study Protocol 
Drug Substance Tremelimumab 
Study Number ESR-14-10744 
Edition Number 8 
 
Date 17 April 2019 
 
Page 48 of 134 
 
 
4.2 
Exclusion criteria 
 
Subjects should not enter the study if any of the following exclusion criteria are fulfilled: 
1. 
Involvement in the planning and/or conduct of the study (applies to both 
AstraZeneca staff and/or staff at the study site)Previous enrollment or 
randomization in the present study 
2. 
Participation in another clinical study with an investigational product during the last 
3 months 
3. 
Any previous treatment with a PD1 or PD-L1 inhibitor, including MEDI4736  
4. 
Receipt of the last dose of anti-cancer therapy (chemotherapy, immunotherapy, 
endocrine therapy, targeted therapy, biologic therapy, tumor embolization, 
monoclonal antibodies, other investigational agent) 30 days prior to the first dose of 
study drug 30 days prior to the first dose of study drug for subjects who have 
received prior TKIs [e.g., erlotinib, gefitinib and crizotinib] and within 6 weeks for 
nitrosourea or mitomycin C).  
5. 
Current or prior use of immunosuppressive medication within 28 days before the 
first dose of MEDI4736, with the exceptions of intranasal and inhaled 
corticosteroids or systemic corticosteroids at physiological doses, which are not to 
exceed 10 mg/day of prednisone, or an equivalent corticosteroid 
6. 
Any unresolved toxicity (>CTCAE grade 2) from previous anti-cancer therapy.   
7. 
Any prior Grade ≥3 immune-related adverse event (irAE) while receiving any 
previous immunotherapy agent, or any unresolved irAE >Grade 1  
8. 
Active or prior documented autoimmune disease within the past 2 years 
NOTE: Subjects with vitiligo, Grave’s disease, or psoriasis not requiring systemic 
treatment (within the past 2 years) are not excluded. 
9. 
Active or prior documented inflammatory bowel disease (e.g., Crohn’s disease, 
ulcerative colitis) 


Clinical Study Protocol 
Drug Substance Tremelimumab 
Study Number ESR-14-10744 
Edition Number 8 
 
Date 17 April 2019 
 
Page 49 of 134 
 
10. 
History of primary immunodeficiency 
11. 
History of allogeneic organ transplant  
12. 
History of hypersensitivity to MEDI4736 or any excipient  
13. 
History of hypersensitivity to tremelimumab or the combination of MEDI4736 + 
tremelimumab 
14. 
Uncontrolled intercurrent illness including, but not limited to, ongoing or active 
infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable 
angina pectoris, cardiac arrhythmia, active peptic ulcer disease or gastritis, active 
bleeding diatheses including any subject known to have evidence of acute or 
chronic hepatitis B, hepatitis C or human immunodeficiency virus (HIV), or 
psychiatric illness/social situations that would limit compliance with study 
requirements or compromise the ability of the subject to give written informed 
consent 
15. 
Known history of previous clinical diagnosis of tuberculosis 
16. 
History of leptomeningeal carcinomatosis 
17. 
Receipt of live attenuated vaccination within 30 days prior to study entry or within 
6 months of receiving MEDI4736 or MEDI + tremelimumab 
18. 
Receipt of drugs with laxative properties and herbal or natural remedies for 
constipation within 90 days of receiving MEDI4736 or MEDI + tremelimumab 
19. 
Receipt of sunitinib within 3 months of receiving tremelimumab 
20. 
Female subjects who are pregnant, breast-feeding or male or female subjects of 
reproductive potential who are not employing an effective method of birth control 
21. 
Any condition that, in the opinion of the investigator, would interfere with 
evaluation of study treatment or interpretation of patient safety or study results 
22. 
Symptomatic or uncontrolled brain metastases requiring concurrent treatment, 
inclusive of but not limited to surgery, radiation and/or corticosteroids.  
23. 
Subjects with uncontrolled seizures. 


Clinical Study Protocol 
Drug Substance Tremelimumab 
Study Number ESR-14-10744 
Edition Number 8 
 
Date 17 April 2019 
 
Page 50 of 134 
 
24. 
N3 nodal disease 
25. 
History of interstitial lung disease/pneumonitis  
26. 
No tissue is obtainable at thoracoscopy 
27. 
Intraabdominal malignancy discovered at laparoscopy and proven pathologically, or 
nodal disease discovered at mediastinoscopy (N2 or N3 disease) and proven 
pathologically 
 
4.3 
Withdrawal of Subjects from Study Treatment and/or Study 
Permanent discontinuation of MEDI4736 and/or tremelimumab  
An individual subject will not receive any further investigational product if any of the 
following occur in the subject in question: 
1. 
Withdrawal of consent or lost to follow-up 
2. 
Subject is determined to have met one or more of the exclusion criteria for study 
participation at study entry and continuing investigational therapy might constitute a 
safety risk 
3. 
Pregnancy or intent to become pregnant 
4. 
Any AE that meets criteria for discontinuation as defined in Section 6.6 
5. 
Adverse event related to tremelimumab, with the exception of toxicities that do not 
meet the criteria for discontinuation as defined in Section 6.6   
6. 
Grade ≥ 3 infusion reaction 
7. 
Subject noncompliance that, in the opinion of the investigator or sponsor, warrants 
withdrawal; e.g., refusal to adhere to scheduled visits 
8. 
Initiation of alternative anticancer therapy including another investigational agent 
9. 
Confirmation of PD and investigator determination that the subject is no longer 
benefiting from treatment with MEDI4736 
Subjects who are permanently discontinued from further receipt of investigational product, 
regardless of the reason (withdrawal of consent, due to an AE, other), will be identified as 
having permanently discontinued treatment.  
 


Clinical Study Protocol 
Drug Substance Tremelimumab 
Study Number ESR-14-10744 
Edition Number 8 
 
Date 17 April 2019 
 
Page 51 of 134 
 
Subjects who are permanently discontinued from receiving investigational product will be 
followed for safety per Section 10.3.1 and Appendix B, including the collection of any 
protocol-specified blood specimens, unless consent is withdrawn or the subject is lost to 
follow-up or enrolled in another clinical study. All subjects will be followed for survival. 
Subjects who decline to return to the site for evaluations will be offered follow-up by phone 
every 3 months as an alternative. 
 
Withdrawal of consent 
Patients are free to withdraw their consent to further participation in this trial without 
prejudice. If consent is withdrawn, the subject will not receive any further investigational 
product or further study observation.  
4.4 
Replacement of subjects 
We plan to replace subjects who are withdrawn from the study. The subject who replaces the 
withdrawn subject will receive the treatment (i.e., MEDI4736 only or MEDI4736 + 
tremelimumab) that was originally intended for the withdrawn subject.  
5. 
INVESTIGATIONAL PRODUCT(S) 
5.1 
MEDI4736 
The Investigational Products Supply section of AstraZeneca/MedImmune will supply 
MEDI4736 to the investigator as a concentrate for solution for infusion. 
5.1.1 
Formulation/packaging/storage 
MEDI4736 is formulated at 50 mg/mL in 26 mM histidine/histidine-HCl, 275 mM trehalose 
dihydrate, 0.02% (w/v) polysorbate 80, pH 6.0.  
The investigational product is supplied as a vialed liquid solution in clear 10R glass vials 
closed with an elastomeric stopper and a flip-off cap over seal. Each vial contains 500 mg 
(nominal) of active investigational product at a concentration of 50 mg/mL (500 mg/vial). The 
solution will be diluted with 0.9% (w/v) saline for IV infusion.  
Unopened vials of liquid MEDI4736 must be stored at 2°C to 8°C (36°F to 46°F). MEDI4736 
must be used within the individually assigned expiry date on the label. 


Clinical Study Protocol 
Drug Substance Tremelimumab 
Study Number ESR-14-10744 
Edition Number 8 
 
Date 17 April 2019 
 
Page 52 of 134 
 
In use storage and stability 
Total in-use storage time from needle puncture of MEDI4736 vial to start of administration 
should not exceed 4 hours at room temperature or 24 hours at 2-8°C (36-46°F). If in-use 
storage time exceeds these limits, a new dose must be prepared from new vials. Infusion 
solutions must be allowed to equilibrate to room temperature prior to commencement of 
administration. MEDI4736 does not contain preservatives and any unused portion must be 
discarded. 
5.1.2 
Doses and treatment regimens 
Subjects will be administered a 15 mg/kg intravenous dose of MEDI4736 once during the 
study.  
5.1.3 
Study drug preparation 
Calculate the dose volume of MEDI4736 and number of vials needed for the subject to 
achieve the accurate dose according to Appendix A. 
Preparation of infusion bags 
The preparation of infusion bags should be done under aseptic conditions by trained 
personnel; it should not be prepared on the ward. 
An additional volume of 0.9% (w/v) saline equal to the calculated volume of MEDI4736 to be 
added to the IV bag must be removed from the bag prior to addition of MEDI4736.  
The calculated volume of MEDI4736 is then added to the IV bag, and the bag is mixed by 
gentle inversion to ensure homogeneity of the dose in the bag. 
Prior to the start of the infusion, ensure that the bag contents are at room temperature to avoid 
an infusion reaction due to the administration of the solution at low temperatures. 
Vials should be used for specific subjects and should not be shared between subjects. 
5.1.4 
Dose administration 
MEDI4736 will be administered at room temperature (approximately 25°C ) by controlled 
infusion via an infusion pump into a peripheral vein.   


Clinical Study Protocol 
Drug Substance Tremelimumab 
Study Number ESR-14-10744 
Edition Number 8 
 
Date 17 April 2019 
 
Page 53 of 134 
 
Following preparation of MEDI4736, the entire contents of the IV bag should be administered 
as an IV infusion over approximately 60 minutes (±5 minutes), using a 0.2-μm in-line filter.  
The IV line will be flushed with a volume of normal saline equal to the priming volume of the 
infusion set used after the contents of the IV bag are fully administered, or complete the 
infusion according to institutional policy to ensure the full dose is administered and document 
if the line was not flushed.  
Since the compatibility of MEDI4736 with other IV medications and solutions, other than 
normal saline (0.9% [weight/volume] sodium chloride for injection), is not known, the 
MEDI4736 solution should not be infused through an IV line in which other solutions or 
medications are being administered. 
5.1.5 
Monitoring of dose administration 
Subjects will be monitored during and after the infusion with assessment of vital signs at the 
times specified in the Schedule of Assessment (see Section 6.2)  
In the event of a ≤Grade 2 infusion-related reaction, the infusion rate of study drug may be 
decreased by 50% or interrupted until resolution of the event (up to 4 hours) and re-initiated at 
50% of the initial rate until completion of the infusion. For subjects with a ≤Grade 2 
infusion-related reaction, subsequent infusions may be administered at 50% of the initial 
rate. Acetaminophen and/or an antihistamine (e.g., diphenhydramine) or equivalent 
medications per institutional standard may be administered at the discretion of the 
investigator. If the infusion-related reaction is ≥Grade 3 or higher in severity, study drug will 
be discontinued. 
As with any antibody, allergic reactions to dose administration are possible. Appropriate drugs 
and medical equipment to treat acute anaphylactic reactions must be immediately available, 
and study personnel must be trained to recognize and treat anaphylaxis. The study site must 
have immediate access to emergency resuscitation teams and equipment in addition to the 
ability to admit subjects to an intensive care unit if necessary. 
5.1.6 
Accountability and dispensation 
The investigator will assure that drug accountability records will maintain a current disposition 
of all investigational drugs, including their inventory and dispensing. Our records will comply 
with applicable regulations and guidelines that include:  


Clinical Study Protocol 
Drug Substance Tremelimumab 
Study Number ESR-14-10744 
Edition Number 8 
 
Date 17 April 2019 
 
Page 54 of 134 
 
1. Amount received and placed in storage; 
2. Label ID number or batch number; 
3. Amount dispensed, including unique subject identifiers; 
4. Amount, if applicable, transferred from one area to another for dispensing or storage; 
5. Non-study disposition (i.e., lost or unused); 
6. Amount destroyed, if applicable; 
7. Dates and initials of person responsible for Investigational Product (IP) 
dispensing/accountability, as per the Delegation of Responsibility Form. 
 
5.1.7 
Disposition of unused investigational study drug.  At the completion of the study, 
all unused MEDI4736 will be returned to the sponsor 
 
5.2 
Tremelimumab 
The Investigational Products Supply section of AstraZeneca/MedImmune will supply 
tremelimumab to the investigator as a concentrate for solution for infusion. 
5.2.1 
Formulation/packaging/storage 
Tremelimumab Drug Product is formulated at a nominal concentration of 20 mg/mL in 20 
mM histidine/histidine hydrochloride, 222 mM trehalose dihydrate, 0.02% (weight/volume 
[w/v]) polysorbate 80, 0.27 mM disodium edetate dihydrate (EDTA), pH 5.5. 
The Drug Product is supplied as a sterile IV solution in 20 mL clear glass vials with a rubber 
stopper and aluminum seal. Each vial contains 20 mg/mL of tremelimumab with a nominal fill 
of 20 mL (accounting to 400 mg/vial). Vials containing tremelimumab must be stored at 2°C 
to 8°C (36°F to 46°F) and must not be frozen. Tremelimumab is administered as an IV 
infusion after dilution in sterile, normal saline for injection. The product should be protected 
from light when not in use.  
5.2.2 
Doses and treatment regimens 
Subjects will be administered MEDI4736 (1500 mg intravenously) + tremelimumab (75 mg 
intravenously) once during the study.  
Subjects under 30 kg will be treated with weight-based dosing for both MEDI4736 and 
Tremelimumab combination therapy. These patients are excluded from fixed based dosing to 
limit endotoxin exposure from the drug preparations. 


Clinical Study Protocol 
Drug Substance Tremelimumab 
Study Number ESR-14-10744 
Edition Number 8 
 
Date 17 April 2019 
 
Page 55 of 134 
 
5.2.3 
Product preparation 
MEDI4736 + tremelimumab will be prepared following the procedures outlined in Section 
5.1.3.  
5.2.4 
Dose administration 
 MEDI4736 + tremelimumab will be administered following the procedures outlined in 
Section 5.1.3.   
5.2.5 
Monitoring of dose administration 
Subjects receiving MEDI4736 + tremelimumab will be monitored during and after the 
infusion following the procedures outlined in Section 5.2.5.  
5.2.6 
Accountability and dispensation  
Drug accountability records will be kept as described in Section 5.1.6. 
5.2.7 
Disposition of unused investigational study drug 
At the completion of the study, all unused MEDI4736 and Tremelimumab will be destroyed at 
the study site with proper documentation. 
TREATMENT PLAN 
5.3 
Subject enrollment and randomization  
We expect to enroll a total of 20 evaluable subjects (if tissue obtained at time of thoracoscopy 
and time of surgical resection) with surgically resectable MPM to this study over a period of 
24 months. Subjects will be randomized. Subjects will be assigned to one of the three 
treatments (n = 8 MEDI4736, n = 8 MEDI4736 + tremelimumab, and n=4 control). All 
subjects will undergo surgical resection one to six weeks after the infusion.  
5.3.1 
Procedures for randomization 
After mediastinoscopy + thoracoscopy, eligible subjects with MPM will be randomized in 2:2:1 
ratio to one of three arms: MEDI4736 alone, MEDI4736 + tremelimumab, and a control group 
of neither MEDI4736 nor tremelimumab. A computer-generated randomization scheme may be 
generated by the Biostatistics Core, Baylor College of Medicine. Randomization will be 
accomplished via access to a secure website developed by the Biostatistics Core and 
automatically notified to the study coordinator or the investigator via email. Randomization will 
be stratified by receiving previous chemotherapy or not. 


Clinical Study Protocol 
Drug Substance Tremelimumab 
Study Number ESR-14-10744 
Edition Number 8 
 
Date 17 April 2019 
 
Page 56 of 134 
 
5.3.2 
Procedures for handling subjects incorrectly enrolled or randomized 
Subjects who are incorrectly enrolled in the study but have not yet received treatment with 
MEDI4736 or MEDI4736 + tremelimumab will be withdrawn from the study and will receive 
standard of care treatment for their MPM.  
Subjects who are found to have been incorrectly enrolled after receiving treatment will be 
withdrawn from the study and will receive standard of care treatment for their MPM. Such 
patients will be replaced by eligible subjects with MPM. These subjects also will be followed 
for 90 days to track any AEs, SAEs, etc. from the treatment. These subjects will not be 
included in any data analyses.   
5.4 
 Blinding and procedures for unblinding the study  
5.4.1 
Methods for ensuring blinding 
This is an open-label study design; both investigators and subjects will know which study 
drug the subject is receiving.  
5.4.2 
Methods for unblinding the study 
Not applicable.   
5.5 
Dosage and Administration 
MEDI4736 (15 mg/kg intravenously) or MEDI4736 (1500 mg intravenously) + tremelimumab 
(75 mg intravenously) will be administered once during the study. 
Subjects under 30 kg will be treated with weight-based dosing for both MEDI4736 and 
Tremelimumab combination therapy. These patients are excluded from fixed based dosing to 
limit endotoxin exposure from the drug preparations. 
 
5.6 
Dose Escalation Decision Rules 
There will be no dose escalation in this study. Subjects randomized to either the MEDI4736 or 
MEDI4736 + tremelimumab will receive a single monotherapy or combination dose.  
5.7 
Definition of DLT 
Dose-limiting toxicities (DLTs) will not be evaluated during this study.   


Clinical Study Protocol 
Drug Substance Tremelimumab 
Study Number ESR-14-10744 
Edition Number 8 
 
Date 17 April 2019 
 
Page 57 of 134 
 
5.8 
Toxicity Management 
5.8.1 
MEDI4736 
For adverse events (AEs) that are considered at least partly due to administration of 
MEDI4736 the following dose adjustment guidance may be applied: 
• Treat each of the toxicities with maximum supportive care (including holding the 
agent suspected of causing the toxicity where required). 
If the symptoms promptly resolve with supportive care, consideration should be given 
to continuing the same dose of MEDI4736 along with appropriate continuing 
supportive care.  
In addition, there are certain circumstances in which MEDI4736 should be permanently 
discontinued. 
 
Based on the mechanism of action of MEDI4736 leading to T-cell activation and proliferation, 
there is the possibility of observing immune related Adverse Events (irAEs) during the 
conduct of this study. Potential irAEs include immune-mediated enterocolitis, dermatitis, 
hepatitis, and endocrinopathies. Subjects should be monitored for signs and symptoms of 
irAEs. In the absence of an alternate etiology (e.g., infection or PD) signs or symptoms of 
enterocolitis, dermatitis, hepatitis, and endocrinopathy should be considered to be immune-
related.   
In addition, management guidelines for adverse events of special interest (AESIs) are detailed 
in Section 10.1.3. All toxicities will be graded according to NCI CTCAE v4.03.  
 
 
 


Clinical Study Protocol 
Drug Substance Tremelimumab 
Study Number ESR-14-10744 
Edition Number 8 
 
Date 17 April 2019 
 
Page 58 of 134 
 
Appendix 1 
Dosing Modification and Toxicity Management Guidelines 
for Immune-Mediated, Infusion-Related, and  
Non-Immune–Mediated Reactions (MEDI4736 
Monotherapy or Combination Therapy With 
Tremelimumab or Tremelimumab Monotherapy) 1 
November 2017 Version 
General Considerations 
Dose Modifications 
Toxicity Management 
Drug administration modifications of study drug/study 
regimen will be made to manage potential immune-related 
AEs based on severity of treatment-emergent toxicities 
graded per NCI CTCAE v4.03. 
In addition to the criteria for permanent discontinuation of 
study drug/study regimen based on CTC grade/severity 
(table below), permanently discontinue study drug/study 
regimen for the following conditions: 
• 
Inability to reduce corticosteroid to a dose of 
≤10 mg of prednisone per day (or equivalent) 
within 12 weeks after last dose of study 
drug/study regimen 
• 
Recurrence of a previously experienced Grade 3 
treatment-related AE following resumption of 
dosing 
Grade 1 
No dose modification 
Grade 2 
Hold study drug/study regimen dose until 
Grade 2 resolution to Grade ≤1. 
If toxicity worsens, then treat as Grade 3 or 
Grade 4. 
Study drug/study regimen can be resumed 
once event stabilizes to Grade ≤1 after 
completion of steroid taper. 
Patients with endocrinopathies who may 
require prolonged or continued steroid 
replacement can be retreated with study 
drug/study regimen on the following 
conditions: 
1. 
The event stabilizes and is controlled. 
2. 
The patient is clinically stable as per 
Investigator or treating physician’s 
clinical judgement. 
3. 
Doses of prednisone are at ≤10 mg/day 
or equivalent. 
It is recommended that management of immune-mediated 
adverse events (imAEs) follows the guidelines presented in 
this table: 
− 
It is possible that events with an inflammatory or 
immune mediated mechanism could occur in 
nearly all organs, some of them not noted 
specifically in these guidelines. 
− 
Whether specific immune-mediated events (and/or 
laboratory indicators of such events) are noted in 
these guidelines or not, patients should be 
thoroughly evaluated to rule out any alternative 
etiology (e.g., disease progression, concomitant 
medications, and infections) to a possible 
immune-mediated event. In the absence of a clear 
alternative etiology, all such events should be 
managed as if they were immune related. General 
recommendations follow. 
− 
Symptomatic and topical therapy should be 
considered for low-grade (Grade 1 or 2, unless 
otherwise specified) events.  
− 
For persistent (>3 to 5 days) low-grade (Grade 2) 
or severe (Grade ≥3) events, promptly start 
prednisone 1 to 2 mg/kg/day PO or IV equivalent. 
− 
Some events with high likelihood for morbidity 
and/or mortality – e.g., myo-carditis, or other 
similar events even if they are not currently noted 
in the guidelines – should progress rapidly to high 
dose IV corticosteroids (methylprednisolone at 2 
to 4 mg/kg/day) even if the event is Grade 2, and 
if clinical suspicion is high and/or there has been 
clinical confirmation. Consider, as necessary, 
discussing with the study physician, and promptly 
pursue specialist consultation. 
− 
If symptoms recur or worsen during corticosteroid 
tapering (28 days of taper), increase the 
corticosteroid dose (prednisone dose [e.g., up to 2 
to 4 mg/kg/day PO or IV equivalent]) until 
stabilization or improvement of symptoms, then 
resume corticosteroid tapering at a slower rate 
(>28 days of taper). 
− 
More potent immunosuppressives such as TNF 
inhibitors (e.g., infliximab) (also refer to the 
individual sections of the imAEs for specific type 


Clinical Study Protocol 
Drug Substance Tremelimumab 
Study Number ESR-14-10744 
Edition Number 8 
 
Date 17 April 2019 
 
Page 59 of 134 
 
Appendix 1 
Dosing Modification and Toxicity Management Guidelines 
for Immune-Mediated, Infusion-Related, and  
Non-Immune–Mediated Reactions (MEDI4736 
Monotherapy or Combination Therapy With 
Tremelimumab or Tremelimumab Monotherapy) 1 
November 2017 Version 
General Considerations 
Dose Modifications 
Toxicity Management 
Grade 3 
Depending on the individual toxicity, study 
drug/study regimen may be permanently 
discontinued. Please refer to guidelines 
below. 
Grade 4 
Permanently discontinue study drug/study 
regimen. 
Note: For Grade ≥3 asymptomatic amylase or lipase levels, 
hold study drug/study regimen, and if complete work up 
shows no evidence of pancreatitis, study drug/study 
regimen may be continued or resumed. 
Note: Study drug/study regimen should be permanently 
discontinued in Grade 3 events with high likelihood for 
morbidity and/or mortality – e.g., myocarditis, or other 
similar events even if they are not currently noted in the 
guidelines. Similarly, consider whether study drug/study 
regimen should be permanently discontinued in Grade 2 
events with high likelihood for morbidity and/or mortality 
– e.g., myocarditis, or other similar events even if they are 
not currently noted in the guidelines – when they do not 
rapidly improve to Grade <1 upon treatment with systemic 
steroids and following full taper 
Note: There are some exceptions to permanent 
discontinuation of study drug for Grade 4 events (i.e., 
hyperthyroidism, hypothyroidism, Type 1 diabetes 
mellitus).  
 
of immunosuppressive) should be considered for 
events not responding to systemic steroids. 
Progression to use of more potent 
immunosuppressives should proceed more rapidly 
in events with high likelihood for morbidity and/or 
mortality – e.g., myocarditis, or other similar 
events even if they are not currently noted in the 
guidelines – when these events are not responding 
to systemic steroids. 
− 
With long-term steroid and other 
immunosuppressive use, consider need for 
Pneumocystis jirovecii pneumonia (PJP, formerly 
known as Pneumocystis carinii pneumonia) 
prophylaxis, gastrointestinal protection, and 
glucose monitoring. 
− 
Discontinuation of study drug/study regimen is 
not mandated for Grade 3/Grade 4 inflammatory 
reactions attributed to local tumor response 
(e.g., inflammatory reaction at sites of metastatic 
disease and lymph nodes). Continuation of study 
drug/study regimen in this situation should be 
based upon a benefit-risk analysis for that patient. 
AE Adverse event; CTC Common Toxicity Criteria; CTCAE Common Terminology Criteria for Adverse Events; imAE 
immune-mediated adverse event; IV intravenous; NCI National Cancer Institute; PO By mouth. 
 


Clinical Study Protocol 
Drug Substance Tremelimumab 
Study Number ESR-14-10744 
Edition Number 8 
 
Date 17 April 2019 
 
Page 60 of 134 
 
Pediatric Considerations 
Dose Modifications 
Toxicity Management 
The criteria for permanent discontinuation of study 
drug/study regimen based on CTC grade/severity is the 
same for pediatric patients as it is for adult patients, as 
well as to permanently discontinue study drug/study 
regimen if unable to reduce corticosteroid ≤ a dose 
equivalent to that required for corticosteroid 
replacement therapy within 12 weeks after last dose of 
study drug/study regimen 
− 
All recommendations for specialist consultation 
should occur with a pediatric specialist in the 
specialty recommended. 
− 
The recommendations for dosing of steroids (i.e., 
mg/kg/day) and for IV IG and plasmapheresis that are 
provided for adult patients should also be used for 
pediatric patients. 
− 
The infliximab 5 mg/kg IV dose recommended for 
adults is the same as recommended for pediatric 
patients ≥ 6 years old.  For dosing in children younger 
than 6 years old, consult with a pediatric specialist. 
− 
For pediatric dosing of mycophenolate mofetil, 
consult with a pediatric specialist. 
− 
With long-term steroid and other immunosuppressive 
use, consider need for PJP prophylaxis, 
gastrointestinal protection, and glucose monitoring. 
 
 


Clinical Study Protocol 
Drug Substance Tremelimumab 
Study Number ESR-14-10744 
Edition Number 8 
 
Date 17 April 2019 
 
Page 61 of 134 
 
Specific Immune-Mediated Reactions 
Adverse Events 
Severity Grade 
of the Event 
(NCI CTCAE 
version 4.03) 
Dose Modifications 
Toxicity Management 
Pneumonitis/Interstitial 
Lung Disease (ILD) 
Any Grade 
General Guidance 
For Any Grade: 
− 
Monitor patients for signs and 
symptoms of pneumonitis or ILD 
(new onset or worsening shortness 
of breath or cough). Patients 
should be evaluated with imaging 
and pulmonary function tests, 
including other diagnostic 
procedures as described below. 
− 
Initial work-up may include 
clinical evaluation, monitoring of 
oxygenation via pulse oximetry 
(resting and exertion), laboratory 
work-up, and high- resolution CT 
scan. 
Grade 1 
(asymptomatic, 
clinical or 
diagnostic 
observations 
only; 
intervention not 
indicated) 
No dose modifications 
required. However, 
consider holding study 
drug/study regimen dose 
as clinically appropriate 
and during diagnostic 
work-up for other 
etiologies. 
For Grade 1 (radiographic changes only): 
− 
Monitor and closely follow up in 
2 to 4 days for clinical symptoms, 
pulse oximetry (resting and 
exertion), and laboratory work-up 
and then as clinically indicated. 
− 
Consider Pulmonary and 
Infectious disease consult. 
Grade 2 
(symptomatic; 
medical 
intervention 
indicated; 
limiting 
instrumental 
ADL) 
Hold study drug/study 
regimen dose until Grade 
2 resolution to Grade ≤1. 
• 
If toxicity worsens, 
then treat as Grade 3 
or Grade 4. 
• 
If toxicity improves 
to Grade ≤1, then the 
decision to reinitiate 
study drug/study 
regimen will be 
based upon treating 
physician’s clinical 
judgment and after 
completion of steroid 
taper. 
For Grade 2 (mild to moderate new 
symptoms): 
− 
Monitor symptoms daily and 
consider hospitalization. 
− 
Promptly start systemic steroids 
(e.g., prednisone 1 to 2 mg/kg/day 
PO or IV equivalent). 
− 
Reimage as clinically indicated. 
− 
If no improvement within 3 to 5 
days, additional workup should be 
considered and prompt treatment 
with IV methylprednisolone 2 to 
4 mg/kg/day started 
− 
If still no improvement within 3 to 
5 days despite IV 
methylprednisolone at 2 to 
4 mg/kg/day, promptly start 
immunosuppressive therapy such 


Clinical Study Protocol 
Drug Substance Tremelimumab 
Study Number ESR-14-10744 
Edition Number 8 
 
Date 17 April 2019 
 
Page 62 of 134 
 
as TNF inhibitors (e.g., infliximab 
at 5 mg/kg every 2 weeks). 
Caution: It is important to rule out 
sepsis and refer to infliximab label 
for general guidance before using 
infliximab. 
− 
Once the patient is improving, 
gradually taper steroids over ≥28 
days and consider prophylactic 
antibiotics, antifungals, or anti-
PJP treatment (refer to current 
NCCN guidelines for treatment of 
cancer-related infections 
[Category 2B recommendation])a 
− 
Consider pulmonary and 
infectious disease consult. 
− 
Consider, as necessary, discussing 
with study physician. 
Grade 3 or 4 
(Grade 3: severe 
symptoms; 
limiting self-care 
ADL; oxygen 
indicated) 
 
(Grade 4: life-
threatening 
respiratory 
compromise; 
urgent 
intervention 
indicated [e.g., 
tracheostomy or 
intubation]) 
Permanently discontinue 
study drug/study regimen. 
For Grade 3 or 4 (severe or new 
symptoms, new/worsening hypoxia, life-
threatening): 
− 
Promptly initiate empiric IV 
methylprednisolone 1 to 
4 mg/kg/day or equivalent. 
− 
Obtain Pulmonary and Infectious 
disease consult; consider, as 
necessary, discussing with study 
physician. 
− 
Hospitalize the patient. 
− 
Supportive care (e.g., oxygen). 
− 
If no improvement within 3 to 5 
days, additional workup should be 
considered and prompt treatment 
with additional 
immunosuppressive therapy such 
as TNF inhibitors (e.g., infliximab 
at 5 mg/kg every 2 weeks’ dose) 
started. Caution: rule out sepsis 
and refer to infliximab label for 
general guidance before using 
infliximab. 
− 
Once the patient is improving, 
gradually taper steroids over ≥28 
days and consider prophylactic 
antibiotics, antifungals, and, in 
particular, anti-PJP treatment 
(refer to current NCCN guidelines 
for treatment of cancer-related 
infections [Category 2B 
recommendation]).a 
 


Clinical Study Protocol 
Drug Substance Tremelimumab 
Study Number ESR-14-10744 
Edition Number 8 
 
Date 17 April 2019 
 
Page 63 of 134 
 
Diarrhea/Colitis 
Any Grade 
General Guidance 
For Any Grade: 
− 
Monitor for symptoms that may 
be related to diarrhea/enterocolitis 
(abdominal pain, cramping, or 
changes in bowel habits such as 
increased frequency over baseline 
or blood in stool) or related to 
bowel perforation (such as sepsis, 
peritoneal signs, and ileus). 
− 
Patients should be thoroughly 
evaluated to rule out any 
alternative etiology (e.g., disease 
progression, other medications, or 
infections), including testing for 
clostridium difficile toxin, etc. 
− 
Steroids should be considered in 
the absence of clear alternative 
etiology, even for low-grade 
events, in order to prevent 
potential progression to higher 
grade event. 
− 
Use analgesics carefully; they can 
mask symptoms of perforation 
and peritonitis. 
Grade 1 
(Diarrhea: stool 
frequency of <4 
over baseline per 
day) 
(Colitis: 
asymptomatic; 
clinical or 
diagnostic 
observations 
only) 
No dose modifications. 
For Grade 1: 
− 
Monitor closely for worsening 
symptoms. 
− 
Consider symptomatic treatment, 
including hydration, electrolyte 
replacement, dietary changes 
(e.g., American Dietetic 
Association colitis diet), and 
loperamide. Use probiotics as per 
treating physician’s clinical 
judgment. 
Grade 2 
(Diarrhea: stool 
frequency of 4 to 
6 over baseline 
per day) (Colitis: 
abdominal pain; 
mucus or blood 
in stool) 
Hold study drug/study 
regimen until resolution 
to Grade ≤1 
• 
If toxicity worsens, 
then treat as Grade 3 
or Grade 4. 
• 
If toxicity improves 
to Grade ≤1, then 
study drug/study 
regimen can be 
resumed after 
completion of steroid 
taper. 
For Grade 2: 
− 
Consider symptomatic treatment, 
including hydration, electrolyte 
replacement, dietary changes 
(e.g., American Dietetic 
Association colitis diet), and 
loperamide and/or budesonide. 
− 
Promptly start prednisone 1 to 2 
mg/kg/day PO or IV equivalent. 
− 
If event is not responsive within 3 
to 5 days or worsens despite 
prednisone at 1 to 2 mg/kg/day 
PO or IV equivalent, GI consult 


Clinical Study Protocol 
Drug Substance Tremelimumab 
Study Number ESR-14-10744 
Edition Number 8 
 
Date 17 April 2019 
 
Page 64 of 134 
 
should be obtained for 
consideration of further workup, 
such as imaging and/or 
colonoscopy, to confirm colitis 
and rule out perforation, and 
prompt treatment with IV 
methylprednisolone 2 to 4 
mg/kg/day started. 
− 
If still no improvement within 3 to 
5 days despite 2 to 4 mg/kg IV 
methylprednisolone, promptly 
start immunosuppressives such as 
infliximab at 5 mg/kg once every 
2 weeksa. Caution: it is important 
to rule out bowel perforation and 
refer to infliximab label for 
general guidance before using 
infliximab. 
− 
Consider, as necessary, discussing 
with study physician if no 
resolution to Grade ≤1 in 3 to 
4 days. 
− 
Once the patient is improving, 
gradually taper steroids over ≥28 
days and consider prophylactic 
antibiotics, antifungals, and anti-
PJP treatment (refer to current 
NCCN guidelines for treatment of 
cancer-related infections 
[Category 2B recommendation]).a 
Grade 3 or 4 
(Grade 3 
diarrhea: stool 
frequency of ≥7 
over baseline per 
day; 
Grade 4 
diarrhea: life 
threatening 
consequences) 
(Grade 3 colitis: 
severe 
abdominal pain, 
change in bowel 
habits, medi-cal 
intervention 
indi-cated, 
peritoneal signs; 
Grade 4 colitis: 
Grade 3 
Permanently discontinue 
study drug/study regimen 
for Grade 3 if toxicity 
does not improve to 
Grade ≤1 within 14 days; 
study drug/study regimen 
can be resumed after 
completion of steroid 
taper. 
 
Grade 4 
Permanently discontinue  
study drug/study regimen.  
For Grade 3 or 4: 
− 
Promptly initiate empiric IV 
methylprednisolone 2 to 
4 mg/kg/day or equivalent. 
− 
Monitor stool frequency and 
volume and maintain hydration. 
− 
Urgent GI consult and imaging 
and/or colonoscopy as 
appropriate. 
− 
If still no improvement within 3 to 
5 days of IV methylprednisolone 
2 to 4 mg/kg/day or equivalent, 
promptly start further 
immunosuppressives (e.g., 
infliximab at 5 mg/kg once every 
2 weeks). Caution: Ensure GI 
consult to rule out bowel 
perforation and refer to infliximab 
label for general guidance before 
using infliximab. 
− 
Once the patient is improving, 
gradually taper steroids over ≥28 
days and consider prophylactic 
antibiotics, antifungals, and anti-


Clinical Study Protocol 
Drug Substance Tremelimumab 
Study Number ESR-14-10744 
Edition Number 8 
 
Date 17 April 2019 
 
Page 65 of 134 
 
life-threatening 
consequences, 
urgent 
intervention 
indicated) 
 
PJP treatment (refer to current 
NCCN guidelines for treatment of 
cancer-related infections 
[Category 2B recommendation]).a 
Hepatitis  
(elevated LFTs) 
Infliximab should not be 
used for management of 
immune-related hepatitis. 
Any Grade 
General Guidance 
For Any Grade: 
− 
Monitor and evaluate liver 
function test: AST, ALT, ALP, 
and TB. 
− 
Evaluate for alternative etiologies 
(e.g., viral hepatitis, disease 
progression, concomitant 
medications). 
Grade 1 
(AST or ALT 
>ULN and 
≤3.0×ULN 
and/or TB > 
ULN and  
≤1.5×ULN) 
• 
No dose 
modifications. 
• 
If it worsens, then 
treat as Grade 2 
event. 
For Grade 1: 
− 
Continue LFT monitoring per 
protocol. 
Grade 2 
(AST or  
ALT >3.0×ULN 
and ≤5.0×ULN 
and/or  
TB >1.5×ULN 
and  ≤3.0×ULN) 
• 
Hold study 
drug/study regimen 
dose until Grade 2 
resolution to Grade 
≤1. 
• 
If toxicity worsens, 
then treat as Grade 3 
or Grade 4. 
• 
If toxicity improves 
to Grade ≤1 or 
baseline, resume 
study drug/study 
regimen after 
completion of steroid 
taper. 
For Grade 2: 
− 
Regular and frequent checking of 
LFTs (e.g., every 1 to 2 days) 
until elevations of these are 
improving or resolved. 
− 
If no resolution to Grade ≤1 in 1 
to 2 days, consider, as necessary, 
discussing with study physician. 
− 
If event is persistent (>3 to 5 
days) or worsens, promptly start 
prednisone 1 to 2 mg/kg/day PO 
or IV equivalent. 
− 
If still no improvement within 3 to 
5 days despite 1 to 2 mg/kg/day of 
prednisone PO or IV equivalent, 
consider additional work up and 
start prompt treatment with IV 
methylprednisolone 2 to 
4 mg/kg/day. 
− 
If still no improvement within 3 to 
5 days despite 2 to 4 mg/kg/day of 
IV methylprednisolone, promptly 
start immunosuppressives (i.e., 
mycophenolate mofetil).a Discuss 
with study physician if 
mycophenolate mofetil is not 
PLEASE SEE 
shaded area 
immediately below 
this section to find 
guidance for 
management of 
“Hepatitis (elevated 
LFTS)” in HCC 
patients 


Clinical Study Protocol 
Drug Substance Tremelimumab 
Study Number ESR-14-10744 
Edition Number 8 
 
Date 17 April 2019 
 
Page 66 of 134 
 
available. Infliximab should 
NOT be used. 
− 
Once the patient is improving, 
gradually taper steroids over ≥28 
days and consider prophylactic 
antibiotics, antifungals, and anti-
PJP treatment (refer to current 
NCCN guidelines for treatment of 
cancer-related infections 
[Category 2B recommendation]).a 
Grade 3 or 4 
(Grade 3: AST 
or  
ALT >5.0×ULN 
and ≤20.0×ULN 
and/or  
TB >3.0×ULN 
and  
≤10.0×ULN) 
 
(Grade 4: AST 
or  
ALT >20×ULN 
and/or  
TB >10×ULN) 
For Grade 3: 
For elevations in 
transaminases ≤8 × ULN, 
or elevations in bilirubin 
≤5 × ULN: 
• Hold study 
drug/study regimen 
dose until resolution 
to Grade ≤1 or 
baseline 
• Resume study 
drug/study regimen if 
elevations downgrade 
to Grade ≤1 or 
baseline within 
14 days and after 
completion of steroid 
taper. 
• Permanently 
discontinue study 
drug/study regimen if 
the elevations do not 
downgrade to Grade 
≤1 or baseline within 
14 days 
For elevations in 
transaminases >8 × ULN 
or elevations in bilirubin 
>5 × ULN, discontinue 
study drug/study regimen. 
Permanently discontinue 
study drug/study regimen 
for any case meeting Hy’s 
law criteria (AST and/or 
ALT >3 × ULN + 
bilirubin >2 × ULN 
without initial findings of 
cholestasis (i.e., elevated 
For Grade 3 or 4: 
− 
Promptly initiate empiric IV 
methylprednisolone at 1 to 
4 mg/kg/day or equivalent. 
− 
If still no improvement within 3 to 
5 days despite 1 to 4 mg/kg/day 
methylprednisolone IV or 
equivalent, promptly start 
treatment with 
immunosuppressive therapy (i.e., 
mycophenolate mofetil). Discuss 
with study physician if 
mycophenolate is not available. 
Infliximab should NOT be used. 
− 
Perform hepatology consult, 
abdominal workup, and imaging 
as appropriate. 
− 
Once the patient is improving, 
gradually taper steroids over ≥28 
days and consider prophylactic 
antibiotics, antifungals, and anti-
PJP treatment (refer to current 
NCCN guidelines for treatment of 
cancer-related infections 
[Category 2B recommendation]).a 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Clinical Study Protocol 
Drug Substance Tremelimumab 
Study Number ESR-14-10744 
Edition Number 8 
 
Date 17 April 2019 
 
Page 67 of 134 
 
alkaline P04) and in the 
absence of any alternative 
cause.b 
 
For Grade 4: 
Permanently discontinue 
study drug/study regimen. 
 
 
 
Hepatitis  
(elevated LFTs) 
Infliximab should not be 
used for management of 
immune-related hepatitis.  
See instructions at  
bottom of shaded area  
if transaminase rise is  
not isolated but (at any 
time) occurs in setting  
of either increasing 
bilirubin or signs of 
DILI/liver 
decompensation 
Any Grade 
 
General Guidance 
 
For Any Grade: 
− 
Monitor and evaluate liver 
function test: AST, ALT, ALP, 
and TB. 
− 
Evaluate for alternative etiologies 
(e.g., viral hepatitis, disease 
progression, concomitant 
medications, worsening of liver 
cirrhosis [e.g., portal vein 
thrombosis]). 
− 
For HBV+ patients: evaluate 
quantitative HBV viral load, 
quantitative HBsAg, or HBeAg 
− 
For HCV+ patients: evaluate 
quantitative HCV viral load 
− 
Consider consulting 
hepatologist/Infectious disease 
specialist regarding 
change/implementation in/of 
antiviral medications for any 
patient with an elevated HBV 
viral load >2000 IU/ml 
− 
Consider consulting 
hepatologist/Infectious disease 
specialist regarding 
change/implementation in/of 
antiviral HCV medications if 
HCV viral load increased by ≥2-
fold 
− 
For HCV+ with HBcAB+: 
Evaluate for both HBV and HCV 
as above 
 
Grade 1 
(Isolated AST or 
ALT >ULN and 
≤5.0×ULN, 
whether normal 
• 
No dose 
modifications. 
• 
If ALT/AST 
elevations represents 
significant worsening 
based on investigator 
 
THIS shaded area 
is guidance only for 
management of 
“Hepatitis (elevated 
LFTs)” in HCC 
patients  


Clinical Study Protocol 
Drug Substance Tremelimumab 
Study Number ESR-14-10744 
Edition Number 8 
 
Date 17 April 2019 
 
Page 68 of 134 
 
or elevated at 
baseline)  
assessment, then treat 
as Grade 2 event. 
For all grades, see 
instructions at bottom of 
shaded area if 
transaminase rise is not 
isolated but (at any time) 
occurs in setting of either 
increasing bilirubin or 
signs of DILI/liver 
decompensation 
 
Grade 2 
(Isolated AST or 
ALT >5.0×ULN 
and ≤8.0×ULN, 
if normal at 
baseline) 
 
(Isolated AST or 
ALT 
>2.0×baseline 
and ≤12.5×ULN, 
if elevated 
>ULN at 
baseline) 
• 
Hold study 
drug/study regimen 
dose until Grade 2 
resolution to Grade 
≤1 or baseline. 
• 
If toxicity worsens, 
then treat as Grade 3 
or Grade 4. 
If toxicity improves to 
Grade ≤1 or baseline, 
resume study drug/study 
regimen after completion 
of steroid taper. 
For Grade 2: 
− 
Regular and frequent checking of 
LFTs (e.g., every 1 to 3 days) 
until elevations of these are 
improving or resolved. 
− 
Recommend consult hepatologist; 
consider abdominal ultrasound, 
including Doppler assessment of 
liver perfusion. 
− 
Consider, as necessary, discussing 
with study physician. 
− 
If event is persistent (>3 to 5 
days) or worsens, and investigator 
suspects toxicity to be immune-
mediated AE, recommend to start 
prednisone 1 to 2 mg/kg/day PO 
or IV equivalent. 
− 
If still no improvement within 3 to 
5 days despite 1 to 2 mg/kg/day of 
prednisone PO or IV equivalent, 
consider additional workup and 
treatment with IV 
methylprednisolone 2 to 
4 mg/kg/day. 
− 
If still no improvement within 3 to 
5 days despite 2 to 4 mg/kg/day of 
IV methylprednisolone, consider 
additional abdominal workup 
(including liver biopsy) and 
imaging (i.e., liver ultrasound), 
and consider starting 
immunosuppressives (i.e., 
mycophenolate mofetil).a Discuss 
with study physician if 
mycophenolate mofetil is not 
available. Infliximab should 
NOT be used. 
 


Clinical Study Protocol 
Drug Substance Tremelimumab 
Study Number ESR-14-10744 
Edition Number 8 
 
Date 17 April 2019 
 
Page 69 of 134 
 
Grade 3 
(Isolated AST or 
ALT >8.0×ULN 
and ≤20.0×ULN, 
if normal at 
baseline) 
 
(Isolated AST or 
ALT 
>12.5×ULN and 
≤20.0×ULN, if  
elevated >ULN 
at baseline) 
• Hold study 
drug/study regimen 
dose until resolution 
to Grade ≤1 or 
baseline 
• Resume study 
drug/study regimen if 
elevations downgrade 
to Grade ≤1 or 
baseline within 
14 days and after 
completion of steroid 
taper. 
• Permanently 
discontinue study 
drug/study regimen if 
the elevations do not 
downgrade to Grade 
≤1 or baseline within 
14 days 
Permanently discontinue 
study drug/study regimen 
for any case meeting Hy’s 
law criteria, in the 
absence of any alternative 
cause.b 
For Grade 3: 
− 
Regular and frequent checking of 
LFTs (e.g., every 1-2 days) until 
elevations of these are improving 
or resolved. 
− 
Consult hepatologist (unless 
investigator is hepatologist); 
obtain abdominal ultrasound, 
including Doppler assessment of 
liver perfusion; and consider liver 
biopsy. 
− 
Consider, as necessary, discussing 
with study physician. 
− 
If investigator suspects toxicity to 
be immune-mediated, promptly 
initiate empiric IV 
methylprednisolone at 1 to 
4 mg/kg/day or equivalent. 
− 
If no improvement within 3 to 5 
days despite 1 to 4 mg/kg/day 
methylprednisolone IV or 
equivalent, obtain liver biopsy (if 
it has not been done already) and 
promptly start treatment with 
immunosuppressive therapy 
(mycophenolate mofetil). Discuss 
with study physician if 
mycophenolate is not available. 
Infliximab should NOT be used. 
− 
Once the patient is improving, 
gradually taper steroids over ≥28 
days and consider prophylactic 
antibiotics, antifungals, and anti-
PCP treatment (refer to current 
NCCN guidelines for treatment of 
cancer-related infections 
[Category 2B recommendation]).a 
 
Grade 4 
(Isolated AST or 
ALT >20×ULN,  
whether normal 
or elevated at 
baseline) 
Permanently discontinue 
study drug/study regimen. 
For Grade 4: 
Same as above  
(except would recommend obtaining liver 
biopsy early) 
 
 
If transaminase rise is not isolated but (at any time) occurs in setting of either increasing total/direct bilirubin 
(≥1.5×ULN, if normal at baseline; or 2×baseline, if >ULN at baseline) or signs of DILI/liver decompensation (e.g., 
fever, elevated INR): 


Clinical Study Protocol 
Drug Substance Tremelimumab 
Study Number ESR-14-10744 
Edition Number 8 
 
Date 17 April 2019 
 
Page 70 of 134 
 
- 
Manage dosing for Grade 1 transaminase rise as instructed for Grade 2 transaminase rise 
- 
Manage dosing for Grade 2 transaminase rise as instructed for Grade 3 transaminase rise 
- 
Grade 3-4: Permanently discontinue study drug/study regimen 
 
Nephritis or renal 
dysfunction 
(elevated serum 
creatinine) 
Any Grade 
General Guidance 
For Any Grade: 
− 
Consult with nephrologist. 
− 
Monitor for signs and symptoms 
that may be related to changes in 
renal function (e.g., routine 
urinalysis, elevated serum BUN 
and creatinine, decreased 
creatinine clearance, electrolyte 
imbalance, decrease in urine 
output, or proteinuria). 
− 
Patients should be thoroughly 
evaluated to rule out any 
alternative etiology (e.g., disease 
progression or infections). 
− 
Steroids should be considered in 
the absence of clear alternative 
etiology even for low-grade 
events (Grade 2), in order to 
prevent potential progression to 
higher grade event. 
 
 
Grade 1 
(Serum 
creatinine > 1 to 
1.5 × baseline; > 
ULN to 1.5 × 
ULN) 
No dose modifications. 
For Grade 1: 
− 
Monitor serum creatinine weekly 
and any accompanying symptoms. 
• 
If creatinine returns to 
baseline, resume its 
regular monitoring per 
study protocol. 
• 
If creatinine worsens, 
depending on the 
severity, treat as Grade 
2, 3, or 4. 
− 
Consider symptomatic treatment, 
including hydration, electrolyte 
replacement, and diuretics. 
Grade 2 
(serum 
creatinine >1.5 
to 3.0 × baseline; 
>1.5 to 3.0 × 
ULN) 
Hold study drug/study 
regimen until resolution 
to Grade ≤1 or baseline.  
• 
If toxicity worsens, 
then treat as Grade 3 
or 4. 
• 
If toxicity improves 
to Grade ≤1 or 
For Grade 2: 
− 
Consider symptomatic treatment, 
including hydration, electrolyte 
replacement, and diuretics. 
− 
Carefully monitor serum 
creatinine every 2 to 3 days and as 
clinically warranted. 


Clinical Study Protocol 
Drug Substance Tremelimumab 
Study Number ESR-14-10744 
Edition Number 8 
 
Date 17 April 2019 
 
Page 71 of 134 
 
baseline, then resume 
study drug/study 
regimen after 
completion of steroid 
taper. 
− 
Consult nephrologist and consider 
renal biopsy if clinically 
indicated. 
− 
If event is persistent (>3 to 5 
days) or worsens, promptly start 
prednisone 1 to 2 mg/kg/day PO 
or IV equivalent. 
− 
If event is not responsive within 3 
to 5 days or worsens despite 
prednisone at 1 to 2 mg/kg/day 
PO or IV equivalent, additional 
workup should be considered and 
prompt treatment with IV 
methylprednisolone at 2 to 
4 mg/kg/day started. 
− 
Once the patient is improving, 
gradually taper steroids over ≥28 
days and consider prophylactic 
antibiotics, antifungals, and anti-
PJP treatment (refer to current 
NCCN guidelines for treatment of 
cancer-related infections 
[Category 2B recommendation]).a 
− 
When event returns to baseline, 
resume study drug/study regimen 
and routine serum creatinine 
monitoring per study protocol. 
Grade 3 or 4 
(Grade 3: serum 
creatinine 
>3.0 × baseline; 
>3.0 to 
6.0 × ULN; 
 
Grade 4: serum 
creatinine >6.0 × 
ULN) 
Permanently discontinue 
study drug/study regimen. 
For Grade 3 or 4: 
− 
Carefully monitor serum 
creatinine on daily basis. 
− 
Consult nephrologist and consider 
renal biopsy if clinically 
indicated. 
− 
Promptly start prednisone 1 to 2 
mg/kg/day PO or IV equivalent. 
− 
If event is not responsive within 3 
to 5 days or worsens despite 
prednisone at 1 to 2 mg/kg/day 
PO or IV equivalent, additional 
workup should be considered and 
prompt treatment with IV 
methylprednisolone 2 to 
4 mg/kg/day started. 
− 
Once the patient is improving, 
gradually taper steroids over ≥28 
days and consider prophylactic 
antibiotics, antifungals, and anti-
PJP treatment (refer to current 
NCCN guidelines for treatment of 
cancer-related infections 
[Category 2B recommendation]).a 
 
 


Clinical Study Protocol 
Drug Substance Tremelimumab 
Study Number ESR-14-10744 
Edition Number 8 
 
Date 17 April 2019 
 
Page 72 of 134 
 
Rash 
(excluding bullous skin 
formations) 
Any Grade 
(refer to NCI 
CTCAE v 4.03 
for definition of 
severity/grade 
depending on 
type of skin 
rash) 
General Guidance 
For Any Grade: 
− 
Monitor for signs and symptoms 
of dermatitis (rash and pruritus). 
− 
IF THERE IS ANY BULLOUS 
FORMATION, THE STUDY 
PHYSICIAN SHOULD BE 
CONTACTED AND STUDY 
DRUG DISCONTINUED. 
Grade 1 
No dose modifications. 
For Grade 1: 
− 
Consider symptomatic treatment, 
including oral antipruritics (e.g., 
diphenhydramine or hydroxyzine) 
and topical therapy (e.g., urea 
cream). 
Grade 2 
For persistent (>1 to 2 
weeks) Grade 2 events, 
hold scheduled study 
drug/study regimen until 
resolution to Grade ≤1 or 
baseline. 
• 
If toxicity worsens, 
then treat as 
Grade 3. 
• 
If toxicity improves 
to Grade ≤1 or 
baseline, then 
resume drug/study 
regimen after 
completion of 
steroid taper. 
For Grade 2: 
− 
Obtain dermatology consult. 
− 
Consider symptomatic treatment, 
including oral antipruritics (e.g., 
diphenhydramine or hydroxyzine) 
and topical therapy (e.g., urea 
cream). 
− 
Consider moderate-strength 
topical steroid. 
− 
If no improvement of rash/skin 
lesions occurs within 3 to 5 days 
or is worsening despite 
symptomatic treatment and/or use 
of moderate strength topical 
steroid, consider, as necessary, 
discussing with study physician 
and promptly start systemic 
steroids such as prednisone 1 to 2 
mg/kg/day PO or IV equivalent. 
− 
Consider skin biopsy if the event 
is persistent for >1 to 2 weeks or 
recurs. 
 
 
Grade 3 or 4 
For Grade 3: 
Hold study drug/study 
regimen until resolution 
to Grade ≤1 or baseline. 
If temporarily holding the 
study drug/study regimen 
does not provide 
improvement of the 
For Grade 3 or 4: 
− 
Consult dermatology. 
− 
Promptly initiate empiric IV 
methylprednisolone 1 to 
4 mg/kg/day or equivalent. 
− 
Consider hospitalization. 
− 
Monitor extent of rash [Rule of 
Nines]. 


Clinical Study Protocol 
Drug Substance Tremelimumab 
Study Number ESR-14-10744 
Edition Number 8 
 
Date 17 April 2019 
 
Page 73 of 134 
 
Grade 3 skin rash to 
Grade ≤1 or baseline 
within 30 days, then 
permanently discontinue 
study drug/study regimen. 
 
For Grade 4: 
Permanently discontinue 
study drug/study regimen. 
 
− 
Consider skin biopsy (preferably 
more than 1) as clinically feasible. 
− 
Once the patient is improving, 
gradually taper steroids over ≥28 
days and consider prophylactic 
antibiotics, antifungals, and anti-
PJP treatment (refer to current 
NCCN guidelines for treatment of 
cancer-related infections 
[Category 2B recommendation]).a 
− 
Consider, as necessary, discussing 
with study physician. 
Endocrinopathy 
(e.g., hyperthyroidism, 
hypothyroidism,  Type 1 
diabetes mellitus, 
hypophysitis, 
hypopituitarism, and 
adrenal insufficiency; 
exocrine event of 
amylase/lipase increased 
also included in this 
section) 
 
Any Grade 
(depending on 
the type of 
endocrinopathy, 
refer to NCI 
CTCAE v4.03 
for defining the 
CTC 
grade/severity) 
General Guidance 
For Any Grade: 
− 
Consider consulting an 
endocrinologist for endocrine 
events. 
− 
Consider, as necessary, discussing 
with study physician. 
− 
Monitor patients for signs and 
symptoms of endocrinopathies. 
Non-specific symptoms include 
headache, fatigue, behavior 
changes, changed mental status, 
vertigo, abdominal pain, unusual 
bowel habits, polydipsia, polyuria, 
hypotension, and weakness. 
− 
Patients should be thoroughly 
evaluated to rule out any 
alternative etiology (e.g., disease 
progression including brain 
metastases, or infections). 
− 
Depending on the suspected 
endocrinopathy, monitor and 
evaluate thyroid function tests: 
TSH, free T3 and free T4 and 
other relevant endocrine and 
related labs (e.g., blood glucose 
and ketone levels, HgA1c). 
− 
For modest asymptomatic 
elevations in serum amylase and 
lipase, corticosteroid treatment is 
not indicated as long as there are 
no other signs or symptoms of 
pancreatic inflammation. 
− 
If a patient experiences an AE that 
is thought to be possibly of 
autoimmune nature (e.g., 
thyroiditis, pancreatitis, 
hypophysitis, or diabetes 
insipidus), the investigator should 
send a blood sample for 
appropriate autoimmune antibody 


Clinical Study Protocol 
Drug Substance Tremelimumab 
Study Number ESR-14-10744 
Edition Number 8 
 
Date 17 April 2019 
 
Page 74 of 134 
 
testing. 
 
Grade 1 
No dose modifications. 
For Grade 1 (including those with 
asymptomatic TSH elevation): 
− 
Monitor patient with appropriate 
endocrine function tests. 
− 
For suspected 
hypophysitis/hypopituitarism, 
consider consultation of an 
endocrinologist to guide 
assessment of early-morning 
ACTH, cortisol, TSH and free T4; 
also consider gonadotropins, sex 
hormones, and prolactin levels, as 
well as cosyntropin stimulation 
test (though it may not be useful 
in diagnosing early secondary 
adrenal insufficiency). 
− 
If TSH < 0.5 × LLN, or TSH >2 × 
ULN, or consistently out of range 
in 2 subsequent measurements, 
include free T4 at subsequent 
cycles as clinically indicated and 
consider consultation of an 
endocrinologist. 
Grade 2 
For Grade 2 
endocrinopathy other than 
hypothyroidism and Type 
1 diabetes mellitus, hold 
study drug/study regimen 
dose until patient is 
clinically stable. 
• 
If toxicity worsens, 
then treat as Grade 3 
or Grade 4. 
Study drug/study regimen 
can be resumed once 
event stabilizes and after 
completion of steroid 
taper. 
Patients with 
endocrinopathies who 
may require prolonged or 
continued steroid 
replacement (e.g., adrenal 
insufficiency) can be 
retreated with study 
For Grade 2 (including those with 
symptomatic endocrinopathy): 
− 
Consult endocrinologist to guide 
evaluation of endocrine function 
and, as indicated by suspected 
endocrinopathy and as clinically 
indicated, consider pituitary scan. 
− 
For all patients with abnormal 
endocrine work up, except those 
with isolated hypothyroidism or 
Type 1 DM, and as guided by an  
endocrinologist, consider 
short-term corticosteroids (e.g., 1 
to 2 mg/kg/day 
methylprednisolone or IV 
equivalent) and prompt initiation 
of treatment with relevant 
hormone replacement (e.g., 
hydrocortisone, sex hormones). 
− 
Isolated hypothyroidism may be 
treated with replacement therapy, 
without study drug/study regimen 
interruption, and without 
corticosteroids. 
− 
Isolated Type 1 diabetes mellitus 
(DM) may be treated with 
appropriate diabetic therapy, 
without study drug/study regimen 


Clinical Study Protocol 
Drug Substance Tremelimumab 
Study Number ESR-14-10744 
Edition Number 8 
 
Date 17 April 2019 
 
Page 75 of 134 
 
drug/study regimen on the 
following conditions: 
1. 
The event stabilizes 
and is controlled. 
2. 
The patient is 
clinically stable as 
per investigator or 
treating physician’s 
clinical judgement. 
3. 
Doses of prednisone 
are ≤10 mg/day or 
equivalent. 
interruption, and without 
corticosteroids. 
− 
Once patients on steroids are 
improving, gradually taper  
immunosuppressive steroids (as 
appropriate and with guidance of 
endocrinologist) over ≥28 days 
and consider prophylactic 
antibiotics, antifungals, and anti-
PJP treatment (refer to current 
NCCN guidelines for treatment of 
cancer-related infections 
[Category 2B recommendation]).a 
− 
For patients with normal 
endocrine workup (laboratory 
assessment or MRI scans), repeat 
laboratory assessments/MRI as 
clinically indicated. 
Grade 3 or 4 
For Grade 3 or 4 
endocrinopathy other than 
hypothyroidism and Type 
1 diabetes mellitus, hold 
study drug/study regimen 
dose until endocrinopathy 
symptom(s) are 
controlled.  
Study drug/study regimen 
can be resumed once 
event stabilizes and after 
completion of steroid 
taper. 
Patients with 
endocrinopathies who 
may require prolonged or 
continued steroid 
replacement (e.g., adrenal 
insufficiency) can be 
retreated with study 
drug/study regimen on the 
following conditions: 
1. 
The event stabilizes 
and is controlled. 
2. 
The patient is 
clinically stable as 
per investigator or 
treating physician’s 
clinical judgement. 
For Grade 3 or 4: 
− 
Consult endocrinologist to guide 
evaluation of endocrine function 
and, as indicated by suspected 
endocrinopathy and as clinically 
indicated, consider pituitary scan. 
Hospitalization recommended. 
− 
For all patients with abnormal 
endocrine work up, except those 
with isolated hypothyroidism or 
Type 1 DM, and as guided by an  
endocrinologist, promptly initiate 
empiric IV methylprednisolone 1 
to 2 mg/kg/day or equivalent, as 
well as relevant hormone 
replacement (e.g., hydrocortisone, 
sex hormones). 
− 
For adrenal crisis, severe 
dehydration, hypotension, or 
shock, immediately initiate IV 
corticosteroids with 
mineralocorticoid activity. 
− 
Isolated hypothyroidism may be 
treated with replacement therapy, 
without study drug/study regimen 
interruption, and without 
corticosteroids. 
− 
Isolated Type 1 diabetes mellitus 
may be treated with appropriate 
diabetic therapy, without study 
drug/study regimen interruption, 
and without corticosteroids. 
− 
Once patients on steroids are 
improving, gradually taper 
immunosuppressive steroids (as 
appropriate and with guidance of 


Clinical Study Protocol 
Drug Substance Tremelimumab 
Study Number ESR-14-10744 
Edition Number 8 
 
Date 17 April 2019 
 
Page 76 of 134 
 
3. 
Doses of prednisone 
are ≤10 mg/day or 
equivalent. 
endocrinologist) over ≥28 days 
and consider prophylactic 
antibiotics, antifungals, and anti-
PJP treatment (refer to current 
NCCN guidelines for treatment of 
cancer-related infections 
[Category 2B recommendation]).a 
 
Neurotoxicity 
(to include but not be 
limited to limbic 
encephalitis and 
autonomic neuropathy, 
excluding Myasthenia 
Gravis and Guillain-
Barre) 
Any Grade 
(depending on 
the type of 
neurotoxicity, 
refer to NCI 
CTCAE v4.03 
for defining the 
CTC 
grade/severity) 
General Guidance 
For Any Grade: 
− 
Patients should be evaluated to 
rule out any alternative etiology 
(e.g., disease progression, 
infections, metabolic syndromes, 
or medications). 
− 
Monitor patient for general 
symptoms (headache, nausea, 
vertigo, behavior change, or 
weakness). 
− 
Consider appropriate diagnostic 
testing (e.g., electromyogram and 
nerve conduction investigations). 
− 
Perform symptomatic treatment 
with neurological consult as 
appropriate. 
− 
 
Grade 1 
No dose modifications. 
For Grade 1: 
− 
See “Any Grade” 
recommendations above. 
Grade 2 
For acute motor 
neuropathies or 
neurotoxicity, hold study 
drug/study regimen dose 
until resolution to Grade 
≤1. 
For sensory 
neuropathy/neuropathic 
pain, consider holding 
study drug/study regimen 
dose until resolution to 
Grade ≤1. 
If toxicity worsens, 
then treat as Grade 3 
or 4. 
Study drug/study regimen 
can be resumed once 
For Grade 2: 
− 
Consider, as necessary, discussing 
with the study physician. 
− 
Obtain neurology consult. 
− 
Sensory neuropathy/neuropathic 
pain may be managed by 
appropriate medications (e.g., 
gabapentin or duloxetine). 
− 
Promptly start systemic steroids 
prednisone 1 to 2 mg/kg/day PO 
or IV equivalent. 
− 
If no improvement within 3 to 5 
days despite 1 to 2 mg/kg/day 
prednisone PO or IV equivalent, 
consider additional workup and 
promptly treat with additional 
immunosuppressive therapy (e.g., 
IV IG). 


Clinical Study Protocol 
Drug Substance Tremelimumab 
Study Number ESR-14-10744 
Edition Number 8 
 
Date 17 April 2019 
 
Page 77 of 134 
 
event improves to Grade 
≤1 and after completion 
of steroid taper. 
Grade 3 or 4 
For Grade 3: 
Hold study drug/study 
regimen dose until 
resolution to Grade ≤1. 
Permanently discontinue 
study drug/study regimen 
if Grade 3 imAE does not 
resolve to Grade ≤1 
within 30 days. 
 
For Grade 4: 
Permanently discontinue 
study drug/study regimen. 
For Grade 3 or 4: 
− 
Consider, as necessary, discussing 
with study physician. 
− 
Obtain neurology consult. 
− 
Consider hospitalization. 
− 
Promptly initiate empiric IV 
methylprednisolone 1 to 
2 mg/kg/day or equivalent. 
− 
If no improvement within 3 to 5 
days despite IV corticosteroids, 
consider additional workup and 
promptly treat with additional 
immunosuppressants (e.g., IV IG). 
− 
Once stable, gradually taper 
steroids over ≥28 days. 
Peripheral neuromotor 
syndromes 
(such as Guillain-Barre 
and myasthenia gravis) 
Any Grade 
General Guidance 
For Any Grade: 
− 
The prompt diagnosis of immune-
mediated peripheral neuromotor 
syndromes is important, since 
certain patients may unpredictably 
experience acute decompensations 
that can result in substantial 
morbidity or in the worst case, 
death. Special care should be 
taken for certain sentinel 
symptoms that may predict a more 
severe outcome, such as 
prominent dysphagia, rapidly 
progressive weakness, and signs 
of respiratory insufficiency or 
autonomic instability. 
− 
Patients should be evaluated to 
rule out any alternative etiology 
(e.g., disease progression, 
infections, metabolic syndromes 
or medications). It should be 
noted that the diagnosis of 
immune-mediated peripheral 
neuromotor syndromes can be 
particularly challenging in 
patients with underlying cancer, 
due to the multiple potential 
confounding effects of cancer 
(and its treatments) throughout the 
neuraxis. Given the importance of 
prompt and accurate diagnosis, it 
is essential to have a low 


Clinical Study Protocol 
Drug Substance Tremelimumab 
Study Number ESR-14-10744 
Edition Number 8 
 
Date 17 April 2019 
 
Page 78 of 134 
 
threshold to obtain a neurological 
consult. 
− 
Neurophysiologic diagnostic 
testing (e.g., electromyogram and 
nerve conduction investigations, 
and “repetitive stimulation” if 
myasthenia is suspected) are 
routinely indicated upon suspicion 
of such conditions and may be 
best facilitated by means of a 
neurology consultation. 
− 
It is important to consider that the 
use of steroids as the primary 
treatment of Guillain-Barre is not 
typically considered effective. 
Patients requiring treatment 
should be started with IV IG and 
followed by plasmapheresis if not 
responsive to IV IG. 
 
Grade 1 
No dose modifications. 
For Grade 1: 
− 
Consider, as necessary, discussing 
with the study physician. 
− 
Care should be taken to monitor 
patients for sentinel symptoms of 
a potential decompensation as 
described above. 
− 
Obtain a neurology consult. 
Grade 2 
Hold study drug/study 
regimen dose until 
resolution to Grade ≤1. 
Permanently discontinue 
study drug/study regimen 
if it does not resolve to 
Grade ≤1 within 30 days 
or if there are signs of 
respiratory insufficiency 
or autonomic instability. 
For Grade 2: 
− 
Consider, as necessary, discussing 
with the study physician. 
− 
Care should be taken to monitor 
patients for sentinel symptoms of 
a potential decompensation as 
described above. 
− 
Obtain a neurology consult 
− 
Sensory neuropathy/neuropathic 
pain may be managed by 
appropriate medications (e.g., 
gabapentin or duloxetine). 
MYASTHENIA GRAVIS: 
o 
Steroids may be 
successfully used to 
treat myasthenia gravis. 
It is important to 
consider that steroid 
therapy (especially with 
high doses) may result 
in transient worsening 
of myasthenia and 
should typically be 
administered in a 


Clinical Study Protocol 
Drug Substance Tremelimumab 
Study Number ESR-14-10744 
Edition Number 8 
 
Date 17 April 2019 
 
Page 79 of 134 
 
monitored setting under 
supervision of a 
consulting neurologist. 
o 
Patients unable to 
tolerate steroids may be 
candidates for treatment 
with plasmapheresis or 
IV IG. Such decisions 
are best made in 
consultation with a 
neurologist, taking into 
account the unique 
needs of each patient. 
o 
If myasthenia gravis-
like neurotoxicity is 
present, consider 
starting AChE inhibitor 
therapy in addition to 
steroids. Such therapy, 
if successful, can also 
serve to reinforce the 
diagnosis. 
GUILLAIN-BARRE: 
o 
It is important to 
consider here that the 
use of steroids as the 
primary treatment of 
Guillain-Barre is not 
typically considered 
effective. 
o 
Patients requiring 
treatment should be 
started with IV IG and 
followed by 
plasmapheresis if not 
responsive to IV IG. 
 
Grade 3 or 4 
For Grade 3: 
Hold study drug/study 
regimen dose until 
resolution to Grade ≤1. 
Permanently discontinue 
study drug/study regimen 
if Grade 3 imAE does not 
resolve to Grade ≤1 
within 30 days or if there 
are signs of respiratory 
insufficiency or 
autonomic instability. 
For Grade 3 or 4 (severe or life-
threatening events): 
− 
Consider, as necessary, discussing 
with study physician. 
− 
Recommend hospitalization. 
− 
Monitor symptoms and obtain 
neurological consult. 
MYASTHENIA GRAVIS: 
o 
Steroids may be 
successfully used to 
treat myasthenia gravis. 
They should typically 
be administered in a 
monitored setting under 


Clinical Study Protocol 
Drug Substance Tremelimumab 
Study Number ESR-14-10744 
Edition Number 8 
 
Date 17 April 2019 
 
Page 80 of 134 
 
 
For Grade 4: 
Permanently discontinue 
study drug/study regimen. 
supervision of a 
consulting neurologist. 
o 
Patients unable to 
tolerate steroids may be 
candidates for treatment 
with plasmapheresis or 
IV IG. 
o 
If myasthenia gravis-
like neurotoxicity 
present, consider 
starting AChE inhibitor 
therapy in addition to 
steroids. Such therapy, 
if successful, can also 
serve to reinforce the 
diagnosis. 
GUILLAIN-BARRE: 
o 
It is important to 
consider here that the 
use of steroids as the 
primary treatment of 
Guillain-Barre is not 
typically considered 
effective. 
o 
Patients requiring 
treatment should be 
started with IV IG and 
followed by 
plasmapheresis if not 
responsive to IV IG. 
 
Myocarditis 
Any Grade 
General Guidance 
Discontinue drug 
permanently if biopsy-
proven immune-mediated 
myocarditis. 
For Any Grade: 
− 
The prompt diagnosis of immune-
mediated myocarditis is 
important, particularly in patients 
with baseline cardiopulmonary 
disease and reduced cardiac 
function.  
− 
Consider, as necessary, discussing 
with the study physician. 
− 
Monitor patients for signs and 
symptoms of myocarditis (new 
onset or worsening chest pain, 
arrhythmia, shortness of breath, 
peripheral edema). As some 
symptoms can overlap with lung 
toxicities, simultaneously evaluate 
for and rule out pulmonary 
toxicity as well as other causes 
(e.g., pulmonary embolism, 
congestive heart failure, malignant 
pericardial effusion). A 
Cardiology consultation should be 


Clinical Study Protocol 
Drug Substance Tremelimumab 
Study Number ESR-14-10744 
Edition Number 8 
 
Date 17 April 2019 
 
Page 81 of 134 
 
obtained early, with prompt 
assessment of whether and when 
to complete a cardiac biopsy, 
including any other diagnostic 
procedures. 
− 
Initial work-up should include 
clinical evaluation, BNP, cardiac 
enzymes, ECG, echocardiogram 
(ECHO), monitoring of 
oxygenation via pulse oximetry 
(resting and exertion), and 
additional laboratory work-up as 
indicated. Spiral CT or cardiac 
MRI can complement ECHO to 
assess wall motion abnormalities 
when needed. 
− 
Patients should be thoroughly 
evaluated to rule out any 
alternative etiology (e.g., disease 
progression, other medications, or 
infections) 
 
Grade 1 
(asymptomatic 
with laboratory 
(e.g., BNP) or 
cardiac imaging 
abnormalities) 
No dose modifications 
required unless clinical 
suspicion is high, in 
which case hold study 
drug/study regimen dose 
during diagnostic work-
up for other etiologies. If 
study drug/study regimen 
is held, resume after 
complete resolution to 
Grade 0. 
For Grade 1 (no definitive findings): 
- 
Monitor and closely follow up in 2 
to 4 days for clinical symptoms,  
BNP, cardiac enzymes, ECG, 
ECHO, pulse oximetry (resting and 
exertion), and laboratory work-up 
as clinically indicated. 
- 
Consider using steroids if clinical 
suspicion is high. 
 
Grade 2, 3 or 4 
(Grade 2: 
Symptoms with 
mild to moderate 
activity or 
exertion) 
 
 (Grade 3: 
Severe with 
symptoms at rest 
or with minimal 
activity or 
exertion; 
- If Grade 2 -- Hold 
study drug/study 
regimen dose until 
resolution to Grade 0. 
If toxicity rapidly 
improves to Grade 0, 
then the decision to 
reinitiate study 
drug/study regimen 
will be based upon 
treating physician’s 
clinical judgment and 
after completion of 
steroid taper. If 
For Grade 2-4: 
− 
Monitor symptoms daily, 
hospitalize. 
− 
Promptly start IV 
methylprednisolone 2 to 
4 mg/kg/day or equivalent after 
Cardiology consultation has 
determined whether and when to 
complete diagnostic procedures 
including a cardiac biopsy. 
− 
Supportive care (e.g., oxygen). 
− 
If no improvement within 3 to 5 
days despite IV 
methylprednisolone at 2 to 
4 mg/kg/day, promptly start 
immunosuppressive therapy such 
as TNF inhibitors (e.g., infliximab 
at 5 mg/kg every 2 weeks). 


Clinical Study Protocol 
Drug Substance Tremelimumab 
Study Number ESR-14-10744 
Edition Number 8 
 
Date 17 April 2019 
 
Page 82 of 134 
 
intervention 
indicated) 
 
(Grade 4: Life-
threatening 
consequences; 
urgent 
intervention 
indicated (e.g., 
continuous IV 
therapy or 
mechanical 
hemodynamic 
support)) 
 
toxicity does not 
rapidly improve, 
permanently. 
discontinue study 
drug/study regimen. 
If Grade 3-4, permanently 
discontinue study 
drug/study regimen. 
Caution: It is important to rule out 
sepsis and refer to infliximab label 
for general guidance before using 
infliximab. 
− 
Once the patient is improving, 
gradually taper steroids over ≥28 
days and consider prophylactic 
antibiotics, antifungals, or anti-
PJP treatment (refer to current 
NCCN guidelines for treatment of 
cancer-related infections 
[Category 2B recommendation]).a 
Myositis/Polymyositis 
(“Poly/myositis”) 
Any Grade 
General Guidance 
For Any Grade: 
− 
Monitor patients for signs and 
symptoms of poly/myositis. 
Typically, muscle weakness/pain 
occurs in proximal muscles 
including upper arms, thighs, 
shoulders, hips, neck and back, 
but rarely affects the extremities 
including hands and fingers; also 
difficulty breathing and/or trouble 
swallowing can occur and 
progress rapidly. Increased 
general feelings of tiredness and 
fatigue may occur, and there can 
be new-onset falling, difficulty 
getting up from a fall, and trouble 
climbing stairs, standing up from 
a seated position, and/or reaching 
up. 
− 
If poly/myositis is suspected, a 
Neurology consultation should be 
obtained early, with prompt 
guidance on diagnostic 
procedures. Myocarditis may co-
occur with poly/myositis; refer to 
guidance under Myocarditis. 
Given breathing complications, 
refer to guidance under 
Pneumonitis/ILD.  
Given possibility of an existent 
(but previously unknown) 
autoimmune disorder, consider 
Rheumatology consultation. 
− 
Consider, as necessary, discussing 
with the study physician. 


Clinical Study Protocol 
Drug Substance Tremelimumab 
Study Number ESR-14-10744 
Edition Number 8 
 
Date 17 April 2019 
 
Page 83 of 134 
 
− 
Initial work-up should include 
clinical evaluation, creatine 
kinase, aldolase, LDH, 
BUN/creatinine, erythrocyte 
sedimentation rate or C-reactive 
protein level, urine myoglobin, 
and additional laboratory work-up 
as indicated, including a number 
of possible 
rheumatological/antibody tests 
(i.e., consider whether a 
rheumatologist consultation is 
indicated and could guide need for 
rheumatoid factor, antinuclear 
antibody, anti-smooth muscle, 
antisynthetase [such as anti-Jo-1], 
and/or signal-recognition particle 
antibodies). Confirmatory testing 
may include electromyography, 
nerve conduction studies, MRI of 
the muscles, and/or a muscle 
biopsy. Consider Barium swallow 
for evaluation of dysphagia or 
dysphonia. 
Patients should be thoroughly evaluated to 
rule out any alternative etiology (e.g., 
disease progression, other medications, or 
infections). 
 
Grade 1 
(mild pain) 
- No dose modifications. 
For Grade 1: 
− 
Monitor and closely follow up in 
2 to 4 days for clinical symptoms 
and initiate evaluation as 
clinically indicated. 
− 
Consider Neurology consult. 
− 
Consider, as necessary, discussing 
with the study physician. 
 
Grade 2 
(moderate pain 
associated with 
weakness; pain 
limiting 
instrumental 
activities of 
daily living 
[ADLs]) 
Hold study drug/study 
regimen dose until 
resolution to Grade ≤1. 
- Permanently 
discontinue study 
drug/study regimen if 
it does not resolve to 
Grade ≤1 within 30 
days or if there are 
signs of respiratory 
insufficiency. 
For Grade 2: 
− 
Monitor symptoms daily and 
consider hospitalization. 
− 
Obtain Neurology consult, and 
initiate evaluation. 
− 
Consider, as necessary, discussing 
with the study physician. 
− 
If clinical course is rapidly 
progressive (particularly if 
difficulty breathing and/or trouble 
swallowing), promptly start IV 
methylprednisolone 2 to 
4 mg/kg/day systemic steroids 
along with receiving input from 
Neurology consultant  


Clinical Study Protocol 
Drug Substance Tremelimumab 
Study Number ESR-14-10744 
Edition Number 8 
 
Date 17 April 2019 
 
Page 84 of 134 
 
− 
If clinical course is not rapidly 
progressive, start systemic 
steroids (e.g., prednisone 1 to 
2 mg/kg/day PO or IV 
equivalent); if no improvement 
within 3 to 5 days, continue 
additional work up and start 
treatment with IV 
methylprednisolone 2 to 
4 mg/kg/day 
− 
If after start of IV 
methylprednisolone at 2 to 
4 mg/kg/day there is no 
improvement within 3 to 5 days, 
consider start of 
immunosuppressive therapy such 
as TNF inhibitors (e.g., infliximab 
at 5 mg/kg every 2 weeks). 
Caution: It is important to rule out 
sepsis and refer to infliximab label 
for general guidance before using 
infliximab. 
− 
Once the patient is improving, 
gradually taper steroids over ≥28 
days and consider prophylactic 
antibiotics, antifungals, or anti-
PJP treatment (refer to current 
NCCN guidelines for treatment of 
cancer-related infections 
[Category 2B recommendation]).a 
 
Grade 3 or 4 
(pain associated 
with severe 
weakness; 
limiting self-care 
ADLs) 
For Grade 3: 
Hold study drug/study 
regimen dose until 
resolution to Grade ≤1. 
Permanently discontinue 
study drug/study regimen 
if Grade 3 imAE does not 
resolve to Grade ≤1 
within 30 days or if there 
are signs of respiratory 
insufficiency. 
 
For Grade 4: 
- Permanently 
discontinue study 
drug/study regimen. 
For Grade 3 or 4 (severe or life-
threatening events): 
− 
Monitor symptoms closely; 
recommend hospitalization. 
− 
Obtain Neurology consult, and 
complete full evaluation. 
− 
Consider, as necessary, discussing 
with the study physician. 
− 
Promptly start IV 
methylprednisolone 2 to 
4 mg/kg/day systemic steroids 
along with receiving input from 
Neurology consultant. 
− 
If after start of IV 
methylprednisolone at 2 to 
4 mg/kg/day there is no 
improvement within 3 to 5 days, 
consider start of 
immunosuppressive therapy such 
as TNF inhibitors (e.g., infliximab 
at 5 mg/kg every 2 weeks). 
Caution: It is important to rule out 
sepsis and refer to infliximab label 


Clinical Study Protocol 
Drug Substance Tremelimumab 
Study Number ESR-14-10744 
Edition Number 8 
 
Date 17 April 2019 
 
Page 85 of 134 
 
aASCO Educational Book 2015 “Managing Immune Checkpoint Blocking Antibody Side Effects” by Michael Postow MD. 
bFDA Liver Guidance Document 2009 Guidance for Industry: Drug Induced Liver Injury – Premarketing Clinical Evaluation. 
AChE Acetylcholine esterase; ADL Activities of daily living; AE Adverse event; ALP Alkaline phosphatase test; ALT 
Alanine aminotransferase; AST Aspartate aminotransferase; BUN Blood urea nitrogen; CT Computed tomography; 
CTCAE Common Terminology Criteria for Adverse Events; ILD Interstitial lung disease; imAE immune-mediated 
adverse event; IG Immunoglobulin; IV Intravenous; GI Gastrointestinal; LFT Liver function tests; LLN Lower limit of 
normal; MRI  Magnetic resonance imaging; NCI  National Cancer Institute; NCCN  National Comprehensive Cancer 
Network; PJP Pneumocystis jirovecii pneumonia (formerly known as Pneumocystis carinii pneumonia); PO  By mouth; 
T3  Triiodothyronine; T4 Thyroxine; TB Total bilirubin; TNF Tumor necrosis factor; TSH Thyroid-stimulating 
hormone; ULN Upper limit of normal. 
 
 
for general guidance before using 
infliximab. 
− 
Consider whether patient may 
require IV IG, plasmapheresis. 
− 
Once the patient is improving, 
gradually taper steroids over ≥28 
days and consider prophylactic 
antibiotics, antifungals, or anti-
PJP treatment (refer to current 
NCCN guidelines for treatment of 
cancer-related infections 
[Category 2B recommendation]).a 


Clinical Study Protocol 
Drug Substance Tremelimumab 
Study Number ESR-14-10744 
Edition Number 8 
 
Date 17 April 2019 
 
Page 86 of 134 
 
Infusion-Related Reactions 
Severity Grade of 
the Event (NCI 
CTCAE 
version 4.03) 
Dose Modifications 
Toxicity Management 
Any Grade 
General Guidance 
For Any Grade: 
− 
Manage per institutional standard at the 
discretion of investigator. 
− 
Monitor patients for signs and symptoms of 
infusion-related reactions (e.g., fever and/or 
shaking chills, flushing and/or itching, 
alterations in heart rate and blood pressure, 
dyspnea or chest discomfort, or skin rashes) 
and anaphylaxis (e.g., generalized urticaria, 
angioedema, wheezing, hypotension, or 
tachycardia). 
Grade 1 or 2 
For Grade 1: 
The infusion rate of study drug/study 
regimen may be decreased by 50% or 
temporarily interrupted until resolution of 
the event. 
 
For Grade 2: 
The infusion rate of study drug/study 
regimen may be decreased 50% or 
temporarily interrupted until resolution of 
the event. 
Subsequent infusions may be given at 
50% of the initial infusion rate. 
For Grade 1 or 2: 
− 
Acetaminophen and/or antihistamines may 
be administered per institutional standard at 
the discretion of the investigator. 
− 
Consider premedication per institutional 
standard prior to subsequent doses. 
− 
Steroids should not be used for routine 
premedication of Grade ≤2 infusion 
reactions. 
Grade 3 or 4 
For Grade 3 or 4: 
Permanently discontinue study drug/study 
regimen. 
For Grade 3 or 4: 
− 
Manage severe infusion-related reactions per 
institutional standards (e.g., IM epinephrine, 
followed by IV diphenhydramine and 
ranitidine, and IV glucocorticoid). 
CTCAE Common Terminology Criteria for Adverse Events; IM intramuscular; IV intravenous; NCI National Cancer 
Institute. 
 
 
 


Clinical Study Protocol 
Drug Substance Tremelimumab 
Study Number ESR-14-10744 
Edition Number 8 
 
Date 17 April 2019 
 
Page 87 of 134 
 
Non–Immune-Mediated Reactions 
Severity Grade of the 
Event (NCI CTCAE 
version 4.03) 
Dose Modifications 
Toxicity Management 
Any Grade 
Note: Dose modifications are not required for 
AEs not deemed to be related to study 
treatment (i.e., events due to underlying 
disease) or for laboratory abnormalities not 
deemed to be clinically significant. 
Treat accordingly, as per institutional 
standard. 
Grade 1 
No dose modifications. 
Treat accordingly, as per institutional 
standard. 
Grade 2 
Hold study drug/study regimen until 
resolution to ≤Grade 1 or baseline. 
Treat accordingly, as per institutional 
standard. 
Grade 3 
Hold study drug/study regimen until 
resolution to ≤Grade 1 or baseline. 
For AEs that downgrade to ≤Grade 2 within 
7 days or resolve to ≤Grade 1 or baseline 
within 14 days, resume study drug/study 
regimen administration. Otherwise, 
discontinue study drug/study regimen. 
Treat accordingly, as per institutional 
standard. 
Grade 4 
 
Discontinue study drug/study regimen (Note: 
For Grade 4 labs, decision to discontinue 
should be based on accompanying clinical 
signs/symptoms, the Investigator’s clinical 
judgment, and consultation with the 
Sponsor.). 
Treat accordingly, as per institutional 
standard. 
Note: As applicable, for early phase studies, the following sentence may be added: “Any event greater than or equal to Grade 
2, please discuss with Study Physician.” 
AE Adverse event; CTCAE Common Terminology Criteria for Adverse Events; NCI National Cancer Institute. 
 


Clinical Study Protocol 
Drug Substance Tremelimumab 
Study Number ESR-14-10744 
Edition Number 8 
 
Date 17 April 2019 
 
Page 88 of 134 
 
6. 
RESTRICTIONS DURING THE STUDY AND CONCOMITANT 
TREATMENT(S) 
6.1 
Restrictions during the study 
Contraception 
Female subjects of childbearing potential who are sexually active with a non-sterilized male 
partner must use at least one highly effective method of contraception (Table 5) from the time 
of screening and must agree to continue using such precautions for 90 days after the last dose 
of mono-therapy MEDI4736 or for 180 days after last dose of combination therapy with 
MEDI4736 and tremelimumab. The male partner of a female subject must also use male 
condom plus spermicide throughout this period. Cessation of birth control after this point 
should be discussed with a responsible physician. Not engaging in sexual activity is an 
acceptable practice; however, occasional abstinence, the rhythm method, and the withdrawal 
method are not acceptable methods of contraception. Female patients should refrain from 
breastfeeding and egg cell donation throughout this period. 
• Females of childbearing potential are defined as those who are not surgically sterile (i.e., 
bilateral tubal ligation, bilateral oophorectomy, or complete hysterectomy) or 
postmenopausal (defined as 12 months with no menses without an alternative medical 
cause). 
• Effective methods (including highly effective methods) of contraception are described in 
Table 5. A highly effective method of contraception is defined as one that results in a low 
failure rate (ie, less than 1% per year) when used consistently and correctly. Note that not 
all methods in Table 1 are considered highly effective.  
• Non-sterilized male subjects who are sexually active with a female partner of childbearing 
potential must use male condom plus spermicide  (see Table 5) from screening through 90 
days after the last dose of mono-therapy MEDI4736 or for 180 days after last dose of 
combination therapy with MEDI4736 and tremelimumab. Not engaging in sexual activity 
is an acceptable practice; however, occasional abstinence, the rhythm method, and the 
withdrawal method are not acceptable methods of contraception.  Male patients should 
refrain from sperm donation throughout this period. Female partners of a male subject 
must use an effective method of contraception throughout this period. 


Clinical Study Protocol 
Drug Substance Tremelimumab 
Study Number ESR-14-10744 
Edition Number 8 
 
Date 17 April 2019 
 
Page 89 of 134 
 
. 
Table 5            Effective Methods of Contraception 
Barrier/Intrauterine Methods 
Hormonal Methods 
• 
Male or female condom with or without 
spermicidea,b,c 
• 
Female cap, diaphragm or sponge with 
spermicidea,b,c   
• 
Copper T intrauterine devicee 
• 
Levonorgesterel-releasing intrauterine 
system (eg, Mirena®)d,e 
• 
Implantse 
• 
Hormone shot or injectione  
• 
Combined pille 
• 
Minipillb 
• 
Patche 
a 
Female partners of male subjects must use an effective method of birth control 
b 
Not highly effective (i.e. failure rate of >1% per year)  
c 
A combination of male condom with either cap, diaphragm or sponge with spermicide (double barrier 
methods) are also considered acceptable, but not highly effective, birth control methods  
d 
This is also considered a hormonal method 
e 
Highly effective (i.e. failure rate of <1% per year)    
 
Blood donation 
Subjects should not donate blood while participating in this study, or for at least 90 days 
following the last infusion of MEDI4736 or tremelimumab. 
6.2 
Concomitant treatment(s) 
6.2.1 
Permitted concomitant medications 
Investigators may prescribe concomitant medications or treatments (e.g., acetaminophen, 
diphenhydramine) deemed necessary to provide adequate prophylactic or supportive care 
except for those medications identified as “excluded” as listed in Section 6.2.2. 
6.2.2 
Excluded Concomitant Medications 
The following medications are considered exclusionary during the study.  
1. Any investigational anticancer therapy other than MEDI4736. 
2. Any concurrent chemotherapy, radiotherapy (except palliative radiotherapy), 
immunotherapy, biologic or hormonal therapy for cancer treatment, other than 
tremelimumab and surgical resection. Concurrent use of hormones for noncancerous-
related conditions (e.g., insulin for diabetes and hormone replacement therapy) is 


Clinical Study Protocol 
Drug Substance Tremelimumab 
Study Number ESR-14-10744 
Edition Number 8 
 
Date 17 April 2019 
 
Page 90 of 134 
 
acceptable. Local treatment of isolated lesions for palliative intent also is acceptable 
(e.g., by local surgery or radiotherapy). 
3. Immunosuppressive medications including, but not limited to systemic corticosteroids 
at doses not exceeding 10 mg/day of prednisone or equivalent, methotrexate, 
azathioprine, and TNF-α blockers. Use of immunosuppressive medications for the 
management of investigational product-related AEs or in subjects with contrast 
allergies is acceptable. In addition, use of inhaled and intranasal corticosteroids is 
permitted. A temporary period of steroids will be allowed for different indications, at 
the discretion of the principal investigator (e.g., chronic obstructive pulmonary 
disease, radiation, nausea, etc.).    
4. Live attenuated vaccines within 30 days of MEDI4736 or tremelimumab dosing (i.e., 
30 days prior to the first dose, during treatment with MEDI4736 and for 30 days post 
discontinuation of MEDI4736). Inactivated viruses, are permitted. 
7. 
STUDY PROCEDURES 
Subjects with MPM who are eligible for the study will be enrolled. Subjects first will undergo 
surgical mediastinal lymph node biopsy (cervical mediastinoscopy) and simultaneous surgical 
biopsy of the pleural tumor by thoracoscopy, at which time tumor tissue (goal of 2 g, which is 
generally available) and 25 ml of peripheral blood will be collected. These procedures are 
performed as our standard of care in the treatment of subjects with MPM. Three days to three 
weeks later subjects will receive either MEDI4736 (15 mg/kg once intravenously) or 
MEDI4736 (1500 mg once intravenously) + tremelimumab (75 mg once intravenously). 
Subjects under 30 kg will be treated with weight-based dosing for both MEDI4736 and 
Tremelimumab combination therapy. These patients are excluded from fixed based dosing to 
limit endotoxin exposure from the drug preparations. A control group will include patients 
who are not treated with MEDI4736 or Tremelimumab. One to six weeks after treatment, 
subjects will undergo resectional surgery including extrapleural pneumonectomy or 
pleurectomy/decortication at which time the tumor will be removed (typically 200-1000g) and 
obtained for study. Blood (25ml) also will be obtained for study. In addition, the sixth rib will 
be extracted at the time of the resectional procedure, as is routinely done during these 
procedures. After the removal of the tumor, our standard protocol (in the presence of 
conserved renal function) includes intraoperative heated chemotherapy using a lavage of 


Clinical Study Protocol 
Drug Substance Tremelimumab 
Study Number ESR-14-10744 
Edition Number 8 
 
Date 17 April 2019 
 
Page 91 of 134 
 
intracavitary cisplatin (Sugarbaker et al, 2013, 2014; Richards et al., 2006). Subjects will be 
followed for at least 90 days following the administration of the study drug for potential AEs 
or SAEs related to the study drug. Subjects will be followed for a longer period of time as 
standard of care.  
7.1 
Schedule of study procedures 
Before study entry, throughout the study, and following study drug discontinuation, various 
clinical and diagnostic laboratory evaluations are outlined. The purpose of obtaining these 
detailed measurements is to ensure adequate safety and tolerability assessments. Clinical 
evaluations and laboratory studies may be repeated more frequently if clinically indicated. The 
Schedules of Assessments during the screening and treatment period is provided following the 
Protocol Synopsis.  
7.1.1 
Screening Phase 
Screening procedures will be performed up to 28 days before or on Day 1, unless otherwise 
specified. All subjects must first read, understand, and sign the IRB/REB/IEC-approved ICF 
before any study-specific screening procedures are performed. After signing the ICF, 
completing all screening procedures, and being deemed eligible for entry, subjects will be 
enrolled in the study. Procedures that are performed prior to the signing of the ICF and are 
considered standard of care may be used as screening assessments if they fall within the 28-
day screening window.  
All subjects who screen for this study will have a clinical diagnosis of MPM (based upon CT, 
and/or PET-CT, and or MRI radiographic findings) but not all subjects will have had this 
diagnosis confirmed by a tissue biopsy. In either case patients undergo thoracoscopy to assess 
resectability of disease, and to obtain tissue or additional tissue, when necessary, for 
diagnosis. Thoracoscopy will be performed in these subjects after signing the ICF.  
The following procedures will be performed during the Screening Visit: 
• Informed Consent 
• Review of eligibility criteria 
• Medical history and demographics 
• Complete physical exam  
• ECOG Performance Status 
• Vitals signs, weight and height  
• Review of prior/concomitant medications  


Clinical Study Protocol 
Drug Substance Tremelimumab 
Study Number ESR-14-10744 
Edition Number 8 
 
Date 17 April 2019 
 
Page 92 of 134 
 
• Imaging by CT/MRI, if applicable to study 
• Clinical laboratory tests for: 
o Hematology (see Table 6) 
o Clinical chemistry (see Table 7) 
o TSH 
o Coagulation (PT, PTT, INR) 
o Creatinine Clearance 
o Serum pregnancy test (for women of childbearing potential only) 
o Hepatitis serologies 
o Urinalysis (see Table 8) 
o Disease-specific tumor markers 
7.1.2 
Treatment Phase  
Procedures to be conducted during the treatment phase of the study are presented in the 
Schedule of Assessments.   
Following the Screening Phase, subjects with MPM who are enrolled in the study will undergo 
surgical mediastinal lymph node biopsy (cervical mediastinoscopy) to evaluate nodal status and 
simultaneous surgical biopsy of the pleural tumor by thoracoscopy under general anesthesia, at 
which time tumor tissue (at least 2 g) and peripheral blood (25ml) will be collected for the study. 
These procedures are performed as our standard of care in the treatment of these subjects. The 
thoracoscopy procedure is part of our standard of care in both in subjects who have had a 
previous tissue biopsy and those who have not had a previous biopsy. It is performed to 
determine resectability of the tumor and to obtain tissue to confirm tissue diagnosis. In subjects 
who are consented to the study who have a suspected (clinical) diagnosis of MPM but not a 
tissue diagnosis, if the thoracoscopy procedure reveals that the subject does not have MPM, 
then these subjects will be removed from the study and their tissue and blood samples will be 
destroyed. These subjects will be replaced in the study.  
Three days to three weeks later subjects will be treated with either MEDI4736 (15 mg/kg once 
intravenously) or MEDI4736 (1500 mg once intravenously) + tremelimumab (75 mg once 
intravenously). Subjects under 30 kg will be treated with weight-based dosing for both 
MEDI4736 and Tremelimumab combination therapy. These patients are excluded from fixed 
based dosing to limit endotoxin exposure from the drug preparations. A control group will 
include patients who are not treated with MEDI4736 or Tremelimumab. One to six weeks 
after treatment, subjects will undergo resectional surgery including extrapleural 
pneumonectomy or pleurectomy/decortication under general anesthesia, at which time the 


Clinical Study Protocol 
Drug Substance Tremelimumab 
Study Number ESR-14-10744 
Edition Number 8 
 
Date 17 April 2019 
 
Page 93 of 134 
 
tumor will be removed (typically 200-1000g) and obtained for study. Blood (25ml) also will 
be obtained for the study. The sixth rib will be obtained at the time of the resectional 
procedure as part of the routine procedure. After the removal of the tumor, our standard 
protocol (in the presence of conserved renal function) includes intraoperative heated 
chemotherapy using a lavage of intracavitary cisplatin. 
7.1.3 
End of Treatment 
Subjects will be followed for a minimum of 12 months following entry into the study.  As per 
standard of care, the great majority of patients will receive care with our group for the rest of 
their life, enabling measurement of disease free and overall survival, in our secondary 
objectives. 
In general, subjects will spend approximately 8-14 days in the hospital following resection. 
After discharge from the hospital, subjects will return for follow-up visits at 1 week, 2 weeks, 
and 4 weeks and then every 4 months until death. Chest CT scans will be obtained every 4 
months starting at the first 4-month visit.  
Assessments for subjects who have completed MEDI4736 or MEDI4736 + tremelimumab but 
did not have resection are provided in APPENDIX B.    
7.2 
Description of study procedures 
7.2.1 
Medical history and physical examination, electrocardiogram, weight and 
vital signs 
Findings from medical history (obtained at screening) and physical examination shall be given 
a baseline grade according to the procedure for AEs. Increases in severity of pre-existing 
conditions during the study will be considered AEs, with resolution occurring when the grade 
returns to the pre-study grade or below. 
Physical examinations will be performed on study days noted in the Schedule of Assessments. 
A complete physical examination will be performed and will include an assessment of the 
following (as clinically indicated): general appearance, respiratory, cardiovascular, abdomen, 
skin, head and neck (including ears, eyes, nose and throat), lymph nodes, thyroid, musculo-
skeletal (including spine and extremities), genital/rectal, and neurological systems and at 
screening only, height.   


Clinical Study Protocol 
Drug Substance Tremelimumab 
Study Number ESR-14-10744 
Edition Number 8 
 
Date 17 April 2019 
 
Page 94 of 134 
 
ECGs are required at baseline, prior to the injection of study drug (MEDI4736 or MEDI4736 
+ tremelimumab) and at the end of treatment as well as at any other time point when clinically 
indicated. 
ECGs recorded at baseline will be obtained in triplicate (all 3 within a 5-minute time period at 
least 1 minute apart); ECGs recorded during the treatment phase will be single tracing. All 12-
lead ECGs should be recorded while the subject is in the supine position. A 12-lead ECG will 
be recorded for all subjects on study days noted in Section 8.1. The same method of 
assessment should be used throughout the study. Twelve-lead ECGs will be obtained after the 
subject has been resting in a supine position for at least 5 minutes in each case. On the 
infusion day, ECGs will be recorded within an hour prior to start of infusion and at least one 
time point 0 to 3 hours after the infusion. 
Vital signs (temperature, blood pressure, pulse rate, and respiratory rate) will be measured on 
study days noted in the Schedule of Assessments. On the treatment day, vital signs will be 
measured within an hour prior to the start of infusion, at 30 minutes during the infusion (± 5 
minutes), at the end of infusion (+ 5 minutes), and at 30 minutes (± 5 minutes) and 60 minutes 
(± 5 minutes) post-infusion. If the infusion takes longer than 60 minutes, then blood pressure 
and pulse measurements should follow the principles described here, or more frequently if 
clinically indicated.   
 
7.2.2 
Clinical laboratory tests 
The following clinical laboratory tests will be performed (see the Schedule of Assessments, 
Appendix B for the timepoints of each test): 
• Coagulation parameters: Activated partial thromboplastin time and International 
normalized ratio to be assessed at baseline and as clinically indicated  
• Pregnancy test (female subjects of childbearing potential only) 
o 
Urine human chorionic gonadotropin 
o 
Serum beta-human chorionic gonadotropin (at screening only) 
• Thyroid Stimulating Hormone 


Clinical Study Protocol 
Drug Substance Tremelimumab 
Study Number ESR-14-10744 
Edition Number 8 
 
Date 17 April 2019 
 
Page 95 of 134 
 
o 
free T3 and free T4 only if TSH is abnormal 
• Other laboratory tests 
o 
Hepatitis A antibody, hepatitis B surface antigen, hepatitis C antibody 
o 
HIV antibody 
 
Table 6 
Hematology Laboratory Tests 
Basophils 
Mean corpuscular volume 
Eosinophils 
Monocytes 
Hematocrit 
Neutrophils 
Hemoglobin 
Platelet count 
Lymphocytes 
Red blood cell count 
Mean corpuscular hemoglobin 
Total white cell count 
Mean corpuscular hemoglobin concentration 
 
 
 
 
Table 7 
Clinical chemistry (serum or plasma) Laboratory Tests 
Albumin 
Glucose 
Alkaline phosphatase 
 
Alanine aminotransferase 
Lipase 
Amylase 
 
Aspartate aminotransferase 
Potassium 
Bicarbonate 
Sodium 
Calcium  
Total bilirubina 
Chloride 
Total protein 
Creatinine 
Urea or blood urea nitrogen, depending on local practice 
 
 
a   If Total bilirubin is ≥2xULN (and no evidence of Gilbert’s syndrome) then fractionate into direct and indirect 
bilirubin 
 


Clinical Study Protocol 
Drug Substance Tremelimumab 
Study Number ESR-14-10744 
Edition Number 8 
 
Date 17 April 2019 
 
Page 96 of 134 
 
Table 8 
Urinalysis Testsa 
Bilirubin 
pH 
Blood 
Protein 
Glucose 
Specific gravity 
Ketones 
Color and appearance 
a  Microscopy should be used as appropriate to investigate white blood cells and use the high power field for red 
blood cells 
7.3 
Biological sampling procedures 
Biological samples will be collected at two primary time points during the study. Tumor tissue 
(generally, at least 2 grams) and peripheral blood (25ml) will be collected during pre-
treatment surgical mediastinal lymph node biopsy (cervical mediastinoscopy) and 
simultaneous surgical biopsy of the pleural tumor by thoracoscopy. One to six weeks after 
treatment, subjects will undergo resectional surgery, including extrapleural pneumonectomy 
or pleurectomy/decortication, at which time the tumor will be removed (typically 200-1000g) 
and blood (25ml) will be collected for the study.  
7.3.1 
Biomarker/Pharmacodynamic sampling and evaluation methods 
Tissue biomarker immune response to MEDI4736 or MEDI4736 + tremelimumab will be 
determined on tissue and blood collected before and after the administration of the study drug(s), 
or in patients not receiving study drugs. The tissue biomarker immune responses that will be 
evaluated in this study include CD8/Treg ratios, percentage of ICOS+ CD4 T cells, and immune 
cell expression of PD-L1. CD8/Treg rations and percentage of ICOS+ CD4 T cells will be 
compared with CyTOF (time-of-flight mass cytometry) and/or flow cytometry. Tumor PD-L1 
expression will be determined by immunohistochemistry. CyTOF and/or flow cytometry will 
be used to compare PD-L1 expression on specific immune cell and non-immune cell 
populations. 
Bone marrow biomarker immune response will also be assessed. Bone marrow will be collected 
from a routinely resected sixth rib during the surgical resection scheduled post-treatment with 
MEDI4736 or MEDI4736 + tremelimumab, or in patients not receiving study drugs. A 
comprehensive evaluation of immune cell composition and phenotype with CyTOF will be 
conducted on bone marrow tissue as well as tumor tissue and peripheral blood. Appendix C 
details the complete CyTOF panel that will be used for each individual specimen. 


Clinical Study Protocol 
Drug Substance Tremelimumab 
Study Number ESR-14-10744 
Edition Number 8 
 
Date 17 April 2019 
 
Page 97 of 134 
 
7.3.2 
Estimate of volume of blood to be collected 
Blood samples will be drawn at two points: during the thoracoscopy procedure and during the 
resection procedure (P/D or EPP). In both cases, the sample will be drawn immediately after 
the induction of general anesthesia via a radial arterial catheter that is routinely placed for 
these procedures. A total of 50 cc will be drawn in the study (25-cc per time point).   
7.3.3 
Fresh tumor biopsies 
Fresh tumor biopsies will be sampled from patients at two time points during the study. Prior 
to treatment with the study drug(s), patients will undergo surgical mediastinal lymph node 
biopsy (cervical mediastinoscopy) and simultaneous surgical biopsy of the pleural tumor by 
thoracoscopy under general anesthesia, at which time tumor tissue (generally 2 g) will be 
collected. One to six weeks after study drug(s) infusion, patients will undergo resectional 
surgery including extrapleural pneumonectomy or pleurectomy/decortication under general 
anesthesia, at which time the tumor will be removed (typically 200-1000 g) and obtained for 
study. These biopsied tissues will be used to determine tissue biomarker immune response to 
MEDI4736 or MEDI4736 + tremelimumab using CyTOF as described in Section 9.1.1 and 
9.1.2.  
7.3.4 
Withdrawal of informed consent for donated biological samples 
If a subject withdraws consent to the use of donated samples, the samples will be disposed 
of/destroyed, and the action documented. As collection of the biological samples is an integral 
part of the study, then the subject is withdrawn from further study participation. 
The Principal Investigator: 
• 
Ensures that biological samples from that subject, if stored at the study site, are 
immediately identified, disposed of /destroyed, and the action documented 
• 
Ensures the laboratory(ies) holding the samples is/are informed about the withdrawn 
consent immediately and that samples are disposed/destroyed, the action documented 
and the signed document returned to the study site 
• 
Ensures that the subject is informed about the sample disposal. 


Clinical Study Protocol 
Drug Substance Tremelimumab 
Study Number ESR-14-10744 
Edition Number 8 
 
Date 17 April 2019 
 
Page 98 of 134 
 
8. 
DISEASE EVALUATION AND METHODS 
8.1.1 
Primary Efficacy Variables 
1) 
The primary objective of this study will be comparison of the ratio of intratumoral 
cytotoxic T cells to regulatory T cells (CD8/Treg) before and after treatment with combination 
MEDI-4736 and Tremelimumab checkpoint inhibitor therapy. CD8/Treg ratios will be 
determined with CyTOF 
8.1.2 
Secondary Efficacy Variables 
The secondary objectives of this study are: 
1) 
Comparison of the percentage of inducible T-cell co-stimulator (ICOS) positive 
intratumoral CD4 T cells before and after treatment with combination MEDI-4736 and 
Tremelimumab checkpoint inhibitor therapy. These data will be obtained using CyTOF  
2) 
Comparison of tumor tissue expression (Ventana assay) of programmed death-ligand 1 
(PD-L1) before and after treatment with combination MEDI-4736 and Tremelimumab 
checkpoint inhibitor therapy. These data will be obtained with IHC. 
3) 
Comparison of the ratio of the intratumoral CD8/Treg ratio in patients treated with 
combination therapy (MEDI-4736 and Tremelimumab) compared to either patients treated 
with MEDI-4736 alone , and separately compare to untreated patients. These data will be 
obtained with CyTOF. 
4) 
Comparison of the percentage of inducible T-cell co-stimulator (ICOS) positive 
intratumoral CD4 T cells in patients treated with combination therapy (MEDI-4736 and 
Tremelimumab) compared to either patients treated with MEDI-4736 alone, and separately 
compare to untreated patients. These data will be obtained with CyTOF. 
5) 
Comparison of tumor tissue expression (Ventana assay) of programmed death-ligand 1 
(PD-L1) in patients treated with combination therapy (MEDI-4736 and Tremelimumab) 
compared to either patients treated with MEDI-4736 alone, and separately compare to 
untreated patients. These data will be obtained with IHC. 
6) 
Comparison of overall survival in patients treated with either MEDI-4736 alone or 
MEDI-4736 plus Tremelimumab with historical untreated controls. These data will be 
obtained from our standard of care follow up of these patients. Given the survival estimates of 
these patients from historical controls, these data can be evaluated approximately 2 year after 
surgery. These analysis will be post-protocol analysis based upon data obtained from the 
standard of care follow up in our post-surgical patients.  


Clinical Study Protocol 
Drug Substance Tremelimumab 
Study Number ESR-14-10744 
Edition Number 8 
 
Date 17 April 2019 
 
Page 99 of 134 
 
7) 
Comparison of recurrence-free survival in patients treated with either MEDI-4736 
alone or MEDI-4736 plus Tremelimumab with historical untreated controls. Given the 
recurrence free survival estimates of these patients from historical controls, these data can be 
evaluated approximately 2 year after surgery. These analysis will be post-protocol analysis 
based upon data obtained from the standard of care follow up in our post-surgical patients. 
8)     Additional tissue biomarker immune response to MEDI4736 or MEDI4736 + 
tremelimumab determined with CyTOF. A comprehensive evaluation of immune cell 
composition and phenotype will be compared between preoperative and postoperative tumor 
tissue and peripheral blood. Appendix C details the complete CyTOF panel that will be used 
for each individual specimen. Substudies will include:  
a. 
Changes in T-cell subset (CD4, CD8, FoxP3) frequency and memory and 
activation phenotype (CD25, CD127, CD45RA, CD62L, CCR4, CCR6, 
Tim1) 
b. 
Changes in T-cell polarization state (intracellular interferon-gamma, 
TNF-alpha, IL-17, IL-2) 
c. 
Changes in myeloid cell composition: dendritic cells, macrophage, 
MDSC, neutrophil (HLA-DR, CD11c, BDCA-1, BDCA-2, BDCA-3, 
BDCA-4, CD68, CD163, CD206, CD66b, CD15) 
d. 
Changes in NK cell and NK T-cell composition (CD56, CD3, V224, 
Vbeta11) 
9)   Bone marrow biomarker immune response to MEDI4736 or MEDI4736 + tremelimumab. 
CyTOF will be used to compare immune cell composition and phenotype, as outlined 
above in number 8, in the bone marrow (from a routinely resected sixth rib) from patients 
treated with MEDI4736 or MEDI4736 + tremelimumab, and untreated controls. 
3) 
Tumor and peripheral blood immune cell expression of PD-1 and CTLA-4 
a. 
CyTOF will be used to compare PD-1 and CTLA-4 expression on 
specific immune cell and non-immune cell populations. 
4) 
Tissue immune gene expression in response to MEDI4736 or MEDI4736 + 
tremelimumab  


Clinical Study Protocol 
Drug Substance Tremelimumab 
Study Number ESR-14-10744 
Edition Number 8 
 
Date 17 April 2019 
 
Page 100 of 134 
 
a. 
NanoString gene expression arrays will be used to compare gene 
expression of 300 immune-related genes in tumor tissue obtained 
preoperatively and postoperatively 
9. 
ASSESSMENT OF SAFETY 
The Principal Investigator is responsible for ensuring that all staff involved in the study is 
familiar with the content of this section. 
9.1.1 
Safety Parameters 
9.1.1.1 
Definition of adverse events 
The International Conference on Harmonization (ICH) Guideline for Good Clinical Practice 
(GCP) E6 (R1) defines an AE as: 
Any untoward medical occurrence in a patient or clinical investigation subject administered a 
pharmaceutical product and which does not necessarily have a causal relationship with this 
treatment. An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease temporally associated with the use of a 
medicinal product, whether or not considered related to the medicinal product. 
An AE includes but is not limited to any clinically significant worsening of a subject’s 
pre-existing condition. An abnormal laboratory finding (including ECG finding) that requires 
an action or intervention by the investigator, or a finding judged by the investigator to 
represent a change beyond the range of normal physiologic fluctuation, should be reported as 
an AE. 
Adverse events may be treatment emergent (i.e., occurring after initial receipt of 
investigational product) or nontreatment emergent. A nontreatment-emergent AE is any new 
sign or symptom, disease, or other untoward medical event that begins after written informed 
consent has been obtained but before the subject has received investigational product.  
Elective treatment or surgery or preplanned treatment or surgery (that was scheduled prior to 
the subject being enrolled into the study) for a documented pre-existing condition, that did not 
worsen from baseline, is not considered an AE (serious or nonserious). An untoward medical 


Clinical Study Protocol 
Drug Substance Tremelimumab 
Study Number ESR-14-10744 
Edition Number 8 
 
Date 17 April 2019 
 
Page 101 of 134 
 
event occurring during the prescheduled elective procedure or routinely scheduled treatment 
should be recorded as an AE or SAE. 
The term AE is used to include both serious and non-serious AEs. 
9.1.2 
Definition of serious adverse events 
A serious adverse event is an AE occurring during any study phase (i.e., screening, run-in, 
treatment, wash-out, follow-up), at any dose of the study drugs that fulfils one or more of the 
following criteria: 
• 
Results in death 
• 
Is immediately life-threatening 
• 
Requires in-patient hospitalization or prolongation of existing hospitalization  
• 
Results in persistent or significant disability or incapacity  
• 
Is a congenital abnormality or birth defect in offspring of the subject 
• 
Is an important medical event that may jeopardize the patient or may require 
medical intervention to prevent one of the outcomes listed above. 
• Medical or scientific judgment should be exercised in deciding 
whether expedited reporting is appropriate in this situation. 
Examples of medically important events are intensive treatment 
in an emergency room or at home for allergic bronchospasm, 
blood dyscrasias, or convulsions that do not result in 
hospitalizations; or development of drug dependency or drug 
abuse. 
The causality of SAEs (their relationship to all study treatment/procedures) will be assessed 
by the investigator(s) and communicated to AstraZeneca. 
9.1.3 
Definition of adverse events of special interest (AESI) 
Adverse events of special interest (AESIs) are events of scientific and medical interest specific 
to the further understanding of the MEDI4736 and tremelimumab safety profile and require 
close monitoring and rapid communication by the investigator to the sponsor. MEDI4736 and 


Clinical Study Protocol 
Drug Substance Tremelimumab 
Study Number ESR-14-10744 
Edition Number 8 
 
Date 17 April 2019 
 
Page 102 of 134 
 
tremelimumab AESIs may be serious or non-serious. The rapid reporting of these AESIs 
allows ongoing analysis of these events in order to characterize and understand them in 
association with the use of this investigational product. 
MEDI4736, an anti-PD-L1 antibody, and tremelimumab, an anti-CTLA-4 antibody both 
belongs to a new class of anticancer therapies, called “checkpoint-inhibitors” that amplify 
antitumor immune responses by blocking inhibitory signaling pathway modulated by the co-
inhibitory or co-stimulatory receptors, PD-1 and  CTLA-4 and, expressed on T cells (Callahan 
and Wolchok, 2013). This class of drugs can have a wide spectrum of immune-mediated 
reactions that have been considered inflammatory in nature and can affect any organs of the 
body. Based on this mechanism of action of MEDI4736 and related molecules Adverse events 
of special interest include immune-mediated reactions such as enterocolitis, dermatitis, 
hepatotoxicity or hepatitis, endocrinopathy, neuropathy and pneumonitis as well as infusion 
related reactions, serious allergic reactions and anaphylaxis.  
 
9.1.3.1 
Pneumonitis 
Immune-mediated pneumonitis is characterized by inflammation focally or diffusely affecting 
the lung parenchyma that may be result of off-target effects of checkpoint inhibitors against 
the normal lung parenchyma. (Chow, 2013) Presentations of pneumonitis range from 
asymptomatic lung infiltrates to a mimic of severe bacterial pneumonia. For symptomatic 
patients, complaints and findings may include dyspnea, cough, tachypnea, pleuritic chest pain, 
and hypoxia. 
Because pneumonitis can quickly escalate and become fatal, early recognition is essential. 
Initial workup includes chest imaging; however, pneumonitis can have highly variable 
appearances on chest CT scans. In patients with pulmonary metastases or cardiopulmonary 
comorbidities, evaluation can be particularly challenging as it can be difficult to differentiate 
between infection, early pulmonary edema, alveolar hemorrhage, immune-mediated 
pneumonitis, immune-related tumor inflammation, and tumor progression (Topalian et al, 
2012). Pneumonitis has also been reported as a complication of cancer treatment associated 
with lung and breast cancer. 


Clinical Study Protocol 
Drug Substance Tremelimumab 
Study Number ESR-14-10744 
Edition Number 8 
 
Date 17 April 2019 
 
Page 103 of 134 
 
As of the DCO dates for the IB, pneumonitis including ILD was reported at a frequency rate 
of Common (44/1645; 2.7%). Most were non-serious and Grade 1 or 2 in severity. CTC Grade 
3 pneumonitis was reported in 7 patients (0.4%); CTC Grade 4 in 2 patients (0.1%) and CTC 
Grade 5 pneumonitis in 2 patients (0.1%). CTC Grade 3 ILD was reported in 3 patients 
(0.2%). There were no CTC Grade 4 or 5 events of ILD. 
 
In the durvalumab + tremelimumab combination in patients receiving 20 mg/kg durvalumab 
iv Q4W and 1 mg/kg tremelimumab, pneumonitis including ILD was reported at a frequency 
of Common (14/560; 2.5%). Most events were CTC Grade 1 or 2. CTC Grade 3 pneumonitis 
was reported in 3 patients (0.5%). There were no reports of CTC Grade 4 or 5 pneumonitis 
reported and no Grade 3 or higher ILD events in the combination patients. 
 
Presentations of pneumonitis can range from asymptomatic lung infiltrates to those that mimic 
severe bacterial pneumonia (Teply and Lipson 2014). Early consideration of pneumonitis 
should be realized when patients present with new onset or worsening of respiratory 
symptoms such as dyspnoea or cough. Prompt treatment with steroids is important as per 
current established toxicity management guidelines. 
 
9.1.3.2 
Infusion-Related Reactions, Anaphylaxis and Allergic Reactions 
Adverse reactions that occur during or shortly after infusion may include fever, chills, 
hypotension, dyspnoea, tachycardia, cyanosis, respiratory failure, urticarial and pruritus, 
angioedema, hypotonia, arthralgia, bronchospasm, wheeze, cough, dizziness, fatigue, 
headache, hypertension rash, headache, flushing, sweating, myalgia, nausea, vomiting, 
unresponsiveness, and haemodynamic instability. The typical onset can be within 30 minutes 
to 2 hours after the initiation of drug infusion, although symptoms may be delayed for up to 
24 hours. The majority of reactions occur after the first or second exposure to the agent, but 
between 10% and 30% occur during subsequent treatments (Lenz 2007). 
 
Anaphylaxis is a systemic, immediate hypersensitivity reaction that is mediated by 
interactions between factors released from IgE and mast cells; these interactions result in an 
antigenantibody reaction. Clinical manifestations of acute allergic reactions may range from 
localised skin reactions at the injection site to AEs, which can include, but are not limited to, 
those events  similar to infusion-related reactions to severe reactions including anaphylaxis, 
and drug hypersensitivity syndromes, These reactions may be more common 
with higher rates of infusion, and in patients with a history of allergies. 
Across the durvalumab monotherapy and durvalumab + tremelimumab combination therapy 
programme 37 (2.2%) and 11 (2.0%) patients respectively have experienced either an infusion 
related reaction or hypersensitivity/anaphylactic reaction. The majority of events were CTC 
Grade 1 or 2 with 5 patients experiencing a CTC Grade 3 event of infusion related reaction 
and 1 patient with a CTC Grade 4 event of drug hypersensitivity (all receiving durvalumab 
monotherapy). There have been no reported CTC Grade 5 events as of the DCO. 


Clinical Study Protocol 
Drug Substance Tremelimumab 
Study Number ESR-14-10744 
Edition Number 8 
 
Date 17 April 2019 
 
Page 104 of 134 
 
Patients participating in durvalumab clinical studies should be closely monitored during 
and after infusions. Severe hypersensitivity reactions should be managed according to 
standard clinical practice, and medical equipment and staff trained to treat acute anaphylactic 
reactions must be immediately available at all sites that perform mAb infusions. 
 
Cytokine release syndrome 
Certain mAb therapeutics have been shown to induce a range of acute infusion reactions 
including cytokine-release syndrome that can lead to AEs in patients. As of the DCO date, 
there have been no reported events of cytokine release syndrome in the ongoing durvalumab 
+/- tremelimumab studies. 
 
Immune-complex disease 
The potential risk of immune complex disease for 
durvalumab is theoretical based on the known risk associated with mAbs and other proteins. 
The incidence of durvalumab ADA-positive patients in clinical studies is low, and hence the 
risk of immune complex disease is likely to be low. 
 
Specifically, of 1124 patients who were treated with durvalumab 10 mg/kg Q2W and 
evaluable for the presence of ADAs, 3.3% (37/1124) patients tested positive for treatment-
emergent ADAs. Neutralising antibodies against durvalumab were detected in 0.3% (3/1124) 
patients. The presence of ADAs did not have a clinically relevant effect on PK. In 
combination with tremelimumab the incidence is 4/60 patients (Study D4190C00006). Studies 
with tremelimumab also showed a low incidence of ADA. There have been no reported events 
of immune complex reactions in patients receiving durvalumab monotherapy or in 
combination with tremelimumab. 
 
Considering the low incidence of immunogenicity of durvalumab and tremelimumab and the 
lack of clinically apparent immune complex disease to date, samples for ADA monitoring 
may be collected in studies if clinical AEs consistent with immune complex disease are 
observed. 
 
For guidance on identifying, evaluating, and treating an imAE please see the toxicity 
management guidelines included in each of the study protocols. 
 
9.1.3.3 
Hepatic function abnormalities (hepatotoxicity) 
Immune-mediated hepatitis/hepatic toxicity is the inflammation of the liver. Hepatic AEs 
induced by PD-1/PD-L1 inhibitors commonly present as asymptomatic increase of AST and 
ALT, rarely total bilirubin. A proportion of patients may be presenting with fatigue, fever and 
radiologic appearances including hepatomegaly, periportal lymphadenopathy and periportal 
oedema (Zhang et al 2016). 
As a grouped term, selected hepatic events including laboratory abnormalities were reported at 


Clinical Study Protocol 
Drug Substance Tremelimumab 
Study Number ESR-14-10744 
Edition Number 8 
 
Date 17 April 2019 
 
Page 105 of 134 
 
a frequency of 15.1% (248 patients) across 1645 patients who have received durvalumab 
monotherapy 10 mg/kg Q2W. Hepatitis events (autoimmune hepatitis, hepatitis toxic, 
hepatocellular injury, hepatotoxicity and hepatitis acute) were reported at a frequency rate of 
Uncommon (14 patients; 0.9%). For 9 of the 14 patients, the events of hepatitis were CTC 
Grade 3 in severity. There were no Grade 4 events. One patient experienced a CTC Grade 5 
event of autoimmune hepatitis. Other AESIs such as hepatic failure (5 patients), jaundice (4 
patients) and laboratory abnormality AESIs have been observed, two of which resulted in a 
fatal outcome (CTC Grade 5 hepatic failure and hyperbilirubinaemia). With the durvalumab + 
tremelimumab combination patients, there were two reports of hepatitis, 1 CTC Grade 1 
hepatitis (1 of 560 patients; 0.2%) and 1 CTC Grade 3 autoimmune hepatitis (0.2%) both of 
which were considered treatment-related by the reporting investigator. Additionally, there was 
1 report of non treatment-related Grade 2 hepatic failure. 
Monitoring liver function tests while receiving study medication is important as hepatitis often 
manifests as asymptomatic elevated levels of hepatic transaminases (ALT, AST, bilirubin; 
Kim et al 2013). Prompt treatment with steroids is important as per current established toxicity 
management guidelines. 
In Ipilimumab-treated patients, clinical manifestations of hepatitis included nonspecific 
symptoms of mild fever, general weakness, fatigue, nausea and/or abdominal pain. In the 
absence of clinical symptoms, treatment-emergent hepatitis presented asymptomatically as 
elevated hepatic transaminases. Ultrasonograms of the liver can appear normal or may 
demonstrate homogenous hepatomegaly, edema, or enlarged perihepatic lymph nodes. Biopsy 
of the liver most commonly shows a diffuse T-cell infiltrate. Other reported pathology 
patterns include inflammation focused around either hepatocytes or bile ducts.  
If subject presents with liver dysfunction, a high suspicion for irAE hepatitis is warranted, 
however, it is important to distinguish treatment-related toxicity and rule out other causes of 
hepatic injury, such as infection, preexisting medical conditions, immunosuppression, 
metabolic or cardiovascular derangements, other medications, or tumor progression. 
 
9.1.3.4 
Rash/Dermatitis 
 
Immune-mediated dermatitis is generally mild and presents as mild local or diffuse 
maculopapular, erythematous rash on the trunk or extremities, which may be accompanied by 
pruritus, alopecia, and vitiligo, suggestive of inflammatory response to melanocytes 


Clinical Study Protocol 
Drug Substance Tremelimumab 
Study Number ESR-14-10744 
Edition Number 8 
 
Date 17 April 2019 
 
Page 106 of 134 
 
(Lacouture et al 2014). In rare cases, severe dermatitis has been reported to manifest as 
Stevens-Johnson syndrome, toxic epidermal necrolysis, or rashes complicated by dermal 
ulceration or necrotic, bullous, or haemorrhagic manifestations (Tarhini 2013, Kaehler et al 
2010). 
 
AESIs of rash (as a composite term) were reported as Very common in 199 (12.1%) patients 
receiving durvalumab monotherapy and Very common in 124 (22.1%) patients receiving the 
combination. The majority of events were CTC Grade 1 or 2, with 7 and 4 patients, 
respectively, experiencing CTC Grade 3 events. 
 
AESIs falling under the grouped term of dermatitis that include milder events such as pruritus, 
eczema and erythema to more specific or severe skin toxicities such as events of dermatitis 
bullous, dermatitis exfoliative or dermatitis psoriasiform, have been observed with 
durvalumab monotherapy. Overall, the range of these events have been reported at a 
frequency of Very common (n=237; 14.4%) in monotherapy treated patients and patients 
receiving durvalumab + tremelimumab combination (n=114; 20.4%). However, most events 
were CTC Grade 1 in severity with 3 patients and 4 patients experiencing CTC Grade 3 events 
in the monotherapy and combination treated groups respectively. 
 
Prompt treatment with steroids (topical or systemic based on severity) is important as per 
current established toxicity management guidelines. 
Pathologic evaluations of biopsy specimens of affected skin often demonstrate eosinophilic 
infiltration or leukocytoclastic vasculitis; or, they may reveal a lymphocytic predominance 
characterized by CD8+ T cells, sometimes with tropism for melanin-containing cells. 
Specifically, in metastatic melanoma patients, the rash associated with immune-checkpoint 
inhibitors may be indicative of immune response to melanocytes and may progress to vitiligo 
in some cases. Biopsies showed severe dermatitis with papillary dermal edema, sometimes 
accompanied by perivascular lymphocytic infiltrate. 
Guidelines for the management of subjects with immune-mediated events including dermatitis 
are outlined in Section 6.6.1. 
 
9.1.3.5 
Colitis 
Diarrhoea is the most frequent AESI reported across the Phase I to Phase III clinical studies 
with durvalumab monotherapy, as of the DCO dates for this IB with a frequency of Very 
common (263/1645; 16.0%) in patients receiving 10 mg/kg durvalumab iv Q2W. Most of 
thesewere CTC Grade 1 in severity. Treatment-emergent colitis-type AESIs were reported at a 


Clinical Study Protocol 
Drug Substance Tremelimumab 
Study Number ESR-14-10744 
Edition Number 8 
 
Date 17 April 2019 
 
Page 107 of 134 
 
frequency of Common (16 of 1645 patients; 1.0%). Most were CTC Grade 2 or 3. CTC Grade 
4 colitis was reported in 1 patient (rare; <0.1%). 
 
In the durvalumab + tremelimumab combination in patients receiving 20 mg/kg durvalumab 
iv Q4W and 1 mg/kg tremelimumab, diarrhoea was reported at a frequency of Very common 
(144/560; 25.7%) with most CTC Grades 1 or 2. Colitis was reported at a frequency of 
Common (26/560; 4.6%). Most colitis events were CTC Grade 3 reported in 17 of the 26 
patients on the combination. There were no CTC Grade 4 or 5 cases reported in the 
combination patients.  Patients should be monitored for signs and symptoms of colitis or 
diarrhoea.  
 
Investigators are instructed to begin diarrhoea management early to minimise the risk of 
colitis (please refer to the toxicity management guidelines in the study protocols). Early 
initiation of diarrhea treatment guidelines has been shown to reduce bowel perforation and 
colectomy rates, drug-related diarrhoea, and serious gastrointestinal imAEs by up to 50% in 
patients treated with ipilimumab (Tarhini 2013). 
 
 
9.1.3.6 
Endocrinopathy (hypothyroidism, hyperthyroidism, hypopituitarism) 
Immune-mediated endocrinopathy is the inflammation of any organ in the hypothalamic 
pituitary- adrenal axis, but is most typically reported to affect the pituitary, thyroid and/or 
adrenal glands in patients treated with checkpoint inhibitors, leading to 
hypophysitis/hypopituitarism, thyroid dysfunction, and/or adrenal insufficiency (Teply and 
Lipson 2014). The clinical presentation of immune-mediated endocrinopathies most often 
include hypothyroidism, hyperthyroidism, and nonspecific symptoms of headache and fatigue, 
but may also include myalgias, visual field defects, behavioural changes, electrolyte 
disturbances, loss of appetite and hypotension (Tarhini 2013). Patients will generally have 
abnormal endocrine laboratory test results that include thyroid-stimulating hormone, free T4, 
total and free T3, cortisol, adrenocorticotrophic hormone, luteinising hormone, 
folliclestimulating hormone, and testosterone. 
 
Most endocrinopathy events reported were CTC Grade 1 or 2. In the monotherapy pool CTC 
Grade 3 events consisted of adrenal insufficiency (2 patients), hypophysitis/hypopituitarism 
(1 patient), hyperthyroidism (1 patient) and hypothyroidism (2 patients). There were no CTC 
Grade 4 or 5 events. In the combination pool there was a slightly increased incidence of 
higher-grade events of adrenal insufficiency with 3 patients experiencing CTC Grade 3 and 1 
patient with CTC Grade 4 in severiyy. There was 1 patient with CTC Grade 3 
hyperthyroidism 
and 1 patient with CTC Grade 3 hypophysitis/hypopituitarism. 
 


Clinical Study Protocol 
Drug Substance Tremelimumab 
Study Number ESR-14-10744 
Edition Number 8 
 
Date 17 April 2019 
 
Page 108 of 134 
 
Prompt initiation of hormone replacement therapy is important for hypothyroidism. Additional 
guidance for other types of endocrinopathies is provided in the toxicity management 
guidelines. 
Type 1 diabetes mellitus 
Type I diabetes mellitus is a heterogeneous disorder characterised by destruction of pancreatic 
beta cells, culminating in absolute insulin deficiency. The majority of cases are attributable to 
an autoimmune-mediated destruction of beta cells (type 1a) while a small minority of cases 
results from an idiopathic destruction or failure of beta cells (type 1b) (Maahs et al 2010). 
Latent autoimmune diabetes in adults (LADA) is the most common term describing patients 
with a type 2 diabetic phenotype combined with islet antibodies and slowly progressive 
betacell failure. Evidence on the occurrence of LADA in relation to adult Type I diabetes 
mellitus in the general population is usually estimated, due, in part, to limited availability of 
diagnostic criteria for the LADA (Leslie et al 2006). 
 
Across the monotherapy and combination pool of studies there have been no reported events 
of type 1 diabetes mellitus. However, 1 patient receiving durvalumab monotherapy in an 
ongoing phase III randomised clinical study outside of the pooled dataset (<0.1%) experienced 
Grade 3 type 1 diabetes mellitus. The patient, a 60 year old Caucasian male with NSCLC 
without a history of diabetes mellitus or hyperglycemia, developed severe autoimmune-
mediated hyperglycemia (blood glucose 458 mg/dL) 43 days after starting durvalumab, was 
tested positive for anti-GAD antibody 322 U/mL (reference range 0 to 5 U/mL) and was 
negative for B-islet antibody. He was diagnosed with type 1 diabetes mellitus by an 
endocrinologist. The type 1 diabetes mellitus was treated with insulin and resolved with 
sequelae (insulin dependency). 
 
For patients with suspected diabetes mellitus investigators should obtain an endocrinology 
consult and institute appropriate management which may include the administration of insulin. 
Also please refer to the endocrinology section of the toxicity management guidelines in the 
study protocols. 
 
Nephritis 
The major clinical syndromes produced by immune-mediated renal injury include nephrotic 
syndrome, rapidly progressive glomerulonephritis, and acute renal failure (Cunard and Kelly 
2003). In association to immune-checkpoint inhibitors, two different forms of 
ipilimumabinduced renal damage are reported, acute kidney injury due to predominant acute 
granulomatous tubulointerstitial nephritis and nephrotic syndrome in lupus nephritis (Izzedine 
et al 2014). Signs and symptoms include increase in serum creatinine, decrease in urine 
output, peripheral oedema, haematuria, loss of appetite. 
 
As a grouped term, selected renal events including laboratory abnormalities were reported at a 


Clinical Study Protocol 
Drug Substance Tremelimumab 
Study Number ESR-14-10744 
Edition Number 8 
 
Date 17 April 2019 
 
Page 109 of 134 
 
frequency of 5.3% (87 patients) across the 1645 patients included in the durvalumab 
monotherapy pool. Nephritis events were reported at a frequency rate of Uncommon (5 
patients; 0.3%) with 1 CTC Grade 2 autoimmune nephritis, 1 CTC Grade 2 
glomerulonephritis, 2 CTC Grade 2 nephritis and 1 CTC Grade 3 tubulointerstitial nephritis. 
There was 1 CTC Grade 3 nephritis reported in the 560 (0.2%; Uncommon) patients in the 
durvalumab + tremelimumab combination pool. An additional AESI of acute kidney injury 
was reported in 26 patients (1.6%) receiving durvalumab monotherapy and 7 patients (1.3%) 
in the combination pool, 1 of which was CTC Grade 5 in severity; the event was considered 
not treatment-related by the reporting investigator. 
 
Patients should be monitored for changes in renal function (eg, that manifest as elevated 
serum blood urea nitrogen and creatinine, decreased creatinine CL, electrolyte imbalance, 
decrease in urine output, or proteinuria and any other findings that may be indicative of 
nephritis) prior to  and periodically during treatment. Prompt treatment with steroids is 
important as per current established toxicity management guidelines in the study protocols. 
 
9.1.3.7 
Neuropathy/Neuromuscular Events (to include MG and GB) 
Neuromuscular toxicity is relatively uncommon but may manifest as a mild peripheral sensory 
neuropathy or muscle weakness. Although they are rare, severe neuropathies and myopathies 
have been observed. Emergent cases of neuropathy can present with Guillain-Barré syndrome, 
transverse myelitis, or myasthenia gravis, among other diagnoses. Depending on presentation, 
patients may require neuroimaging, nerve conduction studies, and, potentially, nerve or 
muscle biopsy to arrive at the diagnosis (Teply and Lipson 2014). Isolated cases of 
myasthenia gravis have been reported in studies combining anti-PD-1/PD-L1 mAb with anti-
CTLA-4 mAb ( Naidoo et al 2015). 
 
As of the DCO for this IB there have been no reports of Guillain-Barre syndrome or 
Myasthenia Gravis in patients receiving durvalumab monotherapy. Two patients receiving the 
durvalumab + tremelimumab combination have reported a case of Myasthenia Gravis but 
none at the recommended dose of 20 mg/kg durvalumab iv Q4W and 1 mg/kg tremelimumab. 
 
Prompt treatment of these conditions as per current toxicity management guidelines is 
important. Patients should be monitored for signs and symptoms that may include peripheral 
sensory neuropathy, muscle weakness, peripheral neuropathy including numbness, tingling, 
and 
sensitivity to touch. 
Neuropathies associated with ipilimumab have been difficult to assess because these irAEs are 
transient and present with vague symptoms. Presentations of neurotoxicity may include a mild 
peripheral sensory neuropathy or muscle weakness. Symptoms of peripheral neuropathy 


Clinical Study Protocol 
Drug Substance Tremelimumab 
Study Number ESR-14-10744 
Edition Number 8 
 
Date 17 April 2019 
 
Page 110 of 134 
 
include numbness, tingling, paresthesia (pins and needles sensations), sensitivity to touch, or 
muscle weakness. In patients with extreme symptoms, they may present with burning pain, 
muscle wasting, paralysis, or organ dysfunction. Symptoms are typically detected with 
physical examination findings ranging from sensory changes to loss of deep-tendon reflexes.  
Depending on presentation, patients may require neuroimaging, nerve conduction studies, and, 
potentially, nerve or muscle biopsy to arrive at the diagnosis. 
Pancreatitis 
Pancreatitis is an inflammatory condition of the pancreas that typically manifests initially as 
asymptomatic elevations of amylase and lipase in patients treated with immune checkpoint 
inhibitors. Clinical presentation frequently includes low-grade abdominal pain with 
accompanying fever and malaise (Weber et al 2012, Di Giacomo et al 2010). Biopsies showed 
diffuse T-cell infiltrate consistent with immune-mediated pancreatitis (Weber et al 2012). 
 
Across the 1645 patients in the monotherapy program, events of pancreatitis were Uncommon 
to rare. Two patients (0.1%) experienced pancreatitis (CTC Grade 3 and Grade 4 in severity) 
and 1 patient (<0.1%) with CTC Grade 3 acute pancreatitis. Elevations in amylase and lipase 
were reported at a frequency rate of Common (0.4% and 0.4%, respectively). In ongoing 
sponsored studies with durvalumab + tremelimumab therapy in 560 patients, events of 
pancreatitis were Uncommon; pancreatitis was reported in 4 patients (0.7%) with 3 of these 
CTC Grade 3 in severity and acute pancreatitis in 1 patient (0.2%). Elevations in amylase and 
lipase were reported at a frequency of Common (6.1% and 7.0%, respectively). Patients 
should be monitored for signs and symptoms of pancreatitis including Grade 3 or 4 elevations 
in lipase and/or amylase.  
 
Prompt treatment of this condition as per current established toxicity management guidelines 
is important. 
 
Other Potential Risks 
Serious Infections 
Serious and/or ≥ Grade 3 infections requiring hospitalisation including, but not limited to, 
sepsis, pneumonia, lung infections, have been reported in clinical studies with durvalumab, 
but are often confounded by underlying disease and use of concomitant medications (ie, 
steroids and other immunosuppressives) that may cause opportunistic infections. As of the 
DCO, events from the MedDRA Infections and Infestations SOC, events with a severity 
≥Grade 3 and frequency of ≥1% included lung infection (n=16; 1%), pneumonia (n=39; 
2.4%), sepsis (n=26; 1.6%) and urinary tract infection  (n=20; 1.2%). CTC Grade 3 events 
were reported in 98 patients (6.0%), CTC Grade 4 events were reported in 25 patients (1.5%) 
and CTC Grade 5 infection events in 15 patients (0.9%). Across the durvalumab + 
tremelimumab combination program, patients experiencing ≥Grade 3 infections at a frequency 


Clinical Study Protocol 
Drug Substance Tremelimumab 
Study Number ESR-14-10744 
Edition Number 8 
 
Date 17 April 2019 
 
Page 111 of 134 
 
of ≥1% included lung infection (n=9; 1.6%), pneumonia (n=14; 2.5%), sepsis (n=6; 1.1%) and 
urinary tract infection (n=9; 1.6%). CTC Grade 3 events were reported in 50 patients (8.9%), 
CTC Grade 4 events were reported in 2 patients (0.4%) and CTC Grade 5 infection events in 4 
patients (0.7%). Patients should be monitored for serious infections while 
receiving durvalumab. 
 
9.2 
Assessment of safety parameters 
9.2.1 
Assessment of severity 
Severity will be graded according to the NCI CTCAE v4.03.The determination of severity for 
all other events not listed in the CTCAE will be made by the investigator based upon medical 
judgment and the severity categories of Grade 1 to 5 as 
defined below. 
Grade 1 (mild)  
 
An event that is usually transient and may require only minimal 
 
treatment or therapeutic intervention. The event does not 
 
generally interfere with usual activities of daily living. 
 
Grade 2 (moderate)   
An event that is usually alleviated with additional specific 
 
therapeutic intervention. The event interferes with usual 
 
activities of daily living, causing discomfort but poses no 
 
significant or permanent risk of harm to the subject. 
 
Grade 3 (severe)  
 
An event that requires intensive therapeutic intervention. The 
 
event interrupts usual activities of daily living, or significantly 
 
affects the clinical status of the subject. 
 
Grade 4 (life threatening)  
An event, and/or its immediate sequelae, that is associated with 
 
an imminent risk of death or with physical or mental disabilities 
 
that affect or limit the ability of the subject to perform activities 
 
of daily living (eating, ambulation, toileting, etc.). 
 
Grade 5 (fatal)  
 
Death (loss of life) as a result of an event. 
 
 
It is important to distinguish between serious criteria and the severity of an AE. Severity is a 
measure of intensity whereas seriousness is defined by the criteria in Section 10.1.2. A Grade 
3 AE need not necessarily be considered an SAE. For example, a Grade 3 headache that 
persists for several hours may not meet the regulatory definition of an SAE and would be 
considered a nonserious event, whereas a Grade 2 seizure resulting in a hospital admission 
would be considered an SAE. 


Clinical Study Protocol 
Drug Substance Tremelimumab 
Study Number ESR-14-10744 
Edition Number 8 
 
Date 17 April 2019 
 
Page 112 of 134 
 
 
9.2.2 
Assessment of relationship 
In this study, patients will receive one infusion of MEDI4736 either alone or in combination 
with tremelimumab. The remaining procedures to be conducted in this study will follow 
standard of care for the treatment of patients with surgically resectable MPM. The study 
investigators will carefully monitor subjects to determine whether adverse events are related 
to the infusion of study drug or are expected complications of standard clinical procedures.  
9.3 
Recording of adverse events and serious adverse events 
Adverse events associated with the investigational product will be recorded in an adverse 
event log maintained by the principal investigator using a recognized medical term or 
diagnosis that accurately reflects the event. Adverse events associated with the investigational 
product will be assessed by the investigator for severity, relationship to the investigational 
product, possible etiologies, and whether the event meets criteria of an SAE and therefore 
requires immediate notification to AstraZeneca/MedImmune Patient Safety.  
The following variables will be collected for each AE associated with the investigational 
product: 
• 
AE (verbatim) 
• 
The date when the AE started and stopped 
• 
Changes in NCI CTCAE grade and the maximum CTC grade attained 
• 
Whether the AE is serious or not 
• 
Investigator causality rating against MEDI4736 (yes or no), tremelimumab (yes/no) 
• 
Action taken with regard to MEDI4736/tremelimumab 
• 
Outcome 
In addition, the following variables will be collected for SAEs associated with the 
investigational product as applicable: 
• 
Date AE met criteria for serious AE 
• 
Date Investigator became aware of serious AE 
• 
AE is serious due to 
• 
Date of hospitalization 
• 
Date of discharge 
• 
Probable cause of death 


Clinical Study Protocol 
Drug Substance Tremelimumab 
Study Number ESR-14-10744 
Edition Number 8 
 
Date 17 April 2019 
 
Page 113 of 134 
 
• 
Date of death 
• 
Autopsy performed 
• 
Description of AE 
• 
Causality assessment in relation to Study procedure(s) 
Causality assessment in relation to tremelimumab 
Events that are unequivocally due to disease progression will not be reported as an AE during 
the study. 
9.3.1 
Study recording period and follow-up for adverse events and serious adverse 
events 
Adverse events and serious adverse events associated with the investigational product will be 
recorded from the time of signature of informed consent, throughout the treatment period and 
including the follow-up period (90 days after the last dose of MEDI4736). 
During the course of the study all AEs and SAEs associated with the investigational product 
will be proactively followed up for each subject. Every effort will be made to obtain a 
resolution for all events, even if the events continue after discontinuation/study completion. 
If a subject discontinues from treatment for reasons other than disease progression, and 
therefore continues to have tumor assessments, drug-related SAEs must be captured until the 
patient is considered to have confirmed PD and will have no further tumor assessments. 
The investigator is responsible for following all SAEs associated with the investigational 
product until resolution, until the subject returns to baseline status, or until the condition has 
stabilized with the expectation that it will remain chronic, even if this extends beyond study 
participation. 
Follow-up of unresolved adverse events 
Any AEs associated with the investigational product that are unresolved at the subject’s last 
visit in the study are followed up by the investigator for as long as medically indicated, but 
without further recording in the adverse event log. After 90 days, only subjects with ongoing 
investigational product-related SAEs will continue to be followed for safety. 
AstraZeneca/MedImmune retains the right to request additional information for any subject 
with ongoing AE(s)/SAE(s) associated with the investigational product at the end of the study, 
if judged necessary. 


Clinical Study Protocol 
Drug Substance Tremelimumab 
Study Number ESR-14-10744 
Edition Number 8 
 
Date 17 April 2019 
 
Page 114 of 134 
 
Post study events 
 
After the subject has been permanently withdrawn from the study, there is no obligation for 
the investigator to actively report information on new AE or SAEs associated with the 
investigational product occurring in former study subjects after the 90-day safety follow-up 
period for patients treated with MEDI4736 or MEDI4736 + tremelimumab. However, if the 
investigator learns of any SAEs associated with the investigational product, including death, at 
any time after the subject has been permanently withdrawn from study, and he/she considers 
there is a reasonable possibility that the event is related to study treatment, the investigator 
will notify the study sponsor and AstraZeneca/MedImmune Drug Safety. 
 
 
9.3.2 
Reporting of adverse events 
Any adverse events or toxicities that are determined to be related to surgery should NOT be 
reported unless they are unusual.  
Such AEs common following surgical resection by EPP or PD can occur within the hospital 
stay immediately following surgery, or can persist once the patient is discharged and seen in 
the outpatient clinic postoperatively. Such AEs may include: 
1) Chest pain or incisional pain 
2) Hypotension (including orthostatic hypotension) 
3) Tachycardia 
4) Atrial fibrillation (or other atrial arrhythmia) 
5) Dsypnea 
6) Anorexia, or loss of appetite 
7) Anemia 
8) Hyponatremia 
9) Hypernatremia 
10) Hypokalemia 


Clinical Study Protocol 
Drug Substance Tremelimumab 
Study Number ESR-14-10744 
Edition Number 8 
 
Date 17 April 2019 
 
Page 115 of 134 
 
11) Hyperkalemia 
12) Hypomagnesemia 
13) Increased creatinine 
14) Leukocytosis  
15) Acidosis 
9.3.3 
Reporting of serious adverse events 
All SAEs associated with the investigational product will be reported, whether or not 
considered causally related to the investigational product.The reporting period for SAEs 
associated with the investigational product is the period immediately following the time that 
written informed consent is obtained through 90 days after the last dose of MEDI4736 or until 
the initiation of alternative anticancer therapy. The investigator and/or Sponsor are responsible 
for informing the Ethics Committee and/or the Regulatory Authority of the SAE associated 
with the investigational product as per local requirements. 
The investigator and/or sponsor must inform the FDA, via a MedWatch/AdEERs form, of any 
serious or unexpected adverse events associated with the investigational product that occur in 
accordance with the reporting obligations of 21 CFR 312.32, and will concurrently forward all 
such reports to AstraZeneca. A copy of the MedWatch/AdEERs report must be faxed to 
AstraZeneca at the time the event is reported to the FDA. It is the responsibility of the sponsor 
to compile all necessary information and ensure that the FDA receives a report according to 
the FDA reporting requirement timelines and to ensure that these reports are also submitted to 
AstraZeneca at the same time. 
* A cover page should accompany the MedWatch/AdEERs form indicating the following: 
• 
“Notification from an Investigator Sponsored Study” 
• 
The investigator IND number assigned by the FDA 
• 
The investigator’s name and address 
• 
The trial name/title and AstraZeneca ISS reference number (ESR-##-
#####) 


Clinical Study Protocol 
Drug Substance Tremelimumab 
Study Number ESR-14-10744 
Edition Number 8 
 
Date 17 April 2019 
 
Page 116 of 134 
 
* Sponsor must also indicate, either in the SAE report or the cover page, the causality of 
events in relation to all study medications and if the SAE is related to disease progression, as 
determined by the principal investigator. 
* Send SAE report and accompanying cover page by way of email to AstraZeneca’s 
designated mailbox: AEMailboxClinicalTrialTCS@astrazeneca.com 
 
 
If a non-serious AE associated with the investigational product becomes serious, this and 
other relevant follow-up information must also be provided to AstraZeneca and the FDA. 
Serious adverse events associated with the investigational product that do not require 
expedited reporting to the FDA still need to be reported to AstraZeneca preferably using the 
MedDRA coding language for serious adverse events. This information should be reported on 
a monthly basis and under no circumstance less frequently than quarterly.  
9.3.3.1 
Reporting of deaths 
All deaths that occur during the study, or within the protocol-defined 90-day post-last dose of 
MEDI4736 or tremelimumab safety follow-up period must be reported as follows: 
• 
Death that is clearly the result of disease progression should be 
documented but should not be reported as an SAE. 
• 
Where death is not due (or not clearly due) to progression of the 
disease under study, the AE causing the death must be reported to as 
a SAE within 24 hours (see Section 10.3.2 for further details). The 
report should contain a comment regarding the co-involvement of 
progression of disease, if appropriate, and should assign main and 
contributory causes of death.   
• 
Deaths with an unknown cause should always be reported as a SAE.   
Deaths that occur following the protocol-defined 90-day post-last-dose of MEDI4736 safety 
follow-up period will be documented as events for survival analysis, but will not be reported 
as an SAE. 


Clinical Study Protocol 
Drug Substance Tremelimumab 
Study Number ESR-14-10744 
Edition Number 8 
 
Date 17 April 2019 
 
Page 117 of 134 
 
9.3.4 
Other events requiring reporting 
9.3.4.1 
Overdose 
An overdose is defined as a subject receiving a dose of MEDI4736 or tremelimumab in excess 
of that specified in the Investigator’s Brochure, unless otherwise specified in this protocol. 
Any overdose of a study subject with MEDI4736 or tremelimumab, with or without associated 
AEs/SAEs, is required to be reported within 24 hours of knowledge of the event to the sponsor 
and AstraZeneca/MedImmune Patient Safety or designee using the designated Safety e-
mailbox (see Section 10.3.2 for contact information). If the overdose results in an AE, the AE 
must also be recorded as an AE (see Section 10.3). Overdose does not automatically make an 
AE serious, but if the consequences of the overdose are serious, for example death or 
hospitalization, the event is serious and must be recorded and reported as an SAE (see Section 
10.1.2 and Section 10.3.2). There is currently no specific treatment in the event of an overdose 
of MEDI4736 or tremelimumab.  
The investigator will use clinical judgment to treat any overdose of MEDI4736 or MEDI4736 
+ tremelimumab. 
9.3.4.2 
Hepatic function abnormality 
Hepatic function abnormality (as defined in Section 10.1.3.3) in a study subject, with or 
without associated clinical manifestations, is required to be reported as “hepatic function 
abnormal” within 24 hours of knowledge of the event to the sponsor and 
AstraZeneca/MedImmune Patient Safety using the designated Safety e-mailbox (see Section 
10.3.2 for contact information), unless a definitive underlying diagnosis for the abnormality 
(e.g., cholelithiasis or bile duct obstruction) that is unrelated to investigational product has 
been confirmed. 
• 
If the definitive underlying diagnosis for the abnormality has been established and is unrelated 
to investigational product, the decision to continue dosing of the study subject will be based on 
the clinical judgment of the investigator. 
• 
If no definitive underlying diagnosis for the abnormality is established, dosing of the study 
subject must be interrupted immediately. Follow-up investigations and inquiries must be 
initiated by the investigational site without delay. 


Clinical Study Protocol 
Drug Substance Tremelimumab 
Study Number ESR-14-10744 
Edition Number 8 
 
Date 17 April 2019 
 
Page 118 of 134 
 
Each reported event of hepatic function abnormality will be followed by the investigator and 
evaluated by the sponsor and AstraZeneca/MedImmune.  
9.3.4.3 
Pregnancy 
Pregnancy itself, or pregnancy of a subject’s partner, is not regarded as an adverse event 
unless there is a suspicion that the investigational product under study may have interfered 
with the effectiveness of a contraceptive medication. Congenital abnormalities/birth defects 
and spontaneous miscarriages should be reported and handled as SAEs. Elective abortions 
without complications should not be handled as AEs. The outcome of any conception 
occurring from the date of the first dose until 90 days after the last dose (spontaneous 
miscarriage, elective termination, ectopic pregnancy, normal birth or congenital abnormality) 
should be followed up and documented even if the subject was withdrawn from the study.  
Pregnancy in a female subject who has received investigational product is required to be 
reported within 24 hours of knowledge of the event to the sponsor and 
AstraZeneca/MedImmune Patient Safety or designee using the designated Safety e-mailbox 
(see Section 10.3.2 for contact information). 
Subjects who become pregnant during the study period must not receive additional doses of 
investigational product but will not be withdrawn from the study. The pregnancy will be 
followed for outcome of the mother and child (including any premature terminations) and 
should be reported to AstraZeneca/MedImmune Patient Safety or designee after outcome. 
Male subjects should refrain from fathering a child or donating sperm during the study and for 
90 days following the last dose of monotherapy MEDI4736 or for 180 days following the last 
dose of combination therapy with MEDI4736 and tremelimumab.   
Should the investigator become aware of a pregnancy in the partner of a male study subject 
who has received investigational product this should be reported within 24 hours of 
knowledge of the event to AstraZeneca/MedImmune Patient Safety or designee using the 
Safety Fax Notification Form for contact information). The sponsor will endeavor to collect 
follow-up information on such pregnancies provided the partner of the study subject provides 
consent. 


Clinical Study Protocol 
Drug Substance Tremelimumab 
Study Number ESR-14-10744 
Edition Number 8 
 
Date 17 April 2019 
 
Page 119 of 134 
 
10. 
STATISTICAL METHODS AND SAMPLE SIZE 
DETERMINATION 
This is a pilot study designed to show that combination therapy with MEDI4736 and 
tremelimumab can have a substantial impact on surgically resectable MPM patients. All 
subjects will be randomized after the mediastinoscopy + thoracoscopy to one of the three arms 
to receive MEDI4736+tremelimumab, MEDI4736 only, or untreated control. The primary 
endpoint will be the ratio of intratumoral cytotoxic T cells to regulatory T cells (CD8/Treg) 
before and after treatment.  The secondary endpoints are the percentage of inducible T-cell co-
stimulator (ICOS) positive intratumoral CD4 T cells and tumor tissue expression (Ventana 
assay) of programmed death-ligand 1 (PD-L1) before and after each treatment. Overall and 
recurrence-free survival will be also measured as the secondary endpoint. These analysis will 
be post-protocol analysis based upon data obtained from the standard of care follow up in our 
post-surgical patients. All subjects will undergo surgical resection One to six weeks after the 
infusion. 
10.1 
Sample size 
10.2 
The primary objective is comparison of the ratio of CD8/Treg before and after 
treatment with combination MEDI4736+Tremelimumab. A total of 20 evaluable 
subjects (if tissue obtained) will be enrolled in this study for 24 months and 8 
subjects will be assigned to combination MEDI4736+Tremelimumab (8 subjects to 
MEDI4736 only and 4 subjects to control). The outcome of interest in this study is a 
change in ratio of CD8/Treg before and after treatment with combination 
MEDI4736+Tremelimumab within subjects. There are no data available to estimate 
a change of ratio of CD8/Treg before and after the treatment but in our pilot data 
from 6 subjects with MPM the log transformed ratio of CD8/Treg was 
approximately normally distributed with a mean of 1.94(6.96 in raw scale) and 
standard deviation of 0.808(2.24 in raw scale). Assuming that repeat values are 
moderately correlated(r=0.5), then the difference between before and after the 
combination treatment will also have a standard deviation of 0.808(2.24 in raw 
scale). We estimate that we will have 80% power (alpha=5%, a paired t-test) to 
detect an increased log ratio CD8/Treg of 2.87(17.71 in raw scale) after the 
combination treatment with 8 subjects. 
10.3 
Analysis plan 
There will be two treatment arms (MEDI4736 only and combination 
MEDI4736+tremelimumab) and one untreated arm (control). Randomization, stratified by 
receiving previous chemotherapy or not, will help to minimize patient selection biases 
between three arms. Preliminary tests will be performed to assess whether our data is normally 
or non-normally distributed. Patient characteristics will be summarized descriptively. Baseline 
characteristics will be compared by treatment assignment. For our primary objective that 
compares outcome variable in tissues before and after treatment with combination MEDI4736 


Clinical Study Protocol 
Drug Substance Tremelimumab 
Study Number ESR-14-10744 
Edition Number 8 
 
Date 17 April 2019 
 
Page 120 of 134 
 
and tremelimumab, we will use a paired t-test in log-transformed ratio of intratumoral 
cytotoxic T cells to regulatory T cells (CD8/Treg) before and after the treatment. In our 
secondary objective numerous variable comparisons are made between tumor tissues from 
untreated patients with from patients undergoing treatment with either MEDI4736 or 
MEDI4736 + tremelimumab, and between tumor tissues from patients undergoing treatment 
with MEDI4736 and tumor tissues from patients undergoing treatment with 
MEDI4736+tremelimumab. In these comparisons, a paired t-test or Student t-tests will be 
performed. Because approximately 20 comparisons of immune cell populations will be 
performed, a Bonferroni correction will be applied to correct for multiple comparisons. For 
the comparison of overall survival and recurrence-free survival between treatment groups, 
log-rank test will be used. These analysis will be post-protocol analysis based upon data 
obtained from the standard of care follow up in our post-surgical patients. SAS software will 
be used for all other statistical analyses. 
11. 
ETHICAL AND REGULATORY REQUIREMENTS 
11.1 
Ethical conduct of the study 
The study will be performed in accordance with ethical principles that have their origin in the 
Declaration of Helsinki and are consistent with ICH/Good Clinical Practice, and applicable 
regulatory requirements Subject data protection. 
11.2 
Ethics and regulatory review 
MEDI4736 and tremelimumab are both investigational drugs not approved for clinical use in 
patients with surgically resectable MPM. Our study will undergo review by the Baylor 
College of Medicine Institutional Review Board. Investigational New Drug applications will 
also be filed with the FDA. 
11.3 
Informed consent 
Informed consent shall be documented by the use of a written consent form approved by the 
IRB and the sponsor and signed and dated by the subject or the subject's legally authorized 
representative at the time of consent. A copy shall be given to the person signing the form. 


Clinical Study Protocol 
Drug Substance Tremelimumab 
Study Number ESR-14-10744 
Edition Number 8 
 
Date 17 April 2019 
 
Page 121 of 134 
 
11.4 
Changes to the protocol and informed consent form 
Any changes to the protocol or informed consent form will be reviewed by the sponsor and 
the local IRB prior to implementation. Any changes to the informed consent form that impact 
currently enrolled subjects (e.g., changes in procedures, changes in the benefit/risk profile) 
will require that subjects are re-consented with the new consent form.  
11.5 
Audits and inspections 
All records and documents pertaining to the study will be maintained in appropriate 
permanent files as per the ICH guidelines for Essential Documents for the Conduct of a 
Clinical Trial and 21 CFR 11, and will be available for inspection by the Sponsor, Sponsor 
designee, the FDA, or any other designated review body at any time. 
12. 
STUDY MANAGEMENT 
The principal investigator assumes all oversight and reporting of the study, including the 
training of study site personnel and monitoring of the study.   
12.1 
Training of study site personnel 
The PI of this study will train the study coordinator in the procedures necessary to identify and 
accrue appropriate individuals to the study. The PI of the study will also train the staff 
scientist in the lab appropriate tissue collection and storage procedures. The co-investigator of 
this study, Dr. Jun Zhang, will train infusion center staff on appropriate administration of 
study drugs. 
12.2 
Monitoring of the study 
12.2.1 
Source data 
Subjects will be monitored closely throughout the course of the study with regular visits with 
the Study PI and direct access to the PI throughout the duration of the study. The PI is directly 
responsible for the study subjects, and the study staff will be instructed to contact the PI 
immediately with any concerns regarding patient safety or other matters.  


Clinical Study Protocol 
Drug Substance Tremelimumab 
Study Number ESR-14-10744 
Edition Number 8 
 
Date 17 April 2019 
 
Page 122 of 134 
 
12.3 
Study timetable and end of study 
The end of the study will be defined as the time point 90 days after the final subject receives 
the infusion of study drug. The recruitment period will take place over a period of 24 months. 
13. 
DATA MANAGEMENT 
The database that will be utilized for data collection and storage will be OnCORE. The PI and 
study staff will adhere to the reporting requirements of the data to the institutional IRB. 
To ensure the privacy and confidentiality of data for this protocol, the data will be stored on a 
restricted access location on our institution’s server. Access to the project directory containing 
the data will be limited to the investigators and research staff. Information about data security 
awareness is promoted through user training and education and supplemented by policies and 
procedures. Password protection will be used for all transactions that involve viewing, editing, 
and analyzing the data or that provide access to data fields derived from the original source 
documents.   
The investigator maintains the confidentiality standards of each patient enrolled in the study 
through the assignment of a unique subject identification number that de-identifies the study 
information from the patient’s health information. The key linking subject code to the patient 
is kept in an additional secure restricted access location on our institution’s server that is only 
accessible to the study staff. No identifying information, such as the patient’s name, will be 
included in the data sets used for reporting the data. The data released to Astrazenica will be 
patient age, histology, and chemotherapy status, as well as CyTOF data, PD-L1 
immunohistochemistry data, and nanostring mRNA data. Patient medical information 
obtained for the study is confidential, and may only be disclosed to third parties as permitted 
in the Informed Consent Form signed by the subject unless permitted or required by law.   
 
 
 
 


Clinical Study Protocol 
Drug Substance Tremelimumab 
Study Number ESR-14-10744 
Edition Number 8 
 
Date 17 April 2019 
 
Page 123 of 134 
 
14. 
LIST OF REFERENCES 
Augello A, Tasso R, Negrini SM, Amateis A, Indiveri F, Cancedda R, Pennesi G. Bone 
marrow mesenchymal progenitor cells inhibit lymphocyte proliferation by activation of the 
programmed death 1 pathway. Eur J Immunol. 2005;35(5):1482-90.  
 
Andorsky DJ, Yamada RE, Said J, Pinkus GS, Betting DJ, and Timmerman JM.  Programmed 
death ligand 1 is expressed by non-hodgkin lymphomas and inhibits the activity of tumor-
associated T cells.  Clin Cancer Res. 2011. 17(13):4232-4244. 
 
Berger R, Rotem-Yehudar R, Slama G, Landes S, Kneller A, Leiba M, et al. Phase I safety 
and pharmacokinetic study of CT-011, a humanized antibody interacting with PD-1, in 
patients with advanced hematologic malignancies. Clin Cancer Res. 2008 May 
15;14(10):3044-51.  
 
Blank C, Kuball J, Voelkl S, Wiendl H, Becker B, Walter B, et al. Blockade of PD-L1 (B7-
H1) augments human tumor-specific T cell responses in vitro. Int J Cancer. 2006;119(2):317-
27.  
 
Bograd AJ, Suzuki K, Vertes E, Colovos C, Morales EA, Sadelain M, et al. Immune responses 
and immunotherapeutic interventions in malignant pleural mesothelioma. Cancer Immunol 
Immunother. 2011;60:1509-27.  
 
Brahmer JR, Drake CG, Wollner I, Powderly JD, Picus J, Sharfman WH, et al. Phase I study 
of single-agent anti-programmed death-1 (MDX-1106) in refractory solid tumors: safety, 
clinical activity, pharmacodynamics, and immunologic correlates. J Clin Oncol. 2010 Jul 
1;28(19):3167- 75. 
 
Brahmer JR, Tykodi SS, Chow LQ, Hwu WJ, Topalian SL, Hwu P, et al. Safety and activity 
of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med. 2012;366(26):2455- 
65.  
 
Brown JA, Dorfman DM, Ma FR, Sullivan EL, Munoz O, Wood CR, et al. Blockade of 
programmed death-1 ligands on dendritic cells enhances T cell activation and cytokine 
production. J Immunol. 2003;170(3):1257-66.  
 
Burt BM, Rodig SJ, Tilleman TR, Elbardissi AW, Bueno R, Sugarbaker DJ. Circulating and 
tumor-infiltrating myeloid cells predict survival in human pleural mesothelioma. Cancer. 
2011;117(22):5234-44.  
 
Brusa D, Serra S, Coscia M, Rossi D, D’Arena G, Laurenti L, et al.  The PD-1/PD-L1 axis 
contributes to T-cell dysfunction in chronic lymphocytic leukemia.  Haematologica. 2013 Jun; 
98(6):953-963. 


Clinical Study Protocol 
Drug Substance Tremelimumab 
Study Number ESR-14-10744 
Edition Number 8 
 
Date 17 April 2019 
 
Page 124 of 134 
 
 
Calabrò L, Morra A, Fonsatti E, Cutaia O, Amato G, Giannarelli D, et al. Tremelimumab for 
patients with chemotherapy-resistant advanced malignant mesothelioma: an open-label, 
single-arm, phase 2 trial. Lancet Oncol. 2013 Sep 10. [Epub ahead of print].  
 
Calabrò L, Morra A, Fonsatti E, Cutaia O, Fazio C, Giannarelli D, et al. A phase 2 single-arm 
study with Tremelimumab at an optimized dosing schedule in second-line mesothelioma 
patients. Poster presented at: The American Society of Clinical Oncology Annual Meeting; 
May 30-June 3, 2014a; Chicago, IL. Abstract 7531.  
 
Calabrò L, Narwal R, Robbins PB, DiPietro A, Cutaia O, Fonsatti E, et al. Pharmacokinetics 
of Tremelimumab, a fully human anti-CTLA-4 monoclonal antibody, in subjects with 
unresectable malignant mesothelioma. Proceedings: American Association for Cancer 
Research 105th Annual Meeting 2014; April 5-9, 2014b; San Diego, CA. Abstract LB-228.  
 
Callahan MK and Wolchok JD. CTLA-4 and PD-1 blocking antibodies in cancer 
immunotherapy.  J Leukoc Biol. 2013; 94(1):41-53. 
 
Camacho LH, Antonia S, Sosman J, Kirkwood JM, Gajewski TF, Redman B, et al. Phase I/II 
trial of tremelimumab in patients with metastatic melanoma. J Clin Oncol. 2009;27(7):1075- 
81.  
 
Canniff PC, Donovan CB, Burkwit JJ, Bruns MJ, Bedian V, Bernstein SH, et al. CP-675,206 
anti-CTLA4 antibody clinical candidate enhances IL-2 production in cancer subject T cells in 
vitro regardless of tumor type or stage of disease [AACR meeting abstract]. Proc Am Assoc 
Cancer Res. 2004;45:Abstract #709.  
 
Chen Y, Zhang J, Li J, Zou L, Zhao T, Tang Y, Wu Y. Expression of B7-H1 in Inflammatory 
Renal Tubular Epithelial Cells. Nephron Exp Nephrol. 2006;102:e81-e92.  
 
Chow et al.  Inflammation and immune surveillance in cancer. Semin Cancer Biol 
2012;22:23-32. 
 
Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron 
1976;16(1):31-41. 
 
Das S, Suarez G, Beswick EJ, Sierra JC, Graham DY, Reyes VE. Expression of B7-H1 on 
Gastric Epithelial Cells: Its Potential Role in Regulating T Cells during Helicobacter pylori 
Infection. J Immunol. 2006;176(5):3000-9.  
 
Dong H, Strome SE, Salomao DR, Tamura H, Hirano F, Flies DB, et al. Tumor-associated 
B7- H1 promotes T-cell apoptosis: a potential mechanism of immune evasion. Nat Med. 
2002;8(8):793-800.  


Clinical Study Protocol 
Drug Substance Tremelimumab 
Study Number ESR-14-10744 
Edition Number 8 
 
Date 17 April 2019 
 
Page 125 of 134 
 
 
Dong H, Strome SE, Matteson EL, Moder KG, Flies DB, Zhu G, et al. Costimulating aberrant 
T cell responses by B7-H1 autoantibodies in rheumatoid arthritis. J Clin Invest. 
2003;111(3):363- 70.  
 
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New 
response evaluation criteria in solid tumors: Revised RECIST guideline (version 1.1). Eur J 
Cancer. 2009;45:228-47. 
 
European Medicines Agency’s “Guideline on the evaluation of anti-cancer medicinal products 
in man” (EMA/CHMP/205/95/Rev.4) 
 
EEC. Production and quality control of monoclonal antibodies (3AB4a). 1994. 75/318/EEC. 
United States Food and Drug Administration/Center for Biologics Evaluation and Research. 
Points to consider in the manufacture and testing of antibody products for human use (Docket 
No. 94D-0259). 1997.  
 
Fife BT, Bluestone JA. Control of peripheral T-cell tolerance and autoimmunity via the 
CTLA-4 and PD-1 pathways. Immunol Rev. 2008 Aug;224:166-82.  
 
Food and Drug Administration Guidance for Industry (issued July 2009) ‘Drug-induced liver 
injury: Premarketing clinical evaluation’.  Available from URL: 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances
/UCM174090.pdf.  Accessed 10 December 2013. 
Freeman GJ, Long AJ, Iwai Y, Bourque K, Chernova T, Nishimura H, et al. Engagement of 
the PD-1 Immunoinhibitory Receptor by a Novel B7 Family Member Leads to Negative 
Regulation of Lymphocyte Activation. J Exp Med. 2000;192(7):1027-34.  
 
Hamanishi J, Mandai M, Iwasaki M, Okazaki T, Tanaka Y, Yamaguchi K, et al. Programmed 
cell death 1 ligand 1 and tumor-infiltrating CD8+ T lymphocytes are prognostic factors of 
human ovarian cancer. Proc Nat Acad Sci U S A. 2007;104(9):3360-5.  
 
Hamid O, Robert C, Daud A, Hodi FS, Hwu WJ, Kefford R, et al. Safety and tumor responses 
with lambrolizumab (anti-PD-1) in melanoma. N Engl J Med. 2013 June 2;DOI: 
10.1056/NEJMoa1305133.  
 
Herbst RS, Gordon MS, Fine GD, Sosman JA, Soria JC, Hamid O, et al. A study of 
MPDL3280A, an engineered PD-L1 antibody in patients with locally advanced or metastatic 
tumors. J Clin Oncol. 2013;31(suppl; abstr 3000).  
 


Clinical Study Protocol 
Drug Substance Tremelimumab 
Study Number ESR-14-10744 
Edition Number 8 
 
Date 17 April 2019 
 
Page 126 of 134 
 
Hirano F, Kaneko K, Tamura H, Dong H, Wang S, Ichikawa M, et al. Blockade of B7-H1 and 
PD-1 by Monoclonal Antibodies Potentiates Cancer Therapeutic Immunity. Cancer Res. 
2005;65(3):1089-96.  
 
Hodi FS, O’Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB, et al. Improved 
survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010;363:11- 
23.  
 
Holets LM, Hunt JS, Petroff MG. Trophoblast CD274 (B7-H1) is Differentially Expressed 
Across Gestation: Influence of Oxygen Concentration. Biol Reprod. 2006;74(2):352-8.  
 
Iwai Y, Ishida M, Tanaka Y, Okazaki T, Honjo T, Minato N. Involvement of PD-L1 on tumor 
cells in the escape from host immune system and tumor immunotherapy by PD-L1 blockade. 
Proc Natl Acad Sci U S A. 2002;99(19):12293-7.  
 
Kähler KC, Hauschild A. Treatment and side effect management of CTLA-4 antibody therapy 
in metastatic melanoma. JDDG [Journal of the German Society of Dermatology]. 2011;9:277-
85.  
 
Keir ME, Butte MJ, Freeman GJ, Sharpe AH. PD-1 and its ligands in tolerance and immunity. 
Annu Rev Immunol. 2008;26:677-704.  
 
Kirkwood J, Lorigan P, Hersey P, Hauschild A, Robert C, McDermott D, et al. Phase II Trial 
of Tremelimumab (CP-675,206) in Patients with Advanced Refractory or Relapsed 
Melanoma. Clin Cancer Res. 2010; 16(3): 1042-1048.  
 
Krambeck AE, Dong H, Thompson RH, Kuntz SM, Lohse CM, Leibovich BC, et al. Survivin 
and B7-H1 are collaborative predictors of survival and represent potential therapeutic targets 
for patients with renal cell carcinoma. Clin Cancer Res. 2007;13(6):1749-56.  
 
Korn EL, Liu PY, Lee SJ, Chapman JA, Niedzwiecki D, Suman VJ, et al. Meta-analysis of 
phase II cooperative group trials in metastatic stage IV melanoma to determine 
progressionfree and overall survival benchmarks for future phase II trials. J Clin Oncol. 
2008;26(4):527- 34.  
 
Krambeck AE, Dong H, Thompson RH, Kuntz SM, Lohse CM, Leibovich BC, et al. 
Survivin and B7-H1 are collaborative predictors of survival and represent potential 
therapeutic targets for patients with renal cell carcinoma. Clin Cancer Res. 2007;13(6):1749- 
56. 
 
Kresowik TP, Griffith TS. Bacillus Calmette–Guerin immunotherapy for urothelial carcinoma 
of the bladder. Immunother. 2009;1(2):281-8.  
 


Clinical Study Protocol 
Drug Substance Tremelimumab 
Study Number ESR-14-10744 
Edition Number 8 
 
Date 17 April 2019 
 
Page 127 of 134 
 
Krummel MF, Sullivan TJ, Allison JP. Superantigen responses and co-stimulation: CD28 and 
CTLA-4 have opposing effects on T cell expansion in vitro and in vivo. Int Immunol. 
1996;8:519-23.  
 
Kwon ED, Hurwitz AA, Foster BA, Madias C, Feldhaus AL, Greenberg NM, et al. 
Manipulation of T cell costimulatory and inhibitory signals for immunotherapy of prostate 
cancer. Proc Natl Acad Sci USA. 1997;94:8099-103.  
 
Kwon ED, Foster BA, Hurwitz AA, Madias C, Allison JP, Greenberg NM, et al. Elimination 
of residual metastatic prostate cancer after surgery and adjunctive cytotoxic T 
lymphocyteassociated antigen 4 (CTLA-4) blockade immunotherapy. Proc Natl Acad Sci 
USA. 1999;96:15074-9.  
 
Latchman YE, Liang SC, Wu Y, Chernova T, Sobel RA, Klemm M, et al. PD-L1-deficient 
mice show that PD-L1 on T cells, antigen-presenting cells, and host tissues negatively 
regulates T cells. Proc Natl Acad Sci U S A. 2004;101(29):10691-6.  
 
Leach DR, Krummel MF, Allison JP. Enhancement of antitumor immunity by CTLA-4 
blockade. Science. 1996;271:1734-6. McDermott DF. Immunotherapy of metastatic renal cell 
carcinoma. Cancer. 2009;115(10 suppl):2298–305.  
 
Lenz HJ. Management and preparedness for infusion and hypersensitivity reactions. 
Oncologist. 2007;12(5):601-9. 
Lin DY, Tanaka Y, Iwasaki M, Gittis AG, Su HP, Mikami B, et al. The PD-1/PD-L1 complex 
resembles the antigen-binding Fv domains of antibodies and T cell receptors. Proc Natl Acad 
Sci U S A. 2008;105(8):3011-6.  
 
Loos M, Giese NA, Kleeff J, Giese T, Gaida MM, Bergmann F, et al. Clinical significance 
and regulation of the costimulatory molecule B7-H1 in pancreatic cancer. Cancer Lett. 
2008;268(1):98-109.  
 
Madan RA, Gulley JL. Sipuleucel-T: harbinger of a new age of therapeutics for prostate 
cancer. Expert Rev Vaccines. 2011 Feb;10(2):141-50.  
 
Mu CY, Huang JA, Chen Y, Chen C, Zhang XG. High expression of PD-L1 in lung cancer 
may contribute to poor prognosis and tumor cells immune escape through suppressing tumor 
infiltrating dendritic cells maturation. Med Oncol. 2011 Sep;28(3):682-8.  
 
Pagès F, Galon J, Dieu-Nosjean M-C, Tartour E, Sautès-Fridman C, Fridman W-H. Immune 
infiltration in human tumors: a prognostic factor that should not be ignored. Oncogene. 
2010;29(8):1093-102.  
 
Loos M, Giese NA, Kleeff J, Giese T, Gaida MM, Bergmann F, et al. Clinical significance 


Clinical Study Protocol 
Drug Substance Tremelimumab 
Study Number ESR-14-10744 
Edition Number 8 
 
Date 17 April 2019 
 
Page 128 of 134 
 
and regulation of the costimulatory molecule B7-H1 in pancreatic adenocarcinoma. Cancer 
Lett. 2008;268(1):98-109. 
 
Morell A, Terry WD, Waldmann TA. Metabolic properties of IgG subclasses in man. J Clin 
Invest. 1970;49:673-80.  
 
Mu CY, Huang JA, Chen Y, Chen C, Zhang XG. High expression of PD-L1 in lung cancer 
may contribute to poor prognosis and tumor cells immune escape through suppressing tumor 
infiltrating dendritic cells maturation. Med Oncol. 2011 Sep;28(3):682-8. 
 
Nakano O, Sato M, Naito Y, Suzuki K, Orikasa S, Aizawa M, et al. Proliferative activity of 
intratumoral CD8+ T-lymphocytes as a prognostic factor in human renal cell carcinoma: 
clinicopathologic demonstration of antitumor immunity. Cancer Res. 2001;61:5132-6.  
 
Nishimura H, Minato N, Nakano T, Honjo T. Immunological studies on PD-1 deficient mice: 
implication of PD-1 as a negative regulator for B cell responses. Int Immunol. 
1998;10(10):1563-72.  
 
Nishimura H, Okazaki T, Tanaka Y, Nakatani K, Hara M, Matsumori A, et al. Autoimmune 
dilated cardiomyopathy in PD-1 receptor-deficient mice. Science. 2001;291(5502):319-22.  
 
Nishino M, Giobbie-Hurder A, Gargano M, Suda M, Ramaiya NH and Hodi FS.  Developing 
a common language for tumor response to immunotherapy: immune-related response criteria 
using unidimensional measurements.  Clin Cancer Res.  2013 Jul; 19(14):3936-3943. 
 
Nomi T, Sho M, Akahori T, Hamada K, Kubo A, Kanehiro H, et al. Clinical significance and 
therapeutic potential of the programmed death-1 ligand/programmed death-1 pathway in 
human pancreatic adenocarcinoma. Clin Cancer Res. 2007 Apr 1;13(7):2151-7. 
 
Oganesyan V, Gao C, Shirinian L, Wu H, Dall'Acqua WF. Structural characterization of a 
human Fc fragment engineered for lack of effector functions. Acta Crystallogr D Biol 
Crystallogr. 2008;64(6):700-4.  
 
Okudaira K, Hokari R, Tsuzuki Y, Okada Y, Komoto S, Watanabe C, et al. Blockade of B7-
H1 or B7-DC induces an anti-tumor effect in a mouse pancreatic cancer model. Int J Oncol. 
2009;35(4):741-9.  
 
Pages F, Galon J, Dieu-Nosjean MC, Tartour E, Sautès-Fridman C, Fridman WH. Immune 
infiltration in human tumors: a prognostic factor that should not be ignored. Oncogene. 
2010;29(8):1093-102.  
 


Clinical Study Protocol 
Drug Substance Tremelimumab 
Study Number ESR-14-10744 
Edition Number 8 
 
Date 17 April 2019 
 
Page 129 of 134 
 
Park J, Omiya R, Matsumura Y, Sakoda Y, Kuramasu A, Augustine MM, et al. B7-H1/CD80 
interaction is required for the induction and maintenance of peripheral T-cell tolerance. Blood. 
2010;116(8):1291-8.  
 
Ribas A, Camacho LH, Lopez-Berestein G, Pavlov D, Bulanhagui CA, Millham R, et al. 
Antitumor activity in melanoma and anti-self responses in a phase 1 trial with the 
anticytotoxic T lymphocyte-associated antigen 4 monoclonal antibody CP-675,206. J Clin 
Oncol. 2005;23:8968-77.  
 
Ribas A, Kefford R, Marshall MA, Punt CJA, Haanen JB, Marmol M, et al. Phase III 
randomized clinical trial comparing tremelimumab with standard-of-care chemotherapy in 
patients with advanced melanoma. J Clin Oncol. 2013;31;616-22.  
 
Robert C, Thomas L, Bondarenko I, O’Day S, Weber J, Garbe C, et al. Ipilimumab plus 
dacarbazine for previously untreated metastatic melanoma. N Engl J Med. 2011;364:2517- 26.  
Sznol M and Chen L. Antagonist antibodies to PD-1 and B7-H1 (PD-L1) in the treatment of 
advanced human cancer.  2013; 19(5):1021-1034. 
 
Roberts C, Hamid O, Daud A, Hodi FS, Hwu WJ, Kefford R, et al. Response rate and safety 
profile of MK-3475 (anti-PD1 monoclonal antibody) in patients with advanced melanoma. 6th 
World Meeting of Interdisciplinary Melanoma Skin Cancer Centers and the 8th Congress of 
the European Association of Dermato-Oncology (EADO). 2012 Barcelona, Spain.  
 
Sangro B, Gomez-Martin C, de la Mata M, Iñarrairaegui M, Garralda E, Barrera P, et al. A 
clinical trial of CTLA-4 blockade with tremelimumab in patients with hepatocellular 
carcinoma and chronic hepatitis C. J Hepatol. 2013;59(1):81-8.  
 
Schmidinger M, Hejna M, Zielinski CC. Aldesleukin in advanced renal cell carcinoma. Expert 
Rev Anticancer Ther. 2004 Dec;4(6):957-80.  
 
Sharpe AH, Wherry EJ, Ahmed R, Freeman GJ. The function of programmed cell death 1 and 
its ligands in regulating autoimmunity and infection. Nat Immunol. 2007;8(3):239-45.  
 
Stebbings R, Findlay L, Edwards C, Eastwood D, Bird C, North D, et al. “Cytokine storm” in 
the phase 1 trial of monoclonal antibody TGN1412: better understanding the causes to 
improve preclinical testing of immunotherapeutics. J Immunol. 2007;179:3325-31.  
 
Suntharalingam G, Perry MR, Ward S, Brett SJ, Castello-Cortes A, Brunner MD, et al. 
Cytokine storm in a phase 1 trial of the anti-CD28 monoclonal antibody TGN1412. N Engl J 
Med. 2006;355(10):1018-28.  
 


Clinical Study Protocol 
Drug Substance Tremelimumab 
Study Number ESR-14-10744 
Edition Number 8 
 
Date 17 April 2019 
 
Page 130 of 134 
 
Suzuki K, Kadota K, Sima CS, Sadelain M, Rusch VW, Travis WD, et al. Chronic 
inflammation in tumor stroma is an independent predictor of prolonged survival in epitheloid 
malignant pleural mesothelioma patients. Cancer Immunol Immunother. 2011;60(12):1721-8.  
 
Tarhini AA, Kirkwood JM. Tremelimumab (CP-675,206): a fully human anticytotoxic T 
lymphocyte-associated antigen 4 monoclonal antibody for treatment of patients with advanced 
cancers. Expert Opin Biol Ther. 2008;8(10):1583-93.  
 
Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, et al. Safety, 
activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med. 
2012;366(26):2443-54.  
 
Tarhini AA. Tremelimumab: a review of development to date in solid tumors. 
Immunotherapy. 2013;5(3):215-29. 
 
Thompson RH, Gillett MD, Chevillem JC, Lohsem CM, Dong H, Webster WS, et al. 
Costimulatory molecule B7-H1 in primary and metastatic clear cell renal cell carcinoma. 
Cancer. 2005;104(10):2084-91. 
 
Thompson RH, Kuntz SM, Leibovich BC, Dong H, Lohse CM, Webster WS, et al. Tumor 
B7-H1 is associated with poor prognosis in renal cell carcinoma patients with long-term 
follow-up. Cancer Res. 2006;66(7):3381-5. 
 
Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, et al. Safety, 
activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med. 2012 Jun 
28;366(26):2443-54.  
 
Tsuda M, Matsumoto K, Inoue H, Matsumura M, Nakano T, Mori A, et al. Expression of B7-
H1 and B7-DC on the airway epithelium is enhanced by double-stranded RNA. Biochem 
Biophys Res Commun. 2005;330(1):263-70.  
 
US Department of Health and Human Services, National Institutes of Health, National 
Cancer Institute. Common Terminology Criteria for Adverse Events Version 4.03. 
 
U.S. Department of Health and Human Services, Food and Drug Administration, Center for 
Drug Evaluation and Research (CDER). Guidance for industry: estimating the maximum safe 
starting dose in initial clinical trials for therapeutics in adult healthy volunteers. July 2005. 
Available at:  
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances
/u cm078932.pdf.  
 


Clinical Study Protocol 
Drug Substance Tremelimumab 
Study Number ESR-14-10744 
Edition Number 8 
 
Date 17 April 2019 
 
Page 131 of 134 
 
Wang E, Kang D, Bae K, Marshall MA, Pavlov D, Parivar K. Population pharmacokinetic and 
pharmacodynamic analysis of tremelimumab in patients with metastatic melanoma. J Clin 
Pharmacol. 2014;54:1108-16.  
 
Wang L, Ma Q, Chen X, Guo K, Li J, Zhang M. Clinical significance of B7-H1 and B7-1 
expressions in pancreatic carcinoma. World J Surg. 2010;34(5):1059-65.  
 
Weber JS, Hamid O, Chasalow SD, Wu DY, Parker SM, Galbraith S, et al. Ipilimumab 
increases activated T cells and enhances humoral immunity in patients with advanced 
melanoma. J Immunother. 2012;35:89-97.  
 
Weber J, Hamid O, Amin A, O'Day S, Masson E, Goldberg SM, Williams D, Parker SM, 
Chasalow SD, Alaparthy S, et al. Randomized phase I pharmacokinetic study of ipilimumab 
with or without one of two different chemotherapy regimens in patients with untreated 
advanced melanoma. Cancer Immun. 2013;13(7. 
 
Wing MG, Waldmann H, Isaacs J, Compston DAS, Hale G. Ex-vivo whole blood cultures for 
predicting cytokine-release syndrome: dependence on target antigen and antibody isotype. 
Therapeutic Immunol. 1995;2:183-90.  
 
Wolchok JD, Hoos A, O’Day S, Weber JS, Hamid O, Lebbe C, et al. Guidelines for the 
evaluation of immune therapy activity in solid tumors: immune-related response criteria. Clin 
Cancer Res. 2009;15(23):7412-20.  
 
Wolchok JD, Weber JS, Hamid O, Lebbé C, Maio M, Schadendorf D, et al. Ipilimumab 
efficacy and safety in patients with advanced melanoma: a retrospective analysis of HLA 
subtype from four trials. Cancer Immun. 2010 Oct 20;10:9. Yervoy™ [package insert]. 
Princeton, NJ, IN: Bristol-Myers Squibb Company; 2011. Available at: 
http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/125377s0000lbl.pdf. Accessed 
December 3, 2011.  
 
Wolchok JD, Weber JS, Hamid O, Lebbé C, Maio M, Schadendorf D, et al. Ipilimumab 
efficacy and safety in patients with advanced melanoma: a retrospective analysis of HLA 
subtype from four trials. Cancer Immun. 2010 Oct 20;10:9. 
 
Zhang C, Wu S, Xue X, Li M, Qin X, Li W, et al. Anti-tumor immunotherapy by blockade of 
the PD-1/PD-L1 pathway with recombinant human PD-1-IgV. Cytotherapy. 2008;10(7):711-
9. Zou W, Chen L. Inhibitory B7-family molecules in the tumor microenvironment. Nat Rev 
Immunol. 2008;8(6):467-77. 
 
Zou W, Chen L. Inhibitory B7-family molecules in the tumor microenvironment. Nat Rev 
Immunol. 2008;8(6):467-77. 
 


Clinical Study Protocol 
Drug Substance Tremelimumab 
Study Number ESR-14-10744 
Edition Number 8 
 
Date 17 April 2019 
 
Page 132 of 134 
 
APPENDIX A: MEDI4736 DOSE CALCULATIONS  
MEDI4736 Dosing 
The MEDI4736 dosing should be done depending on subject weight: 
1. Cohort dose: X mg/kg 
2. Subject weight: Y kg 
3. Dose for subject: XY mg = X (mg/kg) × Y (kg) 
4. Dose to be added into infusion bag:  
Dose (mL) = XY mg / 50 (mg/mL) where 50 mg/mL is MEDI4736 nominal concentration  
The corresponding volume of MEDI4736 should be rounded to the nearest tenth mL (0.1 mL). 
Dose adjustments for each cycle only needed for greater than 10% change in weight. 
5. The theoretical number of vials required for dose preparation is the next greatest whole 
number of vials from the following formula: 
Number of vials = Dose (mL) / 10 (mL/vial) 
Example:  
1. Cohort dose: 10 mg/kg 
2. Subject weight: 80 kg 
3. Dose for subject: 800 mg = 10 (mg/kg) × 80 (kg) 
4. Dose to be added into infusion bag:  
Dose (mL) = 800 mg / 50 (mg/mL) = 16.0 mL 
5. The theoretical number of vials required for dose preparation:  
Number of vials = 16.0 (mL) / 10 (mL/vial) = 2 vials 


Clinical Study Protocol 
Drug Substance Tremelimumab 
Study Number ESR-14-10744 
Edition Number 8 
 
Date 17 April 2019 
 
Page 133 of 134 
 
APPENDIX B 
Schedule of study procedures: follow-up for subjects who have completed 
MEDI4736 or MEDI4736 plus Tremelimumab but did not have resection. 
Evaluation 
Time Since Last Dose of MEDI4736 
Day (±3) 
Months (±1 week) 
12 Months and 
Every 6 Months  
(±2 weeks) 
30 
2 
3 
4 
6 
8 
10 
Physical examinationa 
X 
 
 
 
 
 
 
 
Vital signs (temperature, respiratory rate, blood 
pressure, pulse) 
X 
 
 
 
 
 
 
 
Weight 
X 
 
 
 
 
 
 
 
Urine hCG or serum βhCG 
X 
 
 
 
 
 
 
 
AE/SAE assessment 
X 
X 
X 
 
 
 
 
 
Concomitant medications 
X 
X 
X 
 
 
 
 
 
Palliative radiotherapy 
As clinically indicated  
<<World Health Organization>> <<ECOG>> 
performance status 
X 
X 
X 
 
X (and 
month 9) 
 
 
X 
Subsequent anti-cancer therapy 
X 
X 
X 
X 
X 
X 
X 
X 
Survival status: phone contact with subjects 
who refuse to return for evaluations and agree 
to be contacted 
 
X 
X 
X 
X 
X 
X 
X (every 2 
months) 
Hematology 
X 
X 
X 
 
 
 
 
X 
Serum chemistry  
X 
X 
X 
 
 
 
 
 
Thyroid function tests (TSH, and fT3 and fT4)b  
X 
 
 
 
 
 
 
 
 
 
a  
Full physical exam 
b 
Free T3 and free T4 will only be measured if TSH is abnormal. They should also be measured if there is clinical 
suspicion of an adverse event related to the endocrine system. 
c 
For patient questionnaires different approaches based on indication and study design 
 
 
 
 


Clinical Study Protocol 
Drug Substance Tremelimumab 
Study Number ESR-14-10744 
Edition Number 8 
 
Date 17 April 2019 
 
Page 134 of 134 
 
APPENDIX C: CyTOF Antibody Panel including cell definitions 
 
Cell Type 
Definition 
Subset or Activation Markers 
Viability 
Cisplatin- 
 
Immune cell 
CD45+ 
 
T cell 
CD3+ 
CD4, CD8, FoxP3, CD25, CD127, 
CD45RA, CD62L, ICOS, CCR4, 
CCR6, Tim1 
Dendritic cells 
HLA-DR+, 
CD3-, 
CD14-, CD19-, CD56- 
BDCA-1, BDCA-2, BDCA-3, BDCA-
4, CD16 
MDSC 
CD11b+, CD15+ 
 
Macrophage 
CD68+ 
CD163, CD206 
Monocyte 
CD14+ 
CD16 
B 
CD19+ 
HLA-DR, CD27, CD38 
NK  
CD56+, CD3- 
CD314, CD69 
NKT 
V224+, Vbeta11+ 
 
PMN 
SSC hi, CD15+ 
CD66b 
RBC 
CD235a/b 
 
Platelet 
CD61+ 
 
Tumor cell 
CD45- 
 
All cells 
 
PD-1, PD-L1, CTLA-4 
All myeloid cells 
 
HLA-DR, CD40, CD80, CD86, ICOSL 
T cell polarization  
 
interferon-gamma, TNF-alpha, IL-17, 
IL-2 
Other 
 
Ki-67