A Randomized Study of Tremelimumab Plus Durvalumab Combination With or Without Radiation in Relapsed Small Cell Lung Cancer
Phase: PHASE2
Conditions: Recurrent Small Cell Lung Carcinoma
Sponsor: Emory University

Investigational Drugs  
Substance(s) 
Durvalumab (MEDI4736)  
Tremelimumab 
Study Number 
ESR-14-10531/WINSHIP3112-15 
Version Number 
3.1 
Date 
May 24, 2018 
IND #: 129242 
Cross-Reference IND #: 010096; 112249 
A randomized study of tremelimumab plus durvalumab combination with or 
without radiation in relapsed small cell lung cancer 
Study Sponsor:   
Taofeek K. Owonikoko, MD, PhD, MSCR 
 
Principal Investigator:  
Taofeek K. Owonikoko, MD, PhD, MSCR 
 
Co-Investigators 
Suresh Ramalingam, MD 
 
Dong M. Shin, MD 
 
Nabil F. Saba, MD 
 
Suchita Pakkala, MD 
 
Rathi Pillai, MD 
 
Gabriel L. Sica, MD, PhD 
Kristin Higgins, MD 
Jonathan Beitler, MD 
Walter J. Curran, MD 
 
Ned Waller, MD, PhD 
 
Conor Steuer, MD 
William Small, MD 
 
Study Statistician 
Zhengjia Chen, PhD 
 
Research Assistant 
Guojing Zhang, MS 
Ernestine Mahar 
 
i 
 

SUMMARY OF CHANGES IN THE AMENDMENTS TO PROTOCOL V. 2.0, MAY 9, 
2016 
Page xviii: Update list of appendix 
Page 26:  Include section 4.5 to provide detailed instructions for registration procedures and 
study ID number 
Page 33: Correct formatting errors in section 6 
Page 71:  In section 8.3.3, replace blue tiger topped tubes with purple topped EDTA bottles and 
update the amount of blood required from 10mls to 30mls for cfDNA analysis 
Page 72: Update table to provide specific instructions in the summary of schedule of sample 
collection for pharmacodynamic analysis 
Page 129:  Include Appendix 7 with details of sample processing for cfDNA assay 
SUMMARY OF CHANGES IN THE AMENDMENT TO PROTOCOL V. 3.0, 
SEPTEMBER 16, 2016 
Page 36: Update Table l  per MEDI4736 Treme Toxicity Management dated 8-19-2016 
SUMMARY OF CHANGES IN THE AMENDMENT TO PROTOCOL V. 3.1, MAY 24, 
2018 
Page 124: Re-included Appendix 7 with details of sample processing for cfDNA assay 
 
 
 
 
ii 
 

PROTOCOL SYNOPSIS 
Clinical Protocol ESR-14-10531/WINSHIP3112-15 
Study Title:  A randomized study of tremelimumab plus durvalumab combination with or without 
radiation in relapsed small cell lung cancer 
Protocol Number:  ESR-14-10531/Winship3112-15 
Clinical Phase:  2 
Study Duration:  36 months 
Investigational Product(s) and Reference Therapy: 
• 
Durvalumab (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 solution for IV infusion, filled in 20 mL clear glass vials with a 
rubber stopper and aluminum seal. Each vial contains 20 mg/mL (with a nominal fill of 20 mL, 
accounting to 400 mg/vial) of tremelimumab, in an isotonic solution at pH 5.5. 
Research Hypothesis 
1. Immune checkpoint therapy will be efficacious and will confer meaningful clinical benefit in relapsed 
SCLC  
2. Priming with XRT prior to immune checkpoint treatment will result in enhanced clinical efficacy of 
immune checkpoint modulators in relapsed SCLC 
Objectives: 
Primary Objectives: 
To compare the efficacy (PFS and ORR) of combined immune checkpoint inhibitor therapy with or 
without radiation as treatment for relapsed SCLC 
Secondary Objective(s): 
Assess the impact of antigen priming using XRT on the efficacy of immune checkpoint inhibitors 
Determine the overall survival (OS) associated with this treatment strategy in relapsed SCLC 
Exploratory Objective(s): 
Characterize tumor infiltrating lymphocytes (TILs) and PD-L1/PD1 expression in paired tumor biopsies 
at baseline, end of cycle 2 and at the time of progression. 
Determine dynamic changes in cell free DNA(cfDNA)  and the immunophenotype of peripheral blood 
repertoire of circulating lymphocytes using multiparameter flow cytometry 
Determine changes in circulating cytokine mediators of inflammation and immunity using Luminex assay 
Study Design: 
iii 
 

Randomized 2-arm, single stage study design. 
Arm I: Durvalumab + Tremelimumab 
Arm II: Radiation followed by Durvalumab + Tremelimumab 
Number of Centers: 1 
Number of Subjects: 20 (10 patients per Arm of study) 
Study Population: Relapsed SCLC patients 
iv 
 

Inclusion Criteria: 
• 
Histology or cytology confirmed diagnosis of small cell lung cancer 
• 
Previously treated with a platinum doublet and not more than 2 prior lines of therapy 
• 
Written informed consent  and any locally-required authorization (e.g.,) obtained from the subject 
prior to performing any protocol-related procedures, including screening evaluations  
• 
Age > 18 years at time of study entry 
• 
Eastern Cooperative Oncology Group (ECOG performance status of 0 or 2 
• 
Adequate normal organ and marrow function as defined below:  
• 
Haemoglobin ≥ 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) 
• 
Serum bilirubin ≤ 1.5 x institutional upper limit of normal (ULN).  This will not apply to subjects 
with confirmed Gilbert’s syndrome (persistent or recurrent hyperbilirubinemia that is predominantly 
unconjugated in the absence of hemolysis or hepatic pathology), who will be allowed only in 
consultation with their physician. 
• 
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>40 mL/min by the Cockcroft-Gault or MDRD formula or by 24-hour urine 
collection for determination of creatinine clearance: 
• 
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.   
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. 
Exclusion Criteria: 
• 
Any previous treatment with a PD1, PD-L1 or CTLA4 inhibitor 
• 
Receipt of the last dose of anti-cancer therapy (chemotherapy, immunotherapy, endocrine therapy, 
targeted therapy, biologic therapy, Tumor embolization, monoclonal antibodies, other investigational 
agent) ≤ 14 days prior to the first dose of study drug (≤ 7 days (five half-lives) prior to the first dose 
of study drug for subjects who have received prior oral TKIs and within 6 weeks for nitrosourea or 
mitomycin C). 
• 
Mean QT interval corrected for heart rate (QTc) ≥470 ms calculated from 3 electrocardiograms 
(ECGs) using Fredericia’s Correction 
• 
Current or prior use of immunosuppressive medication within 28 days before the first dose of 
Durvalumab or Tremelimumab, 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 
• 
Any unresolved toxicity (>CTCAE grade 2) from previous anti-cancer therapy.  Subjects with 
irreversible toxicity that is not reasonably expected to be exacerbated by the investigational product 
may be included (e.g., hearing loss, peripherally neuropathy)  
• 
Any prior Grade ≥3 immune-related adverse event (irAE) while receiving any previous 
v 
 

immunotherapy agent, or any unresolved irAE >Grade 1  
• 
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. 
• 
Active or prior documented inflammatory bowel disease (e.g., Crohn’s disease, ulcerative colitis) 
• 
History of primary immunodeficiency 
• 
History of allogeneic organ transplant  
• 
History of hypersensitivity to Tremelimumab, MEDI4736 or any excipient  
• 
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 
• 
Known history of previous clinical diagnosis of tuberculosis 
• 
Receipt of live attenuated vaccination within 30 days prior to study entry or within 30 days of 
receiving Durvalumab or tremelimumab 
• 
Female subjects who are pregnant, breast-feeding or male or female patients of reproductive potential 
who are unwilling to employ an effective method of birth control 
• 
Any condition that, in the opinion of the investigator, would interfere with evaluation of study 
treatment or interpretation of patient safety or study results 
• 
Symptomatic or uncontrolled brain metastases requiring concurrent treatment, inclusive of but not 
limited to surgery, radiation and/or corticosteroids.  
• 
Subjects with uncontrolled seizures. 
• 
Patients may not be receiving any other investigational agents or non-investigational agents 
administered with the purpose of controlling cancer growth (Use of conventional external beam 
radiation therapy will be allowed during protocol therapy solely for palliation of localised painful 
lesions or bone lesions at risk of fracture provided the radiation field does not encompass any selected 
target lesions required for assessment). 
• 
Patients with uncontrolled symptomatic brain metastases.  
• 
Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, 
symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric 
illness/social situations that would limit compliance with study requirements.  
• 
Patients who require ongoing treatment with any hematopoietic colony-stimulating growth factors 
(e.g., G-CSF, GM-CSF) ≤ 2 weeks prior to starting study drug.  
• 
Patients who have undergone major surgery ≤ 2 weeks prior to starting study drug or who have not 
recovered from side effects of such therapy 
• 
Patient is unable or unwilling to abide by the study protocol or cooperate fully with the investigator 
see Section 4.2 for durvalumab-specific and tremelimumab requirements 
vi 
 

Investigational Product(s), Dose, and Mode of Administration: 
Durvalumab, 1500 mg Q4W (equivalent to 20 mg/kg Q4W) for 12 months in patients > 30 kg 
Tremelimumab 75 mg Q4W (equivalent to 1 mg/kg Q4W) for up to 4 doses/cycles in patients >30 kg 
Weight-based dosing should be utilized for patients <30 kg durvalumab 20 mg/kg Q4 and tremelimumab 
1 mg/kg Q4 
Standard Treatment: 
Priming XRT (Arm II only) up to 30Gy in 1 week 
Study Assessments and Criteria for Evaluation: 
Safety Assessments: 
Safety and toxicity will be assessed and graded using CTCAE v. 4.0 
Patient reported outcome assessed using FACT-L questionnaire  
Efficacy Assessments: 
Primary: 
i. 
Progression free survival (PFS) 
PFS will be measured from time of enrolment until objective disease progression or death 
 
ii. 
Objective response rate 
Objective response (ORR, DoR, DCR) will be assessed using cross sectional imaging and 
categorized according to RECIST 1.1 criteria 
 
Secondary: 
i. 
Immune related objective response rate 
ii. 
Overall survival  
Exploratory: 
Pharmacodynamic / Pharmacokinetic Assessments (if applicable):  
i. 
Immunophenotype of TILs and peripheral circulating lymphocyte 
ii. 
Changes in circulating (cfDNA) 
iii. 
PD-L1 expression in paired tumor biopsy following treatment using the Ventana assay 
iv. 
Tumor infiltrating lymphocytes (TILs) repertoire and PD-L1/PD1 expression in tumor 
biopsies collected at: 
a. Baseline 
b. End of cycle 2 
c. At progression. 
vii 
 

v. 
Dynamic changes in (cfDNA) and the immunophenotype of peripheral blood repertoire of 
circulating lymphocytes using multiparameter flow cytometry 
Changes in circulating cytokine mediators of inflammation, type I and type II immune response using 
Luminex assay 
Statistical Methods and Data Analysis: 
Data on patient demographics, tumor characteristics, response rate and pharmacodynamic (PD) 
biomarkers will be summarized using descriptive statistics.  
Randomization by blocked randomization at the end  of screening for all eligible patients 
OS and PFS time will be analyzed using Kaplan Meier method 
Inferential statistics will be employed to correlate PD biomarkers and efficacy outcome. Two-sided 
paired t-test will be used to compare biomarkers expressions between pre and post treatment samples. 
ANOVA and Kruskal-Wallis tests will be used to compare the degree of biomarker changes between the 
treatment groups. The proportion of patients with objective response will be estimated with exact 95% 
confidence intervals. Changes in pharmacodynamic endpoints will be correlated with response using 
Fisher exact test. 
All analysis will be performed using SAS software version 9.3. 
Sample Size Determination: 
For sample size determination, efficacy comparison was based on historical data with topotecan. 
Assuming a median PFS of 3 months if the intervention is no better than the historical PFS associated 
with topotecan based on the PFS from two recent randomized phase III studies of topotecan (Evans et al., 
2015),(von Pawel et al., 2014) and a promising median PFS of 7 months if the investigational treatment is 
superior (based on the duration of response recorded in a phase II study of combined PD-1 and CTLA-4 
blockade in relapsed SCLC), 10 patients treated in each arm of the study will provide 87% power to 
demonstrate the hypothesized efficacy improvement at  a 1-sided 10% alpha level test.  
Similarly, with the same sample size of 10 patients in each arm, we will have 64% power at a 1-sided 
alpha of 10% to demonstrate a promising response rate of 30% for the investigational therapy versus the 
historical response rate of 10% with topotecan in the same patient population. Assuming an observed 
response rate of 30% (3 out of 10 patients) the 95% exact confidence interval of the response rate will be 
[6.7%, 65.2%] and 90% exact confidence internal of the response rate will be [8.7%, 60.7%]. 
 
 
 
viii 
 

SCHEDULE OF STUDY ASSESSMENTS 
Schedule of study assessments: Screening and Treatment Period  
Visit  
(Assessments to be 
performed at the times 
stipulated in the table and as 
clinically required in the 
management of the subject.) 
Screening 
period  
Radiation 
window 
All assessments to be performed pre-infusion unless stated otherwise 
Baseline 
assessment Every 2 weeks 
Every 4 weeks 
Every 8 Weeks 
Every 12 weeks 
Day 
-21 to -7 
-7 to -1 
1 
Day 1 of the week 
Week 
-3 to -2 
 -1 
1 
3, 5, 7, 9, 11, 13, etc. 
5, 9, 13, 17, 21,  etc. 
9, 17, 25, 33, 41 and 
49 
13, 25, 37, 49 
(±3 days) 
(±7 days) 
Written informed 
consent/assignment of  
subject identification number 
X 
 
 
 
 
 
 
Fresh Tumor biopsy  
X 
 
 
 
 
Xk 
 
Eligibility Verification and 
Randomization 
X 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
Hepatitis B and C; HIV 
X 
 
 
 
 
 
 
Urine hCG or serum βhCGb 
X 
 
As clinically applicable 
Durvalumab administration$   
 
X 
 
X 
 
 
Tremelimumab$ 
 
 
X 
 
X 
 
 
Physical examinationc 
X 
 
X 
 
X 
 
 
Vital signs (pre- during and 
post-infusion vital signs 
assessments)d 
X 
 
X 
 
X 
 
 
Pre-treatments XRT (Arm II 
only) 
 
X 
 
 
 
 
 
Electrocardiograme 
X 
 
X 
 
 
X (week 9 only) 
 
Adverse event/serious 
adverse event assessmentl 
 
X 
X 
All visits 
Concomitant medications 
X 
 
X 
All visits 
ix 
 

Schedule of study assessments: Screening and Treatment Period  
Visit  
(Assessments to be 
performed at the times 
stipulated in the table and as 
clinically required in the 
management of the subject.) 
Screening 
period  
Radiation 
window 
All assessments to be performed pre-infusion unless stated otherwise 
Baseline 
assessment Every 2 weeks 
Every 4 weeks 
Every 8 Weeks 
Every 12 weeks 
Day 
-21 to -7 
-7 to -1 
1 
Day 1 of the week 
Week 
-3 to -2 
 -1 
1 
3, 5, 7, 9, 11, 13, etc. 
5, 9, 13, 17, 21,  etc. 
9, 17, 25, 33, 41 and 
49 
13, 25, 37, 49 
(±3 days) 
(±7 days) 
Palliative radiotherapy 
 
 
 
As clinically indicated for symptomatic non target lesions 
Liver enzyme panelf 
X 
 
X 
 
X 
 
 
Serum Chemistry (complete 
clin chem. panel including 
Liver enzymes)f 
X 
 
X 
 
X  
 
 
Thyroid function tests (TSH 
and fT3 and fT4)g 
X 
 
X 
 
X 
 
 
Hematologyf 
X 
X 
X 
 
X 
 
 
Urinalysish 
X 
 
 
 
X 
 
 
 
Coagulation parametersi 
X 
As clinically indicted 
Plasma sample for cfDNA, 
circulating immune 
mediating cytokines and  
chemokinesa 
 
X 
 
X 
X 
X 
 
Peripheral blood for FACS a  
X 
 
Week 3 
Week 5 
Week 9 
 
Patient questionnaires# 
 
X 
 
 
Week 5 only 
X 
 
Tumor assessment (CT or 
MRI)  j 
X 
 
 
 
 
X 
X 
a  
Sample collection at baseline, (end of XRT for Arm II patients), at C1D15 week, C2D1; C3D1 and at progression 
b   
Pre-menopausal female subjects of childbearing potential only; urine or serum test allowed for screening but only serum pregnancy test allowed while on treatment.  
c  
Full physical examination at baseline; targeted physical examination at other time points 
d  
Subjects will have their vital signs (blood pressure and pulse) measured before, during and after the infusion at the following times (based on a 60-minute infusion): 
x 
 

• 
Baseline at the beginning of the infusion  
• 
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. 
e 
Baseline ECG on C1D1 and on treatment ECG on C3D1 (Week 9). 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.   
f 
See section 8.2.5 for list of labs. 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. Gamma glutamyltransferase tested at Screening, Day 1 and as clinically indicated.    
g 
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. 
h 
Urinalysis performed at Screening, Day 1, every 4 weeks and as clinically indicated. 
i 
Coagulation tests: prothrombin time, APTT and INR – only performed at Screening and as clinically indicated. 
j 
Timing of CT scans: default is every 8 weeks for the first 6 months and then every 12 weeks until confirmed PD.  
k 
collect fresh tumor biopsy at the end of cycle 2 and at the time of confirmed disease progression  
l 
For AEs/SAEs reported  during prescreening additional information such as medical history and concomitant medications may be needed. 
$:  
Concurrent administration Q 4 weeks for four doses thereafter continue durvalumab alone Q4 weeks (total of 1 year or until treatment discontinuation). 
#:  
Functional Assessment of Cancer Therapy - Lung (FACT-L) questionnaire
xi 
 

Clinical Study Protocol  
Investigational Drug Substance: Durvalumab and Tremelimumab 
Study Number ESR-14-10531/WINSHIP3112-15; Edition Number 3.1; Date 09/16/2016 
 
TABLE OF CONTENTS 
PAGE 
SUMMARY OF CHANGES IN THE AMENDMENTS TO PROTOCOL 
V. 2.0, MAY 9, 2016 .............................................................................................. II 
PROTOCOL SYNOPSIS ....................................................................................... III 
TABLE OF CONTENTS ..................................................................................... XII 
ABBREVIATIONS AND DEFINITION OF TERMS ..................................... XVII 
1. 
INTRODUCTION ................................................................................................... 1 
1.1 
Disease Background ................................................................................................. 1 
1.1.1 
Immunotherapies ...................................................................................................... 4 
1.1.2 
Durvalumab .............................................................................................................. 4 
1.1.3 
Tremelimumab ......................................................................................................... 6 
1.1.4 
Durvalumab in combination with tremelimumab .................................................... 6 
1.2 
Research hypothesis ................................................................................................. 7 
1.3 
Rationale for conducting this study ......................................................................... 7 
1.3.1 
Durvalumab  + tremelimumab combination therapy dose rationale ........................ 9 
1.3.2 
Rationale for 4 cycles of combination therapy followed by durvalumab  
monotherapy........................................................................................................... 11 
1.4 
Benefit/risk and ethical assessment ........................................................................ 12 
1.4.1 
Potential benefits .................................................................................................... 12 
1.4.1.1 
Durvalumab ............................................................................................................ 12 
1.4.1.2 
Tremelimumab ....................................................................................................... 12 
1.4.1.3 
Durvalumab + tremelimumab ................................................................................ 13 
1.4.2 
Potential risks ......................................................................................................... 14 
1.4.2.1 
Durvalumab ............................................................................................................ 14 
1.4.2.2 
Tremelimumab ....................................................................................................... 16 
1.4.2.3 
Durvalumab + tremelimumab ................................................................................ 16 
1.4.2.4 
Fixed Dosing for durvalumab and tremelimumab ................................................. 17 
2. 
STUDY OBJECTIVE ............................................................................................ 19 
2.1.1 
Primary objective(s) ............................................................................................... 19 
2.1.2 
Secondary objective(s) ........................................................................................... 19 
2.1.3 
Exploratory objective(s) ......................................................................................... 19 
3. 
STUDY DESIGN ................................................................................................... 19 
3.1 
Overview of study design ...................................................................................... 19 
3.2 
Study schema ......................................................................................................... 20 
3.3 
Study Oversight for Safety Evaluation .................................................................. 21 
xii 
 

Clinical Study Protocol  
Investigational Drug Substance: Durvalumab and Tremelimumab 
Study Number ESR-14-10531/WINSHIP3112-15; Edition Number 3.1; Date 09/16/2016 
 
4. 
PATIENT SELECTION, ENROLLMENT, RANDOMIZATION, 
RESTRICTIONS, DISCONTINUATION AND WITHDRAWAL ...................... 21 
4.1 
Inclusion criteria .................................................................................................... 21 
4.2 
Exclusion criteria ................................................................................................... 23 
4.3 
Withdrawal of Subjects from Study Treatment and/or Study ................................ 25 
4.4 
Replacement of subjects......................................................................................... 26 
4.5 
Subject Registration ............................................................................................... 26 
5. 
INVESTIGATIONAL PRODUCT(S) ................................................................... 27 
5.1 
Durvalumab and tremelimumab............................................................................. 27 
5.1.1 
Formulation/packaging/storage .............................................................................. 27 
5.2 
Dose and treatment regimens ................................................................................. 27 
5.2.1 
Treatment regimens................................................................................................ 27 
5.2.2 
Duration of treatment and criteria for retreatment ................................................. 28 
5.2.3 
Study drug preparation of durvalumab and tremelimumab ................................... 29 
5.2.4 
Monitoring of dose administration ......................................................................... 32 
5.2.5 
Accountability and dispensation ............................................................................ 32 
5.2.6 
Disposition of unused investigational study drug .................................................. 33 
5.3 
Radiation Treatment ............................................................................................... 33 
6. 
TREATMENT PLAN ............................................................................................ 33 
6.1 
Subject enrollment and randomization .................................................................. 33 
6.1.1 
Procedures for randomization ................................................................................ 33 
6.2 
Blinding and procedures for unblinding the study ................................................. 33 
6.3 
Dosage and Administration .................................................................................... 34 
6.4 
Dose Escalation Decision Rules ............................................................................ 34 
6.5 
Definition of DLT .................................................................................................. 34 
6.6 
Dose Modification and Toxicity Management ...................................................... 34 
6.6.1 
Durvalumab and tremelimumab............................................................................. 34 
7. 
RESTRICTIONS DURING THE STUDY AND CONCOMITANT 
TREATMENT(S)................................................................................................... 55 
7.1 
Restrictions during the study.................................................................................. 55 
7.2 
Concomitant treatment(s) ....................................................................................... 56 
7.2.1 
Permitted concomitant medications ....................................................................... 56 
7.2.2 
Excluded Concomitant Medications ...................................................................... 56 
8. 
STUDY PROCEDURES ....................................................................................... 58 
8.1 
Schedule of study procedures ................................................................................ 58 
xiii 
 

Clinical Study Protocol  
Investigational Drug Substance: Durvalumab and Tremelimumab 
Study Number ESR-14-10531/WINSHIP3112-15; Edition Number 3.1; Date 09/16/2016 
 
8.1.1 
Screening Phase ..................................................................................................... 58 
8.1.2 
Treatment Phase ..................................................................................................... 59 
8.1.3 
End of Treatment ................................................................................................... 61 
8.2 
Description of study procedures ............................................................................ 61 
8.2.1 
Medical history and physical examination, electrocardiogram, weight and 
vital signs ............................................................................................................... 61 
8.2.2 
Physical examination ............................................................................................. 61 
8.2.3 
Electrocardiograms ................................................................................................ 62 
8.2.4 
Vital signs .............................................................................................................. 62 
8.2.5 
Clinical laboratory tests ......................................................................................... 63 
8.2.6 
Patient reported outcomes (PRO) .......................................................................... 65 
8.2.6.1 
Name of PRO method or questionnaire ................................................................. 65 
8.3 
Biological sampling procedures ............................................................................. 65 
8.3.1 
Pharmacokinetic sampling and evaluation methods .............................................. 65 
8.3.2 
Immunogenicity sampling and evaluation methods............................................... 65 
8.3.3 
Biomarker/Pharmacodynamic sampling and evaluation methods ......................... 65 
8.3.4 
Estimate of volume of blood to be collected .......................................................... 72 
8.3.5 
Archival tumor samples and fresh tumor biopsies ................................................. 73 
8.3.5.1 
Archival tumor samples ......................................................................................... 73 
8.3.5.2 
Fresh tumor biopsies .............................................................................................. 73 
8.3.6 
Withdrawal of informed consent for donated biological samples ......................... 73 
9. 
DISEASE EVALUATION AND METHODS ...................................................... 73 
9.1.1 
Efficacy variable .................................................................................................... 77 
10. 
ASSESSMENT OF SAFETY ................................................................................ 78 
10.1.1 
Safety Parameters ................................................................................................... 78 
10.1.1.1 Definition of adverse events .................................................................................. 78 
10.1.2 
Definition of serious adverse events ...................................................................... 78 
10.1.3 
Durvalumab + tremelimumab adverse events of special interest .......................... 79 
10.1.4 
Immune-related adverse events .............................................................................. 82 
10.2 
Assessment of safety parameters ........................................................................... 84 
10.2.1 
Assessment of severity ........................................................................................... 84 
10.2.2 
Assessment of relationship..................................................................................... 85 
10.3 
Recording of adverse events and serious adverse events ....................................... 85 
10.3.1 
Study recording period and follow-up for adverse events and serious 
adverse events ........................................................................................................ 86 
10.3.2 
Reporting of serious adverse events ....................................................................... 87 
10.3.2.1 Reporting of deaths ................................................................................................ 88 
10.3.3 
Other events requiring reporting ............................................................................ 88 
10.3.3.1 Overdose ................................................................................................................ 88 
10.3.3.2 Hepatic function abnormality................................................................................. 89 
10.3.3.3 Pregnancy ............................................................................................................... 89 
10.3.3.4 Maternal exposure .................................................................................................. 89 
xiv 
 

Clinical Study Protocol  
Investigational Drug Substance: Durvalumab and Tremelimumab 
Study Number ESR-14-10531/WINSHIP3112-15; Edition Number 3.1; Date 09/16/2016 
 
10.3.4 
Paternal exposure ................................................................................................... 90 
11. 
STATISTICAL METHODS AND SAMPLE SIZE DETERMINATION ............ 90 
11.1 
Description of analysis sets .................................................................................... 90 
11.1.1 
Safety analysis set .................................................................................................. 90 
11.1.2 
Efficacy analysis set ............................................................................................... 91 
11.1.3 
Randomization ....................................................................................................... 91 
11.2 
Methods of statistical analyses ............................................................................... 91 
11.2.1 
Safety Analyses ...................................................................................................... 91 
11.2.2 
Efficacy Analyses .................................................................................................. 92 
11.2.3 
Exploratory Analyses ............................................................................................. 92 
11.2.4 
Interim analyses ..................................................................................................... 92 
11.3 
Determination of sample size ................................................................................. 93 
12. 
ETHICAL AND REGULATORY REQUIREMENTS ......................................... 93 
12.1 
Ethical conduct of the study ................................................................................... 93 
12.2 
Ethics and regulatory review .................................................................................. 93 
12.3 
Informed consent.................................................................................................... 94 
12.4 
Changes to the protocol and informed consent form ............................................. 94 
13. 
STUDY MANAGEMENT .................................................................................... 94 
13.1 
Training of study site personnel ............................................................................. 95 
13.2 
Monitoring of the study.......................................................................................... 95 
13.2.1 
Source data and documents .................................................................................... 95 
13.3 
Study timetable and end of study ........................................................................... 98 
14. 
DATA MANAGEMENT ....................................................................................... 99 
14.3 
Study governance and oversight ............................................................................ 99 
15. 
INVESTIGATIONAL PRODUCT AND OTHER TREATMENTS .................. 100 
15.1 
Identity of investigational product(s) ................................................................... 100 
16. 
LIST OF REFERENCES ..................................................................................... 101 
 
LIST OF TABLES 
Table 1. Dosing modification and toxicity management guidelines for immune-mediated, 
infusion-related, and non immune-mediated reactions (durvalumab combination therapy with 
tremelimumab) 36 
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Clinical Study Protocol  
Investigational Drug Substance: Durvalumab and Tremelimumab 
Study Number ESR-14-10531/WINSHIP3112-15; Edition Number 3.1; Date 09/16/2016 
 
Table 2. Infusion-Related Reactions 58 
Table 3. Non-immune Mediated Reactions 59 
Table 4. Effective methods of contraception (2 methods must be used) 60 
Table 5. Prohibited and Rescue Medications 62 
Table 6. Hematology Laboratory Tests 69 
Table 7. Clinical chemistry (serum or plasma) Laboratory Tests 69 
Table 8. Urinalysis Tests 69 
Table 9. List of investigational products for this study 105 
LIST OF FIGURES 
Figure 1. Study flow chart 20 
 
LIST OF APPENDICES 
Appendix 1 
Schedule of study procedures: follow-up for subjects who have completed 
durvalumab + tremelimumab treatment and achieved disease control (until 
confirmed progression of disease) and subjects who have discontinued 
durvalumab + tremelimumab due to toxicity in the absence of confirmed 
progression of disease 
Appendix 2 
Schedule of study procedures: follow-up for subjects who have 
discontinued durvalumab + tremelimumab treatment due to confirmed 
progression of disease 
Appendix 3 
Durvalumab dose calculations 
Appendix 4 
Durvalumab dose volume calculations 
Appendix 5 
Tremelimumab dose calculations 
Appendix 6 
Tremelimumab dose volume calculations 
Appendix 7 
cfDNA Lab Blood Processing Protocol 
 
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Investigational Drug Substance: Durvalumab and Tremelimumab 
Study Number ESR-14-10531/WINSHIP3112-15; Edition Number 3.1; Date 09/16/2016 
 
ABBREVIATIONS AND DEFINITION OF TERMS 
 
The following abbreviations and special terms are used in this study Clinical Study Protocol. 
Abbreviation 
or 
special term 
Explanation 
AChE 
Acetylcholine esterase 
ADA 
Anti-drug antibody 
AE 
Adverse event 
AESI 
Adverse event of special interest 
ALK 
Anaplastic lymphoma kinase 
ALT 
Alanine aminotransferase 
APF12 
Proportion of patients alive and progression free at 12 months from 
randomization 
AST 
Aspartate aminotransferase 
AUC 
Area under the curve 
AUC0-28day 
Area under the plasma drug concentration-time curve from time zero to 
Day 28 post-dose 
AUCss 
Area under the plasma drug concentration-time curve at steady state 
BICR 
Blinded Independent Central Review 
BoR 
Best objective response 
BP 
Blood pressure 
C 
Cycle 
CD 
Cluster of differentiation 
CI 
Confidence interval 
CL 
Clearance 
Cmax 
Maximum plasma concentration 
Cmax,ss 
Maximum plasma concentration at steady state 
CR 
Complete response 
CSA 
Clinical study agreement 
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Study Number ESR-14-10531/WINSHIP3112-15; Edition Number 3.1; Date 09/16/2016 
 
Abbreviation 
or 
special term 
Explanation 
CSR 
Clinical study report 
CT 
Computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Event 
CTLA-4 
Cytotoxic T–lymphocyte-associated antigen 4 
Ctrough,ss 
Trough concentration at steady state 
CXCL 
Chemokine (C-X-C motif) ligand 
DoR 
Duration of response 
EC 
Ethics Committee, synonymous to Institutional Review Board and 
Independent Ethics Committee 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic case report form 
EDoR 
Expected duration of response 
EGFR 
Epidermal growth factor receptor 
EU 
European Union 
FAS 
Full analysis set 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GI 
Gastrointestinal 
GMP 
Good Manufacturing Practice 
hCG 
Human chorionic gonadotropin 
HIV 
Human immunodeficiency virus 
HR 
Hazard ratio 
IB 
Investigator’s Brochure 
ICF 
Informed consent form 
ICH 
International Conference on Harmonisation 
IDMC 
Independent Data Monitoring Committee 
IFN 
Interferon 
IgE 
Immunoglobulin E 
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Investigational Drug Substance: Durvalumab and Tremelimumab 
Study Number ESR-14-10531/WINSHIP3112-15; Edition Number 3.1; Date 09/16/2016 
 
Abbreviation 
or 
special term 
Explanation 
IgG 
Immunoglobulin G 
IHC 
Immunohistochemistry 
IL 
Interleukin 
ILS 
Interstitial lung disease 
IM 
Intramuscular 
IMT 
Immunomodulatory therapy 
IP 
Investigational product  
irAE 
Immune-related adverse event 
IRB 
Institutional Review Board 
irRECIST 
Immune-related Response Evaluation Criteria in Solid Tumors 
ITT 
Intent-to-Treat 
IV 
Intravenous 
IVRS 
Interactive Voice Response System 
IWRS 
Interactive Web Response System 
mAb 
Monoclonal antibody 
MDSC 
Myeloid-derived suppressor cell 
MedDRA 
Medical Dictionary for Regulatory Activities 
MHLW 
Minister of Health, Labor, and Welfare 
miRNA 
Micro-ribonucleic acid 
MRI 
Magnetic resonance imaging 
NCI 
National Cancer Institute 
NE 
Not evaluable 
NSCLC 
Non–small-cell lung cancer 
OAE 
Other significant adverse event 
ORR 
Objective response rate 
OS 
Overall survival 
PBMC 
Peripheral blood mononuclear cell 
PD 
Progressive disease 
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Clinical Study Protocol  
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Study Number ESR-14-10531/WINSHIP3112-15; Edition Number 3.1; Date 09/16/2016 
 
Abbreviation 
or 
special term 
Explanation 
PD-1 
Programmed cell death 1 
PD-L1 
Programmed cell death ligand 1 
PD-L2 
Programmed cell death ligand 2 
PDx 
Pharmacodynamic(s) 
PFS 
Progression-free survival 
PFS2 
Time to second progression 
PGx 
Pharmacogenetic research 
PK 
Pharmacokinetic(s) 
PR 
Partial response 
q2w 
Every 2 weeks 
q3w 
Every 3 weeks 
q4w 
Every 4 weeks 
q6w 
Every 6 weeks 
q8w 
Every 8 weeks 
QTcF 
QT interval corrected for heart rate using Fridericia’s formula 
RECIST 1.1 
Response Evaluation Criteria in Solid Tumors, version 1.1 
RNA 
Ribonucleic acid 
RR 
Response rate 
RT-QPCR 
Reverse transcription quantitative polymerase chain reaction 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SAS 
Safety analysis set 
SCLC 
Small cell lung cancer 
SD 
Stable disease 
SNP 
Single nucleotide polymorphism 
SoC 
Standard of Care 
sPD-L1 
Soluble programmed cell death ligand 1 
T3 
Triiodothyronine 
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Clinical Study Protocol  
Investigational Drug Substance: Durvalumab and Tremelimumab 
Study Number ESR-14-10531/WINSHIP3112-15; Edition Number 3.1; Date 09/16/2016 
 
Abbreviation 
or 
special term 
Explanation 
T4 
Thyroxine 
TSH 
Thyroid-stimulating hormone 
ULN 
Upper limit of normal 
US 
United States 
WBDC 
Web-Based Data Capture 
WHO 
World Health Organization 
 
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Clinical Study Protocol  
Investigational Drug Substance: Durvalumab and Tremelimumab 
Study Number ESR-14-10531/WINSHIP3112-15; Edition Number 3.1; Date 09/16/2016 
 
1. 
INTRODUCTION 
 
1.1 
Disease Background 
SCLC is one of the most lethal cancers with more than 20,000 newly diagnosed patients in the 
US in 2014 (Siegel et al., 2014). More than 80% of these patients die from their disease within 
2 years of diagnosis and less than 5% of patients are alive at 5 years (Owonikoko et al., 2007). 
There has not been any meaningful improvement in the survival of SCLC patients in the past 
3 decades (Behera et al., 2014). Although the majority of SCLC patients (70%) will respond 
to frontline chemotherapy, there is a near universal recurrence of disease, which is oftentimes 
resistant to further treatment leading to early death (Pillai and Owonikoko, 2014). The 
relapsed disease setting therefore represents the area of greatest unmet need for novel 
treatments in SCLC. Different strategies to improve outcomes following relapse have met 
with limited success (Owonikoko et al., 2012). Indeed, single agent topotecan remains the 
only approved treatment for relapsed SCLC more than 2 decades after its initial approval 
based on toxicity profile rather than superior efficacy compared to conventional multi-agent 
chemotherapy (Schiller et al., 2001; Schiller et al., 1996). While the use of targeted biologic 
agents has led to astounding success in the treatment of non-small cell lung cancer (Shaw et 
al., 2013a; Shaw et al., 2013b) novel approaches have not been successful to date in SCLC. 
Tumor-Directed Immunity and SCLC 
SCLC patients with paraneoplastic syndrome achieve prolonged and durable disease control in 
contrast to patients without paraneoplastic syndrome in the setting of SCLC diagnosis 
(Maddison et al., 1999; Tani et al., 2008). Also, high levels of suppressor T-reg and low 
effector T cells were observed in the peripheral circulation of patients with extensive stage 
(SCLC-ED) and limited stage small cell lung cancer (SCLC-LD) who progress following 
frontline therapy. Similarly, a high ratio of effector cells to T-regs was associated with 
improved survival in SCLC-LD (Koyama et al., 2008). Recent data indicates potential benefit 
of immune checkpoint inhibitors in SCLC where phased, (but not concurrent) administration 
of ipilimumab, an anti-CTLA4 antibody, with chemotherapy demonstrated improved efficacy 
in SCLC-ED (Reck et al., 2013).  
Limited institutional experience and large randomized studies also suggest survival benefit of 
XRT in SCLC-ED (Ben J. Slotman, 2014; Guy C. Jones, 2014). Moreover, XRT can induce 
PD-L1 expression on Tumor and stromal cells along with increase in myeloid-derived 
suppressor cells (MDSCs) in preclinical models (Deng et al., 2014a; Deng et al., 2014b). 
Furthermore, the release of Tumor-associated antigens following cell death induced by XRT 
may be highly immunogenic (Deng et al., 2014a; Deng et al., 2014b), leading to potent 
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Clinical Study Protocol  
Investigational Drug Substance: Durvalumab and Tremelimumab 
Study Number ESR-14-10531/WINSHIP3112-15; Edition Number 3.1; Date 09/16/2016 
 
abscopal effect at distant Tumor sites (Blanquicett et al., 2005). The combination of an anti-
PD-L1 inhibitor and XRT was also synergistic in xenograft models of pancreatic, colon and 
breast cancer (Blanquicett et al., 2005; Deng et al., 2014a; Deng et al., 2014b).  
Immune responses directed against tumors are one of the body’s natural defense 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 allowing them to develop 
unchecked. One such mechanism involves 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. 
Programmed cell death ligand 1 is part of a complex system of receptors and ligands that are 
involved in controlling T-cell activation. PD-L1 acts at multiple sites in the body to help 
regulate normal immune responses and is utilized by tumors to help evade detection and 
elimination by the host immune system tumor response. In the lymph nodes, PD-L1 on 
antigen-presenting cells binds to PD-1 or CD80 on activated T cells and delivers an inhibitory 
signal to the T cell (Keir et al, 2008; Park et al, 2010). This results in reduced T-cell activation 
and fewer activated T cells in circulation. In the tumor microenvironment, PD-L1 expressed 
on tumor cells binds to PD-1 and CD80 on activated T cells reaching the tumor. This delivers 
an inhibitory signal to those T cells, preventing them from killing target cancer cells and 
protecting the tumor from immune elimination (Zou and Chen, 2008). 
Immune responses directed against tumors are one of the body’s natural defenses against 
the growth and proliferation of cancer cells. T cells play a critical role in antitumor 
immunity and their infiltration and activity have been linked to improved prognosis 
in a number of cancers (Pagès et al, 2010; Nakano et al, 2001; Suzuki et al, 2011; Burt et al, 
2011). Immune evasion, primarily through suppression of T-cell activity, is now recognized as 
one of the hallmarks of cancer. Such evasion can occur via a range of mechanisms including 
production of suppressive cytokines such as IL-10, secretion of chemokines and growth 
factors that recruit and sustain suppressive regulatory T cells (Tregs) and inflammatory 
macrophages, and expression of inhibitory surface molecules such as B7-H1. Tumor types 
characterized as being responsive to immunotherapy-based approaches include melanoma 
(Weber et al, 2012), renal cell carcinoma (RCC; McDermott, 2009), bladder cancer (Kresowik 
and Griffith, 2009), and malignant mesothelioma (Bograd et al, 2011). Inhibition of CTLA-4 
signaling is a validated approach to cancer therapy, as shown by the approval in 2011 of 
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Clinical Study Protocol  
Investigational Drug Substance: Durvalumab and Tremelimumab 
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ipilimumab for the treatment of metastatic melanoma based on statistically significant and 
clinically meaningful improvement in OS (Hodi et al, 2010; Robert et al, 2011).  
In general, tumor response rates to anti-CTLA-4 therapy are low (~10%). However, in patients 
who respond, the responses are generally durable, lasting several months even in patients with 
aggressive tumors such as refractory metastatic melanoma. Because these agents work 
through activation of the immune system and not by directly targeting the tumor, responses 
can occur late and some patients may have perceived progression of their disease in advance 
of developing disease stabilization or a tumor response. In some cases, early growth of pre-
existing lesions or the appearance of new lesions may have been due to immune-cell 
infiltration into the tumor and not due to proliferation and extension of neoplastic cells, per se 
(Wolchok et al, 2009). Overall, although the impact on conventionally-defined PFS can be 
small, durable response or stable disease seen in a proportion of patients can lead to 
significant prolongation of OS. The melanoma data with ipilimumab clearly demonstrate that 
a small proportion of patients with an objective response had significant prolongation of OS, 
supporting the development of this class of agents in other tumors. Although Phase 2 and 
Phase 3 studies of tremelimumab in metastatic melanoma did not meet the primary endpoints 
of response rate and OS, respectively, the data suggest activity of tremelimumab in melanoma 
(Kirkwood et al, 2010; Ribas et al, 2013). In a large Phase 3 randomized study comparing 
tremelimumab with dacarbazine (DTIC)/temozolomide in patients with advanced melanoma, 
the reported median OS in the final analysis was 12.58 months for tremelimumab versus 
10.71 months for DTIC/temozolomide (HR = 1.1416, p = 0.1272; Ribas et al, 2013).   
Immune checkpoint inhibitor therapy in relapsed SCLC 
There is limited experience with checkpoint inhibitors in relapsed SCLC compared to NSCLC 
where this class of agents is now an approved standard of care option. Preliminary results of 
early phase clinical trials of anti PD-1 and anti PD-L1 inhibitors in SCLC showed strong 
promise. IN KEYNOTE-028 study, pembrolizumab was tested in relapsed SCLC patients who 
have failed standard therapy. Pembrolizumab (10 mg/kg) was given every 2 weeks for up to 2 
year or until confirmed progression or unacceptable toxicity. A total of 157 patients with 
SCLC were screened of which 42 (29%) had PD-L1+ tumors (defined as >1% staining). 
Twenty patients were treated with pembrolizumab (55% men; median age, 59 y; 75% ECOG 
PS 1). All 20 treated patients received prior platinum and etoposide. Grade 3-5 adverse events 
were Asthenia (5%), elevated bilirubin (5%) and colitis (5%).  Seven of 20 (35%) evaluable 
patients had a partial response; one (5%) patient had stable disease while the remaining 
patients either had progressive disease (9; 45%) or had not yet had an assessment performed 
(3; 15%). The time to response was 8.6 weeks (7.7-16.1 weeks) and responses were durable, 
with all responders on treatment for 16+ weeks (Ott et al., 2015).  
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Clinical Study Protocol  
Investigational Drug Substance: Durvalumab and Tremelimumab 
Study Number ESR-14-10531/WINSHIP3112-15; Edition Number 3.1; Date 09/16/2016 
 
CHECKMATE 032 was a phase I/II trial that studied nivolumab, anti PD-1 antibody as a 
single agent and in combination with ipilimumab, an antibody targeting CTLA4. The study 
enrolled 128 patients (regardless of PD-L1 expression) and assign them to nivolumab alone 
(3mg/kg Q3W); nivolumab (1mg/kg Q3W) plus ipilimumab (1mg/kg Q3W); nivolumab 
(1mg/kg Q3W) plus ipilimumab (3mg/kg Q3W) and nivolumab (3mg/kg Q3W) plus 
ipilimumab (1mg/kg Q3W). After four cycles of treatment, all patients continued with single 
agent nivolumab (3mg/kg Q2W). Pooled data from 90 patients treated with single agent (40 
patients) or combination (50 patients) showed intriguing signal of efficacy especially for the 
combination. The median age was 63 and 65 in both groups respectively with approximately 
35% with platinum refractory disease. Treatment-related adverse events were uncommon 
(7.5% versus 11%) and treatment-related death in a patient treated with the combination. The 
response rate was 18% and 32% respectively and disease control rate of 38 and 54% in the 
single agent nivolumab and combination groups respectively.  The median duration of 
response was not yet reached (4.1; 11+) for the Nivolumab single agent arm and 6.9 months 
(1.5; 11.1+) for the combination arm. The median OS was 4.4 (2.9, 9.4) months versus 8.2 
(3.7, NR) months in the single agent and the combination groups respectively (Antonia et al., 
2015). 
1.1.1 
Immunotherapies 
It is increasingly understood that cancers are recognized by the immune system, and, under 
some circumstances, the immune system may control or even eliminate tumors (Dunn 
et al 2004).  Studies in mouse models of transplantable tumors have demonstrated that 
manipulation of co-stimulatory or co-inhibitory signals can amplify T-cell responses against 
tumors.  This amplification may be accomplished by blocking co-inhibitory molecules, such 
as cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) or programmed cell death 1 
(PD-1), from binding with their ligands, B7 or B7-H1 (programmed cell death ligand 1 [PD-
L1]).   
1.1.2 
Durvalumab  
The non-clinical and clinical experience is fully described in the current version of the 
durvalumab Investigator’s Brochure (IB Version 8.0).   
Durvalumab is a human monoclonal antibody (mAb) of the immunoglobulin G (IgG) 1 kappa 
subclass that inhibits binding of PD-L1 and is being developed by AstraZeneca/MedImmune 
for use in the treatment of cancer.  (MedImmune is a wholly owned subsidiary of 
AstraZeneca; AstraZeneca/MedImmune will be referred to as AstraZeneca throughout this 
document.)  As durvalumab is an engineered mAb, it does not induce antibody-dependent 
cellular cytotoxicity or complement-dependent cytotoxicity.  The proposed mechanism of 
action for durvalumab is interference of the interaction of PD-L1. 
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Clinical Study Protocol  
Investigational Drug Substance: Durvalumab and Tremelimumab 
Study Number ESR-14-10531/WINSHIP3112-15; Edition Number 3.1; Date 09/16/2016 
 
PD-L1 is expressed in a broad range of cancers with a high frequency, up to 88% in some 
types of cancers.  In a number of these cancers, including lung, the expression of PD-L1 is 
associated with reduced survival and an unfavorable prognosis.  In lung cancer, only 12% of 
patients with tumors expressing PD-L1 survived for more than 3 years, compared with 20% of 
patients with tumors lacking PD-L1 (Mu et al 2011).  Based on these findings, an anti-PD-L1 
antibody could be used therapeutically to enhance anti-tumor immune responses in patients 
with cancer.  Results of several non-clinical studies using mouse tumor models support this 
hypothesis, where antibodies directed against PD-L1 or its receptor PD-1 showed anti-tumor 
activity (Hirano et al 2005, Iwai et al 2002). 
Durvalumab has been given to humans as part of ongoing studies as a single drug or in 
combination with other drugs As of the DCO dates (15Apr2015 to 12Jul2015, durvalumab IB 
version 8.0), a total of 1,883 subjects have been enrolled and treated in 30 ongoing 
durvalumab clinical studies, including 20 sponsored and 10 collaborative studies. Of the 1,883 
subjects, 1,279 received durvalumab monotherapy, 440 received durvalumab 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.  
As of 09Feb2015, PK data were available for 378 subjects in the dose-escalation and dose-
expansion phases of Study CD-ON-durvalumab-1108 following treatment with durvalumab 
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 
durvalumab 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 durvalumab 
≥ 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 
durvalumab 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. 
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Clinical Study Protocol  
Investigational Drug Substance: Durvalumab and Tremelimumab 
Study Number ESR-14-10531/WINSHIP3112-15; Edition Number 3.1; Date 09/16/2016 
 
1.1.3 
Tremelimumab 
The non-clinical and clinical experience is fully described in the current version of the 
tremelimumab Investigator’s Brochure (IB Version 5.0). Tremelimumab is an IgG 2 kappa 
isotype mAb directed against the cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) also 
known as CD152 (cluster of differentiation 152)  This is an immunomodulatory therapy (IMT) 
that is being developed by AstraZeneca for use in the treatment of cancer.   
Binding of CTLA-4 to its target ligands (B7-1 and B7-2) provides a negative regulatory 
signal, which limits T-cell activation.  Anti-CTLA-4 inhibitors antagonize the binding of 
CTLA-4 to B7 ligands and enhance human T-cell activation as demonstrated by increased 
cytokine (interleukin [IL]-2 and interferon [IFN] gamma) production in vitro in whole blood 
or peripheral blood mononuclear cell (PBMC) cultures.  In addition, blockade of CTLA-4 
binding to B7 by anti-CTLA-4 antibodies results in markedly enhanced T-cell activation and 
anti-tumor activity in animal models, including killing of established murine solid tumors and 
induction of protective anti-tumor immunity.  (Refer to the tremelimumab IB, Edition 5.0, for 
more information.)  Therefore, it is expected that treatment with an anti-CTLA-4 antibody, 
such as tremelimumab, will lead to increased activation of the human immune system, 
increasing anti-tumor activity in patients with solid tumors.   
An extensive program of non-clinical and clinical studies has been conducted for 
tremelimumab both as monotherapy and combination therapy with conventional anticancer 
agents to support various cancer indications using different dose schedules.  As of the data 
cut-off date of 12 November 2014 (for all studies except D4190C00006, which has a cut-off 
date of 4 December 2014), 973 patients have received tremelimumab monotherapy (not 
including 497 patients who have been treated in the blinded Phase 2b study, D4880C00003) 
and 208 patients have received tremelimumab in combination with other agents.  Details on 
the safety profile of tremelimumab monotherapy are summarized in Section 1.4.2.2.  Refer to 
the current tremelimumab IB for a complete summary of non-clinical and clinical information; 
see Section 6.6 for guidance on management of tremelimumab-related toxicities.   
Tremelimumab exhibited a biphasic PK profile with a long terminal phase half-life of 22 days.  
Overall, a low incidence of ADAs (<6%) was observed for treatment with tremelimumab.   
1.1.4 
Durvalumab in combination with tremelimumab 
Targeting both PD-1 and CTLA-4 pathways may have additive or synergistic activity because 
the mechanisms of action of CTLA-4 and PD-1 are non-redundant; therefore, AstraZeneca is 
also investigating the use of durvalumab + tremelimumab combination therapy for the 
treatment of cancer. 
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Clinical Study Protocol  
Investigational Drug Substance: Durvalumab and Tremelimumab 
Study Number ESR-14-10531/WINSHIP3112-15; Edition Number 3.1; Date 09/16/2016 
 
Study D4190C00006 is a Phase Ib dose-escalation study to establish safety, PK/PDx, and 
preliminary anti-tumor activity of durvalumab + tremelimumab combination therapy in 
patients with advanced NSCLC.  The dosing schedule utilized is durvalumab every 2 weeks 
(q2w) or every 4 weeks (q4w) up to Week 50 and 48 (12 months), combined with 
tremelimumab q4w up to Week 24 for 7 doses then every 12 weeks for 2 additional doses for 
up to 12 months.  The study is ongoing and continues to accrue.   
Study D4190C00006: As of 20Feb2015, durvalumab 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 
durvalumab 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 durvalumab and 
tremelimumab was observed over the dose range of 3 to 15 mg/kg durvalumab Q4W and 1 to 
10 mg/kg tremelimumab Q4W. Exposures following multiple doses demonstrated 
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 durvalumab 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 durvalumab and 53 subjects 
for tremelimumab in Study D4190C00006. Four of 60 subjects were ADA positive for 
anti-durvalumab 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 durvalumab or tremelimumab, and no obvious association between 
ADA and safety or efficacy. 
Durvalumab has also been combined with other anticancer agents, including gefitinib, 
dabrafenib, and trametinib. To date, no PK interaction has been observed between durvalumab 
and these agents.  
1.2 
Research hypothesis 
1. Immune checkpoint therapy will be efficacious and will confer meaningful clinical benefit 
in relapsed SCLC  
2. Concomitant immune checkpoint treatment with XRT will enhance the clinical efficacy of 
immune checkpoint modulators in relapsed SCLC 
1.3 
Rationale for conducting this study 
SCLC patients with paraneoplastic syndrome achieve prolonged and durable disease control in 
contrast to patients without paraneoplastic syndrome in the setting of SCLC diagnosis. (10, 
7 
 

Clinical Study Protocol  
Investigational Drug Substance: Durvalumab and Tremelimumab 
Study Number ESR-14-10531/WINSHIP3112-15; Edition Number 3.1; Date 09/16/2016 
 
11) Also, high levels of suppressor T-reg and low effector T cells were observed in the 
peripheral circulation of patients with extensive stage (SCLC-ED) and limited stage small cell 
lung cancer (SCLC-LD) who progress following frontline therapy. Similarly, a high ratio of 
effector cells to T-regs was associated with improved survival in SCLC-LD. (12) Recent data 
indicates potential benefit of immune checkpoint inhibitors in SCLC where phased, (but not 
concurrent) administration of ipilimumab, an anti-CTLA4 antibody, with chemotherapy 
demonstrated improved efficacy in SCLC-ED.(13) Preliminary report of studies of PD-1 
pathway targeted therapy showed reliable signal of activity in relapsed SCLC. Moreover, the 
combination of a CTLA-4 and PD-1 pathway targeting agents showed greater benefit over 
single agent. Nonetheless, only a third of patients derived significant benefit from this 
combination therapy strategy. The incorporation of a complementary intervention likely to 
further enhance immune checkpoint therapy without increasing the risk of toxicity is likely to 
further extend the benefit of immune checkpoint inhibitors to a greater proportion of SCLC 
patients. Emerging data indicates efficacy of immune checkpoint inhibitors in SCLC including 
published data from the study of pembrolizumab and nivolumab in relapsed SCLC. However, 
the efficacy impact in unselected patients appears somewhat modest thereby calling for 
strategies to both identify patients likely to benefit and to further enhance the efficacy of the 
treatment. 
Limited institutional experience and large randomized studies also suggest survival benefit of 
XRT in SCLC-ED (Ben J. Slotman, 2014; Guy C. Jones, 2014). Moreover, XRT can induce 
PD-L1 expression on tumor and stromal cells along with increase in myeloid-derived 
suppressor cells (MDSCs) in preclinical models (Deng et al., 2014a; Deng et al., 2014b). 
Furthermore, the release of tumor-associated antigens following cell death induced by XRT 
may be highly immunogenic (Deng et al., 2014a; Deng et al., 2014b), leading to potent 
abscopal effect at distant tumor sites (Blanquicett et al., 2005). The combination of an anti-
PD-L1 inhibitor and XRT was also synergistic in xenograft models of pancreatic, colon and 
breast cancer (Blanquicett et al., 2005; Deng et al., 2014a; Deng et al., 2014b).  
The biologic premise behind the strategy of combining immune modulating agent and XRT is 
the expectation that the tumor-antigen release achieved by localized radiation will activate 
tumor specific adaptive immune response, which can be further enhanced by systemic 
immune-stimulating agents. Thus, XRT is able to induce local tumor response at the site of 
XRT delivery but also at distant sites through the abscopal effect phenomenon, whereby 
localized radiation results in immune-mediated tumor regression in disease sites well outside 
of the radiation field (Tang et al., 2014). This study will also allow us to demonstrate the 
safety of the combination of irradiation along with combined immune checkpoint blockade. 
As an antibody that blocks the interaction between PD-L1 and its receptors, durvalumab may 
relieve PD-L1-dependent immunosuppressive effects and, therefore, enhance the cytotoxic 
activity of anti-tumor T-cells.  This hypothesis is supported by emerging clinical data from 
other mAbs targeting the PD-L1/PD-1 pathway, which provide early evidence of clinical 
activity and a manageable safety profile (Brahmer et al 2012,).  Responses have been 
observed in patients with PD-L1-positive tumors and patients with PD-L1-negative tumors.  In 
8 
 

Clinical Study Protocol  
Investigational Drug Substance: Durvalumab and Tremelimumab 
Study Number ESR-14-10531/WINSHIP3112-15; Edition Number 3.1; Date 09/16/2016 
 
addition, durvalumab monotherapy has shown durable responses in NSCLC in Study 1108 
(see Section 1.4.1.1). 
The rationale for combining durvalumab and tremelimumab is that the mechanisms of 
CTLA-4 and PD-1 are non-redundant, suggesting that targeting both pathways may have 
additive or synergistic activity ().  In fact, combining immunotherapy agents has been shown 
to result in improved response rates (RRs) relative to monotherapy.  For example, the 
concurrent administration of nivolumab and ipilimumab to patients with advanced melanoma 
induced higher objective response rates (ORRs) than those obtained with single-agent therapy.  
Importantly, responses appeared to be deep and durable.  Similar results have been observed 
in an ongoing study of durvalumab + tremelimumab in NSCLC, with further updated details 
presented in this clinical study protocol.   
The current study will test whether combined immune checkpoint along with or without XRT 
will confer greater benefit over immune checkpoint therapy alone in relapsed SCLC. The 
study design also allows the assessment of the safety of the combination of irradiation along 
with combined immune checkpoint blockade. 
1.3.1 
Durvalumab  + tremelimumab combination therapy dose rationale 
The durvalumab + tremelimumab doses and regimen selected for this study are based on the 
goal of selecting an optimal combination dose of durvalumab and tremelimumab that would 
yield sustained target suppression (sPD-L1), demonstrate promising efficacy, and have an 
acceptable safety profile.   
In order to reduce the dosing frequency of durvalumab to align with the q4w dosing of 
tremelimumab, while ensuring an acceptable PK/PDx, safety, and efficacy profile, cohorts 
were narrowed to 15 and 20 mg/kg durvalumab q4w.  PK simulations from the durvalumab 
monotherapy data indicated that a similar area under the plasma drug concentration-time 
curve at steady state (AUCss; 4 weeks) was expected following both 10 mg/kg q2w and 
20 mg/kg q4w durvalumab.  The observed durvalumab PK data from the D4190C00006 study 
were well in line with the predicted monotherapy PK data developed preclinically.  This 
demonstrates similar exposure of durvalumab 20 mg/kg q4w and 10 mg/kg q2w, with no 
alterations in PK when durvalumab and tremelimumab (doses ranging from 1 to 3 mg/kg) are 
dosed together.  While the median Cmax at steady state (Cmax,ss) is expected to be higher with 
20 mg/kg q4w (approximately 1.5 fold) and median trough concentration at steady state 
(Ctrough,ss) is expected to be higher with 10 mg/kg q2w (approximately 1.25 fold), this is not 
expected to impact the overall safety and efficacy profile, based on existing preclinical and 
clinical data. 
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Clinical Study Protocol  
Investigational Drug Substance: Durvalumab and Tremelimumab 
Study Number ESR-14-10531/WINSHIP3112-15; Edition Number 3.1; Date 09/16/2016 
 
Monotonic increases in PDx activity were observed with increasing doses of tremelimumab 
relative to the activity observed in patients treated with durvalumab monotherapy.  There was 
evidence of augmented PDx activity relative to durvalumab monotherapy with combination 
doses containing 1 mg/kg tremelimumab, inclusive of the 15 and 20 mg/kg durvalumab plus 1 
mg/kg tremelimumab combinations.  
Patients treated with doses of tremelimumab above 1 mg/kg had a higher rate of adverse 
events (AEs), including discontinuations due to AEs, serious AEs (SAEs), and severe AEs.  
Between the 10 mg/kg durvalumab + 1 mg/kg tremelimumab and 10 mg/kg Durvalumab + 
3 mg/kg tremelimumab cohorts treated at the q2w schedule, the number of patients reporting 
any AE, Grade 3 AEs, SAEs, and treatment-related AEs was higher in the 10 mg/kg 
durvalumab + 3 mg/kg tremelimumab cohort than the 10 mg/kg durvalumab + 1 mg/kg 
tremelimumab cohort.  A similar pattern was noted in the q4w regimens, suggesting that, as 
the dose of tremelimumab increased above 1 mg/kg, a higher rate of treatment-related events 
may be anticipated.  Further, the SAEs frequently attributed to immunotherapy, pneumonitis 
and colitis, were more commonly seen in cohorts using either 3 or 10 mg/kg of tremelimumab 
compared to the 1-mg/kg dose cohorts.  Together, these data suggest that a combination using 
a tremelimumab dose of 1 mg/kg appeared to minimize the rate of toxicity when combined 
with durvalumab.  As a result, all combination doses utilizing either the 3 or 10 mg/kg doses 
of tremelimumab were eliminated in the final dose selection.   
In contrast, cohorts assessing higher doses of durvalumab with a constant dose of 
tremelimumab did not show an increase in the rate of AEs.  The data suggested that increasing 
doses of durvalumab may not impact the safety of the combination as much as the 
tremelimumab dose.  Further, safety data between the 10-mg/kg and 20-mg/kg cohorts were 
similar, with no change in safety events with increasing dose of durvalumab.  
In Study D4190C00006, of all treatment cohorts, the cohort of 11 patients treated in the 
20 mg/kg durvalumab + 1 mg/kg tremelimumab group had the fewest AEs, Grade ≥3 AEs, 
SAEs, and treatment discontinuations due to AEs, but still showed strong evidence of clinical 
activity.  This cohort had a lower number of treatment-related Grade ≥3 AEs or 
treatment-related SAEs.  No dose-limiting toxicities were reported.   
Preliminary clinical activity of the durvalumab and tremelimumab combination did not appear 
to change with increasing doses of tremelimumab.  The 15- and 20-mg/kg durvalumab q4w 
cohorts demonstrated objective responses at all doses of tremelimumab, and increasing doses 
of tremelimumab did not provide deeper or more rapid responses. 
Efficacy data suggested that the 20 mg/kg durvalumab + 1 mg/kg tremelimumab dose cohort 
may demonstrate equivalent clinical activity to other dose combinations.  A total of 5 of 
10 
 

Clinical Study Protocol  
Investigational Drug Substance: Durvalumab and Tremelimumab 
Study Number ESR-14-10531/WINSHIP3112-15; Edition Number 3.1; Date 09/16/2016 
 
11 patients in the 20 mg/kg durvalumab + 1 mg/kg tremelimumab cohort were evaluable for 
efficacy with at least 8 weeks of follow-up.  Of these, there were 2 patients (40%) with partial 
response (PR), 1 patient (20%) with stable disease (SD), and 1 patient (20%) with progressive 
disease (PD).  (The fifth patient had only a single scan, which was conducted outside the 
window for these evaluations.) 
Additionally, of all cohorts, the 20 mg/kg durvalumab + 1 mg/kg tremelimumab dose cohort 
had the fewest AEs, Grade ≥3 AEs, SAEs, and treatment discontinuations due to AEs, but still 
showed some evidence of clinical activity.  All together, the data suggested that a 20 mg/kg 
durvalumab + 1 mg/kg tremelimumab dose combination should be selected for further 
development.   
1.3.2 
Rationale for 4 cycles of combination therapy followed by durvalumab  
monotherapy 
Long-term follow up on melanoma patients treated with ipilimumab, an anti-CTLA-4 
targeting antibody (dosed every 3 weeks [q3w] for 4 doses and then discontinued), shows that 
patients responding to ipilimumab derive long-term benefit, with a 3-year OS rate of 
approximately 22%.  Furthermore, the survival curve in this population reached a plateau at 
3 years and was maintained through 10 years of follow up.  
Similar data have been presented for other anti-PD-1/PD-L1 targeting antibodies:  
Nivolumab (anti-PD-1) was dosed q2w for up to 96 weeks in a large Phase I dose-escalation 
and expansion study, and showed responses were maintained for a median of 22.94 months 
for melanoma (doses 0.1 mg/kg to 10 mg/kg), 17 months for NSCLC (doses 1, 3, and 
10 mg/kg), and 12.9 months for renal cell carcinoma patients (doses 1 and 10 mg/kg) at the 
time of data analysis (Hodi et al 2014, Brahmer et al 2014, Drake et al 2013).  Furthermore, 
responses were maintained beyond treatment discontinuation in the majority of patients who 
stopped nivolumab treatment (either due to protocol specified end of treatment, complete 
response [CR], or toxicity) for up to 56 weeks at the time of data analysis.  
MPDL3280a (anti-PD-L1) and the combination of nivolumab with ipilimumab, in which 
patients were dosed for a finite time period and responses maintained beyond treatment 
discontinuation have been reported (Herbst et al 2013). 
Similar long term results may be expected with use of other immune-mediated cancer 
therapeutics including anti-CTLA-4 antibodies such as tremelimumab, anti PD-L1 antibodies 
such as durvalumab, or the combination of the two.   
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Clinical Study Protocol  
Investigational Drug Substance: Durvalumab and Tremelimumab 
Study Number ESR-14-10531/WINSHIP3112-15; Edition Number 3.1; Date 09/16/2016 
 
1.4 
Benefit/risk and ethical assessment 
Patients with relapsed SCLC have limited therapeutic options. Topotecan is the only approved 
therapy in this setting and is associated with a meager response rate of ~10% in unselected 
patients. The combination of inhibitors targeting PD1 and CTLA4 signaling pathways have 
been established to be safe. Moreover, this combination appears quite promising in early 
phase testing with response rate of >30%. Therefore, the risk-benefit balance is positive 
overall for the proposed study.  
1.4.1 
Potential benefits 
1.4.1.1 
Durvalumab 
The majority of the safety and efficacy data currently available for durvalumab are based on 
the first time in-human, single-agent study (Study 1108) in patients with advanced solid 
tumors.  Data from Study 1108 were presented at the European Society for Medical Oncology 
2014 Congress.  Overall, 456 of 694 subjects treated with durvalumab 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 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%). 
(Antonia et al 2014b).   
1.4.1.2 
Tremelimumab 
In a single-arm, Phase II study (Study A3671008) of tremelimumab administered at 15 mg/kg 
every 90 days to patients with refractory melanoma, an RR of 7% and a median OS of 
10 months in the second-line setting (as compared to approximately 6 months with best 
supportive care reported from a retrospective analysis; Korn et al 2008) were observed 
(Kirkwood et al 2010).  In a randomized, open-label, first-line Phase III study of 
tremelimumab (administered at 15 mg/kg every 90 days) versus chemotherapy (dacarbazine or 
temozolomide) in advanced melanoma (Study A3671009), results of the final analysis showed 
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Clinical Study Protocol  
Investigational Drug Substance: Durvalumab and Tremelimumab 
Study Number ESR-14-10531/WINSHIP3112-15; Edition Number 3.1; Date 09/16/2016 
 
an RR of 11% and a median OS of 12.58 months in this first-line setting as compared to 
10.71 months with standard chemotherapy; however, these results were not statistically 
significant .  Additionally, a Phase II maintenance study (Study A3671015) in patients with 
Stage IIIB or IV NSCLC who had responded or remained stable failed to achieve statistical 
significance.  The primary endpoint of PFS at 3 months was 22.7% in the tremelimumab arm 
(15 mg/kg) compared with 11.9% in the best supportive care arm (Study A3671015).   
1.4.1.3 
Durvalumab + tremelimumab 
The preclinical and clinical justification for this combination as noted in Section 1.1.4 also 
supports the synergy of this combination.  Available data, such as those presented by 
Wolchok et al, suggest that the combination of agents targeting PD-1/PD-L1 and CTLA-4 
may have profound and durable benefits in patients with melanoma.  Of the 102 subjects with 
advanced NSCLC treated with durvalumab 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. 
Current experience with single-agent IMT studies suggests that clinical responses may be 
restricted to a subset of any given patient population and that it might be beneficial to enrich 
the patient population by selecting patients likely to respond to therapy.  To date, no assay has 
been established or validated, and no single approach has proven accurate, for patient 
enrichment for IMTs.  However, independent data from multiple sources using different 
assays and scoring methods suggests that PD-L1 expression on tumor cells and/or tumor 
infiltrating cells may be associated with greater clinical benefit. 
Data from ongoing studies with durvalumab and other agents targeting the PD-1/PD-L1 
pathway suggest, as shown in a number of tumor types (e.g., NSCLC, renal cell carcinoma, 
and melanoma), that monotherapy may be more efficacious (in terms of ORR) in patients who 
are PD-L1-positive.  
Given these findings, a number of ongoing studies are assessing the activity of agents in 
patients with PD-L1–positive tumors.  There is also an unmet medical need in patients with 
PD-L1–negative tumors that needs to be addressed.  Data, as of 27 January 2015 from 
Study 006 show that with the addition of tremelimumab to durvalumab, the ORR can be 
increased to 25% in patients with PD-L1 negative NSCLC.  As patients with PD-L1 positive 
disease can also have an increase in ORR, from 25% with durvalumab monotherapy, to 36% 
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Clinical Study Protocol  
Investigational Drug Substance: Durvalumab and Tremelimumab 
Study Number ESR-14-10531/WINSHIP3112-15; Edition Number 3.1; Date 09/16/2016 
 
with the combination of durvalumab and tremelimumab, the study will enroll all patients with 
NSCLC, with an emphasis on those determined to be PD-L1 negative.   
1.4.2 
Potential risks 
1.4.2.1 
Durvalumab 
Potential risks, based on the mechanism of action of durvalumab and related molecules, 
include immune-mediated reactions, such as enterocolitis, dermatitis, hepatitis/hepatotoxicity, 
endocrinopathy, pneumonitis, and neuropathy or neurologic events.  Additional important 
potential risks include infusion-related reactions, hypersensitivity, anaphylaxis or serious 
allergic reactions, serious infections, and immune complex disease.   
Study CD-ON-durvalumab-1108: The safety profile of durvalumab monotherapy in the 
694 subjects with advanced solid tumors treated at 10 mg/kg Q2W in Study 
CD-ON-durvalumab-1108 has been broadly consistent with that of the overall 1,279 subjects 
who have received durvalumab 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 
durvalumab 10 mg/kg Q2W in Study CD-ON-durvalumab-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 (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 durvalumab 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 
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Clinical Study Protocol  
Investigational Drug Substance: Durvalumab and Tremelimumab 
Study Number ESR-14-10531/WINSHIP3112-15; Edition Number 3.1; Date 09/16/2016 
 
the treatment-related AEs resulting in discontinuation of durvalumab were ≥ Grade 3 in 
severity and resolved with or without sequelae.  
Study D4191C00003/ATLANTIC: The safety profile of durvalumab monotherapy in 
Study CD-ON-durvalumab-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 durvalumab 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 durvalumab 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 durvalumab. 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 
durvalumab. Twenty-three of 303 subjects (7.6%) permanently discontinued durvalumab 
treatment due to AEs. Events that led to discontinuation of durvalumab 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. 
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Clinical Study Protocol  
Investigational Drug Substance: Durvalumab and Tremelimumab 
Study Number ESR-14-10531/WINSHIP3112-15; Edition Number 3.1; Date 09/16/2016 
 
1.4.2.2 
Tremelimumab 
Potential risks, based on the mechanism of action of tremelimumab and related molecules 
(ipilimumab) include potentially immune-mediated gastrointestinal (GI) events including 
enterocolitis, intestinal perforation, abdominal pain, dehydration, nausea and vomiting, and 
decreased appetite (anorexia); dermatitis including urticaria, skin exfoliation, and dry skin; 
endocrinopathies including hypophysitis, adrenal insufficiency, and hyperthyroidism and 
hypothyroidism; hepatitis including autoimmune hepatitis and increased serum ALT and AST; 
pancreatitis including autoimmune pancreatitis and lipase and amylase elevation; respiratory 
tract events including pneumonitis and interstitial lung disease (ILD); nervous system events 
including encephalitis, peripheral motor and sensory neuropathies, and Guillain-Barré 
syndrome; cytopenias including thrombocytopenia, anemia, and neutropenia; infusion-related 
reactions; anaphylaxis; and serious allergic reactions.  The profile of AEs and the spectrum of 
event severity have remained stable across the tremelimumab clinical program and are 
consistent with the pharmacology of the target.  To date, no tumor type or stage appears to be 
associated with unique AEs (except for vitiligo that appears to be confined to patients with 
melanoma).  Overall, 944 of the 973 patients (97.0%) treated with tremelimumab 
monotherapy as of the data cutoff date of 12 November 2014 (for all studies except 
D4190C00006 that has a cutoff date of 04 December 2014 and not including 497 patients who 
have been treated in the ongoing blinded Phase IIb Study D4880C00003) experienced at least 
1 AE.  The events resulted in discontinuation of tremelimumab in 10.0% of patients, were 
serious in 36.5%, were Grade ≥3 in severity in 49.8%, were fatal in 67.7%, and were 
considered to be treatment related in 79.1% of patients.  The frequency of any AEs and 
Grade ≥3 AEs was generally similar across the tremelimumab dose groups.  However, a 
higher percentage of patients in the 10 mg/kg every 28 days and 15 mg/kg every 90 days 
groups compared with the All Doses <10 mg/kg group experienced treatment-related AEs, 
SAEs, AEs resulting in discontinuation of investigational product (IP), and deaths.   
1.4.2.3 
Durvalumab + tremelimumab 
No safety studies in animals have been performed combining tremelimumab with durvalumab.  
As both CTLA-4 and PD-L1 have mechanisms of actions that enhance activation of immune 
cells, their potential to induce cytokine release was tested in a whole-blood assay system.  
Durvalumab and tremelimumab, either alone or in combination, did not induce cytokine 
release in blood from any donor. 
Study D4190C00006: The safety profile of durvalumab 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 Durvalumab 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 
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Clinical Study Protocol  
Investigational Drug Substance: Durvalumab and Tremelimumab 
Study Number ESR-14-10531/WINSHIP3112-15; Edition Number 3.1; Date 09/16/2016 
 
tremelimumab 3 and 10 mg/kg dose cohorts experienced AEs; subjects in the durvalumab 
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).Additional safety results from this study are 
presented in Section 1.3.1 and the durvalumab IB.  
In the literature, using the combination of the same class of drugs (e.g., anti-PD-1 and anti-
CTLA4 antibodies), specifically nivolumab + ipilimumab in a study involving patients with 
malignant melanoma, the safety profile of this combination had shown occurrences of AEs 
assessed by the Investigator as treatment-related in 93% of treated patients, with the most 
frequent events being rash (55% of patients), pruritus (47% of patients), fatigue (38% of 
patients), and diarrhea (34% of patients).  Grade 3 or 4 AEs, regardless of causality, were 
noted in 72% of patients, with Grade 3 or 4 events assessed by the Investigator as treatment-
related in 53%.  The most frequent of these Grade 3 or 4 events assessed by the Investigator as 
treatment-related include increased lipase (in 13% of patients), AST (in 13%), and ALT levels 
(in 11%).  Frequent Grade 3 or 4 selected AEs assessed by the Investigator as treatment-
related in the combination therapy included hepatic events (in 15% of patients), GI events (in 
9%), and renal events (in 6%).  Isolated cases of pneumonitis and uveitis were also observed.   
1.4.2.4 
Fixed Dosing for durvalumab and tremelimumab  
A population PK model was developed for durvalumab using monotherapy data from a Phase 
1 study (study 1108; N=292; doses= 0.1 to 10 mg/kg Q2W or 15 mg/kg Q3W; solid tumors). 
Population PK analysis indicated only minor impact of body weight (WT) on PK of 
durvalumab (coefficient of ≤ 0.5). The impact of body WT-based (10 mg/kg Q2W) and fixed 
17 
 

Clinical Study Protocol  
Investigational Drug Substance: Durvalumab and Tremelimumab 
Study Number ESR-14-10531/WINSHIP3112-15; Edition Number 3.1; Date 09/16/2016 
 
dosing (750 mg Q2W) of durvalumab was evaluated by comparing predicted steady state PK 
concentrations (5th, median and 95th percentiles) using the population PK model. A fixed dose 
of 750 mg was selected to approximate 10 mg/kg (based on median body WT of ~75 kg). A 
total of 1000 patients were simulated using body WT distribution of 40–120 kg. Simulation 
results demonstrate that body WT-based and fixed dosing regimens yield similar median 
steady state PK concentrations with slightly less overall between-subject variability with fixed 
dosing regimen.   
 
Similarly, a population PK model was developed for tremelimumab using data from Phase 1 
through Phase 3 (N=654; doses= 0.01 to 15 mg/kg Q4W or Q90D; metastatic melanoma) 
[Wang et al. 2014]. Population PK model indicated minor impact of body WT on PK of 
tremelimumab (coefficient of ≤ 0.5). The WT-based (1 mg/kg Q4W) and fixed dosing (75 
mg/kg Q4W; based on median body WT of ~75 kg) regimens were compared using predicted 
PK concentrations (5th, median and 95th percentiles) using population PK model in a simulated 
population of 1000 patients with body weight distribution of 40 to 120 kg. Similar to 
durvalumab, simulations indicated that both body WT-based and fixed dosing regimens of 
tremelimumab yield similar median steady state PK concentrations with slightly less between-
subject variability with fixed dosing regimen.  
 
Similar findings have been reported by others [Ng et al 2006, Wang et al. 2009, Zhang et al, 
2012, Narwal et al 2013]. Wang and colleagues investigated 12 monoclonal antibodies and 
found that fixed and body size-based dosing perform similarly, with fixed dosing being better 
for 7 of 12 antibodies . In addition, they investigated 18 therapeutic proteins and peptides and 
showed that fixed dosing performed better for 12 of 18 in terms of reducing the between-
subject variability in pharmacokinetic/pharmacodynamics parameters [Zhang et al 2012].  
 
A fixed dosing approach is preferred by the prescribing community due to ease of use and 
reduced dosing errors. Given expectation of similar pharmacokinetic exposure and variability, 
we considered it feasible to switch to fixed dosing regimens. Based on average body WT of 75 
kg, a fixed dose of 1500 mg Q4W durvalumab (equivalent to 20 mg/kg Q4W) and 75 mg 
Q4W tremelimumab (equivalent to 1 mg/kg Q4W) is included in the current study.  
 
Fixed dosing of durvalumab and tremelimumab is recommended only for subjects with > 30kg 
body weight due to endotoxin exposure.  Patients with a body weight less than or equal to 30 
kg should be dosed using a weight-based dosing schedule.   
 
18 
 

Clinical Study Protocol  
Investigational Drug Substance: Durvalumab and Tremelimumab 
Study Number ESR-14-10531/WINSHIP3112-15; Edition Number 3.1; Date 09/16/2016 
 
2. 
STUDY OBJECTIVE 
2.1.1 
Primary objective(s) 
To assess the efficacy (PFS and ORR) of combined immune checkpoint inhibitor therapy as 
treatment for relapsed SCLC  
2.1.2 
Secondary objective(s) 
Assess the impact of antigen priming using XRT on the efficacy of immune checkpoint 
inhibitors  
Determine immune related objective response rate 
Estimate overall survival measured as time from randomization to death from any cause 
2.1.3 
Exploratory objective(s) 
Characterize tumor infiltrating lymphocytes (TILs) and PD-L1/PD1 expression in paired 
tumor biopsies at baseline, end of cycle 2 and at the time of progression. 
Determine dynamic changes in cell free DNA (cfDNA) and the immunophenotype of 
peripheral blood repertoire of circulating lymphocytes using multiparameter flow cytometry 
Determine changes in circulating cytokine mediators of inflammation and immunity using 
Luminex assay 
3. 
STUDY DESIGN 
3.1 
Overview of study design 
This is a prospective, proof-of-concept, 2-cohort clinical trial in relapsed SCLC. Consenting 
patients who have failed frontline platinum-based chemotherapy, with good performance 
status (0-2 on ECOG scale) and adequate end-organ function will be enrolled. Ten patients 
will be enrolled in Arm I and will be treated with Durvalumab and Tremelimumab 
combination every 4 weeks for 4 doses followed by single agent Durvalumab every 4 weeks 
for up to 1 year or until disease progression. Arm II patients will first undergo XRT (up to 
30Gy in 3-5 fractions) to a known site of disease involvement prior to starting systemic 
treatment. This will be followed by systemic therapy similar to Arm I consisting of 
Durvalumab and Tremelimumab combination for 4 doses and then single agent Durvalumab 
for up to 1 year or until disease progression with tremelimumab and Durvalumab. Patients 
who continue to derive benefit from treatment with the Durvalumab/Tremelimumab 
combination may be allowed to continue treatment with single agent durvalumab for up to 2 
years in the absence of intolerable toxicity or disease progression.  
19 
 

Clinical Study Protocol  
Investigational Drug Substance: Durvalumab and Tremelimumab 
Study Number ESR-14-10531/WINSHIP3112-15; Edition Number 3.1; Date 09/16/2016 
 
This design enables us to assess the clinical efficacy of combined immune checkpoint 
treatment (Arm I and II pooled); to establish the safety of sequential combination of immune 
checkpoint inhibitors and XRT (Arm II) and also to explore the priming effect of XRT on 
immune checkpoint therapy (Arm I vs II). 
All enrolled patients will have a baseline plasma sample for circulating tumor free DNA 
(ctfDNA) to measure disease burden and antigen release, as well as a tumor biopsy for 
assessment of PD-L1 expression and to characterize the phenotype of the tumor infiltrating 
lymphocytes (TILs). A repeat ctfDNA sample will be collected at the end of radiation 
treatment (Arm II only). Repeat tumor biopsy will be obtained at the end of cycle 2 for all 
patients in both arms of the study. These samples will be employed to characterize the same 
endpoints of tumor burden, PD-L1 expression and TILs with comparison of immune cell 
repertoire between responding and non responding patients.  
Treatment with durvalumab will continue for up to 1 year in the absence of toxicity or disease 
progression in all patients. Treatment may be extended for another year if continuing clinical 
benefit in the patient and there are no safety concerns. 
Restaging scans will be obtained after every 2 cycles of therapy (for the first 6 months) and 
every 3 cycles thereafter.  
3.2 
Study schema 
Figure 1. Study flow chart 
 
 
20 
 

Clinical Study Protocol  
Investigational Drug Substance: Durvalumab and Tremelimumab 
Study Number ESR-14-10531/WINSHIP3112-15; Edition Number 3.1; Date 09/16/2016 
 
3.3 
Study Oversight for Safety Evaluation 
The study may be stopped if, in the judgment of the Sponsor or the Winship Data Safety 
Monitoring Committee (DSMC), study patients are placed at undue risk because of clinically 
significant findings that meet any of the following criteria: 
• Meet individual stopping criteria or are otherwise considered significant 
• Are assessed as causally related to study drug 
• Are not considered to be consistent with continuation of the study 
In terminating the study, adequate consideration will be given to the protection of the patients’ 
interests. 
4. 
PATIENT SELECTION, ENROLLMENT, RANDOMIZATION, 
RESTRICTIONS, DISCONTINUATION AND WITHDRAWAL  
Each patient must meet all of the inclusion criteria (Section 4.1) and none of the exclusion 
criteria (Section 4.2) for this study.  Under no circumstances will there be exceptions to this 
rule.   
4.1 
Inclusion criteria 
For inclusion in the study, patients should fulfill the following criteria: 
1. 
Written informed consent  and any locally-required authorization (e.g.,) 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, 1 or 2 
4. 
Adequate normal organ and marrow function as defined below: 
− 
Haemoglobin ≥ 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) 
21 
 

Clinical Study Protocol  
Investigational Drug Substance: Durvalumab and Tremelimumab 
Study Number ESR-14-10531/WINSHIP3112-15; Edition Number 3.1; Date 09/16/2016 
 
− 
Serum bilirubin ≤ 1.5 x institutional upper limit of normal (ULN).  <<This will 
not apply to subjects with confirmed Gilbert’s syndrome (persistent or recurrent 
hyperbilirubinemia that is predominantly unconjugated in the absence of 
hemolysis or hepatic pathology), who will be allowed only in consultation with 
their physician. 
− 
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>40 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 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. 
Patients must have baseline evaluations performed prior to the first dose of study 
drug and must meet all inclusion and exclusion criteria.  
8. 
Patients must have histologically or cytologically confirmed   small cell lung 
cancer 
9. 
Patients must have measurable disease, defined as at least one lesion (excluding the 
lesion for palliative XRT) that can be accurately measured in at least one 
dimension (longest diameter to be recorded for non-nodal lesions and short axis for 
22 
 

Clinical Study Protocol  
Investigational Drug Substance: Durvalumab and Tremelimumab 
Study Number ESR-14-10531/WINSHIP3112-15; Edition Number 3.1; Date 09/16/2016 
 
nodal lesions) as >20 mm with conventional techniques or as >10 mm with spiral 
CT scan.  See Section 9 for the evaluation of measurable disease. 
10. 
Patient must have failed or found to be intolerant of standard frontline platinum-
based regimens and must not have received > 2 prior lines of therapy (NB: 
Retreatment with a platinum-based doublet for sensitive relapse counts as another 
line therapy; however substitution of cisplatin with carboplatin or vice versa due to 
toxicity does not count as a separate regimen).  
11. 
Negative urine or serum pregnancy test within 48 hours before starting study 
treatment in women with childbearing potential 
12. 
Ability to understand and the willingness to sign a written informed consent 
document. 
 
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) 
2. Previous enrolment or randomization in the present study 
3. Treatment with an investigational product during the last 2 weeks 
4. Any previous treatment with a PD1 or PD-L1 inhibitor, including durvalumab or an 
anti-CTLA4, including tremelimumab  
5. Receipt of the last dose of anti-cancer therapy (chemotherapy, immunotherapy, 
endocrine therapy, targeted therapy, biologic therapy, tumor embolization, monoclonal 
antibodies, other investigational agent) ≤ 14 days prior to the first dose of study drug 
(≤ 7 days or four half-lives, whichever is longer, 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).  
6. Mean QT interval corrected for heart rate (QTc) ≥470 ms calculated from 3 
electrocardiograms (ECGs) using  Fredericia’s Correction 
7. Current or prior use of immunosuppressive medication within 28 days before the first 
dose of durvalumab or tremelimumab, 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 
23 
 

Clinical Study Protocol  
Investigational Drug Substance: Durvalumab and Tremelimumab 
Study Number ESR-14-10531/WINSHIP3112-15; Edition Number 3.1; Date 09/16/2016 
 
8. Any unresolved toxicity (>CTCAE grade <<2>>) from previous anti-cancer therapy. 
Subjects with irreversible toxicity that is not reasonably expected to be exacerbated by 
the investigational product may be included (e.g., hearing loss, peripherally 
neuropathy)  
9. Any prior Grade ≥3 immune-related adverse event (irAE) while receiving any previous 
immunotherapy agent, or any unresolved irAE >Grade 1  
10. 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.  
11. Active or prior documented inflammatory bowel disease (e.g., Crohn’s disease, 
ulcerative colitis) 
12. History of primary immunodeficiency 
13. History of allogeneic organ transplant  
14. History of hypersensitivity to durvalumab or any excipient  
15. History of hypersensitivity to the combination or comparator agent 
16. 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 
17. Known history of previous clinical diagnosis of tuberculosis 
18. History of leptomeningeal carcinomatosis 
19. Receipt of live attenuated vaccination within 30 days prior to study entry or within 30 
days of receiving durvalumab or tremelimumab 
20. Female subjects who are pregnant, breast-feeding or male or female patients of 
reproductive potential who are not employing an effective method of birth control 
24 
 

Clinical Study Protocol  
Investigational Drug Substance: Durvalumab and Tremelimumab 
Study Number ESR-14-10531/WINSHIP3112-15; Edition Number 3.1; Date 09/16/2016 
 
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. 
24. Female patients who are pregnant or breastfeeding or male or female patients of 
reproductive potential who are not willing to employ effective birth control from 
screening to 180 days after the last dose of durvalumab + tremelimumab combination 
therapy or 90 days after the last dose of durvalumab monotherapy, whichever is the 
longer time period 
25. Patients receiving any other investigational agents for any reason or non-
investigational agents administered for the purpose of controlling cancer growth (Use 
of conventional external beam radiation therapy will be allowed during protocol 
therapy solely for palliation of localised painful lesions or bone lesions at risk of 
fracture provided the radiation field does not encompass any selected target lesions 
required for assessment). 
Procedures for withdrawal of incorrectly enrolled patients are presented in Section 4.3 
4.3 
Withdrawal of Subjects from Study Treatment and/or Study 
Permanent discontinuation of study treatment 
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. 
Adverse event that, in the opinion of the investigator or the sponsor, contraindicates 
further dosing 
3. 
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 
4. 
Pregnancy or intent to become pregnant 
5. 
Any AE that meets criteria for discontinuation as defined in Section 6.6. 
6. 
Grade ≥ 3 infusion reaction 
25 
 

Clinical Study Protocol  
Investigational Drug Substance: Durvalumab and Tremelimumab 
Study Number ESR-14-10531/WINSHIP3112-15; Edition Number 3.1; Date 09/16/2016 
 
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 durvalumab + tremelimumab 
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.  
 
Subjects who are permanently discontinued from receiving investigational product will be 
followed for safety per Section 10.0 and Appendix 1 or 2, including the collection of any 
protocol-specified blood specimens, unless consent is withdrawn or the subject is lost to 
follow-up or enrolled I 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 
If consent is withdrawn, the subject will not receive any further investigational product or 
further study observation.  
4.4 
Replacement of subjects 
Eligible patients who come off study not due to disease progression prior to undergoing the 
first restaging scan will be replaced.  
4.5 
Subject Registration 
Eligible patients will be entered sequentially as identified by the investigators. To register a 
patient, the following documents should be obtained and confirmed by the Study Coordinator: 
• 
Copy of required laboratory tests and other source documents including records of 
prior therapy and pathology  
• 
Signed patient consent form 
• 
HIPAA authorization form 
• 
Assignation of a patient study number and randomization  
26 
 

Clinical Study Protocol  
Investigational Drug Substance: Durvalumab and Tremelimumab 
Study Number ESR-14-10531/WINSHIP3112-15; Edition Number 3.1; Date 09/16/2016 
 
• 
Register the patient on the study as per Winship Cancer Institute (WCI) standard 
operating procedures for participant registration. All consenting patients will be assigned an 
ID number consisting of the Winship study number (WINSHIP3112) followed by Arm on 
study (A for radiation arm and B for no radiation arm) the patients’ first and last initials and 
the serial number at enrolment e.g. John Doe, the first enrolled patient on study, randomized 
to the no radiation arm will have the number WINSHIP3112AJD01. 
5. 
INVESTIGATIONAL PRODUCT(S) 
5.1 
Durvalumab and tremelimumab 
The Investigational Products Supply section of AstraZeneca/MedImmune will supply 
durvalumab and tremelimumab to the investigator as a solution for infusion after dilution.   
5.1.1 
Formulation/packaging/storage 
Durvalumab 
Durvalumab will be supplied by AstraZeneca as a 500-mg vial solution for infusion after 
dilution. The solution contains 50 mg/mL durvalumab, 26 mM 
histidine/histidine-hydrochloride, 275 mM trehalose dihydrate, and 0.02% (weight/volume) 
polysorbate 80; it has a pH of 6.0. The nominal fill volume is 10 mL.  Investigational product 
vials are stored at 2°C to 8°C (36°F to 46°F) and must not be frozen. Durvalumab must be 
used within the individually assigned expiry date on the label. 
Tremelimumab 
Tremelimumab will be supplied by AstraZeneca as a 400-mg vial solution for infusion after 
dilution. The solution contains 20 mg/mL of tremelimumab, 20 mM histidine/histidine 
hydrochloride, 222 mM trehalose dihydrate, 0.02% (w/v) polysorbate 80, and 0.27 mM 
disodium edetate dihydrate (EDTA); it has a pH of 5.5. The nominal fill volume is 20 mL. 
Investigational product vials are stored at 2°C to 8°C (36°F to 46°F) and must not be frozen. 
Tremelimumab must be used within the individually assigned expiry date on the label. 
5.2 
Dose and treatment regimens 
5.2.1 
Treatment regimens 
Durvalumab + tremelimumab combination therapy 
Patients in the durvalumab + tremelimumab combination therapy group will receive 1500 mg 
durvalumab via IV infusion q4w for up to 4 doses/cycles and 75 mg tremelimumab via IV 
infusion q4w for up to 4 doses/cycles, and then continue 1500 mg durvalumab q4w starting on 
27 
 

Clinical Study Protocol  
Investigational Drug Substance: Durvalumab and Tremelimumab 
Study Number ESR-14-10531/WINSHIP3112-15; Edition Number 3.1; Date 09/16/2016 
 
Week 17 for up to 8 months (9 doses) (see Figure 2).  Dosing outside the window should be 
discussed with the Study Physician.  Tremelimumab will be administered first.  Durvalumab 
infusion will start approximately 1 hour after the end of tremelimumab infusion.  The duration 
will be approximately 1 hour for each infusion.  A 1-hour observation period is required after 
the first infusion of durvalumab and tremelimumab.  If no clinically significant infusion 
reactions are observed during or after the first cycle, subsequent infusion observation periods 
can be at the Investigator’s discretion (suggested 30 minutes after each durvalumab and 
tremelimumab infusion).   
5.2.2 
Duration of treatment and criteria for retreatment 
For patients receiving durvalumab + tremelimumab, retreatment is allowed (once only) for 
patients meeting the retreatment criteria below.  The same treatment guidelines followed 
during the initial 12-month treatment period will be followed during the retreatment period, 
including the same dose and frequency of treatments and the same schedule of assessments.   
Patients receiving the combination of durvalumab and tremelimumab may undergo 
retreatment in 2 clinical scenarios, described below:   
1. Patients who achieve and maintain disease control (i.e., CR, PR, or SD) through to the 
end of the 12-month treatment period may restart treatment with the combination upon 
evidence of PD, with or without confirmation according to RECIST 1.1, during 
follow-up.  
2. Patients who complete the 4 dosing cycles of the combination of durvalumab and 
tremelimumab portion of the regimen (with clinical benefit per Investigator judgment), 
but subsequently have evidence of PD during the durvalumab monotherapy portion of 
the combination regimen, with or without confirmation according to RECIST 1.1, may 
restart treatment with the combination.   
3. For the durvalumab + tremelimumab treatment group, before restarting their assigned 
treatment, the Investigator should ensure that the patient:   
a. Does not have any significant, unacceptable, or irreversible toxicities that 
indicate continuing treatment will not further benefit the patient 
b. Still fulfils the eligibility criteria for this study, including re-consenting to 
restart durvalumab and tremelimumab 
c. Has not have received an intervening systemic anticancer therapy after their 
assigned treatment discontinuation.   
28 
 

Clinical Study Protocol  
Investigational Drug Substance: Durvalumab and Tremelimumab 
Study Number ESR-14-10531/WINSHIP3112-15; Edition Number 3.1; Date 09/16/2016 
 
d. Has had a baseline tumor assessment within 28 days of restarting their assigned 
treatment; all further scans should occur with the same frequency as during the 
initial 12 months of treatment (relative to the date of randomization) until study 
treatment is stopped (maximum of 12 months of further treatment).   
During the retreatment period, patients receiving durvalumab + tremelimumab may resume 
durvalumab dosing at 1500 mg q4w with 75 mg of tremelimumab q4w for 4 doses each.  
Patients will then continue with durvalumab monotherapy at 1500 mg q4w, beginning at 
Week 16, 4 weeks after the last dose of combination therapy (a total of 9 additional doses).   
Treatment through progression is at the Investigator’s discretion, and the Investigator should 
ensure that patients do not have any significant, unacceptable, or irreversible toxicities that 
indicate that continuing treatment will not further benefit the patient.  A patient with a 
confirmed progression receiving durvalumab + tremelimumab cannot continue therapy or 
obtain retreatment if dosing is ongoing in the combination portion of therapy (q4w dosing) 
and progression occurs in a target lesion that has previously shown a confirmed response. 
Patients will be required to provide written consent prior to restarting treatment or 
continuation of treatment in the presence of radiologic progression of disease,. 
Patients who AstraZeneca and/or the Sponsor-Investigator determine may not continue 
treatment will enter follow-up.   
5.2.3 
Study drug preparation of durvalumab and tremelimumab 
Based on average body weight of 75 kg, a fixed dose of 1500 mg Q4W durvalumab 
(equivalent to 20 mg/kg Q4W) and 75 mg Q4W tremelimumab (equivalent to 1 mg/kg Q4W) 
is included in the current study.  
Preparation of durvalumab doses for administration with an IV bag 
The dose of durvalumab for administration must be prepared by the Investigator’s or site’s 
designated IP manager using aseptic technique.  Total time from needle puncture of the 
durvalumab vial to the start of administration should not exceed:  
• 
24 hours at 2°C to 8°C (36°F to 46°F) 
• 
4 hours at room temperature 
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.  
29 
 

Clinical Study Protocol  
Investigational Drug Substance: Durvalumab and Tremelimumab 
Study Number ESR-14-10531/WINSHIP3112-15; Edition Number 3.1; Date 09/16/2016 
 
No incompatibilities between durvalumab and polyvinylchloride or polyolefin IV bags have 
been observed. Dose of 1500mg durvalumab for patients >30 kg will be administered using an 
IV bag containing 0.9% (w/v) saline, with a final durvalumab concentration ranging from 1 to 
20 mg/mL, and delivered through an IV administration set with a 0.2- or 0.22-μm in-line 
filter.  Remove 30.0 mL of IV solution from the IV bag prior to addition of 
durvalumab.  Next, 30.0 mL of durvalumab (i.e., 1500 mg of durvalumab) is added to the IV 
bag such that final concentration is within 1 to 20 mg/mL (IV bag volumes 100 to 1000 
mL).  Mix the bag by gently inverting to ensure homogeneity of the dose in the bag. 
Patient weight at baseline should be used for dosing calculations unless there is a 
≥10% change in weight.  Dosing day weight can be used for dosing calculations instead of 
baseline weight per institutional standard.   
For patients <30kg, Calculate the dose volume of durvalumab and tremelimumab and number 
of vials needed for the subject to achieve the accurate dose. 
Durvalumab will be administered at room temperature (approximately 25°C) by controlled 
infusion via an infusion pump into a peripheral or central vein. Following preparation of 
durvalumab, the entire contents of the IV bag should be administered as an IV infusion over 
approximately 60 minutes (±5 minutes), using a 0.2, or 0.22-μm in-line filter. Less than 55 
minutes is considered a deviation. 
The IV line will be flushed with a volume of IV solution (0.9% [w/v] 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. 
Standard infusion time is 1 hour.  However, if there are interruptions during infusion, the total 
allowed time should not exceed 8 hours at room temperature.  The table below summarizes 
time allowances and temperatures. 
Durvalumab hold and infusion times 
Maximum time from needle puncture to start of 
administration 
4 hours at room temperature, 24 hours at 2°C to 8°C 
Maximum time for IV bag infusion, including 
interruptions 
8 hours at room temperature 
 
30 
 

Clinical Study Protocol  
Investigational Drug Substance: Durvalumab and Tremelimumab 
Study Number ESR-14-10531/WINSHIP3112-15; Edition Number 3.1; Date 09/16/2016 
 
In the event that either preparation time or infusion time exceeds the time limits outlined in 
the table, a new dose must be prepared from new vials.  Durvalumab does not contain 
preservatives, and any unused portion must be discarded. 
Preparation of tremelimumab doses for administration with an IV bag 
The dose of tremelimumab for administration must be prepared by the Investigator’s or site’s 
designated IP manager using aseptic technique.  Total time from needle puncture of the 
tremelimumab vial to the start of administration should not exceed:  
• 
24 hours at 2°C to 8°C (36°F to 46°F) 
• 
4 hours at room temperature 
It is recommended that the prepared final IV bag be stored in the dark at 2ºC-8°C (36°F-46°F) 
until needed. If storage time exceeds these limits, a new dose must be prepared from new 
vials. The refrigerated infusion solutions in the prepared final IV bag should be equilibrated at 
room temperature for about 2 hours prior to administration. Tremelimumab does not contain 
preservatives and any unused portion must be discarded. 
No incompatibilities between tremelimumab and polyvinylchloride or polyolefin IV bags have 
been observed. Doses of 75 mg tremelimumab for patients >30 kg will be administered using 
an IV bag containing 0.9% (w/v) saline, with a final tremelimumab concentration ranging 
from 0.1 mg/mL to 10 mg/mL, and delivered through an IV administration set with a 0.2 μm 
or 0.22 μm in-line filter. Remove 3.8 mL of IV solution from the IV bag prior to addition of 
tremelimumab.  Next, 3.8 mL of tremelimumab (i.e., 75 mg of tremelimumab) is added to the 
IV bag such that final concentration is within 0.1 mg/mL to 10 mg/mL (IV bag volumes 50 to 
500 mL).  Mix the bag by gently inverting to ensure homogeneity of the dose in the bag. 
Patient weight at baseline should be used for dosing calculations unless there is a 
≥10% change in weight.  Dosing day weight can be used for dosing calculations instead of 
baseline weight per institutional standard.   
For patients <30 kg, Calculate the dose volume for tremelimumab and number of vials needed 
for subject to achieve the accurate dose. 
Tremelimumab will be administered at room temperature (approximately 25°C) by controlled 
infusion via an infusion pump into a peripheral or central vein. Following preparation of 
tremelimumab, the entire contents of the IV bag should be administered as an IV infusion over 
approximately 60 minutes (±5 minutes), using a 0.2, or 0.22-μm in-line filter. Less than 55 
minutes is considered a deviation. 
31 
 

Clinical Study Protocol  
Investigational Drug Substance: Durvalumab and Tremelimumab 
Study Number ESR-14-10531/WINSHIP3112-15; Edition Number 3.1; Date 09/16/2016 
 
The IV line will be flushed with a volume of 0.9% (w/v) 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. 
Standard infusion time is 1 hour.  However, if there are interruptions during infusion, the total 
allowed time should not exceed 8 hours at room temperature.  The table below summarizes 
time allowances and temperatures. 
Tremelimumab hold and infusion times 
Maximum time from needle puncture to start of 
administration 
4 hours at room temperature, 24 hours at 2°C to 8°C 
Maximum time for IV bag infusion, including 
interruptions 
8 hours at room temperature 
In the event that either preparation time or infusion time exceeds the time limits outlined in 
the table, a new dose must be prepared from new vials.  Tremelimumab does not contain 
preservatives, and any unused portion must be discarded. 
5.2.4 
Monitoring of dose administration 
Patients will be monitored during and after the infusion with assessment of vital signs at the 
times specified in the Study Protocol. 
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 and re-initiated at 50% of the 
initial rate until completion of the infusion.  For patients 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 patients to an intensive care unit if necessary 
5.2.5 
Accountability and dispensation 
The study drug provided for this study will be used only as directed in the study protocol. The 
IDS personnel will account for all study drugs. Drug accountability should be performed until 
32 
 

Clinical Study Protocol  
Investigational Drug Substance: Durvalumab and Tremelimumab 
Study Number ESR-14-10531/WINSHIP3112-15; Edition Number 3.1; Date 09/16/2016 
 
the patient stops study treatment completely. Study site personnel will account for all study 
drugs received at the site. 
5.2.6 
Disposition of unused investigational study drug 
All unused study drugs will be destroyed on site according to standard practice employed by 
the IDS for appropriate destruction of study drugs. The site will account for all investigational 
study drug dispensed and also for appropriate destruction.  Certificates of delivery and 
destruction must be signed. 
5.3 
Radiation Treatment 
Patients in Arm II will receive palliative radiation (up to 30 Gy given as 5 fractions of 6 Gy 
administered daily for 1 week or 27 Gy given as 3 fractions of 9 Gy administered every other 
day for 1 week). Additional fractionation will be allowed based on site of lesion provided total 
radiation dose is completed within 1 week. The lesion selected for radiation will be safe for 
focal irradiation and medically appropriate for palliative doses of radiation. The target dose 
for a patient should conform to the normal tissue requirements in accord with standard 
radiation oncology practice. 
6. 
TREATMENT PLAN 
6.1 
Subject enrollment and randomization  
Eligible patients who have satisfied all the required inclusion and exclusion criteria will be 
randomized to Arm I or Arm II of the study. Patients in Arm I will receive systemic antibody 
therapy without preceding treatment with XRT while patients in Arm II will first receive 
priming radiation to a known site of disease involvement separate from the designated target 
lesions to be used for response assessment.  
Radiation therapy will be delivered using standard XRT technique as deemed appropriate for 
the patient status and location of tumor. Treatment will be delivered within a week of 
randomization.  
 
6.1.1 
Procedures for randomization  
Block randomization method will be used to assign patients randomly to the two groups. The 
block size of randomization is 2 to guarantee that each group will have equal number of 10 
patients. 
6.2 
Blinding and procedures for unblinding the study 
Not applicable  
33 
 

Clinical Study Protocol  
Investigational Drug Substance: Durvalumab and Tremelimumab 
Study Number ESR-14-10531/WINSHIP3112-15; Edition Number 3.1; Date 09/16/2016 
 
 
6.3 
Dosage and Administration 
Durvalumab (1500 mg durvalumab via IV infusion) + tremelimumab (75 mg tremelimumab 
via IV infusion) combination therapy will be administered to patients in Arm I and Arm II 
once every 4 weeks for up to 4 doses/cycles. Each 4-week interval is considered a cycle. 
Patients in Arm I will only receive the combination of Durvalumab and Tremelimumab while 
those randomized to Arm II will receive radiation treatment prior to starting treatment with 
Durvalumab/Tremelimumab. Following completion of 4 cycles of combination therapy, 
patients in both arms will continue 1500 mg durvalumab q4w starting on Week 16 for up to 8 
months (9 doses) for a total of 1 year.  Dosing outside the window should be discussed with 
the Study Physician.  Tremelimumab will be administered first.  Durvalumab infusion will 
start approximately 1 hour after the end of tremelimumab infusion.  The duration will be 
approximately 1 hour for each infusion.  A 1-hour observation period is required after the first 
infusion of durvalumab and tremelimumab.  If no clinically significant infusion reactions are 
observed during or after the first cycle, subsequent infusion observation periods can be at the 
Investigator’s discretion (suggested 30 minutes after each durvalumab and tremelimumab 
infusion).   
Refer to Section 5.1.2, 5.1.3, and 5.2.4 for the administration and monitoring of administration 
of durvalumab and tremelimumab. Refer to Section 5.3 for radiation treatment administration 
for patients in Arm II. 
6.4 
Dose Escalation Decision Rules 
Not applicable 
6.5 
Definition of DLT 
Not applicable 
6.6 
Dose Modification and Toxicity Management 
• 
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 patients to an intensive care unit if necessary. 
6.6.1 
Durvalumab and tremelimumab 
For adverse events (AEs) that are considered at least partly due to administration of 
durvalumab the following dose adjustment guidance may be applied: 
34 
 

Clinical Study Protocol  
Investigational Drug Substance: Durvalumab and Tremelimumab 
Study Number ESR-14-10531/WINSHIP3112-15; Edition Number 3.1; Date 09/16/2016 
 
• 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 durvalumab or tremelimumab along with appropriate 
continuing supportive care.  If medically appropriate, dose modifications are permitted 
for durvalumab and tremelimumab (see below). 
• All dose modifications should be documented with clear reasoning and documentation 
of the approach taken. 
 
In addition, there are certain circumstances in which durvalumab or tremelimumab should be 
permanently discontinued. 
 
Following the first dose of durvalumab or tremelimumab, subsequent administration of 
durvalumab or tremelimumab can be modified based on toxicities observed (see Table 1, 2, 
and 3 below).   
Based on the mechanism of action of durvalumab or tremelimumab 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.   
Dose modification recommendations and toxicity management guidelines for immune-
mediated reactions, for infusion-related reactions, and for non-immune-mediated reactions are 
detailed in Tables 1, 2, and 3, respectively.   
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 v4.0.
35 
 

Clinical Study Protocol  
Investigational Drug Substance: Durvalumab and Tremelimumab 
Study Number ESR-14-10531/WINSHIP3112-15; Edition Number 3.1; Date 09/16/2016 
 
Table 1- Immune-Mediated Reactions 
 
 
Dose Modifications 
Toxicity Management 
Immune-related 
Adverse Events 
(Overall 
Management For 
toxicities not 
noted below) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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/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/regimen 
• 
Recurrence of a previously experienced Grade 3 treatment-
related AE following resumption of dosing. 
It is recommended that management of irAEs follow the guidelines 
presented in this table 
- 
Patients should be thoroughly evaluated to rule out any 
alternative etiology (e.g., disease progression, concomitant 
medications, infections, etc.) 
- 
In the absence of a clear alternative etiology, all events should 
be considered potentially immune related. 
- 
Symptomatic and topical therapy should be considered for low-
grade (Grade 1 or 2, unless otherwise specified) events  
- 
For persistent  (greater than 3 to 5 days) low-grade (Grade 2)  or 
severe (Grade ≥3) events  promptly start prednisone 1-
2mg/kg/day PO or IV equivalent  
- 
If symptoms recur or worsen during corticosteroid tapering 28 
days of taper), increase the corticosteroid dose (prednisone dose  
[e.g. up to 2-4mg/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 immune 
related adverse event for specific type of immunosuppressive) 
should be considered for events not responding to systemic 
steroids.   
- 
Discontinuation of study drug is not mandated for Grade 3 / 
Grade 4 inflammatory reactions attributed to local tumour 
response (e.g. inflammatory reaction at sites of metastatic 
disease, lymph nodes etc.). Continuation of study drug in this 
situation should be based upon a benefit/risk analysis for that 
patient  
 
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 treatment can be resumed once 
event stabilizes to Grade ≤1 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 judgment, and 3) doses of 
prednisone are at less than or equal to 
10mg/day or equivalent. 
36 
 

Clinical Study Protocol  
Investigational Drug Substance: Durvalumab and Tremelimumab 
Study Number ESR-14-10531/WINSHIP3112-15; Edition Number 3.1; Date 09/16/2016 
 
 
Grade 3 
Depending on the individual toxicity, may 
permanently discontinue study drug/study 
regimen. Please refer to guidelines below 
 
 
 
Grade 4 
Permanently discontinue study drug/study 
regimen  
Note:  For Grade 3 and above asymptomatic amylase or lipase levels 
hold study drug/regimen and if complete work up shows no evidence 
of pancreatitis, may continue or resume study drug/regimen 
 
 
Grade of the 
Event (NCI 
CTCAE version 
4.03) 
Dose Modifications 
Toxicity Management 
 
Pneumonitis/ILD 
Grade of 
Pneumonitis 
(CTCAE version 
4.03)  
General Guidance 
- 
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 modification required. 
However, consider holding study 
drug/study regimen dosing as 
clinically appropriate and during 
diagnostic work-up for other 
etiologies 
For Grade 1 (Radiographic Changes Only) 
-      Monitor and closely follow up in 2-4 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            
For Grade 2 (Mild to Moderate New Symptoms) 
- 
Monitor symptoms daily and consider hospitalization 
- 
Promptly start systemic steroids (e.g., prednisone 1-2mg/kg/day PO or IV 
equivalent) 
- 
Reimaging as clinically indicated 
37 
 

Clinical Study Protocol  
Investigational Drug Substance: Durvalumab and Tremelimumab 
Study Number ESR-14-10531/WINSHIP3112-15; Edition Number 3.1; Date 09/16/2016 
 
 
Grade of the 
Event (NCI 
CTCAE version 
4.03) 
Dose Modifications 
Toxicity Management 
≤ Grade 1, then the decision 
to reinitiate study 
drug/regimen will be based 
upon treating physician’s 
clinical judgment and after 
completion of steroid taper.  
  
  
- 
If no improvement within 3-5 days, additional workup should be considered 
and prompt treatment with IV methylprednisolone 2-4mg/kg/day started  
- 
If still no improvement within 3-5 days despite IV methylprednisone at 2-
4/g/kg/day, promptly start immunosuppressive therapy such as TNF inhibitors 
(e.g. infliximab at 5mg/kg every 2 weeks). Caution: Important to rule out 
sepsis and refer to infliximab label for general guidance before using 
infliximab  
- 
Once improving, gradually taper steroids over ≥28 days  and consider 
prophylactic antibiotics, antifungal or anti PCP 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 
- 
Hospitalize the patient 
- 
Supportive Care (oxygen, etc.) 
- 
If no improvement within 3-5 days, additional workup should be considered 
and prompt treatment with additional immunosuppressive therapy such as 
TNF inhibitors (e.g. infliximab at 5mg/kg every 2 weeks dose) started. 
Caution: rule out sepsis and refer to infliximab label for general guidance 
before using infliximab  
- 
Once improving, gradually taper steroids over ≥28 days  and consider 
prophylactic antibiotics, antifungals and in particular,  anti PCP treatment 
(please refer to current  NCCN guidelines for treatment of  cancer-related 
infections (Category 2B recommendation)a 
38 
 

Clinical Study Protocol  
Investigational Drug Substance: Durvalumab and Tremelimumab 
Study Number ESR-14-10531/WINSHIP3112-15; Edition Number 3.1; Date 09/16/2016 
 
 
Grade of the 
Event (NCI 
CTCAE version 
4.03) 
Dose Modifications 
Toxicity Management 
Diarrhea/ 
Enterocolitis 
Grade of Diarrhea 
(CTCAE version 
4.03) 
General Guidance 
- 
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, 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)  
No dose modification 
For Grade 1 diarrhea :  
-      Close monitoring for worsening symptoms 
-      Consider symptomatic treatment including hydration, electrolyte replacement, 
dietary changes (e.g., American Dietetic Association colitis diet), and 
loperamide. Use of probiotics as per treating physician’s clinical judgment. 
Grade 2 diarrhea 
(stool frequency of 
4-6 over baseline 
per day)  
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 diarrhea:  
- 
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 3-5 days or worsens despite prednisone at 1-
2 mg/kg/day PO or IV equivalent, GI consult 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 2-4mg/kg/day started.  
- 
If still no improvement within 3-5 days despite 2-4mg/kg IV 
39 
 

Clinical Study Protocol  
Investigational Drug Substance: Durvalumab and Tremelimumab 
Study Number ESR-14-10531/WINSHIP3112-15; Edition Number 3.1; Date 09/16/2016 
 
 
Grade of the 
Event (NCI 
CTCAE version 
4.03) 
Dose Modifications 
Toxicity Management 
methylprednisolone, promptly start immunosuppressives such as (infliximab 
at 5mg/kg once every 2 weeks1). Caution: Important to rule out bowel 
perforation and refer to infliximab label for general guidance before using 
infliximab   
- 
Consult study physician if no resolution to ≤ Grade 1 in 3-4 days 
- 
Once improving, gradually taper steroids over ≥28 days  and consider 
prophylactic antibiotics, antifungals and anti PCP treatment (please refer to 
current  NCCN guidelines for treatment of  cancer-related infections 
[Category 2B recommendation])a 
Grade 3 or 4 
diarrhea  
 
(Grade 3: stool 
frequency of ≥7 
over baseline per 
day;  
 
Grade 4: life 
threatening 
consequences) 
Permanently discontinue study 
drug/study regimen 
For Grade 3 or 4 diarrhea: 
- 
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 3-5 days of IV methylprednisolone 2 to 
4mg/kg/day or equivalent, promptly start further immunosuppressives (e.g. 
infliximab at 5mg/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 improving, gradually taper steroids over ≥28 days and consider 
prophylactic antibiotics, antifungals and anti PCP treatment (please refer to 
current  NCCN guidelines for treatment of  cancer-related infections 
[Category 2B recommendation]a) 
 
40 
 
                                                 

Clinical Study Protocol  
Investigational Drug Substance: Durvalumab and Tremelimumab 
Study Number ESR-14-10531/WINSHIP3112-15; Edition Number 3.1; Date 09/16/2016 
 
 
Grade of the 
Event (NCI 
CTCAE version 
4.03) 
Dose Modifications 
Toxicity Management 
Hepatitis 
(Elevated LFTs) 
Infliximab 
should not be 
used for 
management of 
Immune Related 
Hepatitis 
Grade of Liver 
Function Test 
Elevation (CTCAE 
version 4.03) 
Any Grade 
  
- 
Monitor and evaluate liver function test: AST, ALT, ALP and total bilirubin  
- 
Evaluate for alternative etiologies (e.g., viral hepatitis, disease progression, 
concomitant medications)  
Grade 1  
(AST or ALT > to 
3 times and/or TB 
> ULN to 1.5 times 
ULN) 
No dose modification 
If  it worsens, treat as Grade 2 
event 
For Grade 1 AST or ALT and/or TB elevation        
  -     Continue LFT monitoring per protocol   
Grade 2  
(AST or ALT > 3 
to 5 times ULN 
and/or TB >1.5-3.0 
times 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 AST or ALT and or TB elevation :  
- 
Regular and frequent checking of LFTs (e.g. every 1-2 days) until elevations 
of these are improving or resolved.   
- 
If no resolution to ≤ Grade 1 in 1-2 days, discuss with study physician. 
- 
If event is persistent (> 3-5 days) or worsens, promptly start prednisone 1-
2mg/kg/day PO or IV equivalent.  
- 
If still no improvement within 3-5 days despite 1-2mg/kg/day of prednisone 
PO or IV equivalent, consider additional workup and prompt treatment with 
IV methylprednisolone 2-4mg/kg/day started. 
- 
If still no improvement within 3-5 days despite 2-4mg/kg/day of IV 
methylprednisolone, promptly start immunosuppressives (mycophenolate 
mofetil)2 . Discuss with study physician if mycophenolate mofetil is not 
available.  Infliximab should NOT be used. 
- 
Once improving, gradually taper steroids over ≥28 days  and consider 
prophylactic antibiotics, antifungals and anti PCP treatment (please refer to 
current  NCCN guidelines for treatment of  cancer-related infections 
[Category 2B recommendation]a) 
 
41 
 
                                                 

Clinical Study Protocol  
Investigational Drug Substance: Durvalumab and Tremelimumab 
Study Number ESR-14-10531/WINSHIP3112-15; Edition Number 3.1; Date 09/16/2016 
 
 
Grade of the 
Event (NCI 
CTCAE version 
4.03) 
Dose Modifications 
Toxicity Management 
Grade 3 
(AST or ALT >5-
20 times ULN 
and/or TB > 3.0-10 
times ULN 
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 ≤ 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 > 3x ULN 
+ bilirubin > 2x ULN without 
initial findings of cholestasis 
(i.e. elevated alkaline P04) 
and  in the absence of any 
alternative cause.b 
For Grade 3 or 4 AST or ALT and/or TB elevation: 
- 
Promptly initiate empiric IV methylprednisolone at 1 to 4 mg/kg/day or 
equivalent  
- 
If still no improvement within 3-5 days despite 1 to 4 mg/kg/day 
methylprednisolone IV or equivalent , promptly start treatment with 
immunosuppressive therapy (mycophenolate mofetil).  Discuss with study 
physician if mycophenolate is not available. Infliximab should NOT be 
used. 
- 
Hepatology consult, abdominal workup, and imaging as appropriate. 
- 
Once improving, gradually taper steroids over ≥28 days  and consider 
prophylactic antibiotics, antifungals and anti PCP treatment (please refer to 
current  NCCN guidelines for treatment of  cancer-related infections 
[Category 2B recommendation]a) 
42 
 

Clinical Study Protocol  
Investigational Drug Substance: Durvalumab and Tremelimumab 
Study Number ESR-14-10531/WINSHIP3112-15; Edition Number 3.1; Date 09/16/2016 
 
 
Grade of the 
Event (NCI 
CTCAE version 
4.03) 
Dose Modifications 
Toxicity Management 
Grade 4  
(AST or ALT > 20 
times ULN and/or 
TB > 10 times 
ULN)  
Permanently discontinue study 
drug/study regimen  
Nephritis or 
Renal 
Dysfunction 
(Elevated Serum 
Creatinine)  
Grade of Elevated 
Serum Creatinine 
(CTCAE version 
4.03) 
 
Any Grade  
General Guidance 
 
 
 
- 
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, proteinuria, etc.)  
- 
Patients should be thoroughly evaluated to rule out any alternative etiology 
(e.g., disease progression, infections etc.) 
- 
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-
1.5X baseline;  > 
ULN to 1.5X ULN]  
No dose modification 
For Grade 1 elevated creatinine:  
-      Monitor serum creatinine weekly and any accompanying symptom 
• 
If creatinine returns to baseline, resume its regular monitoring per 
study protocol. 
• 
If it worsens, depending on the severity , treat as Grade 2 or Grade 3 
or 4  
-      Consider symptomatic treatment including hydration, electrolyte replacement, 
diuretics, etc. 
43 
 

Clinical Study Protocol  
Investigational Drug Substance: Durvalumab and Tremelimumab 
Study Number ESR-14-10531/WINSHIP3112-15; Edition Number 3.1; Date 09/16/2016 
 
 
Grade of the 
Event (NCI 
CTCAE version 
4.03) 
Dose Modifications 
Toxicity Management 
Grade 2 [Serum 
Creatinine>1.5-
3.0X baseline; 
>1.5X-3.0XULN] 
 
Hold study drug/study regimen 
until 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 then 
resume study drug/study 
regimen after completion of 
steroid taper 
 
For Grade 2 elevated creatinine:  
- 
Consider symptomatic treatment including hydration, electrolyte replacement, 
diuretics, etc.  
- 
Carefully monitor serum creatinine  every 2-3 days and as clinically 
warranted 
- 
Consult Nephrologist and consider renal biopsy if clinically indicated 
- 
If event is persistent (> 3-5 days) or worsens,  promptly start  prednisone 1 to 
2 mg/kg/day PO or IV equivalent  
- 
If event is not responsive within 3-5 days or worsens despite prednisone at 1-
2 mg/kg/day PO or IV equivalent, additional workup should be considered 
and prompt treatment with IV methylprednisolone at 2-4mg/kg/day started.  
- 
Once improving gradually taper steroids over ≥28 days and consider 
prophylactic antibiotics, antifungals and anti PCP treatment (please 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 X 
baseline; >3.0-6.0 
X ULN 
 
Grade 4: Serum 
Creatinine > 6.0 X 
ULN)  
Permanently discontinue study 
drug/study regimen 
- 
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 3-5 days or worsens despite prednisone at 1-
2 mg/kg/day PO or IV equivalent, additional workup should be considered 
and prompt treatment with IV methylprednisolone 2-4mg/kg/day started.  
- 
Once improving,  gradually taper steroids over ≥28 days  and consider 
prophylactic antibiotics, antifungals and anti PCP treatment (please refer to 
current  NCCN guidelines for treatment of  cancer-related infections 
[Category 2B recommendation]a  
Rash (excluding 
Bullous skin 
formations) 
Grade of Skin Rash  
(Please refer to 
NCICTCAE 
General Guidance 
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** 
44 
 

Clinical Study Protocol  
Investigational Drug Substance: Durvalumab and Tremelimumab 
Study Number ESR-14-10531/WINSHIP3112-15; Edition Number 3.1; Date 09/16/2016 
 
 
Grade of the 
Event (NCI 
CTCAE version 
4.03) 
Dose Modifications 
Toxicity Management 
version 4.03 for 
definition of 
severity/grade 
depending on  type 
of skin rash)  
Grade 1  
No dose modification 
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- 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 3-5 days or is worsening 
despite symptomatic treatment and/or use of moderate strength topical 
steroid, discuss with study physician and promptly start systemic steroids 
prednisone  1-2 mg/kg/day PO or IV equivalent   
- 
Consider skin biopsy if persistent for >1-2 weeks or recurs 
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 
Grade 3 skin rash  to ≤ Grade 
1 or baseline within 30 days, 
then permanently discontinue 
Study drug/study regimen  
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] 
- 
Consider skin biopsy (preferably more than 1) as clinically feasible. 
- 
Once improving, gradually taper steroids over ≥28 days and consider 
45 
 

Clinical Study Protocol  
Investigational Drug Substance: Durvalumab and Tremelimumab 
Study Number ESR-14-10531/WINSHIP3112-15; Edition Number 3.1; Date 09/16/2016 
 
 
Grade of the 
Event (NCI 
CTCAE version 
4.03) 
Dose Modifications 
Toxicity Management 
Grade 4 
Permanently discontinue study 
drug/study regimen 
prophylactic antibiotics, antifungals and anti PCP treatment (please refer to 
current NCCN guidelines for treatment of  cancer-related infections 
[Category 2B recommendation])a 
- 
Discuss with Study Physician 
Endocrinopathy 
(e.g., 
hyperthyroidism, 
hypothyroidism, 
hypopituitarism, 
adrenal 
insufficiency, 
etc.) 
Any Grade  
(Depending on the 
type of 
endocrinopathy, 
refer to NCI 
CTCAE version 
4.03 for defining 
the CTC 
grade/severity)  
General Guidance 
- 
Consult Endocrinologist 
- 
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, hypotension and 
weakness. 
- 
Patients should be thoroughly evaluated to rule out any alternative etiology 
(e.g., disease progression including brain metastases, infections, etc.) 
- 
Monitor and evaluate thyroid function tests: TSH, free T3 and free T4 and 
other relevant endocrine labs depending on suspected endocrinopathy.  
- 
If a patient experiences an AE that is thought to be possibly of autoimmune 
nature (e.g., thyroiditis, pancreatitis, hypophysitis, diabetes insipidus), the 
investigator should send a blood sample for appropriate autoimmune antibody 
testing  
Grade 1 
(Depending on the 
type of 
endocrinopathy, 
refer to NCI 
CTCAE version 
4.03 for defining 
the CTC grade 1) 
No dose modification 
For Grade 1: (including those with asymptomatic TSH elevation) 
- 
Monitor patient with appropriate endocrine function tests 
- 
If TSH < 0.5X LLN, or TSH >2X ULN or consistently out of range in 2 
subsequent measurements, include FT4 at subsequent cycles as clinically 
indicated and consider endocrinology consult. 
46 
 

Clinical Study Protocol  
Investigational Drug Substance: Durvalumab and Tremelimumab 
Study Number ESR-14-10531/WINSHIP3112-15; Edition Number 3.1; Date 09/16/2016 
 
 
Grade of the 
Event (NCI 
CTCAE version 
4.03) 
Dose Modifications 
Toxicity Management 
Grade 2  
(Depending on the 
type of 
endocrinopathy, 
refer to NCI 
CTCAE version 
4.03 for defining 
the CTC 
grade/severity 2) 
 
 
For Grade 2 endocrinopathy 
other than hypothyroidism, 
hold study drug/study regimen 
dose until  subject 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 
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, and 3) doses of 
prednisone are at less than or 
equal to 10mg/day or 
equivalent. 
For Grade 2: (including those with symptomatic endocrinopathy) 
- 
Isolated hypothyroidism may be treated with replacement therapy without 
treatment interruption and without corticosteroids 
- 
Initiate hormone replacement as needed for management 
- 
Evaluate endocrine function, and as clinically indicated,  consider pituitary 
scan 
- 
For patients with abnormal endocrine work up, except for those  with isolated 
hypothyroidism,  consider short-term, corticosteroids (e.g., 1-2mg/kg/day 
methylprednisolone or IV equivalent) and prompt initiation of treatment with 
relevant hormone replacement (e.g. Levothyroxine, hydrocortisone, or sex 
hormones). - 
 
- 
Once improving, gradually taper steroids over ≥28 days and consider 
prophylactic antibiotics, antifungals and anti PCP treatment (please refer to 
current NCCN guidelines for treatment of  cancer-related infections 
[Category 2B recommendation])a 
- 
For patients with normal endocrine work up (lab or MRI scans), repeat 
labs/MRI as clinically indicated. 
47 
 

Clinical Study Protocol  
Investigational Drug Substance: Durvalumab and Tremelimumab 
Study Number ESR-14-10531/WINSHIP3112-15; Edition Number 3.1; Date 09/16/2016 
 
 
Grade of the 
Event (NCI 
CTCAE version 
4.03) 
Dose Modifications 
Toxicity Management 
Grade 3 or 4 
(Depending on the 
type of 
endocrinopathy, 
refer to NCI 
CTCAE version 
4.03 for defining 
the CTC 
grade/severity 3 or 
4)  
For Grade 3 or 4 endocrinopathy 
other than hypothyroidism, hold 
study drug/study regimen dose 
until endocrinopathy symptom(s) 
are controlled 
Study drug/study regimen can be 
once event stabilizes after 
completion of steroid taper    
 
For Grade 3 or 4: 
- 
Consult endocrinologist 
- 
Isolated hypothyroidism may be treated with replacement therapy without 
treatment interruption and without corticosteroids 
- 
Promptly initiate empiric IV methylprednisolone 1 to 2 mg/kg/day or 
equivalent 
- 
Administer hormone replacement therapy as necessary. 
- 
For adrenal crisis, severe dehydration, hypotension, or shock: immediately 
initiate intravenous corticosteroids with mineralocorticoid activity 
- 
Once improving, gradually taper immunosuppressive steroids over ≥28 days 
and consider prophylactic antibiotics, antifungals and anti PCP treatment 
(please refer to current NCCN guidelines for treatment of  cancer-related 
infections [Category 2B recommendation])a 
- 
Discuss with study physician 
Immune mediated  
Neurotoxicity (to 
include but not 
limited to limbic 
encephalitis . 
autonomic 
neuropathy, 
excluding 
Myasthenia 
Gravis and 
Guillain-Barre)   
 
Grade of 
Neurotoxicity  
Depending on the 
type of 
neurotoxicity , refer 
to NCI CTCAE 
version 4.03 for 
defining the CTC 
grade/severity 
 
Any Grade  
 
 
 
 
General Guidance 
- 
Patients should be evaluated to rule out any alternative etiology (e.g., 
disease progression, infections, metabolic syndromes and medications, etc.)  
- 
Monitor patient  for general symptoms (headache, nausea, vertigo, behavior 
change, or weakness) 
- 
Consider appropriate diagnostic testing (e.g. electromyogram and nerve 
conduction investigations) 
- 
Symptomatic treatment with neurological consult as appropriate 
48 
 

Clinical Study Protocol  
Investigational Drug Substance: Durvalumab and Tremelimumab 
Study Number ESR-14-10531/WINSHIP3112-15; Edition Number 3.1; Date 09/16/2016 
 
 
Grade of the 
Event (NCI 
CTCAE version 
4.03) 
Dose Modifications 
Toxicity Management 
 
 
Grade 1 
 No dose modifications 
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. 
o If toxicity worsens then treat as 
Grade 3 or Grade 4  
• Study drug/study regimen can 
be resumed once event 
improves to Grade ≤1 and after 
completion of steroid taper    
- 
Discuss with the study physician  
- 
Obtain  Neurology Consult  
- 
Sensory neuropathy/neuropathic pain may be managed by appropriate 
medications (e.g., gabapentin, duloxetine, etc.) 
- 
Promptly start systemic steroids prednisone 1-2mg/kg/day or IV equivalent  
- 
If no improvement within 3-5 days despite 1-2mg/kg/day prednisone or IV 
equivalent consider additional workup and promptly treat with additional 
immunosuppressive therapy (e.g. IVIG)  
 
 
Grade 3 
• Hold Study drug/study 
regimen dose until resolution 
to ≤ Grade 1 
• Permanently discontinue study 
drug/study regimen if Grade 3 
irAE does not resolve to ≤ 
Grade 1 within 30 days. 
For Grade 3 or 4: 
- 
Discuss 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 3-5 days despite IV corticosteroids, consider 
additional workup and promptly treat with additional immunosuppressants 
(e.g. IVIG)  
- 
Once stable, gradually taper steroids over ≥28 days 
Grade 4 
 
• Permanently discontinue study 
drug/study regimen 
Immune-
 
General Guidance 
- 
The prompt diagnosis of immune-mediated peripheral neuromotor 
49 
 

Clinical Study Protocol  
Investigational Drug Substance: Durvalumab and Tremelimumab 
Study Number ESR-14-10531/WINSHIP3112-15; Edition Number 3.1; Date 09/16/2016 
 
 
Grade of the 
Event (NCI 
CTCAE version 
4.03) 
Dose Modifications 
Toxicity Management 
mediated 
peripheral 
neuromotor 
syndromes, such 
as Guillain-Barre 
and Myasthenia 
Gravis 
syndromes is important, since certain patients may unpredictably experience 
acute decompensations which can result in substantial morbidity or in the 
worst case, death. Special care should be taken for certain sentinel 
symptoms which 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 and medications, etc.). 
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 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  
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 IVIG and followed by plasmapheresis if 
not responsive to IVIG  
Grade 1 
No dose modification 
- 
Discuss 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 unless the symptoms are very minor and stable 
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 
Grade 2  
- 
Discuss 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 
50 
 

Clinical Study Protocol  
Investigational Drug Substance: Durvalumab and Tremelimumab 
Study Number ESR-14-10531/WINSHIP3112-15; Edition Number 3.1; Date 09/16/2016 
 
 
Grade of the 
Event (NCI 
CTCAE version 
4.03) 
Dose Modifications 
Toxicity Management 
30 days or if there are signs of 
respiratory insufficiency or 
autonomic instability 
 
medications (e.g., gabapentin, duloxetine, etc.) 
MYASTHENIA GRAVIS 
o 
Steroids may be successfully used to treat Myasthenia Gravis. 
Important to consider that steroid therapy (especially with high 
doses) may result in transient worsening of myasthenia and should 
typically be administered in a monitored setting under supervision 
of a consulting neurologist. 
o 
Patients unable to tolerate steroids may be candidates for treatment 
with plasmapheresis or IVIG. 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 present, consider starting 
acetylcholine esterase (AChE) inhibitor therapy in addition to 
steroids. Such therapy, if successful, can also serve to reinforce the 
diagnosis. 
GUILLAIN-BARRE:  
o 
Important to consider here that the use of steroids as the primary 
treatment of Guillain-Barre is not typically considered effective. 
Patients requiring treatment should be started with IVIG and 
followed by plasmapheresis if not responsive to IVIG. 
Grade 3 
Hold study drug/study regimen 
dose until resolution to ≤ Grade 
1 
Permanently discontinue Study 
drug/study regimen if Grade 3 
irAE does not resolve to ≤ 
Grade 1 within 30 days or if 
there are signs of respiratory 
insufficiency or autonomic 
instability 
For severe or life threatening (Grade 3 or 4) events:  
- 
Discuss with study physician 
- 
Recommend hospitalization 
- 
Monitor symptoms and obtain neurological consult 
MYASTHENIA GRAVIS 
o 
Steroids may be successfully used to treat Myasthenia Gravis.  It 
should typically be administered in a monitored setting under 
supervision of a consulting neurologist. 
o 
Patients unable to tolerate steroids may be candidates for treatment 
with plasmapheresis or IVIG. 
51 
 

Clinical Study Protocol  
Investigational Drug Substance: Durvalumab and Tremelimumab 
Study Number ESR-14-10531/WINSHIP3112-15; Edition Number 3.1; Date 09/16/2016 
 
 
Grade of the 
Event (NCI 
CTCAE version 
4.03) 
Dose Modifications 
Toxicity Management 
Grade 4 
Permanently discontinue study 
drug/study regimen  
o 
If Myasthenia Gravis-like neurotoxicity present, consider starting 
acetylcholine esterase (AChE) inhibitor therapy in addition to 
steroids. Such therapy, if successful, can also serve to reinforce the 
diagnosis. 
GUILLAIN-BARRE:  
Important to consider here that the use of steroids as the primary 
treatment of Guillain-Barre is not typically considered effective. 
Patients requiring treatment should be started with IVIG and 
followed by plasmapheresis if not responsive to IVIG 
 
 
 
 
 
52 
 

Clinical Study Protocol  
Investigational Drug Substance: Durvalumab and Tremelimumab 
Study Number ESR-14-10531/WINSHIP3112-15; Edition Number 3.1; Date 09/16/2016 
 
 
Table 2- Infusion-Related Reactions 
Severity Grade 
of the Event 
(NCI CTCAE 
version 4.03) 
Dose Modifications 
Toxicity Management 
Any Grade 
General Guidance 
- 
Management 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, skin rashes 
etc.) and anaphylaxis (e.g., generalized urticaria, angioedema, 
wheezing, hypotension, tachycardia, etc.) 
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 1 or Grade 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 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 
Grade 3/4 
 
 
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) 
 
 
 
53 
 

Clinical Study Protocol  
Investigational Drug Substance: Durvalumab and Tremelimumab 
Study Number ESR-14-10531/WINSHIP3112-15; Edition Number 3.1; Date 09/16/2016 
 
 
Table 3- Non-immune Mediated Reactions 
(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”  
Severity Grade of the 
Event (NCI CTCAE 
version 4.03) 
Dose Modification  
Toxicity Management  
Any Grade 
Note: dose modifications are not required for adverse events 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  
1 
No dose adjustment  
Treat accordingly as per institutional 
standard  
2 
Hold study drug/study regimen until resolution to ≤ Grade 1 or baseline 
Treat accordingly as per institutional 
standard  
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  
 
 
4 
Discontinue Study drug/study regimen (Note for Grade 4 labs, decision to discontinue would be 
based on accompanying clinical signs/symptoms and as per Investigator’s clinical judgment and 
in consultation with the sponsor)  
Treat accordingly as per institutional 
standard  
Abbreviations: 
AChE = acetylcholine esterase; ADA = American Dietetic Association; AE = adverse event; ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = 
aspartate aminotransferase; CT = computed tomography; GI = gastrointestinal; IDS=Infectious Disease Service; ILD = interstitial lung disease; IM = intramuscular; irAE 
= immune-related adverse event; IV = intravenous; NCI CTCAE = National Cancer Institute Common Terminology Criteria for Adverse Events; PO = by mouth; TNF = 
tumor necrosis factor; TSH = thyroid stimulating hormone; ULN = upper limit of normal. 
a ASCO Educational Book 2015 “Managing Immune Checkpoint Blocking Antibody Side Effects” by Michael Postow MD  
b FDA Liver Guidance Document 2009 Guidance for Industry: Drug Induced Liver Injury – Premarketing Clinical Evaluation NCI NCI CTCAE version 4.03 
 
54 
 

Clinical Study Protocol  
Investigational Drug Substance: Durvalumab and Tremelimumab 
Study Number ESR-14-10531/WINSHIP3112-15; Edition Number 3.1; Date 09/16/2016 
 
7. 
RESTRICTIONS DURING THE STUDY AND CONCOMITANT 
TREATMENT(S) 
7.1 
Restrictions during the study 
The following restrictions apply while the patient is receiving study treatment and for the 
specified times before and after: 
Females of childbearing potential who are sexually active with a non-sterilized male partner 
must use 2 methods of effective contraception (Table 2) from the time of screening and must 
agree to continue using such precautions for 180 days after the last dose of durvalumab + 
tremelimumab combination therapy or 90 days after the last dose of durvalumab 
monotherapy, whichever is the longer time period; cessation of birth control after this point 
should be discussed with a responsible physician.  Periodic abstinence, the rhythm method, 
and the withdrawal method are not acceptable methods of birth control. 
− 
Females of childbearing potential are defined as those who are not surgically 
sterile (i.e., bilateral tubal ligation, bilateral oophorectomy, or complete 
hysterectomy) or post-menopausal (defined 12 months with no menses without 
an alternative medical cause). 
Non-sterilized males who are sexually active with a female partner of childbearing potential 
must use 2 acceptable methods of effective contraception (see Table 2) from 
screening through 180 days after receipt of the final dose of durvalumab + 
tremelimumab combination therapy or 90 days after receipt of the final dose of 
durvalumab monotherapy, whichever is the longer time period.   
Restrictions relating to concomitant medications are described in Section 7.2. 
Table 4. Effective methods of contraception (2 methods must be used) 
Barrier methods 
Intrauterine device methods 
Hormonal methods 
Male condom plus spermicide 
Cap plus spermicide 
Diaphragm plus spermicide 
Copper T 
Progesterone Ta  
Levonorgestrel-releasing 
intrauterine 
system 
(e.g., Mirena®)a 
Implants 
Hormonal shot or injection 
Combined pill 
Minipill 
Patch 
a 
This is also considered to be a hormonal method. 
55 
 

Clinical Study Protocol  
Investigational Drug Substance: Durvalumab and Tremelimumab 
Study Number ESR-14-10531/WINSHIP3112-15; Edition Number 3.1; Date 09/16/2016 
 
Blood donation 
Subjects should not donate blood while participating in this study, or for at least 90 days 
following the last infusion of durvalumab or tremelimumab or until after 4-5X the half-life of 
durvalumab or tremelimumab or until the time specified in the prescribing information of 
durvalumab or tremelimumab, whichever occurs longest. 
7.2 
Concomitant treatment(s) 
The Principal Investigator must be informed as soon as possible about any medication taken 
from the time of screening until the end of the clinical phase of the study (final study visit).  
Any concomitant medication(s), including herbal preparations, taken during the study will be 
recorded in the CRF.   
Restricted, prohibited, and permitted concomitant medications are described in the following 
tables.  Refer to Section 6.6 for guidance on management of IP-related toxicities. 
7.2.1 
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 7.2.2. 
All supportive measures consistent with optimal patient care will be given throughout the 
study. Supportive care (including IVF hydration) is not considered non-protocol therapy. 
Suggested supportive care medications may be substituted at the discretion of the investigator 
based on drug availability.  
Enteral feeding and hyperalimentation may be used, but details must be clearly outlined on 
treatment forms.  
The use of bisphosphonates or denosumab is allowed for patients with bone metastasis or 
hypercalcemia.  
7.2.2 
Excluded Concomitant Medications 
The following medications are considered exclusionary during the study.  
1. Any investigational anticancer therapy <<other than the protocol specified therapies>> 
2. Any concurrent chemotherapy, radiotherapy (except palliative radiotherapy), 
immunotherapy, biologic or hormonal therapy for cancer treatment, <<other than any 
stated comparator or combination regimens. Concurrent use of hormones for 
56 
 

Clinical Study Protocol  
Investigational Drug Substance: Durvalumab and Tremelimumab 
Study Number ESR-14-10531/WINSHIP3112-15; Edition Number 3.1; Date 09/16/2016 
 
noncancer-related conditions (e.g., insulin for diabetes and hormone replacement 
therapy) is acceptable.  NOTE: Local treatment of isolated lesions for palliative intent 
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 durvalumab and tremelimumab dosing (i.e., 
30 days prior to the first dose, during treatment with durvalumab and tremelimumab 
for 30 days post discontinuation of durvalumab and tremelimumab.  Inactivated 
vaccines, such as the injectable influenza vaccine, are permitted. 
   
Table 5. Prohibited and Rescue Medications 
Prohibited medication/class of drug: 
Usage: 
Additional investigational anticancer therapy 
concurrent with those under investigation in 
this study 
Should not be given whilst the patient is on IP 
treatment   
mAbs against CTLA-4, PD-1, or PD-L1 
Should not be given whilst the patient is on IP 
treatment through 90 days after the last dose of IP. 
Any concurrent chemotherapy, local therapy 
(except palliative radiotherapy for non-target 
lesions, 
e.g., 
radiotherapy, 
surgery, 
radiofrequency ablation), biologic therapy, or 
hormonal therapy for cancer treatment 
Should not be given whilst the patient is on IP 
treatment (including SoC).  (Concurrent use of 
hormones 
for 
non-cancer-related 
conditions 
[e.g., insulin for diabetes and hormone replacement 
therapy] is acceptable.) 
Immunosuppressive medications, including, 
but not limited to, systemic corticosteroids at 
doses exceeding 10 mg/day of prednisone or 
its equivalent, methotrexate, azathioprine, and 
tumor necrosis factor α blockers   
Should not be given whilst the patient is on IP 
treatment 
(including 
SoC). 
 
(Use 
of 
immunosuppressive medications for the management 
of IP-related AEs or in patients with contrast allergies 
is acceptable.  In addition, use of inhaled, topical, and 
intranasal corticosteroids is permitted. 
57 
 

Clinical Study Protocol  
Investigational Drug Substance: Durvalumab and Tremelimumab 
Study Number ESR-14-10531/WINSHIP3112-15; Edition Number 3.1; Date 09/16/2016 
 
Prohibited medication/class of drug: 
Usage: 
Live attenuated vaccines 
Should not be given through 30 days after the last 
dose of IP (including SoC) during the study 
 
Rescue/supportive medication/class of drug: 
Usage: 
Concomitant 
medications 
or 
treatments 
(e.g., acetaminophen 
or 
diphenhydramine) 
deemed necessary by the Investigator to 
provide adequate prophylactic or supportive 
care, except for those medications identified as 
“prohibited” as listed above 
To be administered as prescribed by the Investigator 
Best supportive care (including antibiotics, 
nutritional support, growth factor support, 
correction of metabolic disorders, optimal 
symptom control, and pain management 
[including palliative radiotherapy, etc.]) 
Should be used when necessary for all patients 
8. 
STUDY PROCEDURES 
8.1 
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.  
8.1.1 
Screening Phase 
Screening procedures will be performed up to 14 days prior to randomization and initiation of 
radiation therapy as applicable, except for baseline imaging (up to 28 days allowed) 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 screening window.  
58 
 

Clinical Study Protocol  
Investigational Drug Substance: Durvalumab and Tremelimumab 
Study Number ESR-14-10531/WINSHIP3112-15; Edition Number 3.1; Date 09/16/2016 
 
The following procedures will be performed during the Screening Visit: 
• Informed Consent 
• Review of eligibility criteria 
• Randomization 
• Medical history and demographics 
• Complete physical exam  
• ECOG Performance Status 
• Vitals signs, weight and height  
• 12-lead ECG (in triplicate [2-5 minutes apart] 
• Tumor biopsy 
• Review of prior/concomitant medications  
• 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 or urine pregnancy test (for women of childbearing potential only) 
o Hepatitis serologies 
o Urinalysis (see Table 8) 
o Baseline PD blood sample for cytokine and lymphocyte estimation (if feasible 
collect baseline samples before and after XRT in patients randomized to Arm II) 
o  
8.1.2 
Treatment Phase  
Procedures to be conducted during the treatment phase of the study are presented in the 
Schedule of Assessments. Screening procedures performed within 72 hours of Cycle 1 Day 1 
(C1D1) do not need to be repeated on C1D1. 
• Brief medical history 
• Symptom-directed physical exam  
• ECOG Performance Status 
• Vitals signs, weight  
• 12-lead ECG (in triplicate [≥1 minute apart]) on C3D1 
• Review of prior/concomitant medications  
• Repeat tumor biopsy prior to C3D1 treatment 
• Clinical laboratory tests for: 
59 
 

Clinical Study Protocol  
Investigational Drug Substance: Durvalumab and Tremelimumab 
Study Number ESR-14-10531/WINSHIP3112-15; Edition Number 3.1; Date 09/16/2016 
 
o Hematology (see Table 6) 
o Clinical chemistry (see Table 7) 
o TSH 
o Serum pregnancy test (for women of childbearing potential only) 
o Hepatitis serologies (if clinically indicated) 
o Urinalysis (see Table 8) 
o PD blood sample for cytokine and lymphocyte estimation (C1D15, C2D1, C3D1 
and at progression) 
 
Arm I: 
• Durvalumab, 1500 mg Q4W (equivalent to 20 mg/kg Q4W) for 12 months in patients 
≥> 30 kg 
• Tremelimumab 75 mg Q4W (equivalent to 1 mg/kg Q4W) for up to 4 doses/cycles in 
patients ≥>30 kg 
Weight-based dosing should be utilized for patients <30 kg durvalumab 20 mg/kg Q4 and 
tremelimumab 1 mg/kg Q4. Patient may continue for an additional year of therapy if 
continuing clinical benefit and no safety concerns. 
Arm II: 
• Radiation to an isolated lesion (up to 30 Gy) by SBRT or hypofractionated 
conventional radiation delivery not to exceed 1 week 
• Durvalumab, 1500 mg Q4W (equivalent to 20 mg/kg Q4W) for 12 months in patients 
≥> 30 kg 
• Tremelimumab 75 mg Q4W (equivalent to 1 mg/kg Q4W) for up to 4 doses/cycles in 
patients ≥>30 kg.  
Weight-based dosing should be utilized for patients <30 kg durvalumab 20 mg/kg Q4 and 
tremelimumab 1 mg/kg Q4. Patient may continue for an additional year of therapy if 
continuing clinical benefit and no safety concerns. 
 
Schedule of infusion of Durvalumab and Tremelimumab 
Week 
1 -4 
5-8 
9-12 
13-16 
17 -52 
Cycle 
1 
2 
3 
4 
5 -18 
60 
 

Clinical Study Protocol  
Investigational Drug Substance: Durvalumab and Tremelimumab 
Study Number ESR-14-10531/WINSHIP3112-15; Edition Number 3.1; Date 09/16/2016 
 
Durvalumab* 
Q4W 
 
Q4W 
 
Q4W 
 
Q4W 
 
Q4W 
 
Tremelimumab 
Q4W 
 
Q4W 
 
Q4W 
 
Q4W 
 
NA 
 
* 1500mg concurrent with tremelimumab in cycles 1to 4; 1500mg as single agent from 
cycle  5 onward 
 
8.1.3 
End of Treatment 
End of treatment is defined as the last planned dosing visit within the 12-month dosing period. 
For subjects who discontinue durvalumab or tremelimumab prior to 12 months, end of 
treatment is considered the last visit where the decision is made to discontinue treatment. All 
required procedures may be completed within  ± 7 days of the end of treatment visit. Repeat 
disease assessment is not required if performed within 28 days prior to the end of treatment 
visit. 
Assessments for subjects who have completed durvalumab and tremelimumab treatment and 
achieved disease control, or have discontinued durvalumab or tremelimumab due to toxicity in 
the absence of confirmed progressive disease are provided in APPENDIX 1.    
Assessments for subjects who have discontinued durvalumab or tremelimumab treatment due 
to confirmed PD are presented in APPENDIX 2.  
All subjects will be followed for survival until the end of the study regardless of further 
treatments, or until the sponsor ends the study. 
8.2 
Description of study procedures 
8.2.1 
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. 
8.2.2 
Physical examination 
Physical examinations will be performed according to the assessment schedule.  Full physical 
examinations will include assessments of the head, eyes, ears, nose, and throat and the 
61 
 

Clinical Study Protocol  
Investigational Drug Substance: Durvalumab and Tremelimumab 
Study Number ESR-14-10531/WINSHIP3112-15; Edition Number 3.1; Date 09/16/2016 
 
respiratory, cardiovascular, GI, urogenital, musculoskeletal, neurological, dermatological, 
hematologic/lymphatic, and endocrine systems.  Height will be measured at screening only.  
Targeted physical examinations are to be utilized by the Investigator on the basis of clinical 
observations and symptomatology.  Situations in which physical examination results should 
be reported as AEs are described in Section 10   
8.2.3 
Electrocardiograms 
Resting 12-lead ECGs will be recorded at screening and as clinically indicated throughout the 
study.  ECGs should be obtained after the patient has been in a supine position for 5 minutes 
and recorded while the patient remains in that position. 
At Screening, a single ECG will be obtained on which QTcF must be <470 ms.   
In case of clinically significant ECG abnormalities, including a QTcF value >470 ms, 
2 additional 12-lead ECGs should be obtained over a brief period (e.g., 30 minutes) to confirm 
the finding.   
Situations in which ECG results should be reported as AEs are described in Section 10.0.   
8.2.4 
Vital signs 
Vital signs (blood pressure [BP], pulse, temperature, and respiration rate) will be evaluated 
according to the assessment schedules.   
On infusion days, patients receiving durvalumab + tremelimumab treatment will be monitored 
during and after infusion of IP as presented in the bulleted list below.   
• Supine BP will be measured using a semi-automatic BP recording device with an 
appropriate cuff size, after the patient has rested for at least 5 minutes.  BP and pulse 
will be collected from patients receiving durvalumab + tremelimumab treatment 
before, during, and after each infusion at the following times (based on a 60-minute 
infusion):   
• Prior to the beginning of the infusion (measured once from approximately 30 minutes 
before up to 0 minutes [i.e., the beginning of the infusion]).   
• Approximately 30 minutes during the infusion (halfway through infusion).   
• At the end of the infusion (approximately 60 minutes ±5 minutes).   
• A 1-hour observation period is required after the first infusion of durvalumab and 
tremelimumab. If no clinically significant infusion reactions are observed during or 
62 
 

Clinical Study Protocol  
Investigational Drug Substance: Durvalumab and Tremelimumab 
Study Number ESR-14-10531/WINSHIP3112-15; Edition Number 3.1; Date 09/16/2016 
 
after the first cycle, subsequent infusion observation periods can be at the 
Investigator’s discretion (suggested 30 minutes after each durvalumab and 
tremelimumab infusion).   
If the infusion takes longer than 60 minutes, then BP and pulse measurements should follow 
the principles as described above or be taken more frequently if clinically indicated.  The date 
and time of collection and measurement will be recorded on the appropriate eCRF.  Additional 
monitoring with assessment of vital signs is at the discretion of the Investigator per standard 
clinical practice or as clinically indicated.   
Body weight is also recorded along with vital signs.   
Situations in which vital signs results should be reported as AEs are described in Section 10.3.  
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.   
8.2.5 
Clinical laboratory tests 
The following clinical laboratory tests will be performed (see the Schedule of Assessments) 
• Coagulation parameters: Activated partial thromboplastin time and International 
normalised ratio to be assessed at baseline and as clinically indicated  
• Pregnancy test (female subjects of childbearing potential only) 
o 
Urine human chorionic gonadotropin (at screening only) 
o 
Serum beta-human chorionic gonadotropin  
• Thyroid Stimulating Hormone 
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 
 
63 
 

Clinical Study Protocol  
Investigational Drug Substance: Durvalumab and Tremelimumab 
Study Number ESR-14-10531/WINSHIP3112-15; Edition Number 3.1; Date 09/16/2016 
 
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 
Lactate dehydrogenase 
Alanine aminotransferase 
Lipase 
Amylase 
Magnesium 
Aspartate aminotransferase 
Potassium 
Bicarbonate 
Sodium 
Calcium  
Total bilirubina 
Chloride 
Total protein 
Creatinine 
Urea or blood urea nitrogen, depending on local practice 
Gamma glutamyltransferaseb 
Uric acid 
a   If Total bilirubin is ≥2xULN (and no evidence of Gilbert’s syndrome) then fractionate into direct and indirect  
bilirubin 
b At baseline and as clinically indicated 
 
Table 8. Urinalysis Testsa 
Bilirubin 
pH 
Blood 
Protein 
Glucose 
Specific gravity 
Ketones 
Colour and appearance 
a  Microscopy should be used as appropriate to investigate white blood cells and use the high power field for red 
blood cells 
64 
 

Clinical Study Protocol  
Investigational Drug Substance: Durvalumab and Tremelimumab 
Study Number ESR-14-10531/WINSHIP3112-15; Edition Number 3.1; Date 09/16/2016 
 
8.2.6 
Patient reported outcomes (PRO) 
Impact of treatment on patients’ quality of life will be assessed by using PRO tools 
administered at baseline and with each restaging scans. 
8.2.6.1 
 Name of PRO method or questionnaire 
FACT-L questionnaire 
8.3 
Biological sampling procedures 
PD marker including serum cytokines, chemokines along with peripheral lymphocyte 
repertoire and tumor infiltrating lymphocytes repertoire will be assessed at baseline, end of 
cycle 2 and at the time of progression if patient is deemed clinically stable and provide 
informed consent. 
8.3.1 
Pharmacokinetic sampling and evaluation methods 
Not applicable 
8.3.2 
Immunogenicity sampling and evaluation methods 
Not applicable 
8.3.3 
Biomarker/Pharmacodynamic sampling and evaluation methods 
Serum Chemokine/Cytokine - Collect 5mls of peripheral blood into red tiger topped tubes at 
the designated time points (baseline, end of radiation, C1D15, C2D1, C3D1 and at the time of 
progression). Process blood sample by centrifugation at 1500g and collect the resultant plasma 
and serum as 1ml aliquots to be stored at -80°F until ready for analysis. Samples will be 
analyzed using the human 63-plex LUMINEX assay ( BDNF, IL-21, SDF-1, bNGF, IL-22, 
sFas ligand, CD40L, IL-23, sICAM-1, EGF, IL-27, sVCAM-1, eotaxin, IL-31, TGF-alpha, 
ENA-78, IL-4, TGF-beta, FGF-2, IL-5, TNF-alpha, G-CSF  IL-6  TNF-beta, GM-CSF, IL-7, 
TRAIL, GRO-alpha, IL-8, VEGF-A, HGF, IL-9, VEGF-D, IFN-alpha, IP-10, IFN-beta, leptin, 
IFN-gamma, LIF , IL-1-alpha, M-CSF, IL-10, MCP-1, IL-12p40  MCP-3, IL-12p70, MIG, 
IL-13, MIP-1-alpha, L-15, MIP-1-beta, IL-17A, PAI-1, L-17F, PDGF-BB, IL-18, PIGF-1, IL-
1RA, RANTES, IL-1-beta, resistin, IL-2 and SCF).    
 
Flow cytometry/FACS – Collect three tubes (5mls each) of whole blood samples into CPT 
tiger blue  topped tubes for FACS to estimate peripheral circulating lymphocyte repertoire.  
65 
 

Clinical Study Protocol  
Investigational Drug Substance: Durvalumab and Tremelimumab 
Study Number ESR-14-10531/WINSHIP3112-15; Edition Number 3.1; Date 09/16/2016 
 
Peripheral blood samples will be collected into cell preparation tubes (BD Biosciences) and 
employed for PBMC isolation. PBMC will be immediately stained or frozen for later analysis.  
Single cell suspension will be isolated from biopsy samples harvested in cold L-15 Leibovitz 
media (HyClone). Tumors will be minced into small pieces and digested for 1h at 37°C with 
shaking by enzymatic cocktail of Collagenase I (125mg/1L), DNase I (50mg/1L), Collagenase 
IV (125mg/1L), Collagenase II (125mg/1L) and Elastase (50mg/1L) (Worthington). Single 
cell suspensions will be collected after RBC ACK lysis and cells will be stained for immediate 
analysis. Blood samples for flow cytometry should be submitted to the lab of Edmund K. 
Waller, MD, PhD 
Winship Building B 
5th Floor  
Attn: Ernestine Mahar 
Research Lab Manager 
Emory University 
Tel: (404)727-3086 
Email: ernestine.a.mahar@emory.edu 
Cell Free DNA (cfDNA) – Collect 30 mls of peripheral blood into Cell-Free DNA™ BCT 
(BCT) (Streck Inc., Omaha, NE) or purple topped EDTA tubes for plasma sample separation. 
Plasma samples for cfDNA should be dropped off in the lab of Taofeek Owonikoko, MD, 
PhD: 
Winship Building C 
3rd Floor Lab, Bench #20 
Attention Guojing Zhang, MS 
Tel: 404-778-1884 
Email: guojing.zhang@emory.edu 
Samples will be processed as detailed in Appendix 7 
Summary of schedule of sample collection for pharmacodynamic analysis 
Biomarker assay and sample Baseline 
End of C1 D15 
C2D1 C3D1 
Progression 
66 
 

Clinical Study Protocol  
Investigational Drug Substance: Durvalumab and Tremelimumab 
Study Number ESR-14-10531/WINSHIP3112-15; Edition Number 3.1; Date 09/16/2016 
 
type 
XRT 
Tumor biopsy 
X 
 
 
 
X 
X* 
FACS: Collect three tubes 
(5mls each) of whole blood 
into CPT tiger blue  topped 
tubes 
X 
X 
X 
X 
X 
X 
Cytokine/Chemokine 
Collect one red tiger topped 
tube 
X 
X 
X 
X 
X 
X 
cfDNA: collect 30mls of 
whole blood into Streck 
tubes or purple topped EDTA 
tubes 
X 
X 
X 
X 
X 
X 
TILS by IHC or FACS: Place 
3 biopsy cores for TILS in 
HyCloneTM media and 1-2 
cores 
for 
IHC 
in 
10% 
buffered formalin. 
X 
 
 
 
X 
X* 
*: optional biopsy 
 
Tumor Biopsy – collect minimum of three to four cores using image guided biopsy (18-
21Gauge needle) at baseline and at the time of 1st restaging scan (end of cycle 2 prior to 
C3D1 treatment) for all patients. Samples for TILS separation should be collected in cold L-
15 Leibovitz media (HyCloneTM) while samples for IHC should be collected in 10% buffered 
formalin. 
In appropriate and consenting patients, repeat biopsy at the time of disease progression. 
Employ 2 core aliquots for TILS assessment by FACS and 1-2 cores for IHC (PDL-1 
expression and TILS). Please  
FACS: PBMC and single cell suspension will be stained with  anti-CD8 (RPA-T8), -CD4 
(RPA-T4), -CD3 (UCHT1), -CD45RA (2H4LDH11LDB9), -CCR7 (150503), -PD-1 
67 
 

Clinical Study Protocol  
Investigational Drug Substance: Durvalumab and Tremelimumab 
Study Number ESR-14-10531/WINSHIP3112-15; Edition Number 3.1; Date 09/16/2016 
 
(EH12.2H7), -HLA-DR (l243), -CD38 (HIT2), -ICOS (ISA-3) -Bcl-2 (Bcl-2/100), -
Ki67(B56), -CTLA-4 (BNI3), -Granzyme B (GB11), Foxp3 (236A/E7).  
Panel 
Markers 
Remarks 
T-Reg Activation Panel ICS* 
CD3, CD4, CD8, ICOS, 
CD25, 
FoxP3*, 
CD69, 
CD38, CTLA4 
 
TIM3/PD-1 Panel 
CD3, CD4, CD8, CD45RA, 
TIM3, PD-1, Lag3, Ki-67 
 
Homing Panel 
CD3, CD4, CD8, Bcl-2, 
Granzyme B, CCR7 
 
ICS* Panel +/- PMA + Ionomycin 
CD3, 
CD4, 
CD8, 
IFN 
gamma, IL-2, TNF, IL-4, 
Ki-67 
 
Dendritic Cell Panel 
Lin-1, HLA-DR, CD123, 
CD11c, 
CD14, 
PD-L1, 
CD80, CD86, ICOS-L 
 
 
PD-L1 Testing 
To ensure comparability of data across all studies of durvalumab and/or tremelimumab and to 
gain real world experience on the performance of this assay, it is strongly encouraged that all 
studies that include PD-L1 testing utilize the Ventana SP263 assay.  Testing should be 
restricted to the Ventana SP263 assay and should be performed in accordance with the 
package insert on the Ventana Benchmark platform (Ultra or XT).   
The Ventana SP263 assay is fully analytically validated test characterized through to the 
completion of reader precision studies in the non-small cell lung cancer (NSCLC) and 
squamous cell carcinoma of the head & neck (SCCHN).  For these tumors, the Ventana SP263 
assay has a fully reproducible data package supporting cut-off and scoring algorithm.  
Following completion of ATLANTIC and HAWK clinical trials, the assay will be associated 
with clinical utility. In other cancer types (bladder, pancreatic, gastric, hepatocellular, triple 
negative breast, ovarian, esophageal, nasopharyngeal, glioblastoma, soft tissue sarcoma, 
68 
 

Clinical Study Protocol  
Investigational Drug Substance: Durvalumab and Tremelimumab 
Study Number ESR-14-10531/WINSHIP3112-15; Edition Number 3.1; Date 09/16/2016 
 
cholangiocarcinoma, small cell lung, melanoma and cervical HPV+ cancers), the Ventana 
SP263 assay has only limited clinical performance data.   
Sample collection for PD-L1 testing 
• The preferred tumor sample for the determination of a patient’s PD-L1 status is the 
one taken following the completion of the most recent prior line of therapy.  Samples 
taken at this time reflect the current PD-L1 status of the tumor and considered 
clinically most relevant.   
• In AstraZeneca studies, the preferred sample for PD-L1 testing was less than or equal 
to 3 months old.  In cases where a sample a less than 3 months old was not available, 
patients were asked to undergo a new biopsy if considered clinically appropriate by 
their treating physician.   
• Samples should be collected via a core needle of 18 gauge or larger or be collected by 
an incisional or excisional tumor biopsy.  Where institutional practice uses a smaller 
gauge needle, samples should be evaluated for tumor cell quantity (i.e. >100 tumor 
cells) to allow for adequate PD-L1 immunohistochemistry analyses.   
• When the collection of a new sample is not clinically appropriate, archival samples 
may be utilized provided the specimen it is not older than 3 years of age.  When 
archival samples are used to assess PD-L1 status, the age of the sample / date of 
collection should be captured.   
• Samples submitted for PD-L1 testing should be formalin fixed and embedded in 
paraffin (please submit to Winship Pathology Core Lab; 5th Floor Winship Building 
C).  Samples from fine needle aspirate (FNA) or decalcified bone are not appropriate 
for PD-L1 analysis.   
Sample data collection for PD-L1 testing 
The following fields of data should be collected from the site/institution collecting and if, 
indicated shipping of the samples:   
• Patient identifier (ecode or unique identifier) 
• Specimen identifier (written on the specimen) 
• Specimen collection date 
• Type of specimen submitted 
• Quantity of specimen 
• Date of sectioning 
• Archival orfresh tumor 
69 
 

Clinical Study Protocol  
Investigational Drug Substance: Durvalumab and Tremelimumab 
Study Number ESR-14-10531/WINSHIP3112-15; Edition Number 3.1; Date 09/16/2016 
 
• Tumor type 
• Primary tumor location 
• Metastatic tumor location (if applicable) 
• Fixative 
The following fields of data should be collected from PD-L1 testing laboratory: 
• Are the negative and positive controls stained correctly 
• Is the H&E material acceptable 
• Is morphology acceptable 
• Total percent positivity of PD-L1 in tumor cells 
• PD-L1 status (positive, negative or NA) in tumor cells  
• Total percent positivity of PD-L1 in infiltrating immune cells 
The Ventana SP263 assay to measure PD-L1 in tumors is experimental. As with all tests, there 
is a chance of false positive (the test shows high PD-L1 when it is not there) or false negative 
(the test does not show PD-L1 when it is there) results may occur.   
Sample processing and if indicated submission process for PD-L1 testing 
Preparing Stored samples for testing 
• Where samples already exist, they should be retrieved from the Bio-Bank storage 
location.  These blocks should undergo quality review, prior to evaluation or shipment.  
Where it is not possible or indicated to ship the block to a testing laboratory, unstained 
slides should be prepared from the paraffin-embedded tumor sample block (described 
below) prior to evaluation or shipment.   
Preparing newly acquired samples for PD-L1 testing 
• If patients are undergoing a biopsy procedure that provides the option to submit newly 
acquired samples, this sample should be used to determine PD-L1 status.  Where 
clinically acceptable, a minimum of 2 core biopsies should be collected and processed 
to FFPE in a single block.  The provision of 2 cores is advised in order to provide 
sufficient tissue for PD-L1 assessment.  
• It is recommended that core needle tumor biopsies are collected using an 18 gauge or 
larger needle and the process should be image-guided.  Excisional or incisional 
samples are also adequate.  If this is not per the institutions normal practice and a 
smaller gauge needle is used then the number of cores collected should be increased to 
allow sufficient material for successful PD-L1 testing (>100 tumor cells) and 
70 
 

Clinical Study Protocol  
Investigational Drug Substance: Durvalumab and Tremelimumab 
Study Number ESR-14-10531/WINSHIP3112-15; Edition Number 3.1; Date 09/16/2016 
 
embedded in the same block.  If available, a single excisional biopsy of at least 4 mm 
in diameter may substitute for all core biopsies.  
Fixation of biopsy samples for PD-L1 testing 
• Previously frozen tissue is not acceptable for processing to FFPE for PD-L1 testing.  
To fix newly acquired tissue, place immediately (within 30 min of excision) into an 
adequate volume of 10% v/v neutral buffered formalin (NBF).  Samples should remain 
in fixative for 24 – 48 hours at room temperature.   
• It is vital that there is an adequate volume of fixative relevant to the tissue (at least a 
10 volume excess) and that large specimens (if any) are incised prior to fixation to 
promote efficient tissue preservation.   
Embedding in paraffin for PD-L1 testing 
• An overnight processing schedule into paraffin wax is recommended  
• Below is the suggested routine overnight processing schedule: 
Storage of tumor blocks for PD-L1 testing 
• FFPE blocks should be stored at ambient temperature and protected from light until 
shipment by courier at ambient temperature. FFPE blocks are stable under these 
conditions for an indefinite period. 
Quality control of samples to be used for PD-L1 testing 
• Tissue should be assessed by the site pathologist prior to PD-L1 testing.   
• Each sample should be reviewed for: 
• Adequate fixation 
• Good preservation of morphology 
• Presence of tumor tissue 
• Histopathology consistent with indication 
 
• Greater than 100 tumor cells are required to determine PD-L1 status – tumor 
cell content must be reviewed prior to testing in order for PD-L1 obtain a valid 
result.   
If indicated, shipping samples to a PD-L1 testing laboratory 
71 
 

Clinical Study Protocol  
Investigational Drug Substance: Durvalumab and Tremelimumab 
Study Number ESR-14-10531/WINSHIP3112-15; Edition Number 3.1; Date 09/16/2016 
 
• When submitting sample to for PD-L1 testing the recommendation is to ship the block 
in order for sectioning to occur at the laboratory. Blocks should be shipped  - 
containing enough  material to  be provided to allow a minimum of 5, and preferably 
10, sections to be cut (each 4  micron thick) to be used for PD-L1 testing.    
Sectioning instructions 
• Where it is not possible or indicated to ship the block to laboratory for PD-L1 testing, 
unstained slides should be prepared from the paraffin-embedded tumor sample block 
as described below:   
• A minimum of 5-10 x 4 micron (μm) thick, unstained sections should be 
provided for PD-L1 testing 
• A new disposable microtome blade must be used for each block to prevent 
contamination between Slides are stable under these conditions for 6 months. 
• patient samples 
• Apply one section per slide to positively-charged Superfrost glass slides  
• The sections should be dried overnight between room temperature and 37°C. 
Do not dry sections at temperatures above 37°C. 
Sections should be stored at ambient temperature and protected from light until use or 
shipment to testing lab by courier at ambient temperature.  It is recommended that slides are 
cut freshly prior to PD-L1 testing and they are used within 90 days of being cut to obtain PD-
L1 status 
8.3.4 
Estimate of volume of blood to be collected 
The total volume of blood that will be drawn from each subject in this study is as follows: 
Table 9 
Volume of blood to be drawn from each subject (per cycle or for defined 
time points) 
Assessment 
Sample 
volume 
(mL) 
No. of /Timepoints 
Total 
volume 
(mL) 
Biomarker 
 
 
 
FACS 
15 
6 
90 
Cytokine/Chemokine 
5 
6 
30 
cfDNA 
10 
6 
60 
Total 
 
 
180 
72 
 

Clinical Study Protocol  
Investigational Drug Substance: Durvalumab and Tremelimumab 
Study Number ESR-14-10531/WINSHIP3112-15; Edition Number 3.1; Date 09/16/2016 
 
 
8.3.5 
Archival tumor samples and fresh tumor biopsies 
8.3.5.1 
Archival tumor samples 
 Archival samples will be collected from all patients where feasible. This sample may be 
substituted for baseline tumor biopsy in the event that the patient does not have easily 
biopsable tumor site.   
8.3.5.2 
Fresh tumor biopsies 
Mandatory fresh tumor biopsies will be collected from all subjects at baseline and prior to the 
administration of cycle 3 therapy (exception as in section 8.3.5.1 above). Samples will be collected by 
image-guided core needle biopsy, minimum of three core needle biopsies required at each time point in 
addition to samples collected for pathologic confirmation. An optional biopsy at the time of 
progression will be collected when feasible. Samples will be stored in three separate aliquots in the 
Winship lung satellite tumor bank refrigerator. Two aliquots will be employed to elute TILs to be 
subjected to FACS analysis while the third aliquot will be employed for IHC to detect PD-L1 
expression and spatial distribution of TILs. Additional samples may be used for future genomic and 
metabolomic research if available.  
8.3.6 
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: Taofeek Owonikoko, MD, PhD 
• 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. 
9. 
DISEASE EVALUATION AND METHODS 
9.1 RECIST Criteria v. 1.1 
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Clinical Study Protocol  
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Patient response to treatment and overall clinical efficacy will be assessed according to 
RECIST 1.1 criteria. This assessment will be used to determine ORR, DoR, DCR, and PFS. 
OS will also be evaluated.  
Cross sectional imaging (CT or MRI) will be the methods of assessment of tumor burden at 
baseline to include at the minimum, chest imaging to include the upper abdomen and any 
other areas of known disease involvement based on the signs and symptoms of individual 
patients.  
The baseline assessment should be performed no more than 28 days before the start of 
treatment and as close as possible to the start of treatment. Efficacy for all patients will be 
assessed by objective tumor assessments Q8 weeks for the first 6 months (counting from the 
date of the first MEDI4736 or tremelimumab infusion) and then Q12 weeks thereafter until 
confirmed objective disease progression as defined by RECIST 1.1 (irrespective of the reason 
for stopping treatment or subsequent therapy).  
If an unscheduled scan is performed in the absence of suspicion of progression within 2 weeks 
of a scheduled scan, the scan does not need to be repeated. The next scan should be obtained 
according to the original schedule of imaging.  
Disease progression requires confirmatory scan to be obtained at the next scheduled visit and 
no earlier than 4 weeks after the initial assessment of PD in the absence of clinically 
significant deterioration. Treatment will continue between the initial assessment of 
progression and confirmation for progression.  
Only patients determined not to have any significant, unacceptable, or irreversible toxicity, or 
continue to receive benefit from therapy can continue therapy through progression during the 
initial 12 months of therapy or restart a second 12 months of retreatment upon suspicion of 
PD. The patient must still meet all of the inclusion criteria and none of the exclusion criteria 
including reconsenting to continue or restart treatment.  
Patients with rapid tumor progression or with symptomatic progression that requires urgent 
medical intervention (e.g., central nervous system metastasis, respiratory failure due to tumor 
compression, or spinal cord compression) will not be eligible to continue to receive study 
drug. Patients with confirmed progression cannot continue therapy or obtain retreatment if the 
progression occurred during dosing and after confirmed response in the target lesions (i.e., the 
response and progression events both occurred while receiving active IP during the same 
treatment period in the target lesions). 
Progression would be considered confirmed if the following criteria are met: 
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Clinical Study Protocol  
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Study Number ESR-14-10531/WINSHIP3112-15; Edition Number 3.1; Date 09/16/2016 
 
• ≥20% increase in the sum diameters of target lesions compared with the nadir at 2 
consecutive visits with an absolute increase of 5 mm(1) 
• And/or significant progression (worsening) of non-target lesions or new lesions at the 
confirmatory PD time point compared with the first time point where progression of 
non-target lesions or new lesions was identified 
• And/or additional new unequivocal lesions at the confirmatory PD time point 
compared with the first time point at which new lesions were identified.(1)  
The assessment of progression requires a ≥20% increase in the sum diameters of target lesions 
at the first progression time point relative to the nadir. The nadir is the smallest sum of 
diameters, and this may be at baseline or subsequent follow-up assessments. The confirmatory 
scan confirms the persistence of the ≥20% increase relative to the nadir. The minimum 
absolute increase in the sum of diameters of target lesions is at least 5 mm at both 
assessments. In the absence of clinically significant deterioration, treatment should continue 
until progression is confirmed. If progression is not confirmed, then the patient should 
continue on study treatment and on treatment assessments.  
Categorization of objective tumor response assessment will be based on the RECIST 1.1 
criteria of response: CR, PR, SD, and PD. Target lesion progression will be calculated in 
comparison to when the tumor burden was at a minimum (i.e., smallest sum of diameters 
previously recorded on study). In the absence of progression, tumor response (CR or PR) and 
SD will be calculated in comparison to the baseline tumor measurements obtained before 
starting treatment. 
Objective tumor response (CR or PR) should be confirmed preferably at the next scheduled 
visit and not less than 4 weeks after the visit when the response was first observed. If the 
Investigator is in doubt as to whether progression has occurred, particularly with response to 
non-target lesion or the appearance of a new lesion, it is advisable to continue treatment until 
the next scheduled assessment or sooner if clinically indicated and reassess the patient’s 
status. If repeat scans confirm progression, then the date of the initial scan should be declared 
as the date of progression.  
To achieve “unequivocal progression” on the basis of non-target disease, there must be an 
overall level of substantial worsening in non-target disease such that, even in presence of SD 
or PR in target disease, the overall tumor burden has increased sufficiently to merit 
discontinuation of therapy. A modest “increase” in the size of one or more non-target lesions 
is usually not sufficient to qualify for unequivocal progression status. Following confirmed 
progression, patients should continue to be followed up for survival every 2-3 months as 
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Clinical Study Protocol  
Investigational Drug Substance: Durvalumab and Tremelimumab 
Study Number ESR-14-10531/WINSHIP3112-15; Edition Number 3.1; Date 09/16/2016 
 
outlined in the study plan. An exception are patients with confirmed PD who continue to 
receive IP at the discretion of the Investigator; these patients can receive treatment for a 
maximum of 12 months and will have scans for RECIST 1.1 assessments every 8 weeks 
(Q8W) (relative to the date of the first infusion) for 6 months and then every 3 months until 
disease progression. 
Patients who achieve and maintain disease control (i.e., CR, PR, or SD) through to the end of 
the initial 12-month treatment period may restart treatment with the durvalumab + 
tremelimumab combination upon evidence of PD, with or without confirmation, during 
follow-up. To be eligible to restart treatment, the patient must not have received an 
intervening systemic anticancer therapy post discontinuation of initial treatment. Patients who 
restart treatment must have a baseline tumor assessment within 28 days of restarting 
treatment; all further scans should occur Q8W (relative to the date of restarting treatment) for 
the next 6 months and then Q12W until study treatment is stopped (maximum of 12 months of 
further treatment).  
Patients who are eligible for retreatment will receive durvalumab (1500 mg/kg) via IV 
infusion Q4W for 4 months (4 doses) and tremelimumab (75 mg) via IV infusion Q4W for 4 
months (up to 4 doses in total). After completion of the initial 4 doses of repeat combination 
therapy, single agent durvalumab will continue at 1500mg Q 4 weeks to complete 12 months 
of therapy. The first durvalumab dose at 1500 mg will be 4 weeks after the final dose of the 
combination of tremelimumab and durvalumab. It is important to follow the assessment 
schedule as closely as possible.  
Immune-related Response Criteria (irRC) 
The response to immunotherapy may differ from the typical responses observed with 
cytotoxic chemotherapy including the following (Wolchok et al 2009, Nishino et al 2013): 
• Response to immunotherapy may be delayed 
• Response to immunotherapy may occur after PD by conventional criteria 
• The appearance of new lesions may not represent PD with immunotherapy 
• SD while on immunotherapy may be durable and represent clinical benefit. 
 
Based on the above-described unique response to immunotherapy and based on guidelines 
from regulatory agencies, e.g., European Medicines Agency’s “Guideline on the evaluation of 
anti-cancer medicinal products in man” (EMA/CHMP/205/95/Rev.4) for immune modulating 
anti-cancer compounds, the study may wish to implement the following in addition to 
standard RECIST 1.1 criteria: 
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Clinical Study Protocol  
Investigational Drug Substance: Durvalumab and Tremelimumab 
Study Number ESR-14-10531/WINSHIP3112-15; Edition Number 3.1; Date 09/16/2016 
 
• RECIST will be modified so that PD must be confirmed at the next scheduled visit, 
preferably, and no earlier than 4 weeks after the initial assessment of PD in the 
absence of clinically significant deterioration.  Treatment with durvalumab + 
tremelimumab would continue between the initial assessment of progression and 
confirmation for progression.  
• In addition, subjects may continue to receive durvalumab + tremelimumab beyond 
confirmed PD in the absence of clinically significant deterioration and if investigators 
consider that subjects continue to receive benefit from treatment.  
Modification of RECIST as described may discourage the early discontinuation of 
durvalumab + tremelimumab and provide a more complete evaluation of its anti-tumor 
activity than would be seen with conventional response criteria.  Nonetheless, the efficacy 
analysis will be conducted by programmatically deriving each efficacy endpoint based on 
RECIST 1.1 criteria. 
Of note, clinically significant deterioration is considered to be a rapid tumor progression that 
necessitates treatment with anti-cancer therapy other than durvalumab + tremelimumab or 
with symptomatic progression that requires urgent medical intervention (e.g., central nervous 
system metastasis, respiratory failure due to tumor compression, spinal cord compression).>> 
9.1.1 
Efficacy variable 
Progression free survival (PFS): Measured from C1D1 until objective disease progression or 
death. 
Objective response rate (ORR): According to RECIST 1.1 criteria based on cross sectional 
imaging obtained Q8W (after every 2 cycles) for the first 6 months and Q12W thereafter. 
Disease control rate (DCR): Sum total of the proportion of patients with best response of 
complete response (CR), partial response (PR) and stable disease (SD). 
Duration of response (DoR): Measured as interval of time from the first documentation of 
objective response (PR or CR) and subsequent progression of disease. 
Subjects who have disease control following completion of 12 months of treatment or subjects 
who are withdrawn from MEDI4736 treatment for reasons other than confirmed PD will 
continue to have objective tumor assessments (see Appendix B).   
Subjects who have disease control following completion of 12 months of treatment or subjects 
who are withdrawn from durvalumab + tremelimumab treatment for reasons other than 
confirmed PD will continue to have objective tumor assessments (see Appendix 3).  
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10. 
ASSESSMENT OF SAFETY 
The Principal Investigator is responsible for ensuring that all staff involved in the study are 
familiar with the content of this section. 
10.1.1 
Safety Parameters 
10.1.1.1 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 
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. 
10.1.2 
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: 
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Clinical Study Protocol  
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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. 
10.1.3 
Durvalumab + tremelimumab adverse events of special interest 
An adverse event of special interest (AESI) is one of scientific and medical interest specific to 
understanding of the Investigational Product and may require close monitoring and rapid 
communication by the investigator to the sponsor. An AESI may be serious or non-serious. 
The rapid reporting of AESIs allows ongoing surveillance of these events in order to 
characterize and understand them in association with the use of this investigational product. 
AESIs for durvalumab and tremelimumab include but are not limited to events with a 
potential inflammatory or immune-mediated mechanism and which may require more 
frequent monitoring and/or interventions such as steroids, immunosuppressants and/or 
hormone replacement therapy. These AESIs are being closely monitored in clinical studies 
with durvalumab monotherapy and combination therapy. An immune-related adverse event 
(irAE) is defined as an adverse event that is associated with drug exposure and is consistent 
with an immune-mediated mechanism of action and where there is no clear alternate 
aetiology. Serologic, immunologic, and histologic (biopsy) data, as appropriate, should be 
used to support an irAE diagnosis. Appropriate efforts should be made to rule out neoplastic, 
infectious, metabolic, toxin, or other etiologic causes of the irAE.  
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Clinical Study Protocol  
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If the Investigator has any questions in regards to an adverse event (AE) being an irAE, the 
Investigator should promptly contact the Sponsor-Investigator. 
AESIs observed with durvalumab and tremelimumab include: 
• Colitis 
• Pneumonitis 
• ALT/AST increases / hepatitis / hepatotoxicity  
• Neuropathy / neuromuscular toxicity (i.e. events of encephalitis, peripheral motor and 
sensory neuropathies, Guillain-Barré, and myasthenia gravis) 
• Endocrinopathy (i.e. events of hypophysitis, adrenal insufficiency, and hyper- and 
hypothyroidism) 
• Dermatitis 
• Nephritis 
• Pancreatitis  (or labs suggestive of pancreatitis - increased serum lipase , increased 
serum amylase)   
Further information on these risks (e.g. presenting symptoms) can be found in the current 
version of the durvalumab and tremelimumab Investigator Brochure. For durvalumab and 
tremelimumab, AESIs will comprise the following:    
AEs of special interest (AESIs) are events of scientific and medical interest specific to the 
further understanding of durvalumab and tremelimumab safety profile and require close 
monitoring and rapid communication by the Investigator to AstraZeneca.  Durvalumab and 
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 these IPs. 
Durvalumab, an anti-PD-L1 antibody, binds with high affinity and specificity to PD-L1 and 
blocks its binding to PD-1 (CD279) and B7-1 (CD80) molecules, thus promoting anti-tumor 
immunity and tumor cell killing.  Tremelimumab, a CTLA-4 antibody, blocks the inhibitory 
signal resulting from CTLA-4 binding to B7 ligands on antigen-presenting cells, thus 
maintaining T-cell homeostasis.  Potential risks based on these mechanisms of action include 
immune-mediated reactions such as enterocolitis, dermatitis, hepatotoxicity or hepatitis, 
endocrinopathy, neuropathy or neurologic events, pancreatitis, and pneumonitis. 
The class including anti-PD-L1 drugs and other immune checkpoint antibodies, such as 
anti-PD-1 or anti-CTLA-4, have a wide spectrum of immune-mediated reactions that have 
been considered inflammatory in nature and can affect any organ of the body.   
For durvalumab and tremelimumab, AESIs will comprise the following:    
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Clinical Study Protocol  
Investigational Drug Substance: Durvalumab and Tremelimumab 
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Pneumonitis 
AEs of pneumonitis are also of interest for AstraZeneca, as pneumonitis has been observed 
with use of anti-PD-1 mAbs (but not with anti-PD-L1 mAbs).  Initial work-up should include 
a high-resolution CT scan, ruling out infection, and pulse oximetry.  Pulmonary consultation 
is highly recommended. Guidelines for the management of patients with immune-related AEs 
(irAEs) including pneumonitis are provided in Table 1.   
Infusion reactions 
AEs of infusion reactions (also termed infusion-related reactions) are of special interest to 
AstraZeneca and are defined, for the purpose of this protocol, as all AEs occurring from the 
start of IP infusion up to 48 hours after the infusion start time.  For all infusion reactions,  
SAEs should be reported to AstraZeneca Patient safety as described in Section 10.3.   
Hypersensitivity reactions 
Hypersensitivity reactions as well as infusion-related reactions have been reported with 
anti-PD-L1 and anti-PD-1 therapy (Brahmer et al 2012).  As with the administration of any 
foreign protein and/or other biologic agents, reactions following the infusion of mAbs can be 
caused by various mechanisms, including acute anaphylactic (IgE-mediated) and 
anaphylactoid reactions against the mAbs and serum sickness.  Acute allergic reactions may 
occur, may be severe, and may result in death.  Acute allergic reactions may include 
hypotension, dyspnea, cyanosis, respiratory failure, urticaria, pruritus, angioedema, hypotonia, 
arthralgia, bronchospasm, wheeze, cough, dizziness, fatigue, headache, hypertension, myalgia, 
vomiting, and unresponsiveness.  Guidelines for the management of patients with 
hypersensitivity (including anaphylactic reaction) and infusion-related reactions are provided 
in Table 1.    
Hepatic function abnormalities (hepatotoxicity) 
Hepatic function abnormality is defined as any increase in ALT or AST to greater than 
3 × ULN and concurrent increase in total bilirubin to be greater than 2 × ULN.  Concurrent 
findings are those that derive from a single blood draw or from separate blood draws taken 
within 8 days of each other.  Follow-up investigations and inquiries will be initiated promptly 
by the investigational site to determine whether the findings are reproducible and/or whether 
there is objective evidence that clearly supports causation by a disease (e.g., cholelithiasis and 
bile duct obstruction with distended gallbladder) or an agent other than the IP.  Guidelines for 
management of patients with hepatic function abnormality are provided in Table 1.    
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Clinical Study Protocol  
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Gastrointestinal disorders 
Diarrhea/colitis is the most commonly observed treatment emergent SAE when tremelimumab 
is used as monotherapy.  In rare cases, colon perforation may occur that requires surgery 
(colectomy) or can lead to a fatal outcome if not properly managed.  Guidelines on 
management of diarrhea and colitis in patients receiving tremelimumab are provided in Table 
1. 
Endocrine disorders 
Immune-mediated endocrinopathies include hypophysitis, adrenal insufficiency, and hyper- 
and hypothyroidism.  Guidelines for the management of patients with immune-mediated 
endocrine events are provided in Table 1. 
Pancreatic disorders 
Immune-mediated pancreatitis includes autoimmune pancreatitis, and lipase and amylase 
elevation.  Guidelines for the management of patients with immune-mediated pancreatic 
disorders are provided in Table 1. 
Neurotoxicity 
Immune-mediated nervous system events include encephalitis, peripheral motor and sensory 
neuropathies, Guillain-Barré, and myasthenia gravis.  Guidelines for the management of 
patients with immune-mediated neurotoxic events are provided in Table 1. 
Nephritis 
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, proteinuria, etc.)  
Patients should be thoroughly evaluated to rule out any alternative etiology (e.g., disease 
progression, infections etc.) 
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.   Guidelines 
for the management of patients with immune-mediated neurotoxic events are provided in 
Table 1. 
10.1.4 
Immune-related adverse events 
Based on the mechanism of action of durvalumab and tremelimumab leading to T-cell 
activation and proliferation, there is a possibility of observing irAEs during the conduct of this 
study.  Potential irAEs may be similar to those seen with the use of ipilimumab, BMS-936558 
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Clinical Study Protocol  
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Study Number ESR-14-10531/WINSHIP3112-15; Edition Number 3.1; Date 09/16/2016 
 
(anti-PD-1 mAb), and BMS-936559 (anti-PD-L1 mAb) and may include immune-mediated 
enterocolitis, dermatitis, hepatitis (hepatotoxicity), pneumonitis, and endocrinopathies (Hodi 
et al 2010, Brahmer et al 2012,).  These AEs are inflammatory in nature and can affect any 
organ.  With anti-PD-L1 and anti-CTLA-4 combination therapy, the occurrence of 
overlapping or increasing cumulative toxicities that include irAEs could potentially occur at 
higher frequencies than with either durvalumab or tremelimumab monotherapy.  Patients 
should be monitored for signs and symptoms of irAEs.  In the absence of an alternate etiology 
(e.g., infection or PD), an immune-related etiology should be considered for signs or 
symptoms of enterocolitis, dermatitis, pneumonitis, hepatitis, and endocrinopathy.  In addition 
to the dose modification guidelines provided in Table 1, it is recommended that irAEs are 
managed according to the general treatment guidelines outlined for ipilimumab.  These 
guidelines recommend the following: 
• 
Patients should be evaluated to identify any alternative etiology. 
• 
In the absence of a clear alternative etiology, all events of an 
inflammatory nature should be considered immune related. 
• 
Symptomatic and topical therapy should be considered for low-grade 
events. 
• 
Systemic corticosteroids should be considered for a persistent low-
grade event or for a severe event. 
• 
More potent immunosuppressives should be considered for events 
not 
responding 
to 
systemic 
steroids 
(e.g., 
infliximab 
or 
mycophenolate). 
• 
If the Investigator has any questions in regards to an AE being an 
irAE, the Investigator should immediately contact the Study 
Physician.  
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Clinical Study Protocol  
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10.2 
Assessment of safety parameters 
10.2.1 
Assessment of severity 
Assessment of severity is one of the responsibilities of the investigator in the evaluation of 
AEs and SAEs. Severity will be graded according to the NCI CTCAE v4.03. 
The determination of severity for all other events not listed in the CTCAE should 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 severity of an AE. Severity is a 
measure of intensity whereas seriousness is defined by the criteria in Section 9.2.1. 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. 
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Clinical Study Protocol  
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10.2.2 
Assessment of relationship 
Attribution will be based on temporal relationship and whether or not the AE is anticipated for 
the procedure or investigational agent. 
10.3 
Recording of adverse events and serious adverse events 
Adverse events will be recorded in the electronic data capture system (OncoreTM) using a 
recognized medical term or diagnosis that accurately reflects the event. Adverse events 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: 
• 
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 durvalumab or tremelimumab (yes or no) 
<<and/or radiation (yes/no)>> 
• 
Action taken with regard to durvalumab + tremelimumab/comparator/combination 
agent 
• 
Outcome 
In addition, the following variables will be collected for SAEs as applicable: 
• 
Date AE met criteria for serious AE 
• 
Date Investigator became aware of serious AE 
• 
AE is serious due to <<criteria>> 
• 
Date of hospitalization 
• 
Date of discharge 
• 
Probable cause of death 
• 
Date of death 
• 
Autopsy performed 
• 
Description of AE 
• 
Causality assessment in relation to Study procedure(s) 
Events, which are unequivocally due to disease progression, should not be reported as an AE 
during the study. 
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Clinical Study Protocol  
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10.3.1 
Study recording period and follow-up for adverse events and serious adverse 
events 
Adverse events and serious adverse events will be recorded from time of signature of 
informed consent, throughout the treatment period and including the follow-up period (90 
days after the last dose of durvalumab + tremelimumab). 
During the course of the study all AEs and SAEs should be proactively followed up for each 
subject. Every effort should 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 or procedure-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 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 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 eCRF.  
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) at the end of the study, if judged necessary. 
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 occurring in former study 
subjects after the 90-day safety follow-up period for patients treated with durvalumab + 
tremelimumab.  However, if an investigator learns of any SAEs, 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 should 
notify the study sponsor and AstraZeneca/MedImmune Drug Safety. 
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10.3.2 
Reporting of serious adverse events 
All SAEs will be reported, whether or not considered causally related to the investigational 
product, or to the study procedure(s). The reporting period for SAEs is the period immediately 
following the time that written informed consent is obtained through 90 days after the last 
dose of durvalumab + tremelimumab 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 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 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-14-10531) 
* 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 becomes serious, this and other relevant follow-up information must also 
be provided to AstraZeneca and the FDA. 
Serious adverse events 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.  
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10.3.2.1 Reporting of deaths 
All deaths that occur during the study or within the protocol-defined 90-day post-last dose of 
durvalumab + 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 
AstraZeneca 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. 
10.3.3 
Other events requiring reporting 
10.3.3.1 Overdose 
An overdose is defined as a subject receiving a dose of durvalumab + tremelimumab in excess 
of that specified in the Investigator’s Brochure, unless otherwise specified in this protocol. 
Any overdose of a study subject with durvalumab + 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 
10.3 and Section 10.3.2). There is currently no specific treatment in the event of an overdose 
of durvalumab or tremelimumab.  
The investigator will use clinical judgment to treat any overdose. 
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Investigational Drug Substance: Durvalumab and Tremelimumab 
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10.3.3.2 Hepatic function abnormality 
Hepatic function abnormality (as defined in Section 10.1.3.) 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. 
Each reported event of hepatic function abnormality will be followed by the investigator and 
evaluated by the sponsor and AstraZeneca/MedImmune.  
10.3.3.3 Pregnancy 
10.3.3.4 Maternal exposure 
If a patient becomes pregnant during the course of the study, the IPs should be discontinued 
immediately.   
Pregnancy itself is not regarded as an AE unless there is a suspicion that the IP under study 
may have interfered with the effectiveness of a contraceptive medication.  Congenital 
abnormalities or 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 all pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, normal 
birth, or congenital abnormality) should be followed up and documented even if the patient 
was discontinued from the study.   
If any pregnancy occurs in the course of the study, then the Investigator or other site personnel 
should inform the appropriate AstraZeneca representatives within 1 day, i.e., immediately, but 
no later than 24 hours of when he or she becomes aware of it.   
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Investigational Drug Substance: Durvalumab and Tremelimumab 
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The designated AstraZeneca representative will work with the Investigator to ensure that all 
relevant information is provided to the AstraZeneca Patient Safety data entry site within 1 to 
5 calendar days for SAEs and within 30 days for all other pregnancies.   
The same timelines apply when outcome information is available.   
10.3.4 
Paternal exposure  
Male patients should refrain from fathering a child or donating sperm during the study and for 
180 days after the last dose of durvalumab + tremelimumab combination therapy or 90 days 
after the last dose of durvalumab monotherapy, whichever is the longer time period.   
Pregnancy of the patient’s partner is not considered to be an AE.  However, the outcome of all 
pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, normal birth, 
or congenital abnormality) occurring from the date of the first dose until 90 days after the last 
dose should, if possible, be followed up and documented.   
Where a report of pregnancy is received, prior to obtaining information about the pregnancy, 
the Investigator must obtain the consent of the patient’s partner.  Therefore, the local study 
team should adopt the generic ICF template in line with local procedures and submit it to the 
relevant Ethics Committees (ECs)/Institutional Review Boards (IRBs) prior to use.   
11. 
STATISTICAL 
METHODS 
AND 
SAMPLE 
SIZE 
DETERMINATION 
All patients meeting eligibility requirement will be randomly assigned to one of two treatment 
groups. Block randomization method will be used to assign patients randomly to the two 
groups. The block size of randomization is 2 to guarantee each group will have equal number 
of 10 patients. The SAS version 9.3 is employed to generate the randomization table for 
patient assignment. 
11.1 
Description of analysis sets 
11.1.1 
Safety analysis set 
All patients who received at least one dose of the study drug will be included in the safety 
analysis population 
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Clinical Study Protocol  
Investigational Drug Substance: Durvalumab and Tremelimumab 
Study Number ESR-14-10531/WINSHIP3112-15; Edition Number 3.1; Date 09/16/2016 
 
11.1.2 
Efficacy analysis set 
All patients who completed at least 2 cycles of therapy and underwent restaging scan will be 
included in the efficacy analysis. Patients who discontinued treatment due to toxicity may be 
replaced for the efficacy endpoint if treatment was stopped prior to the first restaging scan. 
11.1.3 
Randomization 
All patients meeting eligibility requirement will be randomly assigned to one of two treatment 
groups. Block randomization method will be used to assign patients randomly to the two 
groups. The block size of randomization is 2 to guarantee each group will have equal number 
of 10 patients. The SAS version 9.3 is employed to generate the randomization table for 
patient assignment. 
11.2 
Methods of statistical analyses 
All data will be listed individually by subject. Continuous variables will be summarized using 
descriptive statistics: mean, standard deviation, median, interquartile range and minimum and 
maximum values. Categorical variables will be summarized using number of subjects and 
proportion expressed as percentage. Baseline value for any specified variable is the last valid 
measurement before the administration of the study drug. Unless otherwise indicated, 
statistical significance will be declared if the two-sided p value is ≤ 0.05. All statistical 
analyses will be performed using SAS® Version 9.3 or higher. 
Two-sided paired t-test will be used to compare biomarkers expressions between pre and post 
treatment samples. ANOVA and Kruskal-Wallis tests will be used to compare the degree of 
biomarker changes between the treatment groups. The proportion of patients with objective 
response will be estimated with exact 95% confidence intervals. Changes in 
pharmacodynamic endpoints will be correlated with response using Fisher exact test. 
Missing Data Handling 
Unresolved missing data may be imputed when the analysis integrity is affected. The 
conservative principle will be used for data imputation. For example, if an adverse event onset 
day is missing but the adverse event onset year and month can not exclude this adverse event 
as a TEAE, the adverse event will be flagged as a TEAE. 
11.2.1 
Safety Analyses 
Safety assessments will consist of monitoring and recording all adverse events and serious 
adverse events, the regular monitoring of hematology, blood chemistry and urine values, 
regular measurement of vital signs and the performance of physical examinations. These 
assessments should be performed within ±2 days of the scheduled day of assessment except 
for adverse events that will be evaluated continuously through the study. Safety and 
tolerability will be assessed according to the NIH/NCI CTC 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/ctcaev4.pdf. 
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Clinical Study Protocol  
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The occurrence of adverse events graded according to NCI CTCAE v. 4.3 criteria will be 
summarized using descriptive statistics. As far as possible, each adverse event should be 
evaluated to determine: 
1. 
The type and severity using CTCAE v. 4.0 criteria 
2. 
Its relationship to the study drug(s) (suspected/not suspected) 
3. 
Its duration (start and end dates or if continuing at final exam 
 
11.2.2 
Efficacy Analyses 
The PFS will be measured from initiation of systemic therapy to first documented disease 
progression by RECIST criteria  
PFS based on irRC guidelines will also be assessed.  
Primary response assessment will be based on RECIST 1.1 criteria. Immune-related response 
criteria will also be assessed.  
Data on patient demographics, tumor characteristics, response rate and pharmacodynamic 
(PD) biomarkers will be summarized using descriptive statistics. OS and PFS time will be 
analyzed using Kaplan Meier method. The proportion of patients with objective response will 
be estimated with exact 95% confidence intervals. 
Comparisons will be performed between all patients (pooled across both arms) and historical 
control (topotecan) in terms of PFS and ORR. In addition, Arm 1 vs Arm II will be compared 
in terms of PFS and ORR, and possibly OS etc. Exploratory comparison of each Arm  vs 
historical control will also be conducted. 
 
11.2.3 
Exploratory Analyses 
Two-sided paired t-test will be used to compare biomarker differences between timed samples 
e.g. pre and post treatment samples. Pharmacodynamic biomarkers will also be correlated with 
efficacy. ANOVA and Kruskal-Wallis tests will be used to compare the degree of biomarker 
changes between the treatment groups and between various components of the FACT-L QoL 
questionnaire. Changes in pharmacodynamic endpoints will be correlated with efficacy (PFS, 
ORR, irRR) using Fisher exact test. 
11.2.4 
Interim analyses 
Not applicable 
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11.3 
Determination of sample size 
For sample size determination, efficacy comparison was based on historical data with 
topotecan. Assuming a median PFS of 3 months if the intervention is no better than the 
historical PFS associated with topotecan based on the PFS from two recent randomized phase 
III studies of topotecan (Evans et al., 2015; von Pawel et al., 2014), and a promising median 
PFS of 7 months if the investigational treatment is superior (based on the duration of response 
recorded in a phase II study of combined PD-1 and CTLA-4 blockade in relapsed SCLC), 10 
patients treated in each arm of the study will provide 87% power to demonstrate the 
hypothesized efficacy improvement at  a 1-sided 10% alpha level test.  
Similarly, with the same sample size of 10 patients in each arm, we will have 64% power at a 
1-sided alpha of 10% to demonstrate a promising response rate of 30% for the investigational 
therapy versus the historical response rate of 10% with topotecan in the same patient 
population. Assuming an observed response rate of 30% (3 out of 10 patients) the 95% exact 
confidence interval of the response rate will be [6.7%, 65.2%] and 90% exact confidence 
internal of the response rate will be [8.7%, 60.7%].  
12. 
ETHICAL AND REGULATORY REQUIREMENTS 
12.1 
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. Copies of the Declaration of Helsinki and amendments will be 
provided upon request or can be accessed via the website of the World Medical Association at 
http://www.wma.net/e/policy/17-c_e.html. 
12.2 
Ethics and regulatory review 
The Emory University Institutional Review Board (IRB) will have oversight responsibility 
and must approve the final study protocol, including the final version of the ICF and any other 
written information and/or materials to be provided to the patients. The protocol will be re-
approved by the EC/IRB annually or at any other interval deemed appropriate by the IRB.  
AstraZeneca will provide Regulatory Authorities, ECs/IRBs, and Principal Investigators with 
safety updates or reports according to local requirements. Each Principal Investigator is 
responsible for providing the EC/IRB with reports of any serious and unexpected adverse drug 
reactions from any other study conducted with the IP. AstraZeneca will provide this 
information to the Principal Investigator so that he/she can meet these reporting requirements. 
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12.3 
Informed consent 
The investigator must explain to each subject (or legally authorized representative) the nature 
of the study, its purpose, the procedures involved, the expected duration, the potential risks 
and benefits involved and any discomfort it may entail. Each subject must be informed that 
participation in the study is voluntary and that he/she may withdraw from the study at any 
time and that withdrawal of consent will not affect his/her subsequent medical treatment or 
relationship with the treating physician. 
This informed consent should be given by means of a standard written statement, written in 
non-technical language. The subject should read and consider the statement before signing and 
should be given a copy of the signed document. If the subject cannot read or sign the 
documents, oral presentation may be made or signature given by the subject’s legally 
appointed representative, if witnessed by a person not involved in the study, mentioning that 
the patient could not read or sign the documents. No patient can enter the study before his/her 
informed consent has been obtained. The informed consent form is considered to be part of 
the protocol, and must be submitted by the investigator with it for IRB/IEC/REB approval. 
12.4 
Changes to the protocol and informed consent form 
Any change or addition (excluding administrative) to this protocol requires a written protocol 
amendment that must be reviewed by AstraZeneca and the investigator before 
implementation. Amendments significantly affecting the safety of subjects, the scope of the 
investigation or the scientific quality of the study require additional approval by the FDA and 
IRB.  Examples of amendments requiring such approval are: 
1. 
Increases in drug dose or duration of exposure of subjects, 
2. 
Significant changes in the study design (e.g. addition or deletion of a control group), 
3. 
Increases in the number of invasive procedures 
4. 
Addition or deletions of a test procedure required for monitoring of safety. 
These requirements for approval should in no way prevent any immediate action from being taken by 
the investigator in the interests of preserving the safety of all patients included in the trial.  If an 
immediate change to the protocol is felt to be necessary by the investigator and is implemented for 
safety reasons Astra Zeneca must be notified and the IRB at the center must be informed immediately.  
13. 
STUDY MANAGEMENT 
 
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Clinical Study Protocol  
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Investigators must enter study data onto case report forms (CRFs) or other data collection 
system. The Investigator will permit study-related audits by Emory IRB, and regulatory 
inspection(s) (e.g., FDA, EMEA, TPP), providing direct access to the facilities where the 
study took place, to source documents, to CRFs, and to all other study documents. 
The Investigator, or a designated member of the Investigator’s staff, must be available at some 
time during audits to review data and resolve any queries and to allow direct access to the 
subject’s records (e.g., medical records, office charts, hospital charts, and study related charts) 
for source data verification. The data collection must be completed prior to each visit and be 
made available to the Novartis representative so that the accuracy and completeness may be 
checked. 
13.1 
Training of study site personnel 
The study PI (sponsor-investigator) will provide training as appropriate to the delegated 
responsibility to all staffs involved in the conduct of the study. Before the first patient is 
enrolled in the study, study staff and co-investigators will review and discuss the requirements 
of the clinical study protocol and related documents including getting trained in any study-
specific procedures and electronic data capture systems to be utilized. 
The Sponsor-Investigator will ensure that appropriate training relevant to the study is given to 
all of these staff and any new information relevant to the performance of this study is 
forwarded to the staff involved. The Principal Investigator will maintain a record of all 
individuals involved in the study (medical, nursing, and other staff). 
13.2 
Monitoring of the study 
13.2.1 
Source data and documents 
In accord with section 1.51 of the ICH E6 document all information in original records and 
certified copies of original records or clinical findings, observations, or other activities 
necessary for the reconstruction and evaluation of the trial is considered source data. Source 
data are contained in source documents, which can be original records or certified copies of 
hospital records, clinical and office charts, laboratory notes, memoranda, subjects' diaries of 
evaluation checklists, pharmacy dispensing records, recorded data from automated 
instruments, copies or transcriptions certified after verification as being accurate and 
complete, microfiches, photographic negatives, microfilm or magnetic media, x-rays, subject 
files, and records kept at the pharmacy, at the laboratories, and at medico-technical 
departments involved in the clinical trial. 
Case Report Forms (CRFs) - Source data may be collected in the source documents or entered 
directly onto the case report forms. 
13.2.2 
Data Monitoring Committee 
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Clinical Study Protocol  
Investigational Drug Substance: Durvalumab and Tremelimumab 
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The Data and Safety Monitoring Committee (DSMC) of the Winship Cancer Institute will 
provide oversight for the conduct of this study.  The DSMC functions independently within 
Winship Cancer Institute to conduct internal monitoring functions to ensure that research 
being conducted by Winship Cancer Institute Investigators produces high-quality scientific 
data in a manner consistent with good clinical practice (GCP) and appropriate regulations that 
govern clinical research. Depending on the risk level of the protocol, the DSMC review may 
occur every 6 months or annually.  For studies deemed High Risk, initial study monitoring 
will occur within 6 months from the date of the first subject accrued, with 2 of the first 5 
subjects being reviewed.  For studies deemed Moderate Risk, initial study monitoring will 
occur within 1 year from the date of the first subject accrued, with 2 of the first 5 subjects 
being reviewed.  Subsequent monitoring will occur in routine intervals per the Winship Data 
and Safety Monitoring Plan (DSMP).  
The DSMC will review pertinent aspects of the study to assess subject safety, compliance with 
the protocol, data collection, and risk-benefit ratio. Specifically, the Winship Cancer Institute 
Internal Monitors assigned to the DSMC may verify informed consent, eligibility, data entry, 
accuracy and availability of source documents, AEs/SAEs, and essential regulatory 
documents.  Following the monitoring review, monitors will provide a preliminary report of 
monitoring findings to the PI and other pertinent individuals involved in the conduct of the 
study. The PI is required to address and respond to all the deficiencies noted in the preliminary 
report. Prior to the completion of the final summary report, monitors will discuss the 
preliminary report responses with the PI and other team members (when appropriate).  A final 
monitoring summary report will then be prepared by the monitor. Final DSMC review will 
include the final monitoring summary report with corresponding PI response, submitted 
CAPA (when applicable), PI Summary statement, and available aggregate toxicity and safety 
data.   
The DSMC will render a recommendation and rating based on the overall trial conduct. The 
PI is responsible for ensuring that instances of egregious data insufficiencies are reported to 
the IRB. Continuing Review submissions will include the DSMC recommendation letter.  
Should any revisions be made to the protocol-specific monitoring plan after initial DSMC 
approval, the PI will be responsible for notifying the DSMC of such changes.  The Committee 
reserves the right to conduct additional audits if necessary.  
13.2.3 
Data Safety and Quality Assessment 
Data safety and quality assurance plan for this study will follow the established Data Safety 
and Monitoring Plan for all investigator-initiated clinical trials at the Winship (please refer 
Winship DSMP version 01/16/2015). The Emory Winship monitoring team will have primary 
responsibility to coordinate, conduct and/or oversee all study auditing. The study will be 
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Clinical Study Protocol  
Investigational Drug Substance: Durvalumab and Tremelimumab 
Study Number ESR-14-10531/WINSHIP3112-15; Edition Number 3.1; Date 09/16/2016 
 
monitored at least annually in addition to the reporting requirement established by the IRB. If 
the Monitoring Committee determined that an external audit should be conducted, the 
committee shall be responsible for appointing the external auditors upon discussion with 
AstraZeneca and its representative. The scope and conduct of the audit will be established by 
the committee and support for the audit will be provided by the Winship Monitoring Office.  
Data integrity and safety information will be assessed as specified below: 
i. 
Continuous monitoring by the PI 
ii. 
DSMC monitoring team as per Winship SOP  
iii. 
At least annually (review records for 2 patients or 20% of participants per year) or 
more frequently as determined by the committee 
iv. 
At study closure. 
The following will be inspected as part of the data monitoring assessment 
i. 
Review of data integrity  
ii. 
Delegation log and protocol training for investigators and other study staff 
iii. 
Eligibility of consented/enrolled patients 
iv. 
Informed consent document and process 
v. 
Verification of adherence to protocol 
vi. 
Accuracy, completeness and timeliness of data 
vii. 
Accuracy and completeness of all source documentation 
viii. 
Response evaluation: verify that responses are identified according to the protocol 
definition of response for any response that is a major endpoint 
ix. 
Toxicity evaluation: verify that treatment-emergent toxicities are captured and graded 
accurately as specified by the protocol 
x. 
Appropriate reporting of all AEs and SAEs as required by GCP, the protocol, IRB, 
regulations, sponsor’s SOPs and other regulatory requirements (refer section 10.3) 
The monitor shall meet with the designated research team members assigned to the trial to:  
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a) provide an itemized review of the deficiencies and remove items from itemized review 
which are corrected during this meeting 
b) review and document corrections/the coordinator should indicate any remaining 
deficiencies and provide corrective action plan for resolution 
c) prepare summary report for PI and Monitoring Committee to include summary of 
systematic deficiencies, significant protocol deviations, summary of remaining 
deficiencies and coordinator corrective action plan, recommendations for data 
collection and protocol revision for clarity 
d) meet with the overall PI to discuss the report and document the PI’s responses prior to 
submitting final report to the Monitoring Committee.  
The final Monitoring Committee review of monitoring or audit report and PI response and PI 
summary of protocol to date will be included in the annual renewal submission. Egregious 
data insufficiencies that may impact the scientific integrity of the trial are reported to the 
Winship Associate Director of Clinical Research. 
 
13.3 
Study timetable and end of study 
Number of patients & centers: A total of twenty eligible patients will be enrolled in the two 
arms of the study. This is a single center study to be conducted at the Emory University 
Winship Cancer Institute, an NCI-designated cancer center. 
Population:  Patients whose disease relapsed SCLC after prior therapy with a platinum-
containing regimen and not more than two prior lines of therapy.   
Study duration/timelines:  
Total accrual duration: 24 months 
Study start (FPFV): 02/01/2016 
Recruitment end (LPFV):  01/31/2018  
End of Study (LPLV): 08/31/2018 
Completion of study report (CSR) - 11/30/2018 
Publication date -03/31/2019 
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14. 
DATA MANAGEMENT 
Data will be collected using an institutional electronic data recording system, Oncore. 
Electronic case report forms and study calendar will be generated prior to study activation.  
14.1 Disclosure and confidentiality 
The investigator will keep all information provided by AstraZeneca in strict confidence and 
will request similar confidentiality from his/her staff and the IRB/IEC/REB. Study documents 
provided by AstraZeneca (investigators' brochures and other material) will be stored 
appropriately to ensure their confidentiality. The information provided to the investigator may 
not be disclosed to others without direct written authorization from AstraZeneca, except to the 
extent necessary to obtain informed consent from patients who wish to participate in the trial. 
14.2 Study records requirements 
The Investigator must ensure that the records and documents pertaining to the conduct of the 
study and the distribution of the protocol therapy, that is copies of CRFs and source 
documents (original documents, data, and records [e.g., hospital records; clinical and office 
charts; laboratory notes; memoranda; subject’s diaries or evaluation checklists; SAE reports, 
pharmacy dispensing records; recorded data from automated instruments; copies or 
transcriptions certified after verification as being accurate copies; microfiches; photographic 
negatives, microfilm, or magnetic media; x-rays; subject files; and records kept at the 
pharmacy, at the laboratories, and at medico-technical departments involved in the clinical 
study; documents regarding subject treatment and drug accountability; original signed 
informed consents, etc.]) be retained by the Investigator for as long as needed to comply with 
national and international regulations (generally 2 years after discontinuing clinical 
development or after the last marketing approval). 
14.3 
Study governance and oversight 
The safety of all AstraZeneca clinical studies is closely monitored on an ongoing basis by 
AstraZeneca representatives in consultation with Patient Safety.  Issues identified will be 
addressed; for instance, this could involve amendments to the study protocol and letters to 
Investigators. 
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15. 
INVESTIGATIONAL PRODUCT AND OTHER TREATMENTS 
15.1 
Identity of investigational product(s) 
Table 9. List of investigational products for this study 
Investigational product 
Dosage form and strength 
Manufacturer 
Durvalumab 
1500 mg, solution, IV 
MedImmune 
Tremelimumab 
75 mg, solution, IV 
MedImmune 
 
 
 
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16. 
LIST OF REFERENCES 
Andorsky et al 2011 
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 
Antonia et al 2014b 
Antonia S, Ou SI, Khleif SN, Brahmer J, Blake-Haskins A, Robbins PB, et al. Clinical activity 
and safety of MEDI4736, an anti-programmed cell death ligand-1 (PD-L1) antibody in 
patients with NSCLC. Poster presented at the European Society for Medical Oncology 
(ESMO) Meeting; 2014 Sep 26-30; Madrid, Spain. 
Antonia et al 2014a 
Antonia S, Goldberg S, Balmanoukian A, Narwal R, Robbins P, D’Angelo G, et al. A Phase 1 
open-label study to evaluate the safety and tolerability of MEDI4736, an anti-programmed cell 
death-ligand 1 (PD-L1) antibody, in combination with tremelimumab in patients with 
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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. 
 
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. 
 
Ott, P.A., Fernandez, M.E.E., Hiret, S., Kim, D.-W., Moss, R.A., Winser, T., Yuan, S., Cheng, 
J.D., Piperdi, B., and Mehnert, J.M. (2015). Pembrolizumab (MK-3475) in patients (pts) with 
extensive-stage small cell lung cancer (SCLC): Preliminary safety and efficacy results from 
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112 
 

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Investigational Drug Substance: Durvalumab and Tremelimumab 
Study Number ESR-14-10531/WINSHIP3112-15; Edition Number 3.1; Date 09/16/2016 
 
Owonikoko, T.K., Behera, M., Chen, Z., Bhimani, C., Curran, W.J., Khuri, F.R., and 
Ramalingam, S.S. (2012). A systematic analysis of efficacy of second-line chemotherapy in 
sensitive and refractory small-cell lung cancer. J Thorac Oncol 7, 866-872. 
 
Owonikoko, T.K., Ragin, C.C., Belani, C.P., Oton, A.B., Gooding, W.E., Taioli, E., and 
Ramalingam, S.S. (2007). Lung cancer in elderly patients: an analysis of the surveillance, 
epidemiology, and end results database. J Clin Oncol 25, 5570-5577. 
 
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. 
 
Pillai, R.N., and Owonikoko, T.K. (2014). Small cell lung cancer: therapies and targets. 
Seminars in oncology 41, 133-142. 
 
Reck, M., Bondarenko, I., Luft, A., Serwatowski, P., Barlesi, F., Chacko, R., Sebastian, M., 
Lu, H., Cuillerot, J.M., and Lynch, T.J. (2013). Ipilimumab in combination with paclitaxel and 
carboplatin as first-line therapy in extensive-disease-small-cell lung cancer: results from a 
randomized, double-blind, multicenter phase 2 trial. Annals of oncology : official journal of 
the European Society for Medical Oncology / ESMO 24, 75-83. 
 
Schiller, J.H., Adak, S., Cella, D., DeVore, R.F., 3rd, and Johnson, D.H. (2001). Topotecan 
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Solomon, B.J., Blackhall, F., et al. (2013a). Crizotinib versus chemotherapy in advanced 
ALK-positive lung cancer. N Engl J Med 368, 2385-2394 
 
Shaw, A.T., Mehra, R., Kim, D.-W., Felip, E., Chow, L.Q.M., Camidge, D.R., Tan, D.S.-W., 
Vansteenkiste, J.F., Sharma, S., De Pas, T., et al. (2013b). Clinical activity of the ALK 
inhibitor LDK378 in advanced, ALK-positive NSCLC. Journal of Clinical Oncology 31, 
abstract 8010. 
 
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Investigational Drug Substance: Durvalumab and Tremelimumab 
Study Number ESR-14-10531/WINSHIP3112-15; Edition Number 3.1; Date 09/16/2016 
 
Siegel, R., Ma, J., Zou, Z., and Jemal, A. (2014). Cancer statistics, 2014. CA Cancer J Clin 64, 
9-29. 
 
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. 
 
Tang, C., Wang, X., Soh, H., Seyedin, S., Cortez, M.A., Krishnan, S., Massarelli, E., Hong, 
D., Naing, A., Diab, A., et al. (2014). Combining radiation and immunotherapy: a new 
systemic therapy for solid tumors? Cancer immunology research 2, 831-838. 
 
Tani, T., Tanaka, K., Idezuka, J., and Nishizawa, M. (2008). Regulatory T cells in 
paraneoplastic neurological syndromes. Journal of neuroimmunology 196, 166-169. 
 
Tarhini et al, 2013;  INSERT REFERENCE 
 
Thompson RH, Gillett MD, Chevillem JC, Lohsem CM, Dong H, Webster WS, et al. 
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Thompson RH, Kuntz SM, Leibovich BC, Dong H, Lohse CM, Webster WS, et al. Tumor 
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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. 
 
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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 et al, 2012;  INSERT REFERENCE 
 
Wolchok JD, Hoos A, O’Day S, Weber JS, Hamid O, Lebbé, et al. Guidelines for the 
evaluation of immune therapy activity in solid tumors: immune-related response criteria. Clin 
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Investigational Drug Substance: Durvalumab and Tremelimumab 
Study Number ESR-14-10531/WINSHIP3112-15; Edition Number 3.1; Date 09/16/2016 
 
 
Zou W, Chen L. Inhibitory B7-family molecules in the tumour microenvironment. Nat Rev 
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Clinical Study Protocol  
Investigational Drug Substance: Durvalumab and Tremelimumab 
Study Number ESR-14-10531/WINSHIP3112-15; Edition Number 3.1; Date 09/16/2016 
 
APPENDIX 1 
Schedule of study procedures: follow-up for subjects who have completed 
durvalumab and tremelimumab treatment and achieved disease control 
(until confirmed progression of disease) and subjects who have discontinued 
durvalumab or tremelimumab due to toxicity in the absence of confirmed 
progression of disease 
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  
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 
 
 
 
 
 
 
 
Pharmacokinetic 
assessment, 
if 
applicable 
 
 
X 
 
 
 
 
 
Immunogenicity assessment (ADA 
sampling 
[including 
ADA 
neutralising antibodies] to identify 
ADA 
responses 
in 
subject 
circulation), if applicable 
 
 
X 
 
X 
 
 
 
sPD-L1 
concentration 
(to 
assess 
target engagement), if applicable 
 
 
X 
 
 
 
 
 
116 
 

Clinical Study Protocol  
Investigational Drug Substance: Durvalumab and Tremelimumab 
Study Number ESR-14-10531/WINSHIP3112-15; Edition Number 3.1; Date 09/16/2016 
 
APPENDIX 1 
Schedule of study procedures: follow-up for subjects who have completed 
durvalumab and tremelimumab treatment and achieved disease control 
(until confirmed progression of disease) and subjects who have discontinued 
durvalumab or tremelimumab due to toxicity in the absence of confirmed 
progression of disease 
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 
Patient 
questionnaire 
(patient 
reported 
outcomes)c 
and 
health 
resource use, if applicable 
X 
 
X 
For subjects who achieve disease control following 12 
months/48 weeks of treatment, patient questionnaires and 
information relating to health resource use should be 
completed every 12 weeks relative to the date of 
randomisation until confirmed PD by RECIST 1.1 by 
investigational site review. 
For subjects who discontinue study drug due to toxicity or a 
reason other than confirmed PD, patient questionnaires and 
information relating to health resource use should be 
completed relative to the date of randomisation as follows: 
every 8 weeks for the first 48 weeks, then every 12 weeks 
until confirmed PD by RECIST 1.1 by investigational site 
review. 
Tumour assessment (CT or MRI) 
For subjects who achieve disease control following 12 months of treatment, 
tumour assessments should be performed every 12 weeks relative to the date of first 
infusion thereafter until confirmed PD by RECIST 1.1 by investigational site review. 
Please refer to Error! Reference source not found. for timings of 
confirmatory scans.   
For subjects who discontinue MEDI4736 due to toxicity (or symptomatic 
deterioration), tumour assessments should be performed relative to the relative to the 
date of first infusion as follows: every 8 weeks for the first 48 weeks, then every 12 
weeks until confirmed PD by RECIST 1.1 by investigational site review.  Please refer 
to Schedule of Events Table  for timings of confirmatory scans.   
Upon confirmed PD, scans should be conducted according to local standard clinical 
practice and submitted for central review until a new treatment is started (these scans 
are optional). 
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 
117 
 

Clinical Study Protocol  
Investigational Drug Substance: Durvalumab and Tremelimumab 
Study Number ESR-14-10531/WINSHIP3112-15; Edition Number 3.1; Date 09/16/2016 
 
APPENDIX 2  
Schedule of study procedures: follow-up for subjects who have 
discontinued durvalumab and tremelimumab treatment due to 
confirmed progression of disease at the investigator discretion 
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 
 
 
 
 
 
 
 
AE/SAE assessment 
X 
X 
X 
 
 
 
 
 
Concomitant medications 
X 
X 
X 
 
 
 
 
 
Palliative radiotherapy 
As clinically indicated 
<<World 
Health 
Organisation>> 
<<ECOG>> performance statusb 
X 
X 
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) 
Urine hCG or serum βhCG 
X 
 
 
 
 
 
 
 
Hematology 
X 
X 
X 
 
 
 
 
 
Serum chemistry  
X 
X 
X 
 
 
 
 
 
Thyroid function tests (TSH, and fT3 and 
fT4)c 
X 
 
 
 
 
 
 
 
Pharmacokinetic assessment, if applicable 
 
 
X 
 
 
 
 
 
Immunogenicity assessment (ADA sampling 
[including ADA neutralising antibodies] to 
identify 
ADA 
responses 
in 
subject 
circulation), if applicable 
 
 
X 
 
 
 
 
 
sPD-L1 concentration (to assess target 
engagement), if applicable 
 
 
X 
 
 
 
 
 
Circulating 
soluble 
factors 
(to 
assess 
cytokines, chemokines, growth factors and 
antibodies against tumor and self antigens in 
circulation), if applicable 
X 
 
 
 
 
 
 
 
118 
 

Clinical Study Protocol  
Investigational Drug Substance: Durvalumab and Tremelimumab 
Study Number ESR-14-10531/WINSHIP3112-15; Edition Number 3.1; Date 09/16/2016 
 
APPENDIX 2  
Schedule of study procedures: follow-up for subjects who have 
discontinued durvalumab and tremelimumab treatment due to 
confirmed progression of disease at the investigator discretion 
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 
miRNA/mRNA (to examine immune cell 
gene expression profiles in circulation), if 
applicable 
X 
 
 
 
 
 
 
 
PBMCs, if applicable 
X 
 
 
 
 
 
 
 
Patient 
questionnaire 
(patient 
reported 
outcomes)d and health resource use, if 
applicable 
X 
 
X 
 
 
 
 
 
Tumour assessment (CT or MRI) 
For subjects who continue on MEDI4736 post-confirmed progression at 
the investigator’s discretion (following consultation with the sponsor), 
tumour assessments should be performed relative to the date of first infusion 
per Schedule of Events table until MEDI4736 is stopped. 
For 
subjects 
who 
discontinue 
MEDI4736 
following 
confirmed 
progression, scans should be conducted according to local clinical 
practice and submitted for central review until a new treatment is started 
(these scans are optional). 
a   
Full physical exam 
b 
PS to be collected if available at the 2 monthly calls to obtain subsequent anti-cancer therapy and survival status 
c 
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. 
d 
For patient questionnaires different approaches based on indication and study design 
 
 
 
119 
 

Clinical Study Protocol  
Investigational Drug Substance: Durvalumab and Tremelimumab 
Study Number ESR-14-10531/WINSHIP3112-15; Edition Number 3.1; Date 09/16/2016 
 
APPENDIX 3: Durvalumab DOSE CALCULATIONS  
For durvalumab dosing 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 durvalumab nominal concentration. 
The corresponding volume of durvalumab should be rounded to the nearest tenth mL (0.1 
mL). Dose adjustments for each cycle are 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) / 10.0 (mL/vial) 
Example:  
1. Cohort dose: 10 mg/kg 
2. Subject weight: 30 kg 
3. Dose for subject: 300 mg = 10 (mg/kg) × 30 (kg) 
4. Dose to be added into infusion bag:  
Dose (mL) = 300 mg / 50 (mg/mL) = 6.0 mL 
5. The theoretical number of vials required for dose preparation:  
Number of vials = 6.0 (mL) / 10.0 (mL/vial) = 1 vials 
 
 
120 
 

Clinical Study Protocol  
Investigational Drug Substance: Durvalumab and Tremelimumab 
Study Number ESR-14-10531/WINSHIP3112-15; Edition Number 3.1; Date 09/16/2016 
 
APPENDIX 4: Durvalumab DOSE VOLUME CALCULATIONS 
For durvalumab flat dosing: 
1. Cohort dose: X g 
2. Dose to be added into infusion bag:  
Dose (mL) = X g × 1000 / 50 (mg/mL)  
where 50 mg/mL is durvalumab nominal concentration. 
The corresponding volume of durvalumab should be rounded to the nearest tenth mL (0.1 
mL).  
3. 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) / 10.0 (mL/vial) 
Example:  
1. Cohort dose: 1.5 g 
2. Dose to be added into infusion bag:  
Dose (mL) = 1.5 g ×1000 / 50 (mg/mL) = 30.0 mL 
3. The theoretical number of vials required for dose preparation:  
Number of vials = 30.0 (mL) / 10.0 (mL/vial) = 3 vials 
 
 
121 
 

Clinical Study Protocol  
Investigational Drug Substance: Durvalumab and Tremelimumab 
Study Number ESR-14-10531/WINSHIP3112-15; Edition Number 3.1; Date 09/16/2016 
 
APPENDIX 5: Tremelimumab DOSE CALCULATIONS  
For tremelimumab dosing 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 / 20 (mg/mL)  
where 20 mg/mL is tremelimumab nominal concentration. 
The corresponding volume of tremelimumab should be rounded to the nearest tenth mL (0.1 
mL). Dose adjustments for each cycle are 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) / 20.0 (mL/vial) 
Example:  
1. Cohort dose: 1 mg/kg 
2. Subject weight: 30 kg 
3. Dose for subject: 30 mg = 1 (mg/kg) × 30 (kg) 
4. Dose to be added into infusion bag:  
Dose (mL) = 30 mg / 20 (mg/mL) = 1.5 mL 
5. The theoretical number of vials required for dose preparation:  
Number of vials = 1.5 (mL) / 20.0 (mL/vial) = 1 vials 
 
 
122 
 

Clinical Study Protocol  
Investigational Drug Substance: Durvalumab and Tremelimumab 
Study Number ESR-14-10531/WINSHIP3112-15; Edition Number 3.1; Date 09/16/2016 
 
APPENDIX 6: Tremelimumab DOSE VOLUME CALCULATIONS  
For tremelimumab flat dosing: 
1. Cohort dose: X mg 
2. Dose to be added into infusion bag:  
Dose (mL) = X mg / 20 (mg/mL)  
where 20 mg/mL is tremelimumab nominal concentration  
The corresponding volume of tremelimumab should be rounded to the nearest tenth mL (0.1 
mL).  
3. 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) / 20 (mL/vial) 
Example:  
1. Cohort dose: 75 mg 
2. Dose to be added into infusion bag:  
Dose (mL) = 75 mg / 20 (mg/mL) = 3.8 mL 
3. The theoretical number of vials required for dose preparation:  
Number of vials = 3.8 (mL) / 20 (mL/vial) = 1 vial 
 
 
 
123 
 

Clinical Study Protocol  
Investigational Drug Substance: Durvalumab and Tremelimumab 
Study Number ESR-14-10531/WINSHIP3112-15; Edition Number 3.1; Date 09/16/2016 
 
 
 
APPENDIX 7: cfDNA Lab Blood Processing Protocol (version 122314 from 
Diehn’s Lab) 
 Materials (check to make sure you have all of it before you start) 
• Filtered P2000 pipette tips  
• P-2000 pipette 
• 2.0-mL Eppendorf tubes 
• Patient’s blood - usually 30 mL in 3 “purple top” tubes (EDTA) per time point. Blood 
should be kept on ice or in refrigerator after drawing and processed as soon as possible 
to minimize lysis of WBCs and release of cellular genomic DNA into plasma 
 
 Methods 
1. Spin samples in the clinical centrifuge using the settings: 3,500rpm, 10min, 4C 
2. While you wait, label tubes 
3. After spinning, carefully remove lavender top tubes from centrifuge. Do not disturb 
the separated plasma and cell-free whole blood 
i. Tip: It helps to put all the tubes into one holder and carefully carry the 
holder to the hood 
4. Using a filtered tip and p-2000 pipet aliquot ~1.8 mL clear plasma (not all the way to 
the top since tops of tubes tend to pop open upon freezing if filled all the way) into a 
2.0 mL Eppendorf tube. Repeat until you have aliquotted the plasma from all the 
purple-top tubes into 2.0 mL Eppendorf tubes. With the tubes that have only the buffy 
coat and RBC remaining, mix the buffy coat and cell-free whole blood using a pipette 
tip and aliquot ~1.8 mL into a 2.0 mL Eppendorf tube. Repeat so you have a second 
2.0 mL Eppendorf tube containing the buffy coat and RBC mixed together. 
5. Put Eppendorf tubes into -80C freezer. 
6. Record # of plasma tubes stored, date of blood draw, time of blood draw, and time 
of storage. 
7. Samples will be shipped to the lab of Max Diehn at Stanford University for cfDNA 
analysis using CAPP-Seq technology.  
 
124